Bethlem myopathy

Mendelian MONDO:0008029 Pathograph 67 Show in embeddings browser Collagen 6-related myopathy Congenital muscular dystrophy

Bethlem myopathy is the usually milder, adult-ambulant end of the collagen VI-related dystrophy spectrum. Pathogenic COL6A1, COL6A2 or COL6A3 variants act through dominant or less commonly recessive mechanisms affecting collagen VI assembly, secretion or extracellular organization. Interstitial fibroblast-derived matrix dysfunction is linked to myofibre injury; autophagy, mitochondrial permeability and TGF-beta abnormalities are supported mainly by experimental models and selected patient studies, with incompletely defined intermediates. Slowly progressive proximal weakness and finger-flexor, elbow and Achilles contractures are characteristic, but onset and contractures vary and respiratory weakness can develop while walking is retained. Keloids, atrophic scars and follicular hyperkeratosis are useful connective-tissue clues. The historical label benign does not capture the possible adult functional decline.

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Definitions

GeneReviews Bethlem muscular dystrophy definition

Bethlem muscular dystrophy is the mild end of the collagen VI-related dystrophy continuum and is characterized by the combination of proximal muscle weakness and joint contractures.

OTHER

Show evidence (2 references)

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"Bethlem muscular dystrophy is characterized by a combination of proximal muscle weakness and joint contractures."

The GeneReviews chapter states the defining clinical combination for Bethlem muscular dystrophy.

PMID:15689448 SUPPORT Human Clinical

"BM is a relatively mild dominantly inherited disorder with proximal weakness and distal joint contractures."

A cohort sequencing study frames Bethlem myopathy as the mild, dominantly inherited COL6 disorder with proximal weakness and distal contractures.

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Inheritance

Autosomal dominant inheritance HP:0000006

Bethlem myopathy is usually inherited in an autosomal dominant manner, typically through dominant-negative COL6A1, COL6A2, or COL6A3 variants that are incorporated into collagen VI monomers.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"Bethlem muscular dystrophy is usually inherited in an autosomal dominant manner"

GeneReviews records autosomal dominant inheritance as the usual mode for Bethlem muscular dystrophy.

PMID:8782832 SUPPORT Human Clinical

"A distinctive feature of this autosomal dominant disorder consists of contractures of multiple joints in addition to generalized muscular weakness and wasting."

The original gene-identification study describes Bethlem myopathy as an autosomal dominant disorder.

Autosomal recessive inheritance HP:0000007

Recessive Bethlem myopathy occurs with biallelic COL6 variants and residual-function mechanisms. COL6A2-related myosclerosis overlaps the spectrum but is clinically distinguishable by severe stiffness and restricted joint movement; it is not synonymous with all recessive Bethlem disease.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"although autosomal recessive inheritance has also been reported"

GeneReviews records that recessive inheritance also occurs in Bethlem muscular dystrophy.

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

"In fact, in populations with a low degree of consanguinity, de novo autosomal-dominant mutations are the most common underlying mechanism of Ullrich CMD.1,30,32,80 Furthermore, although the typical genetic mechanism and pattern of inheritance for Bethlem myopathy is dominant, recessive mutations..."

The review documents a recessive (myosclerosis) form of Bethlem myopathy caused by a homozygous COL6A2 nonsense variant.

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Subtypes

Bethlem myopathy 1A (COL6A1-related) MONDO:0024530

COL6A1 hgnc:2211

COL6A1-related Bethlem myopathy (OMIM:158810). Exon 14 skipping is recurrent; although compatible with the Bethlem end of the COL6 spectrum, it is not a marker of a benign adult course.

Show evidence (3 references)

PMID:8782832 SUPPORT Human Clinical

"Sequence analysis in four families reveals a mutation in COL6A1 in one and a COL6A2 mutation in two other kindreds."

Family sequencing identified a COL6A1 mutation in Bethlem myopathy.

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

"Omissions of exon 16 in the α3(VI) chain account for the single most common mutation of this type, which is usually associated with a severe Ullrich CMD phenotype.32,80 Mutations that delete crucial cysteine residues in the collagenous triple helix domains of collagen VI subunits, as is the case..."

The review identifies COL6A1 exon 14 skipping as the most common Bethlem mutation type.

PMID:25535305 SUPPORT DIRECT Human Clinical

"Skipping of exon 14 of COL6A1 was found in 35% of index cases and was mostly associated with a severe clinical evolution."

Twenty-three index cases in a 35-patient cohort; common does not mean benign.

Bethlem myopathy 1B (COL6A2-related) MONDO:0958233

COL6A2 hgnc:2212

COL6A2-related Bethlem myopathy (OMIM:620725) includes dominant and recessive forms. The allelic myosclerosis phenotype is distinguished clinically rather than treated as the definition of this subtype.

Show evidence (1 reference)

PMID:8782832 SUPPORT Human Clinical

"Sequence analysis in four families reveals a mutation in COL6A1 in one and a COL6A2 mutation in two other kindreds."

Family sequencing identified COL6A2 mutations in two Bethlem myopathy kindreds.

Bethlem myopathy 1C (COL6A3-related) MONDO:0958234

COL6A3 hgnc:2213

COL6A3-related Bethlem myopathy corresponding to OMIM:620726. Linkage in one Bethlem kindred mapped to markers on chromosome 2q37 near COL6A3.

Show evidence (1 reference)

PMID:8782832 SUPPORT Human Clinical

"Nine kindreds show genetic linkage to the COL6A1-COL6A2 cluster on chromosome 21q22.3 (refs 3,4; manuscript submitted) whereas one family shows linkage to markers on chromosome 2q37 close to COL6A3 (ref."

Linkage evidence supports a COL6A3-related Bethlem myopathy subtype.

Discussions and Knowledge Gaps

Does the Col6a1-null mouse, which lacks collagen VI entirely, faithfully model dominant-negative Bethlem myopathy, in which an abnormal collagen VI network is still present in the matrix?

HUMAN MODEL MISMATCH OPEN disc_bethlem_col6a1_null_model_fidelity

Attached to

pathophysiology#Myofibre mitochondrial dysfunction and permeability transition pore dysregulation pathophysiology#Defective autophagic clearance of damaged organelles

Complete Col6a1-null mice reproduce selected mitochondrial and autophagy defects but differ from human dominant structural variants. Many dominant Bethlem muscle biopsies have normal collagen VI localization as well as preserved signal. Neither normal staining nor a null model resolves the exact molecular dysfunction in every patient. Genotype-stratified functional assays are needed to assess transferability of therapeutic mechanisms.

Proposed experiments

Permeability transition and autophagic flux by COL6 genotype class

exp_bethlem_dominant_negative_ptp_flux

Measure permeability transition pore sensitivity and autophagic flux in myofibres or myoblasts from genotyped patients carrying dominant-negative COL6A1 exon 14 skipping, and compare against recessive collagen VI null patients and unaffected controls.

Bethlem dominant-negative knock-in mouse

exp_bethlem_knockin_mouse

Generate a knock-in mouse carrying a Bethlem dominant-negative Col6a1 in-frame exon deletion and compare its mitochondrial, autophagic, and contracture phenotype with the existing Col6a1-null mouse.

Posed 2026-07-31T00:00:00Z

Show evidence (2 references)

PMID:21691338 SUPPORT REVIEW SYNTHESIS Other

"In contrast to the human disease, these mice only show a mild neuromuscular disorder without much overt weakness."

The review states directly that the Col6a1-null mouse phenotype is milder than human disease, which is the translational mismatch at issue.

PMID:37569848 SUPPORT DIRECT Human Clinical

"Muscle biopsies from 13 out of 15 BM patients with dominant mutations exhibited a normal collagen VI pattern, as evidenced by the continuous overlap with the anti-perlecan staining (Table 2)."

Normal abundance and basal-lamina colocalization in most dominant Bethlem biopsies in this series; a normal result does not exclude disease.

Which molecular partner mediates the interaction of collagen VI with the muscle basement membrane and links the microfibrillar network to the sarcolemma?

KNOWLEDGE GAP OPEN disc_bethlem_matrix_sarcolemma_receptor

Attached to

pathophysiology#Impaired matrix-to-sarcolemma anchoring of the myofibre

The matrix-to-myofibre link remains incompletely resolved. The 2025 Col6a2-null study identified collagen VI-associated proteins and altered TGF-beta-containing complexes, but co-immunoprecipitation does not prove direct pairwise binding or identify a universal receptor pathway in human Bethlem disease. Whether altered mechanical coupling, extracellular growth-factor availability and mitochondrial/autophagy pathways act in sequence or partly in parallel remains unresolved.

Proposed experiments

Muscle basement membrane collagen VI interactome

exp_bethlem_basement_membrane_interactome

Perform proximity labeling or crosslinking mass spectrometry on the muscle basement membrane to identify the collagen VI binding partners present at the myofibre surface.

Biglycan and dystroglycan complex phenocopy test

exp_bethlem_biglycan_dgc_phenocopy

Test whether disruption of biglycan or of the dystrophin-associated protein complex phenocopies the collagen VI mitochondrial defect in otherwise wild-type myofibres.

Posed 2026-07-31T00:00:00Z

Show evidence (3 references)

PMID:21691338 SUPPORT REVIEW SYNTHESIS Other

"The identity of the molecular partner (or partners) mediating the interaction of collagen VI in the muscle basement membrane is not yet known."

The review states this gap explicitly.

PMID:21691338 SUPPORT REVIEW SYNTHESIS Other

"Additional data suggest that the increased opening of mitochondrial permeability transition pores is not specific to the collagen VI-related disorders, but can also be seen in other neuromuscular disorders,103 which would mean that the treatment approach outlined above would be applicable in..."

The review names this as the crucial unresolved mechanistic step.

PMID:40309777 SUPPORT DIRECT Model Organism

"Together, these findings suggest that absence of collagen VI from the muscle ECM increases active TGF-β without an increase in total TGF-β transcription or translation."

Col6a2-null mouse tissue and fibroblast assays; altered activation rather than increased overall production.

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Pathophysiology

Collagen VI alpha-chain gene defects

Pathogenic COL6A1, COL6A2 or COL6A3 variants alter the obligatory collagen VI chains. Dominant structural alleles and recessive residual-function combinations can cause Bethlem myopathy. Their consequences depend on the affected domain and assembly step: entry into a monomer does not imply that mutant protein reaches tetramers or the extracellular matrix. Ordinary heterozygous loss-of-function alleles can be clinically tolerated; pathogenic structural alleles should not be equated with simple gene dosage reduction.

COL6A1 hgnc:2211 COL6A2 hgnc:2212 COL6A3 hgnc:2213

extracellular matrix structural constituent GO:0005201 ⚠ ABNORMAL

Downstream

Defective intracellular collagen VI assembly A studied COL6A1 splice variant permits mutant monomer formation but blocks later intracellular assembly.

Endomysial collagen VI network dysfunction Some structural variants impair extracellular network function through mechanisms distinct from complete secretion failure.

Show evidence (3 references)

PMID:15689448 SUPPORT Human Clinical

"INTRODUCTION: Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD)."

Establishes the three collagen VI genes as the genetic cause of Bethlem myopathy.

PMID:8782832 SUPPORT Human Clinical

"Both mutations disrupt the Gly-X-Y motif of the triple helical domain by substitution of Gly for either Val or Ser."

Identifies the triple-helix-disrupting substitutions that constitute the primary molecular lesion.

PMID:10419498 SUPPORT DIRECT In Vitro

"The mutant alpha1(VI) chains associated intracellularly with alpha2(VI) and alpha3(VI) to form disulfide-bonded monomers, but further assembly into dimers and tetramers was prevented, and molecules containing the mutant chain were not secreted."

Direct assembly/secretion study of one patient exon-14-skipping allele, not a universal mechanism for all COL6 variants.

Defective intracellular collagen VI assembly

Variant-specific defects impair intracellular collagen VI oligomerization. For the studied COL6A1 exon-14-skipping allele, mutant chains enter heterotrimeric monomers but fail to form dimers and tetramers. Other assembly-competent dominant alleles may instead interfere with later extracellular organization; the one-in-sixteen normal-tetramer argument is not applicable to every Bethlem allele.

Experimental models

COL6A1 exon-14-skipping patient fibroblasts PRIMARY CELL CULTURE

Downstream

Impaired collagen VI secretion Failure to assemble export-competent oligomers prevents secretion of mutant-containing molecules.

Show evidence (1 reference)

PMID:10419498 SUPPORT DIRECT In Vitro

Direct assembly/secretion study of one patient exon-14-skipping allele, not a universal mechanism for all COL6 variants.

Impaired collagen VI secretion

Some Bethlem alleles cause intracellular retention and reduced extracellular delivery of collagen VI. This is demonstrated for one COL6A1 exon-14-skipping allele and in fibroblasts from a recessive COL6A2 proband, rather than an obligatory defect in every patient.

fibroblast CL:0000057

protein secretion GO:0009306 ↓ DECREASED

Experimental models

COL6A1 exon-14-skipping patient fibroblasts PRIMARY CELL CULTURE

Recessive COL6A2 patient fibroblasts PRIMARY CELL CULTURE

Downstream

Endomysial collagen VI network dysfunction Reduced secretion impairs extracellular collagen VI network deposition.

Show evidence (2 references)

PMID:10419498 SUPPORT DIRECT In Vitro

Direct assembly/secretion study of one patient exon-14-skipping allele, not a universal mechanism for all COL6 variants.

PMID:40550965 SUPPORT DIRECT In Vitro

"The proband’s cells (III:2) presented the absence of secreted protein and collagen VI network; collagen staining was observable only in the cell’s cytoplasm as in NT well (63X)."

Patient fibroblast phenotype in a recessive COL6A2 family; individual variant effects were not isolated.

Endomysial collagen VI network dysfunction

Collagen VI is supplied to muscle by interstitial fibroblasts. Variant-dependent defects affect extracellular matrix organization or function, but routine muscle staining can be normal in Bethlem disease, including preserved colocalization with basal-lamina perlecan in 13 of 15 dominant cases in a 2023 series. Normal staining does not prove normal molecular interactions; conversely, basement-membrane mislocalization is not a universal Bethlem finding.

muscle interstitial fibroblast CL:0011027

extracellular matrix organization GO:0030198 ⚠ ABNORMAL

extracellular matrix GO:0031012

Downstream

Impaired matrix-to-sarcolemma anchoring of the myofibre Loss of the functional collagen VI network at the muscle basement membrane removes the microfibrillar bridge between the myofibre surface and the surrounding matrix.

Tendon and periarticular connective tissue involvement Collagen VI is also a pericellular matrix component of tendon, so the same network defect alters tendon and periarticular connective tissue.

Dermal extracellular matrix dysfunction The same collagen VI network defect is expressed in skin, producing the characteristic follicular and scarring phenotype.

Defective autophagic clearance of damaged organelles Extracellular collagen VI deficiency is linked to defective autophagy in knockout models, with unresolved matrix-to-intracellular intermediates.

Dysregulated extracellular TGF-beta bioavailability Loss of collagen VI changes extracellular TGF-beta availability and protein associations in Col6a2-null models.

Neonatal hypotonia Early matrix-muscle dysfunction may produce congenital weakness before the later progressive degenerative course; the intervening developmental mechanisms remain incompletely resolved.

Decreased fetal movement Early matrix-muscle dysfunction may produce congenital weakness before the later progressive degenerative course; the intervening developmental mechanisms remain incompletely resolved.

Show evidence (2 references)

PMID:37569848 SUPPORT DIRECT Human Clinical

"Muscle biopsies from 13 out of 15 BM patients with dominant mutations exhibited a normal collagen VI pattern, as evidenced by the continuous overlap with the anti-perlecan staining (Table 2)."

Normal abundance and basal-lamina colocalization in most dominant Bethlem biopsies in this series; a normal result does not exclude disease.

PMID:21691338 SUPPORT DIRECT REVIEW SYNTHESIS Other

"In muscle, the cell of origin for collagen VI is the interstitial fibroblast."

Review of the cellular source of collagen VI.

Impaired matrix-to-sarcolemma anchoring of the myofibre

Abnormal collagen VI interactions may compromise matrix-to-cell coupling and force transmission. Biglycan and the dystrophin-associated complex were proposed partners in the earlier review, but the specific interaction defect is not demonstrated in every Bethlem patient. Human ultrastructural abnormalities and mouse mechanical measurements support matrix dysfunction without establishing a universal receptor-to-mitochondria signaling chain.

skeletal muscle fiber CL:0008002

cell-matrix adhesion GO:0007160 ↓ DECREASED

Downstream

Progressive myofibre degeneration Defective matrix-based force transmission contributes directly to loss of contractile strength and to the dystrophic muscle process.

Show evidence (4 references)

PMID:8782832 SUPPORT INDIRECT BACKGROUND Other

"Among the diverse family of collagens, the widely expressed microfibrillar type VI collagen is believed to play a role in bridging cells with the extracellular matrix."

States the anchoring function of collagen VI whose loss is proposed as the Bethlem mechanism.

PMID:21691338 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Since collagen VI binds to biglycan,55 which interacts with the sarcoglycan and dystroglycan complex,56,57 collagen VI might be indirectly linked to muscle cell surface receptors via biglycan and the dystrophin-associated protein complex."

Proposes the molecular route linking the collagen VI network to the sarcolemma.

PMID:21691338 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"A mouse model of collagen VI deficiency has been generated by knockout of the collagen VI Col6a1 locus, resulting in a complete absence of collagen VI expression in muscle.69 In contrast to the human disease, these mice only show a mild neuromuscular disorder without much overt weakness.69..."

Cell-culture data support reduced matrix adherence, although the precise myofibre receptor remains unidentified.

+ 1 more reference

Myofibre mitochondrial dysfunction and permeability transition pore dysregulation

Col6a1-null mouse myofibres have abnormal mitochondrial and sarcoplasmic-reticulum ultrastructure and latent permeability-transition susceptibility. Cyclosporin A or genetic cyclophilin-D ablation rescues experimental abnormalities. Muscle biopsies in a short open human pilot also showed mitochondrial dysfunction and increased apoptosis. These selected COL6-disease observations do not establish identical abnormalities in every Bethlem patient or clinical benefit from pore modulation.

skeletal muscle fiber CL:0008002

mitochondrion GO:0005739

Animal models

Col6a1-null mouse Mus musculus partially recapitulates

Col6a1-null cyclophilin-D-deficient mouse Mus musculus perturbs

Downstream

Myofibre apoptosis Inappropriate permeability transition pore opening triggers apoptotic death of individual muscle fibres.

Show evidence (4 references)

PMID:14625552 SUPPORT Model Organism

"We previously generated collagen VI-deficient (Col6a1-/-) mice and showed that they have a muscle phenotype that strongly resembles Bethlem myopathy."

Establishes the Col6a1-null mouse as a Bethlem myopathy model, so its mechanism is directly relevant to this entry.

PMID:14625552 SUPPORT Model Organism

"We found a latent mitochondrial dysfunction in myofibers of Col6a1-/- mice on incubation with the selective F1F(O)-ATPase inhibitor oligomycin, which caused mitochondrial depolarization, Ca2+ deregulation and increased apoptosis."

Documents the latent mitochondrial defect unmasked in collagen VI-deficient myofibres.

PMID:18362356 SUPPORT Human Clinical

"Before treatment, all patients displayed mitochondrial dysfunction and increased frequency of apoptosis, as determined in muscle biopsies."

Confirms the mitochondrial and apoptotic abnormality in human collagen VI myopathy muscle.

+ 1 more reference

Defective autophagic clearance of damaged organelles

Col6a1-null mouse muscle has impaired autophagic flux, inadequate autophagosome induction and persistence of damaged organelles. Human Bethlem/UCMD biopsies show reduced beclin-1 and BNIP3 abundance, consistent with this pathway but not a direct measurement of human autophagic flux. Experimental activation of autophagy improves mouse myofibre survival.

skeletal muscle fiber CL:0008002

autophagy GO:0006914 ↓ DECREASED

mitochondrion GO:0005739

Animal models

Col6a1-null mouse Mus musculus partially recapitulates

Downstream

Myofibre apoptosis Failure to clear damaged mitochondria amplifies the apoptotic drive on the muscle fibre.

Myofibre mitochondrial dysfunction and permeability transition pore dysregulation Deficient organelle clearance allows mitochondrial abnormalities to persist; pore dysregulation also has independent experimental support.

Show evidence (3 references)

PMID:21037586 SUPPORT Model Organism

"Skeletal muscles of collagen VI-knockout (Col6a1(-/-)) mice had impaired autophagic flux, which matched the lower induction of beclin-1 and BCL-2/adenovirus E1B-interacting protein-3 (Bnip3) and the lack of autophagosomes after starvation."

Demonstrates the autophagy machinery defect in collagen VI-deficient muscle.

PMID:21037586 SUPPORT Human Clinical

"Furthermore, muscle biopsies from subjects with Bethlem myopathy or Ullrich congenital muscular dystrophy had reduced protein amounts of beclin-1 and Bnip3."

Confirms the autophagy defect directly in Bethlem myopathy patient muscle.

PMID:21037586 SUPPORT Model Organism

"Here we demonstrate that this persistence of abnormal organelles and apoptosis are caused by defective autophagy."

Places defective autophagy causally upstream of organelle persistence and apoptosis.

Myofibre apoptosis

Increased myofibre apoptosis is a measured downstream injury process in collagen VI-deficient mouse muscle and selected human biopsies. Reducing apoptosis is an experimental outcome and does not by itself establish improved patient function.

skeletal muscle fiber CL:0008002

apoptotic process GO:0006915 ↑ INCREASED

Animal models

Col6a1-null cyclophilin-D-deficient mouse Mus musculus perturbs

Downstream

Progressive myofibre degeneration Cumulative loss of individual muscle fibres drives the slowly progressive dystrophic process.

Show evidence (2 references)

PMID:14625552 SUPPORT Model Organism

"Col6a1-/- muscles have a loss of contractile strength associated with ultrastructural alterations of sarcoplasmic reticulum (SR) and mitochondria and spontaneous apoptosis."

Documents spontaneous myofibre apoptosis alongside loss of contractile strength.

PMID:19293339 SUPPORT Model Organism

"Mice lacking ColVI (Col6a1(-/-)) display a myopathic phenotype associated with ultrastructural alterations of mitochondria and sarcoplasmic reticulum, mitochondrial dysfunction with abnormal opening of the permeability transition pore (PTP) and increased apoptosis of muscle fibers."

Links pore opening to increased apoptosis of muscle fibres.

Progressive myofibre degeneration

Myofibre injury and loss produce progressive proximal-predominant weakness and variable enzyme leakage and myopathic electromyography. Functional decline can occur over decades, and wheelchair use for longer distances is distinct from complete loss of independent walking. Fibrotic replacement is a related, separately represented tissue process.

skeletal muscle fiber CL:0008002

Animal models

Bethlem-like col6a1 exon-13 morphant zebrafish Danio rerio partially recapitulates

Downstream

Proximal muscle weakness Cumulative myofibre loss produces proximal-predominant weakness.

Muscle weakness

Motor delay

Elevated circulating creatine kinase concentration

EMG: myopathic abnormalities

Increased variability in muscle fiber diameter

Loss of ambulation The combination of slowly progressive weakness and worsening contractures eventually limits ambulation in later adult life.

Restrictive respiratory involvement Involvement of respiratory muscles produces a restrictive ventilatory pattern, which is variable and not a consistent feature of Bethlem myopathy.

Endomysial fibrosis Chronic tissue injury is associated with fibrotic replacement.

Axial muscle weakness Disease-associated manifestation; the precise tissue-specific causal intermediates remain incompletely characterized.

Waddling gait Disease-associated manifestation; the precise tissue-specific causal intermediates remain incompletely characterized.

Gowers sign Disease-associated manifestation; the precise tissue-specific causal intermediates remain incompletely characterized.

Lumbar hyperlordosis Disease-associated manifestation; the precise tissue-specific causal intermediates remain incompletely characterized.

Show evidence (2 references)

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

"In samples from patients in more-advanced stages of the disease, overtly dystrophic features are evident, including rare degenerating and regenerating fibers and a prominent build-up of interstitial fibrous tissue in the muscle."

Describes the dystrophic and fibrotic muscle pathology of the collagen VI-related myopathies.

PMID:24339618 SUPPORT Human Clinical

"Creatinine kinase was mildly elevated and electromyography revealed myopathic features."

A Bethlem family series documents the mild creatine kinase elevation and myopathic electromyography.

Endomysial fibrosis

Interstitial collagen accumulation accompanies chronic dystrophic muscle remodeling. It can contribute to stiffness and impaired force transmission, but mouse weakness precedes overt fibrosis, so fibrosis is not assumed to explain all early weakness.

extracellular matrix organization GO:0030198 ⚠ ABNORMAL

Animal models

Col6a2-null mouse Mus musculus partially recapitulates

Downstream

Increased endomysial connective tissue Histological endomysial connective-tissue increase reflects fibrosis.

Show evidence (1 reference)

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

Describes the dystrophic and fibrotic muscle pathology of the collagen VI-related myopathies.

Tendon and periarticular connective tissue involvement

Collagen VI-associated connective-tissue dysfunction accompanies early distal laxity and later contractures. The long finger-flexor, elbow and Achilles pattern is characteristic, but human tendon pathology has not established a single mechanism for every contracture. On wrist dorsiflexion, finger-flexor shortening can prevent full finger extension. Some recessive cases have little or no contracture despite substantial weakness.

tendon fibroblast CL:0000388

extracellular matrix GO:0031012

Downstream

Achilles tendon contracture

Elbow flexion contracture

Flexion contracture of finger

Flexion contracture

Spinal rigidity

Scoliosis

Torticollis

Joint hypermobility

Congenital hip dislocation Disease-associated manifestation; the precise tissue-specific causal intermediates remain incompletely characterized.

Clubfoot Disease-associated manifestation; the precise tissue-specific causal intermediates remain incompletely characterized.

Knee flexion contracture Disease-associated manifestation; the precise tissue-specific causal intermediates remain incompletely characterized.

Shoulder contracture Connective-tissue restriction is associated with reduced joint excursion; detailed intermediates remain unresolved.

Limited mouth opening Connective-tissue restriction is associated with reduced joint excursion; detailed intermediates remain unresolved.

Show evidence (3 references)

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"By adulthood, there is evidence of proximal weakness and contractures of the elbows, Achilles tendons, and long finger flexors."

GeneReviews specifies the characteristic Bethlem contracture distribution.

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

"On dorsiflexion of the wrist, contractures of the long finger flexors prevent complete finger extension—the typical ‘Bethlem sign’ (Figure 1e).13 Even in patients whose muscle weakness progresses only very slowly, progression of the contractures can be the cause of serious disability in their..."

Describes the Bethlem sign produced by long finger flexor contracture.

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

"Young children might exhibit evidence of mild weakness only, and at this early age display distal joint hyperlaxity rather than contractures."

Documents the early-childhood distal hyperlaxity that later converts to contracture.

Dermal extracellular matrix dysfunction

Collagen VI dysfunction affects dermal matrix organization and is associated with follicular hyperkeratosis, soft skin and abnormal scarring. The detailed route to each skin manifestation remains uncertain. Col6a1-null mice have mechanically weaker skin and altered wound ultrastructure but do not reproduce the human keloid phenotype or an overt wound-healing delay.

dermal fibroblast CL:0002551

extracellular matrix organization GO:0030198 ⚠ ABNORMAL

Animal models

Col6a1-null mouse Mus musculus partially recapitulates

Downstream

Follicular hyperkeratosis

Keratosis pilaris

Soft skin

Abnormal cutaneous scarring Altered dermal matrix is associated with abnormal scar formation through unresolved repair intermediates.

Show evidence (2 references)

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

"The most notable manifestations are prominent keratosis pilaris of the extensor surfaces of the arms and legs, giving the skin a rough appearance, the propensity for abnormal (keloid or atrophic) scar formation, and/or a particularly soft and velvety texture to the palmar skin of the hands and..."

Describes the characteristic collagen VI skin phenotype.

PMID:24339618 SUPPORT Human Clinical

"All had flexion contractures, keloids, and follicular hyperkeratosis without muscle hypertrophy."

A three-patient Bethlem family shows the full contracture plus skin combination.

Abnormal cutaneous scarring

Keloid or atrophic scarring is a clinical skin-repair manifestation of collagen VI disease. Its occurrence is variable, and the null mouse does not recreate the full human scar phenotype.

Animal models

Col6a1-null mouse Mus musculus fails to recapitulate

Downstream

Keloids

Atrophic scars

Show evidence (1 reference)

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

Describes the characteristic collagen VI skin phenotype.

Restrictive respiratory involvement

Respiratory muscle weakness can reduce vital capacity and cause nocturnal hypoventilation even while patients remain ambulant. Severity is variable: 13 of 22 tested Bethlem patients in one cohort had FVC below 80% predicted, and two began noninvasive ventilation at ages 24 and 49. These clinic-based observations do not establish a population prevalence.

skeletal muscle fiber CL:0008002

Downstream

Restrictive ventilatory defect

Nocturnal hypoventilation Disease-associated manifestation; the precise tissue-specific causal intermediates remain incompletely characterized.

Show evidence (3 references)

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"Respiratory involvement is not a consistent feature."

GeneReviews states that respiratory involvement is inconsistent in Bethlem muscular dystrophy.

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

"Patients with Bethlem myopathy have an increased risk of restrictive lung disease, with the possibility of resulting respiratory insufficiency, particularly if this impairment occurs in combination with other causes of obstructive sleep apnea."

Documents the increased but variable restrictive respiratory risk in Bethlem myopathy.

PMID:37569848 SUPPORT DIRECT Human Clinical

"However, only nine of the 22 patients with BM had a normal %FVC value (≥80%), seven had values of 79–60%, while six had values below 60%."

Bethlem-specific measured respiratory distribution; denominator is 22 tested patients, not all 33 in the cohort.

Dysregulated extracellular TGF-beta bioavailability

Col6a2-null mice have excessive resting TGF-beta activity, but a blunted early release after injury and relatively prolonged later activity. Protein-complex and fibroblast reporter assays implicate altered extracellular sequestration or activation without increased total ligand transcription or protein. This is a COL6 model mechanism, not a demonstrated universal Bethlem patient defect. Disrupting Ltbp4-TGF-beta binding did not rescue the mouse phenotype.

transforming growth factor beta receptor signaling pathway GO:0007179 ↕ DYSREGULATED

Experimental models

Col6a2-null fibroblast TGF-beta reporter system PRIMARY CELL CULTURE

Animal models

Col6a2-null mouse Mus musculus partially recapitulates

Downstream

Endomysial fibrosis Persistent signaling is a proposed contributor to model fibrosis, but its isolated causal contribution and relevance across human variants remain unresolved.

Show evidence (1 reference)

PMID:40309777 SUPPORT DIRECT Model Organism

"Together, these findings suggest that absence of collagen VI from the muscle ECM increases active TGF-β without an increase in total TGF-β transcription or translation."

Col6a2-null mouse tissue and fibroblast assays; altered activation rather than increased overall production.

✶

Histopathology

Mild dystrophic changes with interstitial fibrosis

Muscle biopsy in advanced disease shows overtly dystrophic features with rare degenerating and regenerating fibres and a prominent build-up of interstitial fibrous tissue; early biopsies may show only fibre atrophy or fibre type disproportion.

Show evidence (2 references)

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

Describes the muscle biopsy pattern of the collagen VI-related myopathies.

PMID:24339618 SUPPORT Human Clinical

"Muscle biopsy in the father showed dystrophic changes with normal immmunostaining for collagen VI, sarcoglycans, and dysferlin."

A Bethlem case series documents dystrophic muscle histology.

⬡

Pathograph

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Phenotypes

Head and Neck 2

Torticollis HP:0000473

Show evidence (2 references)

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

"Although often understood to be a myopathy of adulthood, the clinical symptoms experienced by patients with Bethlem myopathy can frequently be traced back to early infancy;13 affected babies might exhibit hypotonia, foot deformities and torticollis (which has been noted in up to 50% of..."

The review reports an upper bound for early-life torticollis, not a point estimate or an obligatory frequency band.

PMID:37569848 SUPPORT DIRECT Human Clinical

"Ten patients with BM (30%) exhibited symptoms at birth, with a varying combination of congenital hip dislocation (CHD) in four, hypotonia in four, club foot in four, torticollis in three, and contractures of the elbow and knee in one."

Torticollis at birth was recorded in three patients in the 33-patient Bethlem subgroup; this is not an estimate of lifetime prevalence.

Limited mouth opening Trismus HP:0000211

Show evidence (1 reference)

PMID:37569848 SUPPORT DIRECT Human Clinical

"Specifically, a mild degree of mouth opening (MO) limitation was observed in only two patients with BM (6%), while INTM (43%) and UCMD (33%) patients displayed a mild–moderate degree of limitation."

Two of 33 Bethlem patients; severe myosclerosis restriction is a separate subgroup.

Integument 5

Follicular hyperkeratosis HP:0007502

Show evidence (1 reference)

PMID:24339618 SUPPORT Human Clinical

"All had flexion contractures, keloids, and follicular hyperkeratosis without muscle hypertrophy."

All three affected members of a Bethlem family had follicular hyperkeratosis.

Keratosis pilaris HP:0032152

Show evidence (1 reference)

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

The review names keratosis pilaris as the most notable skin manifestation.

Keloids HP:0010562

Show evidence (2 references)

PMID:24339618 SUPPORT Human Clinical

"All had flexion contractures, keloids, and follicular hyperkeratosis without muscle hypertrophy."

All three affected members of a Bethlem family had keloids.

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

The review documents keloid scarring as a collagen VI connective-tissue feature.

Atrophic scars HP:0001075

Show evidence (1 reference)

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

The review records atrophic as well as keloid scarring.

Soft skin HP:0000977

Show evidence (1 reference)

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

The review documents the soft velvety palmar skin of collagen VI-related myopathy.

Limbs 6

Achilles tendon contracture HP:0001771

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"By adulthood, there is evidence of proximal weakness and contractures of the elbows, Achilles tendons, and long finger flexors."

GeneReviews lists Achilles tendon contracture among the defining adult features.

Elbow flexion contracture HP:0002987

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"By adulthood, there is evidence of proximal weakness and contractures of the elbows, Achilles tendons, and long finger flexors."

GeneReviews lists elbow contracture among the defining adult features.

Flexion contracture of finger HP:0012785

Course: PROGRESSIVE

Show evidence (2 references)

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"By adulthood, there is evidence of proximal weakness and contractures of the elbows, Achilles tendons, and long finger flexors."

GeneReviews lists long finger flexor contracture among the defining adult features.

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

Describes the clinical manoeuvre that elicits the Bethlem sign.

Congenital hip dislocation OCCASIONAL HP:0001374

Show evidence (1 reference)

PMID:37569848 SUPPORT DIRECT Human Clinical

Ten of 33 Bethlem patients; individual congenital findings each have their own count.

Clubfoot OCCASIONAL Talipes equinovarus HP:0001762

Show evidence (1 reference)

PMID:37569848 SUPPORT DIRECT Human Clinical

Ten of 33 Bethlem patients; individual congenital findings each have their own count.

Knee flexion contracture HP:0006380

Show evidence (1 reference)

PMID:37569848 SUPPORT DIRECT Human Clinical

Ten of 33 Bethlem patients; individual congenital findings each have their own count.

Metabolism 1

Elevated circulating creatine kinase concentration Elevated circulating creatine kinase activity HP:0003236

Show evidence (3 references)

PMID:24339618 SUPPORT Human Clinical

"Creatinine kinase was mildly elevated and electromyography revealed myopathic features."

A Bethlem family series documents mild creatine kinase elevation.

PMID:37569848 SUPPORT DIRECT Human Clinical

"Among them, 13 had normal CK levels, 38 (16 BM, five MM, four INTM, and 13 UCMD) had slightly elevated levels (up to five times the upper normal value), while eight BM patients had maximum values ranging from 9 to 28 times the upper limit of normal."

All normal measurements are pooled across COL6 subgroups; the eight markedly elevated cases are specifically Bethlem.

PMID:30706156 SUPPORT DIRECT Human Clinical

"CK levels did not correlate with severity of the disease."

Sixteen-patient retrospective Bethlem series.

Musculoskeletal 14

Proximal muscle weakness HP:0003701

Course: PROGRESSIVE

Show evidence (2 references)

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"Bethlem muscular dystrophy is characterized by a combination of proximal muscle weakness and joint contractures."

GeneReviews names proximal muscle weakness as a defining feature.

PMID:15689448 SUPPORT Human Clinical

"BM is a relatively mild dominantly inherited disorder with proximal weakness and distal joint contractures."

A cohort study confirms proximal weakness as a core Bethlem feature.

Muscle weakness HP:0001324

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:8782832 SUPPORT Human Clinical

"A distinctive feature of this autosomal dominant disorder consists of contractures of multiple joints in addition to generalized muscular weakness and wasting."

The original description records generalized weakness and wasting.

Flexion contracture HP:0001371

Show evidence (1 reference)

PMID:24339618 SUPPORT Human Clinical

"All had flexion contractures, keloids, and follicular hyperkeratosis without muscle hypertrophy."

All three affected members of a Bethlem family had flexion contractures.

Spinal rigidity HP:0003306

Show evidence (1 reference)

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

"These contractures progress to involve the long finger flexors and the shoulders; they can also affect the spine and cause a degree of spinal rigidity in some patients."

The review notes spinal rigidity in a subset of Bethlem patients.

Scoliosis HP:0002650

Show evidence (1 reference)

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"annual clinical and radiographic assessment of scoliosis"

GeneReviews prescribes annual scoliosis surveillance for Bethlem muscular dystrophy.

Joint hypermobility HP:0001382

Show evidence (2 references)

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

"Young children might exhibit evidence of mild weakness only, and at this early age display distal joint hyperlaxity rather than contractures."

The review documents early distal hyperlaxity in Bethlem myopathy.

PMID:24339618 SUPPORT Human Clinical

"Bethlem phenotype is relatively benign and is characterized by proximal dominant myopathy, keloids, contractures, distal hyperextensibility, and follicular hyperkeratosis."

The case series lists distal hyperextensibility among the defining Bethlem features.

Neonatal hypotonia HP:0001319

Show evidence (1 reference)

PMID:10219778 SUPPORT Human Clinical

"Early features include diminished foetal movements, neonatal hypotonia and congenital contractures which are of a dynamic nature during childhood."

The natural-history cohort lists neonatal hypotonia among early features.

EMG: myopathic abnormalities HP:0003458

Show evidence (1 reference)

PMID:24339618 SUPPORT Human Clinical

"Creatinine kinase was mildly elevated and electromyography revealed myopathic features."

A Bethlem family series documents myopathic electromyography.

Increased endomysial connective tissue HP:0100297

Show evidence (1 reference)

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

The review describes the fibrotic muscle pathology of the collagen VI-related myopathies.

Increased variability in muscle fiber diameter HP:0003557

Show evidence (1 reference)

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

"In biopsy samples taken very early in the course of disease, however, the findings can be inconspicuous, often just showing evidence of fiber atrophy or even fiber type disproportion without overt dystrophic features.28 Immunohistochemical examination for the amount and localization of collagen..."

The review describes early-biopsy fibre-size abnormality in collagen VI-related myopathy.

Axial muscle weakness HP:0003327

Show evidence (1 reference)

PMID:37569848 SUPPORT DIRECT BACKGROUND Human Clinical

"BM is a relatively mild, slowly progressive disorder, with variable onset from prenatal to adulthood, characterized by axial and proximal muscle weakness; variable contractures of the neck, fingers, elbow, knee, and ankles; distal laxity; and skin changes."

Clinical background of the COL6 cohort report.

Gowers sign HP:0003391

Show evidence (1 reference)

PMID:31471117 SUPPORT DIRECT Human Clinical

"Two adult siblings presented with muscle weakness and wasting, elbows and Achilles tendon retractions, lumbar hyperlordosis, waddling gait and positive Gowers' sign."

Two siblings with biallelic COL6A2 variants; no general frequency can be inferred.

Lumbar hyperlordosis HP:0002938

Show evidence (1 reference)

PMID:31471117 SUPPORT DIRECT Human Clinical

"Two adult siblings presented with muscle weakness and wasting, elbows and Achilles tendon retractions, lumbar hyperlordosis, waddling gait and positive Gowers' sign."

Two siblings with biallelic COL6A2 variants; no general frequency can be inferred.

Shoulder contracture HP:0034665

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1503/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Joint contractures, typically affecting the long finger flexors, elbows, ankles, and shoulders"

Bethlem-specific suggestive findings in GeneReviews.

Nervous System 3

Motor delay HP:0001270

Show evidence (1 reference)

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"Hypotonia and delayed motor milestones occur in early childhood"

GeneReviews records delayed motor milestones in Bethlem muscular dystrophy.

Loss of ambulation HP:0002505

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:37569848 SUPPORT DIRECT Human Clinical

"The mean age at loss of ambulation was 44.6 years (SD 9.7 years) in five BM, 17.0 years (SD 1.8 years) in five INTM, and 8.1 years (SD 2.5 years) in 15 UCMD."

Five of 33 Bethlem patients lost ambulation; intermediate/UCMD figures are separate comparators.

Waddling gait HP:0002515

Show evidence (1 reference)

PMID:31471117 SUPPORT DIRECT Human Clinical

"Two adult siblings presented with muscle weakness and wasting, elbows and Achilles tendon retractions, lumbar hyperlordosis, waddling gait and positive Gowers' sign."

Two siblings with biallelic COL6A2 variants; no general frequency can be inferred.

Prenatal and Birth 1

Decreased fetal movement HP:0001558

Show evidence (1 reference)

PMID:10219778 SUPPORT Human Clinical

"Early features include diminished foetal movements, neonatal hypotonia and congenital contractures which are of a dynamic nature during childhood."

The natural-history cohort lists diminished fetal movements among early features.

Respiratory 2

Restrictive ventilatory defect HP:0002091

Show evidence (3 references)

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

The review supports restrictive lung disease risk in Bethlem myopathy.

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"Respiratory involvement is not a consistent feature."

GeneReviews describes variable respiratory involvement; this sentence does not establish a numeric frequency or a frequency band.

PMID:37569848 SUPPORT DIRECT Human Clinical

"However, only nine of the 22 patients with BM had a normal %FVC value (≥80%), seven had values of 79–60%, while six had values below 60%."

Bethlem-specific measured respiratory distribution; denominator is 22 tested patients, not all 33 in the cohort.

Nocturnal hypoventilation HP:0002877

Show evidence (1 reference)

PMID:21691338 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Sleep studies are, therefore, useful to diagnose nocturnal hypoventilation proactively."

Clinical review describes sleep-related hypoventilation in the respiratory discussion.

🧬

Genetic Associations

COL6A1 (Causative)

Gene: COL6A1 hgnc:2211 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:15689448 SUPPORT Human Clinical

"INTRODUCTION: Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD)."

Sequencing evidence establishes the three collagen VI genes as Bethlem myopathy causes.

PMID:8782832 SUPPORT Human Clinical

"Sequence analysis in four families reveals a mutation in COL6A1 in one and a COL6A2 mutation in two other kindreds."

The original study identified a COL6A1 mutation segregating in a Bethlem kindred.

PMID:10419498 SUPPORT DIRECT In Vitro

Direct assembly/secretion study of one patient exon-14-skipping allele, not a universal mechanism for all COL6 variants.

+ 1 more reference

COL6A2 (Causative)

Gene: COL6A2 hgnc:2212 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:8782832 SUPPORT Human Clinical

"Both mutations disrupt the Gly-X-Y motif of the triple helical domain by substitution of Gly for either Val or Ser."

The original study characterizes the Gly-X-Y disrupting substitutions found in Bethlem kindreds.

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

The review documents recessive COL6A2 disease at the Bethlem end of the spectrum.

PMID:31471117 SUPPORT DIRECT In Vitro

"Fibroblast studies in both affected patients showed the concomitant reduction in the amount of normal Collagen VI (p.Gln889*) and impairment of Collagen VI secretion and assembly (p.Pro260_Lys261insProPro)."

Compound-heterozygous siblings; each heterozygous parent was asymptomatic.

+ 1 more reference

COL6A3 (Causative)

Gene: COL6A3 hgnc:2213 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:8782832 SUPPORT Human Clinical

Linkage in a Bethlem kindred implicates the COL6A3 locus.

PMID:30706156 SUPPORT DIRECT Human Clinical

"The most frequent mutation was the COL6A3 variant c.7447A>G, p.Lys2486Glu, with either an homozygous or compound heterozygous presentation."

Recessive COL6A3 association in the sixteen-patient series.

PMID:37569848 SUPPORT DIRECT Human Clinical

"In COL6A3, two BM patients had the p.Gly2053Val (c.6158G>T) missense mutation, and the c.6210+1G>A splicing mutation was present in one INTM and one UCDM patient."

The p.Gly2053Val observation is Bethlem-specific; splice-variant cases belong to different clinical subgroups.

💊

Medical Actions

Physical and occupational therapy for contracture management

Action: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Physical therapy and occupational therapy provide recommendations for joint stretching, swimming, and aquatherapy. Contracture management is the central supportive intervention in Bethlem myopathy, because contracture progression causes disability in its own right even when weakness progresses only slowly.

Target Phenotypes: Flexion contracture HP:0001371 Achilles tendon contracture HP:0001771 Muscle weakness HP:0001324

Show evidence (2 references)

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"physical therapy and occupational therapy to provide recommendations for joint stretching, swimming, and aquatherapy"

GeneReviews recommends physical and occupational therapy for Bethlem muscular dystrophy.

PMID:21078917 SUPPORT REVIEW SYNTHESIS Human Clinical

"Physical therapy should be focused on the maintenance of function and mobility, prevention or treatment of joint contractures and spine deformities"

Consensus standard-of-care guidance supports physical therapy targeting contractures.

Orthopedic management of Achilles tendon contracture and scoliosis

Action: orthopedic surgical procedure Ontology label: Orthopedic Surgical Procedure NCIT:C16186

Specialist care can include serial casting and selected Achilles tendon release followed by casting when severe or asymmetric shortening impairs gait. Surgery disrupting other joint capsules is generally discouraged because fixed postoperative contractures and loss of motion can result. Scoliosis surgery requires coordinated pulmonary, anesthesia, intensive-care and orthopedic planning.

Target Phenotypes: Achilles tendon contracture HP:0001771 Scoliosis HP:0002650

Show evidence (4 references)

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"treatment of Achilles tendon contractures per orthopedist"

GeneReviews prescribes orthopedic treatment of Achilles tendon contracture.

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"if surgical treatment for scoliosis is needed, coordinate with orthopedics, anesthesia, intensive care, and pulmonary specialists"

GeneReviews specifies multidisciplinary coordination for scoliosis surgery.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1503/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Surgical intervention on any joint contractures (beyond Achilles tendon release surgery) is not recommended, given the high postoperative risk of fixed contractures with complete loss of range of motion in individuals with Bethlem muscular dystrophy who have undergone joint surgery."

Bethlem-specific caution from the full GeneReviews chapter.

+ 1 more reference

Nocturnal noninvasive ventilation

Action: noninvasive ventilation Ontology label: Non-Invasive Mechanical Ventilation NCIT:C171457

Respiratory support is guided by upright/supine pulmonary testing and polysomnography, including carbon-dioxide monitoring. GeneReviews recommends initiation of nocturnal BiPAP when FVC is 60% predicted or lower, with pressures titrated during a sleep study. Respiratory weakness can require treatment while independent walking is retained.

Target Phenotypes: Restrictive ventilatory defect HP:0002091

Show evidence (2 references)

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"BiPAP as needed to support nocturnal ventilation and prevent right heart strain"

GeneReviews prescribes BiPAP for Bethlem muscular dystrophy as needed.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1503/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"For forced vital capacity (FVC) measurements of 60% predicted or lower, noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) should be initiated during a polysomnogram – with pressures adjusted to ensure adequate ventilation – and then consistently used while sleeping."

Bethlem-specific threshold in the treatment section.

Respiratory, cardiac, and orthopedic surveillance

Action: supportive care Ontology label: Supportive Care NCIT:C15747

At least annual upright and supine FVC, sleep evaluation for hypoventilation, clinical/radiographic scoliosis assessment and rehabilitation review are recommended for Bethlem disease. Initial pulmonary testing begins in childhood, around age five when feasible. GeneReviews recommends annual ECG/echocardiography to assess secondary right-heart strain from inadequate ventilation; this does not imply primary cardiomyopathy is a characteristic Bethlem feature. Mobility-device needs and joint function should be reassessed over time.

Show evidence (2 references)

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"Respiratory surveillance including annual pulmonary function tests (PFTs) in the upright and supine positions and polysomnogram for assessing for nocturnal hypoventilation"

GeneReviews defines the respiratory surveillance schedule for Bethlem muscular dystrophy.

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"annual cardiac evaluation with echocardiogram and EKG"

GeneReviews prescribes annual cardiac surveillance.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

A person with an autosomal dominant pathogenic variant has a 50% transmission risk in each pregnancy; sibling risk is 50% when a parent is heterozygous. Parental somatic/germline mosaicism can complicate apparently de novo families, and clinical severity varies within families. For recessive disease with two carrier parents, each pregnancy has a 25% affected, 50% carrier and 25% noncarrier chance. Once familial variants are established, prenatal and preimplantation genetic testing are possible.

Show evidence (5 references)

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"Parental somatic mosaicism (and concomitant germline mosaicism) is not uncommon in the autosomal dominant COL6-RDs."

GeneReviews highlights parental mosaicism as a counseling consideration.

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"The severity of COL6-RD manifestations may vary among family members who are heterozygous for the same pathogenic variant."

GeneReviews notes intrafamilial variability, a key counseling point.

PMID:20301676 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"If a parent of the proband has the pathogenic variant identified in the proband and/or is affected, the risk to the sibs of inheriting the variant is 50%. The severity of COL6-RD manifestations may vary among family members who are heterozygous for the same pathogenic variant."

GeneReviews genetic-counseling guidance.

+ 2 more references

Cyclophilin D and permeability transition pore modulation

Action: Pharmacotherapy NCIT:C15986

Agent: cyclosporin A CHEBI:4031

Platform: Small molecule

Cyclosporin A is investigational for COL6 myopathy. A one-month open pilot in five patients (four UCMD and one Bethlem) showed improved mitochondrial and apoptotic biopsy readouts, without establishing functional benefit or long-term Bethlem efficacy. Genetic cyclophilin-D ablation supports the target in Col6a1-null mice. Immunosuppression and toxicity preclude treating a biopsy response as a routine-care recommendation.

Mechanism Target:

INHIBITS Myofibre mitochondrial dysfunction and permeability transition pore dysregulation — Investigational cyclophilin-D-dependent pore desensitization can improve mitochondrial biopsy readouts; functional and long-term benefit in Bethlem disease remains unproved.

Show evidence (2 references)

PMID:18362356 SUPPORT BACKGROUND Other

"cyclosporin A, a widely used immunosuppressant that desensitizes the permeability transition pore independently of calcineurin inhibition"

Names the molecular target and mechanism of the intervention.

PMID:19293339 SUPPORT Model Organism

"These findings (i) demonstrate that lack of Cyp-D is equivalent to its inhibition with CsA at curing the mouse dystrophic phenotype; (ii) establish a cause-effect relationship between Cyp-D-dependent PTP regulation and pathogenesis of the ColVI muscular dystrophy and (iii) validate Cyp-D and the..."

Target validation in the Col6a1-null mouse, not proof of efficacy in patients.

Show evidence (2 references)

PMID:18362356 SUPPORT Human Clinical

"report the results of an open pilot trial with cyclosporin A in five patients with collagen VI myopathies"

An open pilot trial tested cyclosporin A in patients with collagen VI myopathies.

PMID:18362356 SUPPORT Human Clinical

"Both of these pathologic signs were largely normalized after 1 month of oral cyclosporin A administration, which also increased muscle regeneration."

Biopsy endpoints improved, but muscle strength was not measured, so this is proof of mechanism rather than proof of clinical benefit.

Investigational low-protein diet for autophagy modulation

Action: Therapeutic Dietary Intervention NCIT:C64892

A one-year open, uncontrolled pilot enrolled eight adults and analyzed seven completers (six Bethlem, one UCMD). Muscle autophagy-associated markers increased and apoptosis decreased, but human flux was not directly quantified. The six ambulant Bethlem patients improved on the four-stair test; six-minute walk, ten-meter walk, strength and the mixed-group FVC change were not statistically significant. Participants lost about 9% body weight and 7% lean mass despite preservation of the lean-to-fat percentage. The diet remains investigational and requires nutritional oversight; the study does not establish long-term clinical efficacy.

Mechanism Target:

MODULATES Defective autophagic clearance of damaged organelles — Human muscle autophagy-associated markers increase during the exploratory diet intervention. Experimental mouse autophagy rescue motivates the approach, but a restoration of human flux or sustained clinical efficacy has not been established.

Show evidence (2 references)

PMID:21037586 SUPPORT Model Organism

"Forced activation of autophagy by genetic, dietary and pharmacological approaches restored myofiber survival and ameliorated the dystrophic phenotype of Col6a1(-/-) mice."

Demonstrates rescue of the dystrophic phenotype by autophagy reactivation in the Bethlem model.

PMID:27656840 SUPPORT DIRECT Human Clinical

"After one y of low-protein diet, autophagic markers were increased in skeletal muscle and blood leukocytes of patients."

Markers in seven completers; increased abundance does not directly measure human autophagic flux.

Show evidence (3 references)

PMID:27656840 SUPPORT DIRECT Human Clinical

"After one y of low-protein diet, autophagic markers were increased in skeletal muscle and blood leukocytes of patients."

Markers in seven completers; increased abundance does not directly measure human autophagic flux.

PMID:27656840 SUPPORT DIRECT Human Clinical

"During the trial, patients lost 9% body weight (4.17 ± 2.01 kg), 7% lean mass (2.26 ± 2.45 kg), and 8% fat mass (1.91 ± 3.15 kg)."

Absolute lean mass fell despite a stable lean-to-fat percentage.

PMID:27656840 SUPPORT DIRECT Human Clinical

"(B) Timed 4-stair climb test (4 steps), measured in seconds (s). P = 0.034, following Wilcoxon signed rank test for paired data, for the comparison between mean values at T0 and T12."

Exploratory paired functional result in six ambulant participants; other functional comparisons did not establish efficacy.

Individualized moderate aerobic exercise

Action: Exercise Intervention NCIT:C62739

Supervised individualized moderate exercise can complement stretching and mobility support. In a ten-week home-training study, four men improved peak oxygen uptake by 16% compared with baseline, while two controls did not improve. CK remained stable and functional tests did not change significantly. The small study supports feasibility and aerobic conditioning, without establishing long-term disease modification or safety of intense eccentric loading.

Show evidence (2 references)

PMID:31026058 SUPPORT DIRECT Human Clinical

"Six men with Bethlem myopathy were included (4 training; 2 controls)."

Small nonrandomized disease-specific exercise study.

PMID:31026058 SUPPORT DIRECT Human Clinical

"Performance in functional tests did not change significantly. Creatine kinase values were stable during the study."

Functional and safety limitations of the small training study.

Pregnancy planning and pulmonary monitoring

Action: Supportive Care NCIT:C15747

Pregnancy care includes close respiratory surveillance for changing ventilatory requirements and assessment of hip range of motion and muscle function to inform delivery planning. Management should account for the individual level of diaphragmatic and limb weakness.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1503/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"For a pregnant woman with COL6-RD, careful pulmonary surveillance during pregnancy for potential increased needs for ventilatory support is recommended, particularly given the disproportionate weakness of the diaphragm in the COL6-RDs."

Full GeneReviews pregnancy guidance across COL6-related dystrophies.

🔬

Biochemical Markers

Variable serum creatine kinase elevation (Elevated)

Context: Skeletal muscle injury marker

Pathograph Readouts

Readout Of Progressive myofibre degeneration Diagnostic

Variable CK supports muscle involvement but is nonspecific and does not quantify functional severity.

Show evidence (1 reference)

PMID:37569848 SUPPORT DIRECT Human Clinical

All normal measurements are pooled across COL6 subgroups; the eight markedly elevated cases are specifically Bethlem.

Show evidence (2 references)

PMID:37569848 SUPPORT DIRECT Human Clinical

All normal measurements are pooled across COL6 subgroups; the eight markedly elevated cases are specifically Bethlem.

PMID:30706156 SUPPORT DIRECT Human Clinical

"CK levels did not correlate with severity of the disease."

Bethlem cohort evidence.

Reduced beclin-1 and Bnip3 protein in muscle (Reduced)

Context: Autophagy-initiation proteins in patient skeletal muscle

Pathograph Readouts

Correlates With Defective autophagic clearance of damaged organelles

Protein abundance is a static correlate; it does not directly measure human flux.

Show evidence (1 reference)

PMID:21037586 SUPPORT Human Clinical

"Furthermore, muscle biopsies from subjects with Bethlem myopathy or Ullrich congenital muscular dystrophy had reduced protein amounts of beclin-1 and Bnip3."

Directly measures reduced autophagy-initiation proteins in Bethlem myopathy muscle.

Show evidence (1 reference)

PMID:21037586 SUPPORT Human Clinical

"Furthermore, muscle biopsies from subjects with Bethlem myopathy or Ullrich congenital muscular dystrophy had reduced protein amounts of beclin-1 and Bnip3."

Directly measures reduced autophagy-initiation proteins in Bethlem myopathy muscle.

Variable collagen VI staining in skeletal muscle (VARIABLE)

Context: Skeletal muscle biopsy collagen VI/perlecan immunofluorescence

Pathograph Readouts

Readout Of Endomysial collagen VI network dysfunction Diagnostic

Normal muscle staining does not exclude molecular collagen VI dysfunction.

Show evidence (1 reference)

PMID:37569848 SUPPORT DIRECT Human Clinical

"Muscle biopsies from 13 out of 15 BM patients with dominant mutations exhibited a normal collagen VI pattern, as evidenced by the continuous overlap with the anti-perlecan staining (Table 2)."

Normal abundance and basal-lamina colocalization in most dominant Bethlem biopsies in this series; a normal result does not exclude disease.

Show evidence (1 reference)

PMID:37569848 SUPPORT DIRECT Human Clinical

"Muscle biopsies from 13 out of 15 BM patients with dominant mutations exhibited a normal collagen VI pattern, as evidenced by the continuous overlap with the anti-perlecan staining (Table 2)."

Normal abundance and basal-lamina colocalization in most dominant Bethlem biopsies in this series; a normal result does not exclude disease.

🔬

Diagnosis

Muscle collagen VI immunohistochemistry

Collagen VI abundance and colocalization with a basement-membrane marker can be normal in Bethlem disease: 13 of 15 dominant cases in one series retained a normal perlecan-overlapping pattern. Thus a normal stain does not exclude the diagnosis. Abnormal staining can support COL6 disease but is not a universal requirement, and expression may vary with age.

diagnostic procedure NCIT:C18020

Results: Retained but mislocalized collagen VI, away from the basement membrane, supports dominant collagen VI disease.

Show evidence (1 reference)

PMID:37569848 SUPPORT DIRECT Human Clinical

"Muscle biopsies from 13 out of 15 BM patients with dominant mutations exhibited a normal collagen VI pattern, as evidenced by the continuous overlap with the anti-perlecan staining (Table 2)."

Normal abundance and basal-lamina colocalization in most dominant Bethlem biopsies in this series; a normal result does not exclude disease.

COL6A1, COL6A2, and COL6A3 molecular genetic testing

Diagnosis requires compatible clinical findings and pathogenic or likely pathogenic COL6A1, COL6A2 or COL6A3 variant(s), with inheritance and segregation assessed. Testing can use a multigene panel or exome/genome sequencing and selected deletion/duplication or RNA studies when standard sequencing is unrevealing. The 62% putative-variant yield in a 2005 coding-exon study is historical and should not be presented as modern sensitivity. Variants of uncertain significance neither confirm nor exclude disease; functional evidence must be interpreted with appropriate controls. Deep-intronic COL6A1 testing is relevant to the wider COL6 diagnostic spectrum, without labeling its typical severe phenotype as Bethlem.

genetic testing NCIT:C15709

Results: A heterozygous or biallelic COL6A1, COL6A2, or COL6A3 pathogenic variant confirms the diagnosis.

Show evidence (3 references)

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"The diagnosis can be confirmed by identification of a heterozygous or biallelic pathogenic variant(s) in COL6A1, COL6A2, or COL6A3."

GeneReviews defines the molecular confirmation criterion.

PMID:15689448 SUPPORT Human Clinical

"We found putative mutations in one of the COL6 genes in 62% of patients."

Quantifies the diagnostic yield of systematic COL6 sequencing.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1503/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis."

GeneReviews explicitly limits interpretation of VUS.

Muscle imaging

MRI may show peripheral involvement of vastus lateralis with central rectus-femoris involvement, supporting a COL6 phenotype and helping select diagnostic testing. Imaging is supportive rather than perfectly specific; overlapping patterns occur in calpainopathy, and some mild Bethlem patients have normal MRI.

diagnostic procedure NCIT:C18020

Results: A concentric outer-to-inner pattern with a rectus femoris central cloud supports collagen VI-related myopathy.

Show evidence (3 references)

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

"This analysis, therefore, is also a useful diagnostic tool (Figure 2).30,32–34 MRI of muscle can be very useful in the recognition of a collagen VI-related myopathy and in the differentiation of collagen VI-related myopathies from LMNA-related Emery–Dreifuss muscular dystrophy, as well as from..."

Describes the concentric muscle imaging signature.

PMID:24339618 SUPPORT Human Clinical

"Muscle imaging revealed severe involvement of glutei and vasti with "central shadow" in rectus femoris."

A Bethlem case series documents the imaging pattern including the rectus femoris central shadow.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1503/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Of note, similar muscle imaging patterns may be seen in other conditions, including ... calpainopathy"

Imaging pattern is not unique to COL6 disease.

Cultured dermal fibroblast collagen VI analysis

Cultured fibroblast immunocytochemistry can reveal disorganized, stippled, sparse or intracellularly retained collagen VI and complement molecular interpretation. The assay compartment differs from muscle immunohistochemistry. A 2025 recessive family showed absent extracellular network in the proband and preserved networks in single-variant relatives; this does not independently classify either allele in isolation.

Diagnostic Procedure NCIT:C18020

Show evidence (1 reference)

PMID:40550965 SUPPORT DIRECT In Vitro

"The proband’s cells (III:2) presented the absence of secreted protein and collagen VI network; collagen staining was observable only in the cell’s cytoplasm as in NT well (63X)."

Patient fibroblast phenotype in a recessive COL6A2 family; individual variant effects were not isolated.

📈

Progression

Variable onset from birth to adulthood

Age: Prenatal life to adulthood

Onset is variable. The 1999 seven-kindred series found manifestations in nearly all affected children by age two, whereas the 2023 cohort included 10 of 33 with symptoms at birth, 11 in early childhood, two in adolescence, six first noticing difficulty in early adulthood and four initially asymptomatic. These ascertainment-specific distributions are not contradictory universal age cutoffs.

Show evidence (4 references)

PMID:10219778 SUPPORT Human Clinical

"Our analysis shows that nearly all children exhibit weakness or contractures during the first 2 years of life."

Natural-history data in seven kindreds establish onset within the first two years.

PMID:10219778 SUPPORT Human Clinical

"Early features include diminished foetal movements, neonatal hypotonia and congenital contractures which are of a dynamic nature during childhood."

The same cohort documents the early prenatal and neonatal features.

PMID:37569848 SUPPORT DIRECT Human Clinical

Ten of 33 Bethlem patients; individual congenital findings each have their own count.

+ 1 more reference

Contracture development in later childhood and adolescence

Age: Late first decade to teenage years

Achilles tendon and elbow contractures typically emerge late in the first decade and during the teenage years and then extend to the long finger flexors and shoulders, sometimes producing spinal rigidity.

Show evidence (2 references)

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

"In Bethlem myopathy, typical contractures of the Achilles tendons (Figure 1d) and elbows tend to develop late in the first decade of life and during teenage years."

The review dates the onset of the characteristic Bethlem contractures.

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

"These contractures progress to involve the long finger flexors and the shoulders; they can also affect the spine and cause a degree of spinal rigidity in some patients."

The review describes progression of contractures to the long finger flexors, shoulders, and spine.

Slow adult progression with late mobility loss

Age: Fourth decade onward

Adult decline may accelerate after age 40. Wheelchair use or outdoor mobility assistance does not necessarily mean loss of independent indoor walking. GeneReviews describes more than two thirds of those over 50 remaining independently ambulant indoors while needing outdoor support. In a separate 33-patient Bethlem cohort, five lost ambulation at a mean age of 44.6 years.

Show evidence (5 references)

PMID:20301676 SUPPORT REVIEW SYNTHESIS Human Clinical

"The progression of weakness is slow, and more than two thirds of affected individuals older than age 50 years remain independently ambulatory indoors, while relying on supportive means for mobility outdoors."

GeneReviews describes the slow adult course and late mobility limitation.

PMID:10219778 SUPPORT Human Clinical

"Due to slow but ongoing progression, more than two-thirds of patients over 50 years of age use a wheelchair."

The natural-history cohort quantifies wheelchair use after age 50.

PMID:37569848 SUPPORT Human Clinical

"In our BM group, only one third had a knee extension strength greater than 50% of the predicted value, while only one in ten showed similar retention of elbow flexion."

A contemporary 33-patient Bethlem cohort quantifies how much strength is actually lost, showing that mild does not mean trivial.

+ 2 more references

📊

Prevalence

Northern England

Point Prevalence 0.77 per 100,000 1–9 per 1,000,000

A northern England population survey gave a Bethlem myopathy prevalence of 0.77 cases per 100,000, equivalent to 7.7 per 1,000,000.

Show evidence (1 reference)

PMID:21691338 SUPPORT REVIEW SYNTHESIS Human Clinical

"In northern England, the prevalence of Ullrich CMD is 0.13 cases per 100,000 of the population, and that of Bethlem myopathy is 0.77 cases per 100,000."

The review reports the northern England population prevalence of Bethlem myopathy.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Bethlem myopathy:

Emery-Dreifuss muscular dystrophy MONDO:0016830

Overlapping Features Early contractures and slowly progressive weakness overlap.

Distinguishing Features

Primary cardiac involvement is a major discriminator for Emery-Dreifuss disease, whereas cardiac review in Bethlem focuses on secondary consequences of hypoventilation.

Show evidence (1 reference)

PMID:21691338 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The presence of cardiac involvement clearly favors the presence of an Emery–Dreifuss muscular dystrophy, as primary cardiac involvement is not seen in the collagen VI-related myopathies."

Clinical differential diagnosis in the COL6 review.

Recessive calpainopathy Not Yet Curated MONDO:0009675

Overlapping Features The recessive CAPN3-related limb-girdle muscular dystrophy can resemble Bethlem disease through limb-girdle weakness and contractures. The source discusses calpainopathy more broadly; this term specifically represents its recessive form.

Distinguishing Features

Periscapular and biceps atrophy may suggest calpainopathy; muscle MRI patterns can overlap, so molecular diagnosis is needed.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1503/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Of note, similar muscle imaging patterns may be seen in other conditions, including ... calpainopathy"

Imaging differential caveat.

Ullrich congenital muscular dystrophy MONDO:0000355

Overlapping Features An allelic COL6-related dystrophy with overlapping matrix disease.

Distinguishing Features

More severe congenital weakness, earlier loss of walking and earlier ventilatory dependence distinguish UCMD; intermediate phenotypes lie between UCMD and adult-ambulant Bethlem disease.

Show evidence (1 reference)

PMID:20301676 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"UCMD is characterized by congenital weakness, hypotonia, proximal joint contractures, and striking hyperlaxity of distal joints."

GeneReviews clinical distinction.

🔬

Clinical Trials

NCT01438788 PHASE_II COMPLETED

Completed uncontrolled low-protein-diet pilot: eight adults enrolled, seven completers (six Bethlem and one UCMD) analyzed in PMID27656840. Biomarker changes and exploratory outcomes do not establish controlled efficacy; loss of lean mass is relevant. Registry has no structured results posted, but a results paper is linked.

Show evidence (2 references)

clinicaltrials:NCT01438788 SUPPORT DIRECT Other

"This is a 2 stage exploratory study with a 3-month observational phase on the natural course, followed by a 12-month, open-label, non-comparative, single-arm, phase II pilot study on the efficacy, safety and tolerability of a low-protein diet (LPD) in 8 adult patients with Bethlem myopathy (BM)..."

Registered study design; status checked separately against the live record on 2026-10-01.

PMID:27656840 SUPPORT DIRECT Human Clinical

"After one y of low-protein diet, autophagic markers were increased in skeletal muscle and blood leukocytes of patients."

Markers in seven completers; increased abundance does not directly measure human autophagic flux.

NCT01895283 NOT_APPLICABLE COMPLETED

Completed Bethlem bike-ergometer training study, seven registered participants. The related 2019 publication analyzed six men (four training, two controls), reporting improved aerobic fitness with stable CK but no significant functional-test changes. Registry has no structured results posted; registration and analysis counts are distinct.

Show evidence (2 references)

clinicaltrials:NCT01895283 SUPPORT DIRECT Other

"Patients will be required to train, three times per week, for 10 weeks, on a bike ergometer with a specific training intensity, under pulse rate monitoring."

Registered study design; status checked separately against the live record on 2026-10-01.

PMID:31026058 SUPPORT DIRECT Human Clinical

"Six men with Bethlem myopathy were included (4 training; 2 controls)."

Related publication analyzed six men, distinct from the seven registry participants.

NCT01836627 NOT_APPLICABLE COMPLETED

Completed randomized feasibility study of lung hyperinsufflation in 34 children and young adults with COL6 or LAMA2 muscular dystrophy. The mixed eligibility includes impaired respiratory function; it is not a Bethlem-specific efficacy trial. No structured registry results are posted.

Show evidence (1 reference)

clinicaltrials:NCT01836627 SUPPORT DIRECT Other

"This research study includes children ages 5 to 20 years old with Collagen Type 6 Congenital Muscular Dystrophy or Laminin α2-related muscular dystrophy (LAMA2-MD)."

Registered study design; status checked separately against the live record on 2026-10-01.

NCT03693898 NOT_APPLICABLE UNKNOWN

Diagnostic MR study in adult Bethlem/UCMD, twenty planned participants. Current registry status is UNKNOWN; the last verified status was recruiting in October 2018. The estimated 2019 completion date is not proof that recruitment ended or results exist.

Show evidence (1 reference)

clinicaltrials:NCT03693898 SUPPORT DIRECT Other

"The primary aim of this study is to investigate the pattern of involved muscles, the function and quality of the muscles and the disease severity using MRI."

Registered study design; status checked separately against the live record on 2026-10-01.

NCT04020159 NOT_APPLICABLE UNKNOWN

Observational global registry for COL6-related dystrophies, one thousand planned participants. It includes Bethlem, UCMD and intermediate disease and explicitly excludes COL12-related Bethlem type 2. Current status is UNKNOWN, last verified recruiting in March 2023; no structured results are posted.

Show evidence (1 reference)

clinicaltrials:NCT04020159 SUPPORT DIRECT Other

"The Global Registry for COL6-related dystrophies (www.collagen6.org) is a database for individuals who have been diagnosed with Bethlem Myopathy, Ullrich Congenital Muscular Dystrophy (UCMD) or an intermediate form of these diseases."

Registered study design; status checked separately against the live record on 2026-10-01.

NCT01403402 NOT_APPLICABLE RECRUITING

Recruiting observational patient/proxy-reported congenital-muscle-disease study with four thousand planned participants across many diagnoses, including dominant and recessive COL6-related Bethlem myopathy. Enrollment is not a count of Bethlem patients and the registry does not establish a treatment effect.

Show evidence (1 reference)

clinicaltrials:NCT01403402 SUPPORT DIRECT Other

"The Congenital Muscle Disease Patient and Proxy Reported Outcome Study (CMDPROS) is a longitudinal 10 year study to identify and trend care parameters, adverse events in the congenital muscle diseases using the Congenital Muscle Disease International Registry (CMDIR) to acquire necessary data..."

Registered study design; status checked separately against the live record on 2026-10-01.

🧫

Experimental Models

COL6A1 exon-14-skipping patient fibroblasts PRIMARY_CELL_CULTURE

Mutant chains entered monomers but not dimers/tetramers, and mutant-containing molecules were not secreted. Normal collagen VI production was approximately halved. The engineered alpha3-chain deletion also studied in SaOS-2 cells was a separate construct, not this patient allele.

Cell source

Skin fibroblasts from the patient carrying the studied COL6A1 splice-donor allele

Pathograph links

Defective intracellular collagen VI assembly recapitulates observes: cellular

Limitations: One structurally characterized splice allele; consequences need not match all dominant COL6 variants.

Show evidence (1 reference)

PMID:10419498 SUPPORT DIRECT In Vitro

Direct assembly/secretion study of one patient exon-14-skipping allele, not a universal mechanism for all COL6 variants.

Impaired collagen VI secretion partially recapitulates observes: cellular

Limitations: Secretion was measured for one patient splice allele; the result does not establish secretion failure for all dominant COL6 variants.

Show evidence (1 reference)

PMID:10419498 SUPPORT DIRECT In Vitro

Direct assembly/secretion study of one patient exon-14-skipping allele, not a universal mechanism for all COL6 variants.

Show evidence (1 reference)

PMID:10419498 SUPPORT DIRECT In Vitro

Direct assembly/secretion study of one patient exon-14-skipping allele, not a universal mechanism for all COL6 variants.

Recessive COL6A2 patient fibroblasts PRIMARY_CELL_CULTURE

Ascorbate-treated proband cells retained collagen VI intracellularly without the secreted network seen in the mother and unaffected brother. Segregation and the paired-variant cell phenotype support the family interpretation; each initially uncertain missense variant was not tested in isolation.

Cell source

Proband skin fibroblasts and single-variant relatives from the 2025 family

Pathograph links

Impaired collagen VI secretion recapitulates observes: cellular

Limitations: One compound-heterozygous family; no isolated-allele functional dissection.

Show evidence (1 reference)

PMID:40550965 SUPPORT DIRECT In Vitro

"The proband’s cells (III:2) presented the absence of secreted protein and collagen VI network; collagen staining was observable only in the cell’s cytoplasm as in NT well (63X)."

Patient fibroblast phenotype in a recessive COL6A2 family; individual variant effects were not isolated.

Show evidence (1 reference)

PMID:40550965 SUPPORT DIRECT In Vitro

"The proband’s cells (III:2) presented the absence of secreted protein and collagen VI network; collagen staining was observable only in the cell’s cytoplasm as in NT well (63X)."

Patient fibroblast phenotype in a recessive COL6A2 family; individual variant effects were not isolated.

Col6a2-null fibroblast TGF-beta reporter system PRIMARY_CELL_CULTURE

Conditioned medium from null mouse fibroblasts increased SMAD-responsive luciferase activity in the reporter. This measures extracellular bioactive ligand and does not prove that total ligand synthesis rises, that every candidate protein binds directly, or that TGF-beta inhibition benefits patients.

Cell source

Mouse skeletal-muscle fibroblasts; HEK293 reporter cells

Pathograph links

Dysregulated extracellular TGF-beta bioavailability partially recapitulates observes: cellular

Limitations: Mouse fibroblast-conditioned medium was tested in a human HEK293 SMAD reporter; this assay does not measure TGF-beta activity in patient muscle or establish benefit from inhibiting it.

Show evidence (1 reference)

PMID:40309777 SUPPORT DIRECT In Vitro

"These experiments showed a marked increase in TGF-β activity in Col6a2–/–-derived conditioned medium compared with controls (Figure 6C)."

Mouse muscle-fibroblast conditioned medium measured with a human HEK293 luciferase reporter.

Show evidence (1 reference)

PMID:40309777 SUPPORT DIRECT In Vitro

"These experiments showed a marked increase in TGF-β activity in Col6a2–/–-derived conditioned medium compared with controls (Figure 6C)."

Mouse muscle-fibroblast conditioned medium measured with a human HEK293 luciferase reporter.

🐁

Animal Models

Col6a1-null mouse

This mild myopathic model supports mitochondrial, apoptotic and autophagy mechanisms, but a complete chain null differs from most dominant Bethlem alleles. Its skin is mechanically weaker with altered wound ultrastructure, yet pathological keloid-like scarring and overt wound-healing disturbance were not reproduced.

Species

Mus musculus

Genotype

Col6a1 homozygous knockout

Pathograph links

Myofibre mitochondrial dysfunction and permeability transition pore dysregulation partially recapitulates observes: cellular

Limitations: Complete Col6a1 loss differs from most dominant structural Bethlem alleles; rescue of this mouse phenotype does not establish treatment efficacy in patients.

Show evidence (1 reference)

PMID:14625552 SUPPORT DIRECT Model Organism

"Here we show that Col6a1-/- muscles have a loss of contractile strength associated with ultrastructural alterations of sarcoplasmic reticulum (SR) and mitochondria and spontaneous apoptosis."

Primary knockout-mouse muscle findings.

Defective autophagic clearance of damaged organelles partially recapitulates observes: cellular

Limitations: Complete Col6a1 loss differs from most dominant structural Bethlem alleles; rescue of this mouse phenotype does not establish treatment efficacy in patients.

Show evidence (1 reference)

PMID:21037586 SUPPORT Model Organism

Demonstrates the autophagy machinery defect in collagen VI-deficient muscle.

Dermal extracellular matrix dysfunction partially recapitulates observes: tissue

Limitations: Complete Col6a1 loss differs from dominant structural alleles. Mechanical skin weakness and altered ultrastructure occurred without reproducing pathological human scarring.

Show evidence (1 reference)

PMID:25158062 SUPPORT DIRECT Model Organism

"Interestingly, we detected a decreased tensile strength of the skin and an altered collagen fibril and basement membrane architecture in Col6a1 null mice, the latter being features that are also found in collagen VI myopathy patients."

Direct mechanical and morphological mouse skin findings.

Abnormal cutaneous scarring fails to recapitulate observes: tissue

Limitations: The reported mouse wounds did not develop the pathological scarring characteristic of some patients.

Show evidence (1 reference)

PMID:25158062 SUPPORT DIRECT Model Organism

"However, in contrast to the hypertrophic scars or keloids occurring in patients with a collagen VI myopathies, we did not observe such disturbed wound healing in the Col6a1 null mice."

Explicit model failure to reproduce pathological human scarring.

Show evidence (3 references)

PMID:14625552 SUPPORT DIRECT Model Organism

"Here we show that Col6a1-/- muscles have a loss of contractile strength associated with ultrastructural alterations of sarcoplasmic reticulum (SR) and mitochondria and spontaneous apoptosis."

Primary knockout-mouse muscle findings.

PMID:25158062 SUPPORT DIRECT Model Organism

Direct mechanical and morphological mouse skin findings.

PMID:25158062 SUPPORT DIRECT Model Organism

"However, in contrast to the hypertrophic scars or keloids occurring in patients with a collagen VI myopathies, we did not observe such disturbed wound healing in the Col6a1 null mice."

Explicit model failure to reproduce pathological human scarring.

Col6a1-null cyclophilin-D-deficient mouse

Removing cyclophilin D genetically rescues mitochondrial, ultrastructural and apoptotic abnormalities in the null model, supporting a permeability-transition mechanism. It does not establish long-term clinical efficacy or immunosuppressant safety in Bethlem disease.

Species

Mus musculus

Genotype

Col6a1 knockout with Ppif/Cyp-D ablation

Pathograph links

Myofibre mitochondrial dysfunction and permeability transition pore dysregulation perturbs observes: cellular

Limitations: Lifelong genetic loss of cyclophilin D in a complete Col6a1-null background does not establish the efficacy or safety of pharmacological inhibition in human Bethlem myopathy.

Show evidence (1 reference)

PMID:19293339 SUPPORT DIRECT Model Organism

"In the absence of Cyp-D, Col6a1(-/-) mice show negligible myofiber degeneration, rescue from mitochondrial dysfunction and ultrastructural defects, and normalized incidence of apoptosis."

Genetic rescue in double-mutant mice; not a patient therapy trial.

Myofibre apoptosis perturbs observes: cellular

Limitations: Lifelong genetic loss of cyclophilin D in a complete Col6a1-null background does not establish the efficacy or safety of pharmacological inhibition in human Bethlem myopathy.

Show evidence (1 reference)

PMID:19293339 SUPPORT DIRECT Model Organism

"In the absence of Cyp-D, Col6a1(-/-) mice show negligible myofiber degeneration, rescue from mitochondrial dysfunction and ultrastructural defects, and normalized incidence of apoptosis."

Genetic rescue in double-mutant mice; not a patient therapy trial.

Show evidence (1 reference)

PMID:19293339 SUPPORT DIRECT Model Organism

"In the absence of Cyp-D, Col6a1(-/-) mice show negligible myofiber degeneration, rescue from mitochondrial dysfunction and ultrastructural defects, and normalized incidence of apoptosis."

Genetic rescue in double-mutant mice; not a patient therapy trial.

Bethlem-like col6a1 exon-13 morphant zebrafish

Transient exon-13 skipping, analogous to human COL6A1 exon 14, caused mild delayed motor and myotendinous/organellar abnormalities. The more severe exon-9 model was used for cyclosporin testing; its partial motor rescue cannot be claimed as a result in the mild arm. Morpholino embryos do not establish adult progression.

Species

Danio rerio

Genotype

Morpholino-induced in-frame col6a1 exon 13 skipping

Pathograph links

Progressive myofibre degeneration partially recapitulates observes: tissue

Limitations: Transient developmental structural and motor phenotype, not adult longitudinal disease.

Show evidence (1 reference)

PMID:20338942 SUPPORT DIRECT Model Organism

"In all, the functional, morphologic and structural changes caused by col6a1 morpholinos are consistent with a mild, Bethlem-like phenotype (exon 13 morpholino) and with a severe, UCMD-like phenotype (exon 9 morpholino)."

Distinct transient zebrafish models; exon 13 is the Bethlem-like arm.

Show evidence (2 references)

PMID:20338942 SUPPORT DIRECT Model Organism

Distinct transient zebrafish models; exon 13 is the Bethlem-like arm.

PMID:20338942 SUPPORT DIRECT Model Organism

"Because we were most interested in generating and studying a model of UCMD, for the remaining analysis we focused on the exon 9 morphant embryos."

Bounds the subsequent drug experiments to the severe model.

Col6a2-null mouse

The model develops weakness before overt fibrosis and abnormal matrix mechanics, with increased resting but disturbed post-injury TGF-beta activity. Disease was milder than human COL6 dystrophy and did not clearly progress through 60 weeks. An Ltbp4 binding-defective cross did not rescue strength, histology or physiology; no clinical treatment effect follows from this pathway finding.

Species

Mus musculus

Genotype

Col6a2 homozygous deletion; Ltbp4 p.Cys1260Ser cross used for intervention

Pathograph links

Dysregulated extracellular TGF-beta bioavailability partially recapitulates observes: tissue

Limitations: The mouse disease was mild and did not clearly progress through 60 weeks; weakness preceded overt fibrosis. The Ltbp4 intervention failed to rescue disease, so pathway involvement alone does not validate a treatment target.

Show evidence (1 reference)

PMID:40309777 SUPPORT DIRECT Model Organism

"Together, these findings suggest that absence of collagen VI from the muscle ECM increases active TGF-β without an increase in total TGF-β transcription or translation."

Col6a2-null mouse tissue and fibroblast assays; altered activation rather than increased overall production.

Endomysial fibrosis partially recapitulates observes: tissue

Show evidence (1 reference)

PMID:40309777 SUPPORT DIRECT Model Organism

"We found a marked increase in endomysial fibrillar collagen content based on the Sirius red staining and hydroxyproline content of gastrocnemius muscle of 25-week-old or older Col6a2–/– mice (Figure 4, A and B, and Supplemental Figure 4)."

Direct tissue evidence of endomysial fibrosis in older Col6a2-null mice; weakness was already present before overt fibrosis.

Show evidence (3 references)

PMID:40309777 SUPPORT DIRECT Model Organism

"Together, these findings suggest that absence of collagen VI from the muscle ECM increases active TGF-β without an increase in total TGF-β transcription or translation."

Col6a2-null mouse tissue and fibroblast assays; altered activation rather than increased overall production.

PMID:40309777 SUPPORT DIRECT Model Organism

"Crossing the Col6a2–/– mice with the Ltbp4c/s mice failed to improve muscle strength, histology, or physiological parameters (Figure 8)."

Negative genetic intervention prevents treating pathway association as validated therapeutic rescue.

PMID:40309777 SUPPORT DIRECT Model Organism

Direct tissue evidence of endomysial fibrosis in older Col6a2-null mice; weakness was already present before overt fibrosis.

{ }

Source YAML

click to show

name: Bethlem myopathy
category: Mendelian
creation_date: "2026-07-31T00:00:00Z"
synonyms:
- Bethlem myopathy 1
- BTHLM1
- Bethlem muscular dystrophy
- Benign autosomal dominant myopathy
description: >-
  Bethlem myopathy is the usually milder, adult-ambulant end of the collagen VI-related dystrophy spectrum.
  Pathogenic COL6A1, COL6A2 or COL6A3 variants act through dominant or less commonly recessive mechanisms affecting
  collagen VI assembly, secretion or extracellular organization. Interstitial fibroblast-derived matrix dysfunction
  is linked to myofibre injury; autophagy, mitochondrial permeability and TGF-beta abnormalities are supported
  mainly by experimental models and selected patient studies, with incompletely defined intermediates. Slowly
  progressive proximal weakness and finger-flexor, elbow and Achilles contractures are characteristic, but
  onset and contractures vary and respiratory weakness can develop while walking is retained. Keloids, atrophic
  scars and follicular hyperkeratosis are useful connective-tissue clues. The historical label benign does
  not capture the possible adult functional decline.
disease_term:
  preferred_term: Bethlem myopathy
  term:
    id: MONDO:0008029
    label: Bethlem myopathy
parents:
- Collagen 6-related myopathy
- Congenital muscular dystrophy
definitions:
- name: GeneReviews Bethlem muscular dystrophy definition
  definition_type: OTHER
  description: >
    Bethlem muscular dystrophy is the mild end of the collagen VI-related
    dystrophy continuum and is characterized by the combination of proximal
    muscle weakness and joint contractures.
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bethlem muscular dystrophy is characterized by a combination of proximal muscle weakness and joint contractures."
    explanation: The GeneReviews chapter states the defining clinical combination for Bethlem muscular dystrophy.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:15689448
    reference_title: "Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BM is a relatively mild dominantly inherited disorder with proximal weakness and distal joint contractures."
    explanation: A cohort sequencing study frames Bethlem myopathy as the mild, dominantly inherited COL6 disorder with proximal weakness and distal contractures.
inheritance:
- name: Autosomal dominant inheritance
  description: >
    Bethlem myopathy is usually inherited in an autosomal dominant manner,
    typically through dominant-negative COL6A1, COL6A2, or COL6A3 variants that
    are incorporated into collagen VI monomers.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bethlem muscular dystrophy is usually inherited in an autosomal dominant manner"
    explanation: GeneReviews records autosomal dominant inheritance as the usual mode for Bethlem muscular dystrophy.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:8782832
    reference_title: Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A distinctive feature of this autosomal dominant disorder consists of contractures of multiple joints in addition to generalized muscular weakness and wasting."
    explanation: The original gene-identification study describes Bethlem myopathy as an autosomal dominant disorder.
- name: Autosomal recessive inheritance
  description: >-
    Recessive Bethlem myopathy occurs with biallelic COL6 variants and residual-function mechanisms. COL6A2-related
    myosclerosis overlaps the spectrum but is clinically distinguishable by severe stiffness and restricted
    joint movement; it is not synonymous with all recessive Bethlem disease.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "although autosomal recessive inheritance has also been reported"
    explanation: GeneReviews records that recessive inheritance also occurs in Bethlem muscular dystrophy.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In fact, in populations with a low degree of consanguinity, de novo autosomal-dominant mutations are
      the most common underlying mechanism of Ullrich CMD.1,30,32,80 Furthermore, although the typical genetic
      mechanism and pattern of inheritance for Bethlem myopathy is dominant, recessive mutations have also
      been seen in affected patients, albeit rarely.81,82 For example, the myosclerosis phenotype15 has emerged
      as a recessive form of Bethlem myopathy, in which a homozygous nonsense mutation in the COL6A2 gene results
      in a stable chain lacking the C2 domain but retaining the C1 domain,16 which presumably interferes with
      its ability to interact with other components in the extracellular matrix.
    explanation: The review documents a recessive (myosclerosis) form of Bethlem myopathy caused by a homozygous COL6A2 nonsense variant.
    quote_role: REVIEW_SYNTHESIS
has_subtypes:
- name: BTHLM1A
  display_name: Bethlem myopathy 1A (COL6A1-related)
  subtype_term:
    preferred_term: Bethlem myopathy 1A
    term:
      id: MONDO:0024530
      label: Bethlem myopathy 1A
  description: >-
    COL6A1-related Bethlem myopathy (OMIM:158810). Exon 14 skipping is recurrent; although compatible with
    the Bethlem end of the COL6 spectrum, it is not a marker of a benign adult course.
  genes:
  - preferred_term: COL6A1
    term:
      id: hgnc:2211
      label: COL6A1
  evidence:
  - reference: PMID:8782832
    reference_title: Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence analysis in four families reveals a mutation in COL6A1 in one and a COL6A2 mutation in two other
      kindreds.
    explanation: Family sequencing identified a COL6A1 mutation in Bethlem myopathy.
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Omissions of exon 16 in the α3(VI) chain account for the single most common mutation of this type, which
      is usually associated with a severe Ullrich CMD phenotype.32,80 Mutations that delete crucial cysteine
      residues in the collagenous triple helix domains of collagen VI subunits, as is the case for skipping
      of exon 14 in the α1(VI) chain, seem to have a more limited dominant-negative effect that shifts the
      clinical phenotype of collagen VI-related myopathy towards the mild end of the spectrum.30,80 Indeed,
      exon-14-skipping mutations are the single most common mutation type seen in patients with Bethlem myopathy.30,85,88,91–93
      In-frame exon-skipping mutations located in the C-terminal end of the collagenous triple-helical domain
      interfere with assembly of the three peptide subunits into collagen VI monomers, with the consequence
      that abnormal peptides are prevented from assembly into tetramers.
    explanation: The review identifies COL6A1 exon 14 skipping as the most common Bethlem mutation type.
    quote_role: REVIEW_SYNTHESIS
  - &id001
    reference: PMID:25535305
    reference_title: 'Bethlem myopathy: long-term follow-up identifies COL6 mutations predicting severe clinical evolution.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Skipping of exon 14 of COL6A1 was found in 35% of index cases and was mostly associated with a severe
      clinical evolution.
    explanation: >-
      Twenty-three index cases in a 35-patient cohort; common does not mean benign.
- name: BTHLM1B
  display_name: Bethlem myopathy 1B (COL6A2-related)
  subtype_term:
    preferred_term: Bethlem myopathy 1B
    term:
      id: MONDO:0958233
      label: Bethlem myopathy 1B
  description: >-
    COL6A2-related Bethlem myopathy (OMIM:620725) includes dominant and recessive forms. The allelic myosclerosis
    phenotype is distinguished clinically rather than treated as the definition of this subtype.
  genes:
  - preferred_term: COL6A2
    term:
      id: hgnc:2212
      label: COL6A2
  evidence:
  - reference: PMID:8782832
    reference_title: Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence analysis in four families reveals a mutation in COL6A1 in one and a COL6A2 mutation in two other
      kindreds.
    explanation: Family sequencing identified COL6A2 mutations in two Bethlem myopathy kindreds.
- name: BTHLM1C
  display_name: Bethlem myopathy 1C (COL6A3-related)
  subtype_term:
    preferred_term: Bethlem myopathy 1C
    term:
      id: MONDO:0958234
      label: Bethlem myopathy 1C
  description: >
    COL6A3-related Bethlem myopathy corresponding to OMIM:620726. Linkage in one
    Bethlem kindred mapped to markers on chromosome 2q37 near COL6A3.
  genes:
  - preferred_term: COL6A3
    term:
      id: hgnc:2213
      label: COL6A3
  evidence:
  - reference: PMID:8782832
    reference_title: Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nine kindreds show genetic linkage to the COL6A1-COL6A2 cluster on chromosome 21q22.3 (refs 3,4; manuscript
      submitted) whereas one family shows linkage to markers on chromosome 2q37 close to COL6A3 (ref.
    explanation: Linkage evidence supports a COL6A3-related Bethlem myopathy subtype.
prevalence:
- population: Northern England
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.77
  notes: >
    A northern England population survey gave a Bethlem myopathy prevalence of
    0.77 cases per 100,000, equivalent to 7.7 per 1,000,000.
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In northern England, the prevalence of Ullrich CMD is 0.13 cases per 100,000 of the population, and that of Bethlem myopathy is 0.77 cases per 100,000."
    explanation: The review reports the northern England population prevalence of Bethlem myopathy.
    quote_role: REVIEW_SYNTHESIS
progression:
- phase: Variable onset from birth to adulthood
  age_range: Prenatal life to adulthood
  notes: >-
    Onset is variable. The 1999 seven-kindred series found manifestations in nearly all affected children by
    age two, whereas the 2023 cohort included 10 of 33 with symptoms at birth, 11 in early childhood, two in
    adolescence, six first noticing difficulty in early adulthood and four initially asymptomatic. These ascertainment-specific
    distributions are not contradictory universal age cutoffs.
  evidence:
  - reference: PMID:10219778
    reference_title: "Bethlem myopathy: a slowly progressive congenital muscular dystrophy with contractures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our analysis shows that nearly all children exhibit weakness or contractures during the first 2 years of life."
    explanation: Natural-history data in seven kindreds establish onset within the first two years.
  - reference: PMID:10219778
    reference_title: "Bethlem myopathy: a slowly progressive congenital muscular dystrophy with contractures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early features include diminished foetal movements, neonatal hypotonia and congenital contractures which are of a dynamic nature during childhood."
    explanation: The same cohort documents the early prenatal and neonatal features.
  - reference: PMID:37569848
    reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Ten patients with BM (30%) exhibited symptoms at birth, with a varying combination of congenital hip
      dislocation (CHD) in four, hypotonia in four, club foot in four, torticollis in three, and contractures
      of the elbow and knee in one.
    explanation: >-
      Ten of 33 Bethlem patients; individual congenital findings each have their own count.
  - reference: PMID:37569848
    reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Six patients only noticed these difficulties during early adulthood, while four were asymptomatic at
      their initial visit.
    explanation: >-
      Adult recognition and initially asymptomatic cases in the Bethlem subgroup.
- phase: Contracture development in later childhood and adolescence
  age_range: Late first decade to teenage years
  notes: >
    Achilles tendon and elbow contractures typically emerge late in the first
    decade and during the teenage years and then extend to the long finger
    flexors and shoulders, sometimes producing spinal rigidity.
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In Bethlem myopathy, typical contractures of the Achilles tendons (Figure 1d) and elbows tend to develop late in the first decade of life and during teenage years."
    explanation: The review dates the onset of the characteristic Bethlem contractures.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These contractures progress to involve the long finger flexors and the shoulders; they can also affect the spine and cause a degree of spinal rigidity in some patients."
    explanation: The review describes progression of contractures to the long finger flexors, shoulders, and spine.
    quote_role: REVIEW_SYNTHESIS
- phase: Slow adult progression with late mobility loss
  age_range: Fourth decade onward
  notes: >-
    Adult decline may accelerate after age 40. Wheelchair use or outdoor mobility assistance does not necessarily
    mean loss of independent indoor walking. GeneReviews describes more than two thirds of those over 50 remaining
    independently ambulant indoors while needing outdoor support. In a separate 33-patient Bethlem cohort,
    five lost ambulation at a mean age of 44.6 years.
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The progression of weakness is slow, and more than two thirds of affected individuals older than age 50 years remain independently ambulatory indoors, while relying on supportive means for mobility outdoors."
    explanation: GeneReviews describes the slow adult course and late mobility limitation.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:10219778
    reference_title: "Bethlem myopathy: a slowly progressive congenital muscular dystrophy with contractures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Due to slow but ongoing progression, more than two-thirds of patients over 50 years of age use a wheelchair."
    explanation: The natural-history cohort quantifies wheelchair use after age 50.
  - reference: PMID:37569848
    reference_title: "New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our BM group, only one third had a knee extension strength greater than 50% of the predicted value, while only one in ten showed similar retention of elbow flexion."
    explanation: >
      A contemporary 33-patient Bethlem cohort quantifies how much strength is
      actually lost, showing that mild does not mean trivial.
  - reference: PMID:25535305
    reference_title: 'Bethlem myopathy: long-term follow-up identifies COL6 mutations predicting severe clinical evolution.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      However, worsening of the functional disability appeared typically after the age of 40 in 47% of our
      patients, and was frequently associated with COL6A1 exon 14 skipping.
    explanation: >-
      Retrospective cohort of 35 molecularly identified Bethlem patients; not a deterministic allele prediction.
  - &id003
    reference: PMID:37569848
    reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The mean age at loss of ambulation was 44.6 years (SD 9.7 years) in five BM, 17.0 years (SD 1.8 years)
      in five INTM, and 8.1 years (SD 2.5 years) in 15 UCMD.
    explanation: >-
      Five of 33 Bethlem patients lost ambulation; intermediate/UCMD figures are separate comparators.
genetic:
- name: COL6A1
  gene_term:
    preferred_term: COL6A1
    term:
      id: hgnc:2211
      label: COL6A1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    COL6A1 encodes the collagen VI alpha 1 chain. Structural variants including glycine substitutions and in-frame
    exon 14 skipping cause Bethlem disease. For one splice-donor allele, patient RNA showed an 18-amino-acid
    in-frame deletion and fibroblast studies found blocked dimer/tetramer assembly and secretion of mutant-containing
    molecules. Exon 14 skipping was associated with worse adult evolution in one cohort; phenotype cannot be
    predicted reliably from the broad variant class alone.
  evidence:
  - reference: PMID:15689448
    reference_title: "Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      INTRODUCTION: Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem
      myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD).
    explanation: Sequencing evidence establishes the three collagen VI genes as Bethlem myopathy causes.
  - reference: PMID:8782832
    reference_title: Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence analysis in four families reveals a mutation in COL6A1 in one and a COL6A2 mutation in two other
      kindreds.
    explanation: The original study identified a COL6A1 mutation segregating in a Bethlem kindred.
  - reference: PMID:10419498
    reference_title: Bethlem myopathy and engineered collagen VI triple helical deletions prevent intracellular multimer assembly and protein secretion.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      The mutant alpha1(VI) chains associated intracellularly with alpha2(VI) and alpha3(VI) to form disulfide-bonded
      monomers, but further assembly into dimers and tetramers was prevented, and molecules containing the
      mutant chain were not secreted.
    explanation: >-
      Direct assembly/secretion study of one patient exon-14-skipping allele, not a universal mechanism for
      all COL6 variants.
  - *id001
- name: COL6A2
  gene_term:
    preferred_term: COL6A2
    term:
      id: hgnc:2212
      label: COL6A2
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    COL6A2 can cause dominant structural-variant disease or recessive Bethlem phenotypes. In one family, p.Gln889*
    and p.Pro260_Lys261insProPro in trans were associated with reduced normal protein and impaired secretion/assembly,
    respectively; carrier parents were asymptomatic. In a separate three-sister family, c.1514G>A (p.Gly505Asp)
    and c.2877G>C (p.Glu959Asp) segregated in trans, and proband fibroblasts showed intracellular retention
    and absent extracellular network. Those two missense variants were initially uncertain; combined segregation
    and functional findings supported the authors' causal interpretation, without separate assays proving the
    effect of each allele. Myosclerosis is an allelic, clinically distinct presentation.
  evidence:
  - reference: PMID:8782832
    reference_title: Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both mutations disrupt the Gly-X-Y motif of the triple helical domain by substitution of Gly for either Val or Ser."
    explanation: The original study characterizes the Gly-X-Y disrupting substitutions found in Bethlem kindreds.
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In fact, in populations with a low degree of consanguinity, de novo autosomal-dominant mutations are
      the most common underlying mechanism of Ullrich CMD.1,30,32,80 Furthermore, although the typical genetic
      mechanism and pattern of inheritance for Bethlem myopathy is dominant, recessive mutations have also
      been seen in affected patients, albeit rarely.81,82 For example, the myosclerosis phenotype15 has emerged
      as a recessive form of Bethlem myopathy, in which a homozygous nonsense mutation in the COL6A2 gene results
      in a stable chain lacking the C2 domain but retaining the C1 domain,16 which presumably interferes with
      its ability to interact with other components in the extracellular matrix.
    explanation: The review documents recessive COL6A2 disease at the Bethlem end of the spectrum.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:31471117
    reference_title: 'Autosomal recessive Bethlem myopathy: A clinical, genetic and functional study.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      Fibroblast studies in both affected patients showed the concomitant reduction in the amount of normal
      Collagen VI (p.Gln889*) and impairment of Collagen VI secretion and assembly (p.Pro260_Lys261insProPro).
    explanation: >-
      Compound-heterozygous siblings; each heterozygous parent was asymptomatic.
  - reference: PMID:40550965
    reference_title: 'Autosomal recessive Bethlem myopathy: a 30-year journey.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      The proband’s cells (III:2) presented the absence of secreted protein and collagen VI network; collagen
      staining was observable only in the cell’s cytoplasm as in NT well (63X).
    explanation: >-
      Patient fibroblast phenotype in a recessive COL6A2 family; individual variant effects were not isolated.
- name: COL6A3
  gene_term:
    preferred_term: COL6A3
    term:
      id: hgnc:2213
      label: COL6A3
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    COL6A3 encodes the alpha 3 chain and has dominant and recessive Bethlem-associated alleles. The founding
    family supplied linkage evidence; subsequent molecular cohorts include p.Lys2486Glu in homozygous or compound-heterozygous
    states and p.Gly2053Val in two Bethlem patients. These genotype observations do not establish a uniform
    molecular effect for all COL6A3 variants.
  evidence:
  - reference: PMID:8782832
    reference_title: Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nine kindreds show genetic linkage to the COL6A1-COL6A2 cluster on chromosome 21q22.3 (refs 3,4; manuscript
      submitted) whereas one family shows linkage to markers on chromosome 2q37 close to COL6A3 (ref.
    explanation: Linkage in a Bethlem kindred implicates the COL6A3 locus.
  - reference: PMID:30706156
    reference_title: 'Bethlem myopathy: a series of 16 patients and description of seven new associated mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The most frequent mutation was the COL6A3 variant c.7447A>G, p.Lys2486Glu, with either an homozygous
      or compound heterozygous presentation.
    explanation: >-
      Recessive COL6A3 association in the sixteen-patient series.
  - reference: PMID:37569848
    reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      In COL6A3, two BM patients had the p.Gly2053Val (c.6158G>T) missense mutation, and the c.6210+1G>A splicing
      mutation was present in one INTM and one UCDM patient.
    explanation: >-
      The p.Gly2053Val observation is Bethlem-specific; splice-variant cases belong to different clinical subgroups.
pathophysiology:
- name: Collagen VI alpha-chain gene defects
  biological_scale: MOLECULAR
  description: >-
    Pathogenic COL6A1, COL6A2 or COL6A3 variants alter the obligatory collagen VI chains. Dominant structural
    alleles and recessive residual-function combinations can cause Bethlem myopathy. Their consequences depend
    on the affected domain and assembly step: entry into a monomer does not imply that mutant protein reaches
    tetramers or the extracellular matrix. Ordinary heterozygous loss-of-function alleles can be clinically
    tolerated; pathogenic structural alleles should not be equated with simple gene dosage reduction.
  genes:
  - preferred_term: COL6A1
    term:
      id: hgnc:2211
      label: COL6A1
  - preferred_term: COL6A2
    term:
      id: hgnc:2212
      label: COL6A2
  - preferred_term: COL6A3
    term:
      id: hgnc:2213
      label: COL6A3
  molecular_functions:
  - preferred_term: extracellular matrix structural constituent
    modifier: ABNORMAL
    term:
      id: GO:0005201
      label: extracellular matrix structural constituent
  evidence:
  - reference: PMID:15689448
    reference_title: "Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      INTRODUCTION: Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem
      myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD).
    explanation: Establishes the three collagen VI genes as the genetic cause of Bethlem myopathy.
  - reference: PMID:8782832
    reference_title: Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both mutations disrupt the Gly-X-Y motif of the triple helical domain by substitution of Gly for either Val or Ser."
    explanation: Identifies the triple-helix-disrupting substitutions that constitute the primary molecular lesion.
  - &id002
    reference: PMID:10419498
    reference_title: Bethlem myopathy and engineered collagen VI triple helical deletions prevent intracellular multimer assembly and protein secretion.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      The mutant alpha1(VI) chains associated intracellularly with alpha2(VI) and alpha3(VI) to form disulfide-bonded
      monomers, but further assembly into dimers and tetramers was prevented, and molecules containing the
      mutant chain were not secreted.
    explanation: >-
      Direct assembly/secretion study of one patient exon-14-skipping allele, not a universal mechanism for
      all COL6 variants.
  downstream:
  - target: Defective intracellular collagen VI assembly
    description: >-
      A studied COL6A1 splice variant permits mutant monomer formation but blocks later intracellular assembly.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10419498
      reference_title: Bethlem myopathy and engineered collagen VI triple helical deletions prevent intracellular multimer assembly and protein secretion.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        The mutant alpha1(VI) chains associated intracellularly with alpha2(VI) and alpha3(VI) to form disulfide-bonded
        monomers, but further assembly into dimers and tetramers was prevented, and molecules containing the
        mutant chain were not secreted.
      explanation: >-
        Direct assembly/secretion study of one patient exon-14-skipping allele, not a universal mechanism for
        all COL6 variants.
  - target: Endomysial collagen VI network dysfunction
    description: >-
      Some structural variants impair extracellular network function through mechanisms distinct from complete
      secretion failure.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21691338
      reference_title: 'The collagen VI-related myopathies: muscle meets its matrix.'
      supports: SUPPORT
      evidence_source: OTHER
      directness: INDIRECT
      snippet: >-
        Dominant and recessive autosomal mutations in the three major collagen VI genes-COL6A1, COL6A2, and
        COL6A3-can underlie this entire clinical spectrum, and result in deficient or dysfunctional microfibrillar
        collagen VI in the extracellular matrix of muscle and other connective tissues, such as skin and tendons.
      explanation: >-
        Review synthesis of COL6 genotype-to-matrix consequences.
      quote_role: REVIEW_SYNTHESIS
- name: Defective intracellular collagen VI assembly
  biological_scale: MOLECULAR
  description: >-
    Variant-specific defects impair intracellular collagen VI oligomerization. For the studied COL6A1 exon-14-skipping
    allele, mutant chains enter heterotrimeric monomers but fail to form dimers and tetramers. Other assembly-competent
    dominant alleles may instead interfere with later extracellular organization; the one-in-sixteen normal-tetramer
    argument is not applicable to every Bethlem allele.
  evidence:
  - *id002
  downstream:
  - target: Impaired collagen VI secretion
    description: >-
      Failure to assemble export-competent oligomers prevents secretion of mutant-containing molecules.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10419498
      reference_title: Bethlem myopathy and engineered collagen VI triple helical deletions prevent intracellular multimer assembly and protein secretion.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        The mutant alpha1(VI) chains associated intracellularly with alpha2(VI) and alpha3(VI) to form disulfide-bonded
        monomers, but further assembly into dimers and tetramers was prevented, and molecules containing the
        mutant chain were not secreted.
      explanation: >-
        Direct assembly/secretion study of one patient exon-14-skipping allele, not a universal mechanism for
        all COL6 variants.
- name: Impaired collagen VI secretion
  description: >-
    Some Bethlem alleles cause intracellular retention and reduced extracellular delivery of collagen VI. This
    is demonstrated for one COL6A1 exon-14-skipping allele and in fibroblasts from a recessive COL6A2 proband,
    rather than an obligatory defect in every patient.
  biological_scale: CELLULAR
  evidence:
  - *id002
  - reference: PMID:40550965
    reference_title: 'Autosomal recessive Bethlem myopathy: a 30-year journey.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      The proband’s cells (III:2) presented the absence of secreted protein and collagen VI network; collagen
      staining was observable only in the cell’s cytoplasm as in NT well (63X).
    explanation: >-
      Patient fibroblast phenotype in a recessive COL6A2 family; individual variant effects were not isolated.
  downstream:
  - target: Endomysial collagen VI network dysfunction
    description: >-
      Reduced secretion impairs extracellular collagen VI network deposition.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40550965
      reference_title: 'Autosomal recessive Bethlem myopathy: a 30-year journey.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        The proband’s cells (III:2) presented the absence of secreted protein and collagen VI network; collagen
        staining was observable only in the cell’s cytoplasm as in NT well (63X).
      explanation: >-
        Patient fibroblast phenotype in a recessive COL6A2 family; individual variant effects were not isolated.
  biological_processes:
  - preferred_term: protein secretion
    term:
      id: GO:0009306
      label: protein secretion
    modifier: DECREASED
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
- name: Endomysial collagen VI network dysfunction
  biological_scale: TISSUE
  description: >-
    Collagen VI is supplied to muscle by interstitial fibroblasts. Variant-dependent defects affect extracellular
    matrix organization or function, but routine muscle staining can be normal in Bethlem disease, including
    preserved colocalization with basal-lamina perlecan in 13 of 15 dominant cases in a 2023 series. Normal
    staining does not prove normal molecular interactions; conversely, basement-membrane mislocalization is
    not a universal Bethlem finding.
  cell_types:
  - preferred_term: muscle interstitial fibroblast
    term:
      id: CL:0011027
      label: skeletal muscle fibroblast
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  locations:
  - preferred_term: extracellular matrix
    term:
      id: GO:0031012
      label: extracellular matrix
  evidence:
  - reference: PMID:37569848
    reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Muscle biopsies from 13 out of 15 BM patients with dominant mutations exhibited a normal collagen VI
      pattern, as evidenced by the continuous overlap with the anti-perlecan staining (Table 2).
    explanation: >-
      Normal abundance and basal-lamina colocalization in most dominant Bethlem biopsies in this series; a
      normal result does not exclude disease.
  - reference: PMID:21691338
    reference_title: 'The collagen VI-related myopathies: muscle meets its matrix.'
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      In muscle, the cell of origin for collagen VI is the interstitial fibroblast.
    explanation: >-
      Review of the cellular source of collagen VI.
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Impaired matrix-to-sarcolemma anchoring of the myofibre
    description: >
      Loss of the functional collagen VI network at the muscle basement membrane
      removes the microfibrillar bridge between the myofibre surface and the
      surrounding matrix.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Tendon and periarticular connective tissue involvement
    description: >
      Collagen VI is also a pericellular matrix component of tendon, so the same
      network defect alters tendon and periarticular connective tissue.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Dermal extracellular matrix dysfunction
    description: >
      The same collagen VI network defect is expressed in skin, producing the
      characteristic follicular and scarring phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Defective autophagic clearance of damaged organelles
    description: >-
      Extracellular collagen VI deficiency is linked to defective autophagy in knockout models, with unresolved
      matrix-to-intracellular intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21037586
      reference_title: Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Here we demonstrate that this persistence of abnormal organelles and apoptosis are caused by defective
        autophagy.
      explanation: >-
        Causal experimental interpretation in the Col6a1-null model; human static protein measurements are
        separate.
  - target: Dysregulated extracellular TGF-beta bioavailability
    description: >-
      Loss of collagen VI changes extracellular TGF-beta availability and protein associations in Col6a2-null
      models.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40309777
      reference_title: Collagen type VI regulates TGF-β bioavailability in skeletal muscle in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Together, these findings suggest that absence of collagen VI from the muscle ECM increases active TGF-β
        without an increase in total TGF-β transcription or translation.
      explanation: >-
        Col6a2-null mouse tissue and fibroblast assays; altered activation rather than increased overall production.
  - target: Neonatal hypotonia
    description: >-
      Early matrix-muscle dysfunction may produce congenital weakness before the later progressive degenerative
      course; the intervening developmental mechanisms remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10219778
      reference_title: "Bethlem myopathy: a slowly progressive congenital muscular dystrophy with contractures."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Early features include diminished foetal movements, neonatal hypotonia and congenital contractures
        which
        are of a dynamic nature during childhood.
      explanation: >-
        Clinical evidence establishes early onset, but does not identify every intermediate between the collagen
        VI matrix defect and this congenital manifestation.
      directness: INDIRECT
  - target: Decreased fetal movement
    description: >-
      Early matrix-muscle dysfunction may produce congenital weakness before the later progressive degenerative
      course; the intervening developmental mechanisms remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10219778
      reference_title: "Bethlem myopathy: a slowly progressive congenital muscular dystrophy with contractures."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Early features include diminished foetal movements, neonatal hypotonia and congenital contractures
        which
        are of a dynamic nature during childhood.
      explanation: >-
        Clinical evidence establishes early onset, but does not identify every intermediate between the collagen
        VI matrix defect and this congenital manifestation.
      directness: INDIRECT
- name: Impaired matrix-to-sarcolemma anchoring of the myofibre
  biological_scale: CELLULAR
  description: >-
    Abnormal collagen VI interactions may compromise matrix-to-cell coupling and force transmission. Biglycan
    and the dystrophin-associated complex were proposed partners in the earlier review, but the specific interaction
    defect is not demonstrated in every Bethlem patient. Human ultrastructural abnormalities and mouse mechanical
    measurements support matrix dysfunction without establishing a universal receptor-to-mitochondria signaling
    chain.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: cell-matrix adhesion
    modifier: DECREASED
    term:
      id: GO:0007160
      label: cell-matrix adhesion
  evidence:
  - reference: PMID:8782832
    reference_title: Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Among the diverse family of collagens, the widely expressed microfibrillar type VI collagen is believed
      to play a role in bridging cells with the extracellular matrix.
    explanation: States the anchoring function of collagen VI whose loss is proposed as the Bethlem mechanism.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Since collagen VI binds to biglycan,55 which interacts with the sarcoglycan and dystroglycan complex,56,57
      collagen VI might be indirectly linked to muscle cell surface receptors via biglycan and the dystrophin-associated
      protein complex.
    explanation: Proposes the molecular route linking the collagen VI network to the sarcolemma.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A mouse model of collagen VI deficiency has been generated by knockout of the collagen VI Col6a1 locus,
      resulting in a complete absence of collagen VI expression in muscle.69 In contrast to the human disease,
      these mice only show a mild neuromuscular disorder without much overt weakness.69 Muscles from these
      animals also show an increased incidence of apoptosis, which correlates with facilitated breakdown of
      the potential across the mitochondrial permeability pore when primed with oligomycin.65 This effect was
      preventable by inactivation of cyclophilin D using ciclosporin, its derivative Debio0025,70–72 or genetic
      inactivation of cyclophilin D.73 These interventions also resulted in decreased apoptosis and improved
      physiological functioning of isolated muscles from the collagen VI-knockout animals.65,72 Subsequent
      work using the same model suggests that impairments in autophagocytic flux (including impaired mitochondrial
      autophagy) also occur in the muscle cells of collagen VI-deficient mice, and possibly exacerbate the
      accumulation of defective mitochondria.74 Attachment of cells to the extracellular matrix is important
      for preventing apoptosis in general,75 which could be particularly relevant for muscle disorders that
      directly involve interactions between matrix and muscle, as is the case for both collagen VI-related
      and LAMA2-related CMDs.76–78 Work in cell cultures has shown that collagen VI-deficient cells exhibit
      decreased adherence to their surroundings,60,79 emphasizing the importance of this muscle cell–extracellular
      matrix interface.
    explanation: Cell-culture data support reduced matrix adherence, although the precise myofibre receptor remains unidentified.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: PMID:36982625
    reference_title: Extracellular Matrix Disorganization and Sarcolemmal Alterations in COL6-Related Myopathy Patients with New Variants of COL6 Genes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It localizes at the cell surface, creating a microfilamentous network that links the cytoskeleton to the extracellular matrix."
    explanation: States the cell-surface bridging role of collagen VI whose loss defines this node.
    quote_role: BACKGROUND
    directness: INDIRECT
  downstream:
  - target: Progressive myofibre degeneration
    description: >
      Defective matrix-based force transmission contributes directly to loss of
      contractile strength and to the dystrophic muscle process.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Myofibre mitochondrial dysfunction and permeability transition pore dysregulation
  biological_scale: CELLULAR
  description: >-
    Col6a1-null mouse myofibres have abnormal mitochondrial and sarcoplasmic-reticulum ultrastructure and latent
    permeability-transition susceptibility. Cyclosporin A or genetic cyclophilin-D ablation rescues experimental
    abnormalities. Muscle biopsies in a short open human pilot also showed mitochondrial dysfunction and increased
    apoptosis. These selected COL6-disease observations do not establish identical abnormalities in every Bethlem
    patient or clinical benefit from pore modulation.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:14625552
    reference_title: Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We previously generated collagen VI-deficient (Col6a1-/-) mice and showed that they have a muscle phenotype that strongly resembles Bethlem myopathy."
    explanation: Establishes the Col6a1-null mouse as a Bethlem myopathy model, so its mechanism is directly relevant to this entry.
  - reference: PMID:14625552
    reference_title: Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found a latent mitochondrial dysfunction in myofibers of Col6a1-/- mice on incubation with the selective
      F1F(O)-ATPase inhibitor oligomycin, which caused mitochondrial depolarization, Ca2+ deregulation and
      increased apoptosis.
    explanation: Documents the latent mitochondrial defect unmasked in collagen VI-deficient myofibres.
  - reference: PMID:18362356
    reference_title: Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Before treatment, all patients displayed mitochondrial dysfunction and increased frequency of apoptosis, as determined in muscle biopsies."
    explanation: Confirms the mitochondrial and apoptotic abnormality in human collagen VI myopathy muscle.
  - reference: PMID:19293339
    reference_title: Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In the absence of Cyp-D, Col6a1(-/-) mice show negligible myofiber degeneration, rescue from mitochondrial dysfunction and ultrastructural defects, and normalized incidence of apoptosis."
    explanation: Genetic rescue establishes a cause-effect relationship between cyclophilin D-dependent pore opening and the myopathy.
  downstream:
  - target: Myofibre apoptosis
    description: >
      Inappropriate permeability transition pore opening triggers apoptotic
      death of individual muscle fibres.
    causal_link_type: DIRECT
- name: Defective autophagic clearance of damaged organelles
  biological_scale: CELLULAR
  description: >-
    Col6a1-null mouse muscle has impaired autophagic flux, inadequate autophagosome induction and persistence
    of damaged organelles. Human Bethlem/UCMD biopsies show reduced beclin-1 and BNIP3 abundance, consistent
    with this pathway but not a direct measurement of human autophagic flux. Experimental activation of autophagy
    improves mouse myofibre survival.
  conforms_to: "disabled_macroautophagy#Failure of Cytoplasmic Quality Control"
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: autophagy
    modifier: DECREASED
    term:
      id: GO:0006914
      label: autophagy
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:21037586
    reference_title: Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Skeletal muscles of collagen VI-knockout (Col6a1(-/-)) mice had impaired autophagic flux, which matched the lower induction of beclin-1 and BCL-2/adenovirus E1B-interacting protein-3 (Bnip3) and the lack of autophagosomes after starvation."
    explanation: Demonstrates the autophagy machinery defect in collagen VI-deficient muscle.
  - reference: PMID:21037586
    reference_title: Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, muscle biopsies from subjects with Bethlem myopathy or Ullrich congenital muscular dystrophy had reduced protein amounts of beclin-1 and Bnip3."
    explanation: Confirms the autophagy defect directly in Bethlem myopathy patient muscle.
  - reference: PMID:21037586
    reference_title: Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we demonstrate that this persistence of abnormal organelles and apoptosis are caused by defective autophagy."
    explanation: Places defective autophagy causally upstream of organelle persistence and apoptosis.
  downstream:
  - target: Myofibre apoptosis
    description: >
      Failure to clear damaged mitochondria amplifies the apoptotic drive on the
      muscle fibre.
    causal_link_type: DIRECT
  - target: Myofibre mitochondrial dysfunction and permeability transition pore dysregulation
    description: >-
      Deficient organelle clearance allows mitochondrial abnormalities to persist; pore dysregulation also
      has independent experimental support.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21037586
      reference_title: Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Here we demonstrate that this persistence of abnormal organelles and apoptosis are caused by defective
        autophagy.
      explanation: >-
        Causal experimental interpretation in the Col6a1-null model; human static protein measurements are
        separate.
- name: Myofibre apoptosis
  biological_scale: CELLULAR
  description: >-
    Increased myofibre apoptosis is a measured downstream injury process in collagen VI-deficient mouse muscle
    and selected human biopsies. Reducing apoptosis is an experimental outcome and does not by itself establish
    improved patient function.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:14625552
    reference_title: Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Col6a1-/- muscles have a loss of contractile strength associated with ultrastructural alterations of sarcoplasmic reticulum (SR) and mitochondria and spontaneous apoptosis."
    explanation: Documents spontaneous myofibre apoptosis alongside loss of contractile strength.
  - reference: PMID:19293339
    reference_title: Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice lacking ColVI (Col6a1(-/-)) display a myopathic phenotype associated with ultrastructural alterations
      of mitochondria and sarcoplasmic reticulum, mitochondrial dysfunction with abnormal opening of the permeability
      transition pore (PTP) and increased apoptosis of muscle fibers.
    explanation: Links pore opening to increased apoptosis of muscle fibres.
  downstream:
  - target: Progressive myofibre degeneration
    description: >
      Cumulative loss of individual muscle fibres drives the slowly progressive
      dystrophic process.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Progressive myofibre degeneration
  biological_scale: TISSUE
  description: >-
    Myofibre injury and loss produce progressive proximal-predominant weakness and variable enzyme leakage
    and myopathic electromyography. Functional decline can occur over decades, and wheelchair use for longer
    distances is distinct from complete loss of independent walking. Fibrotic replacement is a related, separately
    represented tissue process.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In samples from patients in more-advanced stages of the disease, overtly dystrophic features are evident, including rare degenerating and regenerating fibers and a prominent build-up of interstitial fibrous tissue in the muscle."
    explanation: Describes the dystrophic and fibrotic muscle pathology of the collagen VI-related myopathies.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:24339618
    reference_title: "Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Creatinine kinase was mildly elevated and electromyography revealed myopathic features."
    explanation: A Bethlem family series documents the mild creatine kinase elevation and myopathic electromyography.
  downstream:
  - target: Proximal muscle weakness
    description: Cumulative myofibre loss produces proximal-predominant weakness.
    causal_link_type: DIRECT
  - target: Muscle weakness
    causal_link_type: DIRECT
  - target: Motor delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Elevated circulating creatine kinase concentration
    causal_link_type: DIRECT
  - target: "EMG: myopathic abnormalities"
    causal_link_type: DIRECT
  - target: Increased variability in muscle fiber diameter
    causal_link_type: DIRECT
  - target: Loss of ambulation
    description: >
      The combination of slowly progressive weakness and worsening contractures
      eventually limits ambulation in later adult life.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Restrictive respiratory involvement
    description: >
      Involvement of respiratory muscles produces a restrictive ventilatory
      pattern, which is variable and not a consistent feature of Bethlem myopathy.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Endomysial fibrosis
    description: >-
      Chronic tissue injury is associated with fibrotic replacement.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21691338
      reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In samples from patients in more-advanced stages of the disease, overtly dystrophic features are evident, including rare degenerating and regenerating fibers and a prominent build-up of interstitial fibrous tissue in the muscle."
      explanation: Describes the dystrophic and fibrotic muscle pathology of the collagen VI-related myopathies.
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
  - target: Axial muscle weakness
    description: >-
      Disease-associated manifestation; the precise tissue-specific causal intermediates remain incompletely
      characterized.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37569848
      reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        BM is a relatively mild, slowly progressive disorder, with variable onset from prenatal to adulthood,
        characterized by axial and proximal muscle weakness; variable contractures of the neck, fingers, elbow,
        knee, and ankles; distal laxity; and skin changes.
      explanation: >-
        Clinical background of the COL6 cohort report.
      quote_role: BACKGROUND
  - target: Waddling gait
    description: >-
      Disease-associated manifestation; the precise tissue-specific causal intermediates remain incompletely
      characterized.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31471117
      reference_title: 'Autosomal recessive Bethlem myopathy: A clinical, genetic and functional study.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Two adult siblings presented with muscle weakness and wasting, elbows and Achilles tendon retractions,
        lumbar hyperlordosis, waddling gait and positive Gowers' sign.
      explanation: >-
        Two siblings with biallelic COL6A2 variants; no general frequency can be inferred.
  - target: Gowers sign
    description: >-
      Disease-associated manifestation; the precise tissue-specific causal intermediates remain incompletely
      characterized.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31471117
      reference_title: 'Autosomal recessive Bethlem myopathy: A clinical, genetic and functional study.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Two adult siblings presented with muscle weakness and wasting, elbows and Achilles tendon retractions,
        lumbar hyperlordosis, waddling gait and positive Gowers' sign.
      explanation: >-
        Two siblings with biallelic COL6A2 variants; no general frequency can be inferred.
  - target: Lumbar hyperlordosis
    description: >-
      Disease-associated manifestation; the precise tissue-specific causal intermediates remain incompletely
      characterized.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31471117
      reference_title: 'Autosomal recessive Bethlem myopathy: A clinical, genetic and functional study.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Two adult siblings presented with muscle weakness and wasting, elbows and Achilles tendon retractions,
        lumbar hyperlordosis, waddling gait and positive Gowers' sign.
      explanation: >-
        Two siblings with biallelic COL6A2 variants; no general frequency can be inferred.
- name: Endomysial fibrosis
  description: >-
    Interstitial collagen accumulation accompanies chronic dystrophic muscle remodeling. It can contribute
    to stiffness and impaired force transmission, but mouse weakness precedes overt fibrosis, so fibrosis is
    not assumed to explain all early weakness.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In samples from patients in more-advanced stages of the disease, overtly dystrophic features are evident, including rare degenerating and regenerating fibers and a prominent build-up of interstitial fibrous tissue in the muscle."
    explanation: Describes the dystrophic and fibrotic muscle pathology of the collagen VI-related myopathies.
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Increased endomysial connective tissue
    description: >-
      Histological endomysial connective-tissue increase reflects fibrosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21691338
      reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In samples from patients in more-advanced stages of the disease, overtly dystrophic features are evident, including rare degenerating and regenerating fibers and a prominent build-up of interstitial fibrous tissue in the muscle."
      explanation: Describes the dystrophic and fibrotic muscle pathology of the collagen VI-related myopathies.
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
- name: Tendon and periarticular connective tissue involvement
  biological_scale: TISSUE
  description: >-
    Collagen VI-associated connective-tissue dysfunction accompanies early distal laxity and later contractures.
    The long finger-flexor, elbow and Achilles pattern is characteristic, but human tendon pathology has not
    established a single mechanism for every contracture. On wrist dorsiflexion, finger-flexor shortening can
    prevent full finger extension. Some recessive cases have little or no contracture despite substantial weakness.
  cell_types:
  - preferred_term: tendon fibroblast
    term:
      id: CL:0000388
      label: tendon cell
  locations:
  - preferred_term: extracellular matrix
    term:
      id: GO:0031012
      label: extracellular matrix
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By adulthood, there is evidence of proximal weakness and contractures of the elbows, Achilles tendons, and long finger flexors."
    explanation: GeneReviews specifies the characteristic Bethlem contracture distribution.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On dorsiflexion of the wrist, contractures of the long finger flexors prevent complete finger extension—the
      typical ‘Bethlem sign’ (Figure 1e).13 Even in patients whose muscle weakness progresses only very slowly,
      progression of the contractures can be the cause of serious disability in their own right (as they are
      for patients with severe forms of collagen VI-related myopathy).
    explanation: Describes the Bethlem sign produced by long finger flexor contracture.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Young children might exhibit evidence of mild weakness only, and at this early age display distal joint
      hyperlaxity rather than contractures.
    explanation: Documents the early-childhood distal hyperlaxity that later converts to contracture.
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Achilles tendon contracture
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Elbow flexion contracture
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Flexion contracture of finger
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Flexion contracture
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Spinal rigidity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Scoliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Torticollis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Joint hypermobility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Congenital hip dislocation
    description: >-
      Disease-associated manifestation; the precise tissue-specific causal intermediates remain incompletely
      characterized.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37569848
      reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Ten patients with BM (30%) exhibited symptoms at birth, with a varying combination of congenital hip
        dislocation (CHD) in four, hypotonia in four, club foot in four, torticollis in three, and contractures
        of the elbow and knee in one.
      explanation: >-
        Ten of 33 Bethlem patients; individual congenital findings each have their own count.
  - target: Clubfoot
    description: >-
      Disease-associated manifestation; the precise tissue-specific causal intermediates remain incompletely
      characterized.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37569848
      reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Ten patients with BM (30%) exhibited symptoms at birth, with a varying combination of congenital hip
        dislocation (CHD) in four, hypotonia in four, club foot in four, torticollis in three, and contractures
        of the elbow and knee in one.
      explanation: >-
        Ten of 33 Bethlem patients; individual congenital findings each have their own count.
  - target: Knee flexion contracture
    description: >-
      Disease-associated manifestation; the precise tissue-specific causal intermediates remain incompletely
      characterized.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37569848
      reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Ten patients with BM (30%) exhibited symptoms at birth, with a varying combination of congenital hip
        dislocation (CHD) in four, hypotonia in four, club foot in four, torticollis in three, and contractures
        of the elbow and knee in one.
      explanation: >-
        Ten of 33 Bethlem patients; individual congenital findings each have their own count.
  - target: Shoulder contracture
    description: >-
      Connective-tissue restriction is associated with reduced joint excursion; detailed intermediates remain
      unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1503/?report=reader
      reference_title: Collagen VI-Related Dystrophies - GeneReviews&reg; - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Joint contractures, typically affecting the long finger flexors, elbows, ankles, and shoulders
      explanation: >-
        Bethlem-specific suggestive findings in GeneReviews.
      quote_role: REVIEW_SYNTHESIS
  - target: Limited mouth opening
    description: >-
      Connective-tissue restriction is associated with reduced joint excursion; detailed intermediates remain
      unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37569848
      reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Specifically, a mild degree of mouth opening (MO) limitation was observed in only two patients with
        BM (6%), while INTM (43%) and UCMD (33%) patients displayed a mild–moderate degree of limitation.
      explanation: >-
        Two of 33 Bethlem patients; severe myosclerosis restriction is a separate subgroup.
- name: Dermal extracellular matrix dysfunction
  biological_scale: TISSUE
  description: >-
    Collagen VI dysfunction affects dermal matrix organization and is associated with follicular hyperkeratosis,
    soft skin and abnormal scarring. The detailed route to each skin manifestation remains uncertain. Col6a1-null
    mice have mechanically weaker skin and altered wound ultrastructure but do not reproduce the human keloid
    phenotype or an overt wound-healing delay.
  cell_types:
  - preferred_term: dermal fibroblast
    term:
      id: CL:0002551
      label: fibroblast of dermis
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most notable manifestations are prominent keratosis pilaris of the extensor surfaces of the arms
      and legs, giving the skin a rough appearance, the propensity for abnormal (keloid or atrophic) scar formation,
      and/or a particularly soft and velvety texture to the palmar skin of the hands and feet, which are marked
      by a fine criss-cross pattern of palmar creases.
    explanation: Describes the characteristic collagen VI skin phenotype.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:24339618
    reference_title: "Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All had flexion contractures, keloids, and follicular hyperkeratosis without muscle hypertrophy."
    explanation: A three-patient Bethlem family shows the full contracture plus skin combination.
  downstream:
  - target: Follicular hyperkeratosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Keratosis pilaris
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Soft skin
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal cutaneous scarring
    description: >-
      Altered dermal matrix is associated with abnormal scar formation through unresolved repair intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21691338
      reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The most notable manifestations are prominent keratosis pilaris of the extensor surfaces of the arms
        and legs, giving the skin a rough appearance, the propensity for abnormal (keloid or atrophic) scar
        formation, and/or a particularly soft and velvety texture to the palmar skin of the hands and feet,
        which are marked by a fine criss-cross pattern of palmar creases.
      explanation: Describes the characteristic collagen VI skin phenotype.
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
- name: Abnormal cutaneous scarring
  description: >-
    Keloid or atrophic scarring is a clinical skin-repair manifestation of collagen VI disease. Its occurrence
    is variable, and the null mouse does not recreate the full human scar phenotype.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most notable manifestations are prominent keratosis pilaris of the extensor surfaces of the arms
      and legs, giving the skin a rough appearance, the propensity for abnormal (keloid or atrophic) scar formation,
      and/or a particularly soft and velvety texture to the palmar skin of the hands and feet, which are marked
      by a fine criss-cross pattern of palmar creases.
    explanation: Describes the characteristic collagen VI skin phenotype.
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Keloids
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Atrophic scars
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Restrictive respiratory involvement
  biological_scale: ORGANISM
  description: >-
    Respiratory muscle weakness can reduce vital capacity and cause nocturnal hypoventilation even while patients
    remain ambulant. Severity is variable: 13 of 22 tested Bethlem patients in one cohort had FVC below 80%
    predicted, and two began noninvasive ventilation at ages 24 and 49. These clinic-based observations do
    not establish a population prevalence.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Respiratory involvement is not a consistent feature."
    explanation: GeneReviews states that respiratory involvement is inconsistent in Bethlem muscular dystrophy.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with Bethlem myopathy have an increased risk of restrictive lung disease, with the possibility
      of resulting respiratory insufficiency, particularly if this impairment occurs in combination with other
      causes of obstructive sleep apnea.
    explanation: Documents the increased but variable restrictive respiratory risk in Bethlem myopathy.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:37569848
    reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      However, only nine of the 22 patients with BM had a normal %FVC value (≥80%), seven had values of 79–60%,
      while six had values below 60%.
    explanation: >-
      Bethlem-specific measured respiratory distribution; denominator is 22 tested patients, not all 33 in
      the cohort.
  downstream:
  - target: Restrictive ventilatory defect
    causal_link_type: DIRECT
  - target: Nocturnal hypoventilation
    description: >-
      Disease-associated manifestation; the precise tissue-specific causal intermediates remain incompletely
      characterized.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21691338
      reference_title: 'The collagen VI-related myopathies: muscle meets its matrix.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Sleep studies are, therefore, useful to diagnose nocturnal hypoventilation proactively.
      explanation: >-
        Clinical review describes sleep-related hypoventilation in the respiratory discussion.
      quote_role: REVIEW_SYNTHESIS
- name: Dysregulated extracellular TGF-beta bioavailability
  description: >-
    Col6a2-null mice have excessive resting TGF-beta activity, but a blunted early release after injury and
    relatively prolonged later activity. Protein-complex and fibroblast reporter assays implicate altered extracellular
    sequestration or activation without increased total ligand transcription or protein. This is a COL6 model
    mechanism, not a demonstrated universal Bethlem patient defect. Disrupting Ltbp4-TGF-beta binding did not
    rescue the mouse phenotype.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:40309777
    reference_title: Collagen type VI regulates TGF-β bioavailability in skeletal muscle in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Together, these findings suggest that absence of collagen VI from the muscle ECM increases active TGF-β
      without an increase in total TGF-β transcription or translation.
    explanation: >-
      Col6a2-null mouse tissue and fibroblast assays; altered activation rather than increased overall production.
  downstream:
  - target: Endomysial fibrosis
    description: >-
      Persistent signaling is a proposed contributor to model fibrosis, but its isolated causal contribution
      and relevance across human variants remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40309777
      reference_title: Collagen type VI regulates TGF-β bioavailability in skeletal muscle in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Thus, TGF-β overactivity in Col6a2–/– mice may cause muscle weakness and atrophy, independent of its
        profibrotic effects that manifest with fibrosis later in the disease course.
      explanation: >-
        Authors' proposed model mechanism; direct therapeutic dissection remains incomplete.
  biological_processes:
  - preferred_term: transforming growth factor beta receptor signaling pathway
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: DYSREGULATED
phenotypes:
- category: Neuromuscular
  name: Proximal muscle weakness
  description: >
    Slowly progressive proximal-predominant weakness is one half of the defining
    Bethlem clinical combination and can occasionally present without notable
    contractures, mimicking limb-girdle muscular dystrophy.
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bethlem muscular dystrophy is characterized by a combination of proximal muscle weakness and joint contractures."
    explanation: GeneReviews names proximal muscle weakness as a defining feature.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:15689448
    reference_title: "Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BM is a relatively mild dominantly inherited disorder with proximal weakness and distal joint contractures."
    explanation: A cohort study confirms proximal weakness as a core Bethlem feature.
- category: Neuromuscular
  name: Muscle weakness
  description: >
    Generalized muscular weakness and wasting accompany the proximal-predominant
    pattern.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:8782832
    reference_title: Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A distinctive feature of this autosomal dominant disorder consists of contractures of multiple joints
      in addition to generalized muscular weakness and wasting.
    explanation: The original description records generalized weakness and wasting.
- category: Musculoskeletal
  name: Achilles tendon contracture
  description: >
    Achilles tendon contractures typically appear late in the first decade or
    during the teenage years and are a signature Bethlem feature.
  phenotype_term:
    preferred_term: Achilles tendon contracture
    term:
      id: HP:0001771
      label: Achilles tendon contracture
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By adulthood, there is evidence of proximal weakness and contractures of the elbows, Achilles tendons, and long finger flexors."
    explanation: GeneReviews lists Achilles tendon contracture among the defining adult features.
    quote_role: REVIEW_SYNTHESIS
- category: Musculoskeletal
  name: Elbow flexion contracture
  description: >
    Elbow contractures develop alongside the Achilles tendon contractures and are
    part of the characteristic Bethlem distribution.
  phenotype_term:
    preferred_term: Elbow flexion contracture
    term:
      id: HP:0002987
      label: Elbow flexion contracture
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By adulthood, there is evidence of proximal weakness and contractures of the elbows, Achilles tendons, and long finger flexors."
    explanation: GeneReviews lists elbow contracture among the defining adult features.
    quote_role: REVIEW_SYNTHESIS
- category: Musculoskeletal
  name: Flexion contracture of finger
  description: >
    Contracture of the long finger flexors is the most distinctive Bethlem
    contracture. On dorsiflexion of the wrist it prevents complete finger
    extension, producing the Bethlem sign.
  phenotype_term:
    preferred_term: Long finger flexor contracture (Bethlem sign)
    term:
      id: HP:0012785
      label: Flexion contracture of finger
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By adulthood, there is evidence of proximal weakness and contractures of the elbows, Achilles tendons, and long finger flexors."
    explanation: GeneReviews lists long finger flexor contracture among the defining adult features.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On dorsiflexion of the wrist, contractures of the long finger flexors prevent complete finger extension—the
      typical ‘Bethlem sign’ (Figure 1e).13 Even in patients whose muscle weakness progresses only very slowly,
      progression of the contractures can be the cause of serious disability in their own right (as they are
      for patients with severe forms of collagen VI-related myopathy).
    explanation: Describes the clinical manoeuvre that elicits the Bethlem sign.
    quote_role: REVIEW_SYNTHESIS
- category: Musculoskeletal
  name: Flexion contracture
  description: >
    Multiple joint flexion contractures are the second half of the defining
    Bethlem clinical combination.
  phenotype_term:
    preferred_term: Flexion contracture
    term:
      id: HP:0001371
      label: Flexion contracture
  evidence:
  - reference: PMID:24339618
    reference_title: "Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All had flexion contractures, keloids, and follicular hyperkeratosis without muscle hypertrophy."
    explanation: All three affected members of a Bethlem family had flexion contractures.
- category: Musculoskeletal
  name: Spinal rigidity
  description: >
    Contractures can extend to the spine and produce a degree of spinal rigidity.
  phenotype_term:
    preferred_term: Spinal rigidity
    term:
      id: HP:0003306
      label: Spinal rigidity
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These contractures progress to involve the long finger flexors and the shoulders; they can also affect
      the spine and cause a degree of spinal rigidity in some patients.
    explanation: The review notes spinal rigidity in a subset of Bethlem patients.
    quote_role: REVIEW_SYNTHESIS
- category: Musculoskeletal
  name: Scoliosis
  description: >
    Scoliosis occurs across the collagen VI-related dystrophy spectrum and is a
    named surveillance and management target for Bethlem muscular dystrophy.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "annual clinical and radiographic assessment of scoliosis"
    explanation: GeneReviews prescribes annual scoliosis surveillance for Bethlem muscular dystrophy.
    quote_role: REVIEW_SYNTHESIS
- category: Musculoskeletal
  name: Torticollis
  description: >-
    Torticollis can occur in infancy. A review reports up to 50% of patients, whereas the 2023 cohort recorded
    torticollis at birth in three of 33 Bethlem patients. These observations use different ascertainment windows
    and do not establish a single population frequency.
  phenotype_term:
    preferred_term: Torticollis
    term:
      id: HP:0000473
      label: Torticollis
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although often understood to be a myopathy of adulthood, the clinical symptoms experienced by patients
      with Bethlem myopathy can frequently be traced back to early infancy;13 affected babies might exhibit
      hypotonia, foot deformities and torticollis (which has been noted in up to 50% of patients).13 However,
      the congenital contractures largely tend to resolve in the first 2 years.
    explanation: >-
      The review reports an upper bound for early-life torticollis, not a point estimate or an obligatory frequency
      band.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:37569848
    reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Ten patients with BM (30%) exhibited symptoms at birth, with a varying combination of congenital hip
      dislocation (CHD) in four, hypotonia in four, club foot in four, torticollis in three, and contractures
      of the elbow and knee in one.
    explanation: >-
      Torticollis at birth was recorded in three patients in the 33-patient Bethlem subgroup; this is not an
      estimate of lifetime prevalence.
- category: Musculoskeletal
  name: Joint hypermobility
  description: >
    Young children with Bethlem myopathy characteristically display distal joint
    hyperlaxity before contractures develop.
  phenotype_term:
    preferred_term: Distal joint hyperlaxity
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Young children might exhibit evidence of mild weakness only, and at this early age display distal joint
      hyperlaxity rather than contractures.
    explanation: The review documents early distal hyperlaxity in Bethlem myopathy.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:24339618
    reference_title: "Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bethlem phenotype is relatively benign and is characterized by proximal dominant myopathy, keloids, contractures, distal hyperextensibility, and follicular hyperkeratosis."
    explanation: The case series lists distal hyperextensibility among the defining Bethlem features.
- category: Neuromuscular
  name: Neonatal hypotonia
  description: >
    Mild hypotonia may be present congenitally and is one of the early features
    that traces Bethlem myopathy back to infancy.
  phenotype_term:
    preferred_term: Neonatal hypotonia
    term:
      id: HP:0001319
      label: Neonatal hypotonia
  evidence:
  - reference: PMID:10219778
    reference_title: "Bethlem myopathy: a slowly progressive congenital muscular dystrophy with contractures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early features include diminished foetal movements, neonatal hypotonia and congenital contractures which
      are of a dynamic nature during childhood.
    explanation: The natural-history cohort lists neonatal hypotonia among early features.
- category: Prenatal
  name: Decreased fetal movement
  description: >
    Diminished fetal movements are reported as an early feature in Bethlem
    myopathy kindreds.
  phenotype_term:
    preferred_term: Decreased fetal movement
    term:
      id: HP:0001558
      label: Decreased fetal movement
  evidence:
  - reference: PMID:10219778
    reference_title: "Bethlem myopathy: a slowly progressive congenital muscular dystrophy with contractures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early features include diminished foetal movements, neonatal hypotonia and congenital contractures which
      are of a dynamic nature during childhood.
    explanation: The natural-history cohort lists diminished fetal movements among early features.
- category: Developmental
  name: Motor delay
  description: >
    Delayed motor milestones occur in early childhood.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypotonia and delayed motor milestones occur in early childhood"
    explanation: GeneReviews records delayed motor milestones in Bethlem muscular dystrophy.
    quote_role: REVIEW_SYNTHESIS
- category: Neuromuscular
  name: Loss of ambulation
  description: >-
    Complete loss of ambulation occurred in five of 33 Bethlem patients in a 2023 referral cohort, at a mean
    age of 44.6 years. This is distinct from using a wheelchair for distance while retaining indoor walking.
  phenotype_term:
    preferred_term: Loss of independent ambulation in later adult life
    term:
      id: HP:0002505
      label: Loss of ambulation
    clinical_course: PROGRESSIVE
  evidence:
  - *id003
- category: Laboratory
  name: Elevated circulating creatine kinase concentration
  description: >-
    CK can be normal, mildly elevated or substantially raised. Eight Bethlem patients in one cohort had recorded
    maxima 9–28 times the upper limit of normal, so mild elevation is not obligatory and CK is not a reliable
    severity measure.
  phenotype_term:
    preferred_term: Variably elevated creatine kinase
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:24339618
    reference_title: "Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Creatinine kinase was mildly elevated and electromyography revealed myopathic features."
    explanation: A Bethlem family series documents mild creatine kinase elevation.
  - &id004
    reference: PMID:37569848
    reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Among them, 13 had normal CK levels, 38 (16 BM, five MM, four INTM, and 13 UCMD) had slightly elevated
      levels (up to five times the upper normal value), while eight BM patients had maximum values ranging
      from 9 to 28 times the upper limit of normal.
    explanation: >-
      All normal measurements are pooled across COL6 subgroups; the eight markedly elevated cases are specifically
      Bethlem.
  - reference: PMID:30706156
    reference_title: 'Bethlem myopathy: a series of 16 patients and description of seven new associated mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      CK levels did not correlate with severity of the disease.
    explanation: >-
      Sixteen-patient retrospective Bethlem series.
- category: Neurophysiology
  name: "EMG: myopathic abnormalities"
  description: >
    Electromyography shows myopathic features.
  phenotype_term:
    preferred_term: "EMG: myopathic abnormalities"
    term:
      id: HP:0003458
      label: "EMG: myopathic abnormalities"
  evidence:
  - reference: PMID:24339618
    reference_title: "Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Creatinine kinase was mildly elevated and electromyography revealed myopathic features.
    explanation: A Bethlem family series documents myopathic electromyography.
- category: Histopathology
  name: Increased endomysial connective tissue
  description: >
    Muscle biopsy shows a prominent build-up of interstitial and endomysial
    fibrous tissue.
  phenotype_term:
    preferred_term: Increased endomysial connective tissue
    term:
      id: HP:0100297
      label: Increased endomysial connective tissue
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In samples from patients in more-advanced stages of the disease, overtly dystrophic features are evident,
      including rare degenerating and regenerating fibers and a prominent build-up of interstitial fibrous
      tissue in the muscle.
    explanation: The review describes the fibrotic muscle pathology of the collagen VI-related myopathies.
    quote_role: REVIEW_SYNTHESIS
- category: Histopathology
  name: Increased variability in muscle fiber diameter
  description: >
    Fibre atrophy and variability in fibre diameter are seen, sometimes with
    fibre type disproportion in early biopsies.
  phenotype_term:
    preferred_term: Increased variability in muscle fiber diameter
    term:
      id: HP:0003557
      label: Increased variability in muscle fiber diameter
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In biopsy samples taken very early in the course of disease, however, the findings can be inconspicuous,
      often just showing evidence of fiber atrophy or even fiber type disproportion without overt dystrophic
      features.28 Immunohistochemical examination for the amount and localization of collagen VI in the muscle
      is a useful diagnostic tool.
    explanation: The review describes early-biopsy fibre-size abnormality in collagen VI-related myopathy.
    quote_role: REVIEW_SYNTHESIS
- category: Dermatologic
  name: Follicular hyperkeratosis
  description: >
    Follicular hyperkeratosis is a signature connective-tissue skin sign of
    Bethlem myopathy.
  phenotype_term:
    preferred_term: Follicular hyperkeratosis
    term:
      id: HP:0007502
      label: Follicular hyperkeratosis
  evidence:
  - reference: PMID:24339618
    reference_title: "Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All had flexion contractures, keloids, and follicular hyperkeratosis without muscle hypertrophy."
    explanation: All three affected members of a Bethlem family had follicular hyperkeratosis.
- category: Dermatologic
  name: Keratosis pilaris
  description: >
    Keratosis pilaris over the extensor surfaces of the arms and legs gives the
    skin a rough appearance.
  phenotype_term:
    preferred_term: Keratosis pilaris
    term:
      id: HP:0032152
      label: Keratosis pilaris
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most notable manifestations are prominent keratosis pilaris of the extensor surfaces of the arms
      and legs, giving the skin a rough appearance, the propensity for abnormal (keloid or atrophic) scar formation,
      and/or a particularly soft and velvety texture to the palmar skin of the hands and feet, which are marked
      by a fine criss-cross pattern of palmar creases.
    explanation: The review names keratosis pilaris as the most notable skin manifestation.
    quote_role: REVIEW_SYNTHESIS
- category: Dermatologic
  name: Keloids
  description: >
    A propensity to keloid scar formation is characteristic of the collagen
    VI-related myopathies and prominent in Bethlem myopathy.
  phenotype_term:
    preferred_term: Keloids
    term:
      id: HP:0010562
      label: Keloids
  evidence:
  - reference: PMID:24339618
    reference_title: "Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All had flexion contractures, keloids, and follicular hyperkeratosis without muscle hypertrophy."
    explanation: All three affected members of a Bethlem family had keloids.
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most notable manifestations are prominent keratosis pilaris of the extensor surfaces of the arms
      and legs, giving the skin a rough appearance, the propensity for abnormal (keloid or atrophic) scar formation,
      and/or a particularly soft and velvety texture to the palmar skin of the hands and feet, which are marked
      by a fine criss-cross pattern of palmar creases.
    explanation: The review documents keloid scarring as a collagen VI connective-tissue feature.
    quote_role: REVIEW_SYNTHESIS
- category: Dermatologic
  name: Atrophic scars
  description: >
    Abnormal scarring may instead be atrophic, described as cigarette-paper
    scars.
  phenotype_term:
    preferred_term: Atrophic scars
    term:
      id: HP:0001075
      label: Atrophic scars
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most notable manifestations are prominent keratosis pilaris of the extensor surfaces of the arms
      and legs, giving the skin a rough appearance, the propensity for abnormal (keloid or atrophic) scar formation,
      and/or a particularly soft and velvety texture to the palmar skin of the hands and feet, which are marked
      by a fine criss-cross pattern of palmar creases.
    explanation: The review records atrophic as well as keloid scarring.
    quote_role: REVIEW_SYNTHESIS
- category: Dermatologic
  name: Soft skin
  description: >
    Palmar skin can have a particularly soft, velvety texture with a fine
    criss-cross pattern of creases.
  phenotype_term:
    preferred_term: Soft skin
    term:
      id: HP:0000977
      label: Soft skin
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most notable manifestations are prominent keratosis pilaris of the extensor surfaces of the arms
      and legs, giving the skin a rough appearance, the propensity for abnormal (keloid or atrophic) scar formation,
      and/or a particularly soft and velvety texture to the palmar skin of the hands and feet, which are marked
      by a fine criss-cross pattern of palmar creases.
    explanation: The review documents the soft velvety palmar skin of collagen VI-related myopathy.
    quote_role: REVIEW_SYNTHESIS
- category: Respiratory
  name: Restrictive ventilatory defect
  description: >-
    Respiratory restriction may occur while ambulation is retained. In the 2023 cohort, nine of 22 tested Bethlem
    patients had FVC at least 80% predicted, seven had 60–79%, and six had less than 60%. Referral-cohort frequencies
    should not be treated as population estimates.
  phenotype_term:
    preferred_term: Restrictive ventilatory defect
    term:
      id: HP:0002091
      label: Restrictive ventilatory defect
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with Bethlem myopathy have an increased risk of restrictive lung disease, with the possibility
      of resulting respiratory insufficiency, particularly if this impairment occurs in combination with other
      causes of obstructive sleep apnea.
    explanation: The review supports restrictive lung disease risk in Bethlem myopathy.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Respiratory involvement is not a consistent feature."
    explanation: >-
      GeneReviews describes variable respiratory involvement; this sentence does not establish a numeric frequency
      or a frequency band.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:37569848
    reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      However, only nine of the 22 patients with BM had a normal %FVC value (≥80%), seven had values of 79–60%,
      while six had values below 60%.
    explanation: >-
      Bethlem-specific measured respiratory distribution; denominator is 22 tested patients, not all 33 in
      the cohort.
- name: Congenital hip dislocation
  description: >-
    Congenital hip dislocation occurred in four of 33 Bethlem patients in one cohort.
  phenotype_term:
    preferred_term: Congenital hip dislocation
    term:
      id: HP:0001374
      label: Congenital hip dislocation
  evidence:
  - reference: PMID:37569848
    reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Ten patients with BM (30%) exhibited symptoms at birth, with a varying combination of congenital hip
      dislocation (CHD) in four, hypotonia in four, club foot in four, torticollis in three, and contractures
      of the elbow and knee in one.
    explanation: >-
      Ten of 33 Bethlem patients; individual congenital findings each have their own count.
  frequency: OCCASIONAL
- name: Clubfoot
  description: >-
    Clubfoot occurred in four of 33 Bethlem patients in one cohort.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: PMID:37569848
    reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Ten patients with BM (30%) exhibited symptoms at birth, with a varying combination of congenital hip
      dislocation (CHD) in four, hypotonia in four, club foot in four, torticollis in three, and contractures
      of the elbow and knee in one.
    explanation: >-
      Ten of 33 Bethlem patients; individual congenital findings each have their own count.
  frequency: OCCASIONAL
- name: Knee flexion contracture
  description: >-
    Knee contractures can contribute to the connective-tissue phenotype, including congenital presentation.
  phenotype_term:
    preferred_term: Knee flexion contracture
    term:
      id: HP:0006380
      label: Knee flexion contracture
  evidence:
  - reference: PMID:37569848
    reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Ten patients with BM (30%) exhibited symptoms at birth, with a varying combination of congenital hip
      dislocation (CHD) in four, hypotonia in four, club foot in four, torticollis in three, and contractures
      of the elbow and knee in one.
    explanation: >-
      Ten of 33 Bethlem patients; individual congenital findings each have their own count.
- name: Axial muscle weakness
  description: >-
    Axial weakness can accompany proximal limb weakness.
  phenotype_term:
    preferred_term: Axial muscle weakness
    term:
      id: HP:0003327
      label: Axial muscle weakness
  evidence:
  - reference: PMID:37569848
    reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      BM is a relatively mild, slowly progressive disorder, with variable onset from prenatal to adulthood,
      characterized by axial and proximal muscle weakness; variable contractures of the neck, fingers, elbow,
      knee, and ankles; distal laxity; and skin changes.
    explanation: >-
      Clinical background of the COL6 cohort report.
    quote_role: BACKGROUND
- name: Waddling gait
  description: >-
    A waddling gait is reported in molecularly characterized recessive Bethlem myopathy.
  phenotype_term:
    preferred_term: Waddling gait
    term:
      id: HP:0002515
      label: Waddling gait
  evidence:
  - reference: PMID:31471117
    reference_title: 'Autosomal recessive Bethlem myopathy: A clinical, genetic and functional study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Two adult siblings presented with muscle weakness and wasting, elbows and Achilles tendon retractions,
      lumbar hyperlordosis, waddling gait and positive Gowers' sign.
    explanation: >-
      Two siblings with biallelic COL6A2 variants; no general frequency can be inferred.
- name: Gowers sign
  description: >-
    Proximal weakness can produce a positive Gowers maneuver.
  phenotype_term:
    preferred_term: Gowers sign
    term:
      id: HP:0003391
      label: Gowers sign
  evidence:
  - reference: PMID:31471117
    reference_title: 'Autosomal recessive Bethlem myopathy: A clinical, genetic and functional study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Two adult siblings presented with muscle weakness and wasting, elbows and Achilles tendon retractions,
      lumbar hyperlordosis, waddling gait and positive Gowers' sign.
    explanation: >-
      Two siblings with biallelic COL6A2 variants; no general frequency can be inferred.
- name: Lumbar hyperlordosis
  description: >-
    Lumbar hyperlordosis accompanies the weakness in reported biallelic COL6A2 cases.
  phenotype_term:
    preferred_term: Lumbar hyperlordosis
    term:
      id: HP:0002938
      label: Lumbar hyperlordosis
  evidence:
  - reference: PMID:31471117
    reference_title: 'Autosomal recessive Bethlem myopathy: A clinical, genetic and functional study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Two adult siblings presented with muscle weakness and wasting, elbows and Achilles tendon retractions,
      lumbar hyperlordosis, waddling gait and positive Gowers' sign.
    explanation: >-
      Two siblings with biallelic COL6A2 variants; no general frequency can be inferred.
- name: Nocturnal hypoventilation
  description: >-
    Diaphragmatic weakness can impair ventilation during sleep and warrants sleep-study surveillance even in
    ambulant patients.
  phenotype_term:
    preferred_term: Nocturnal hypoventilation
    term:
      id: HP:0002877
      label: Nocturnal hypoventilation
  evidence:
  - reference: PMID:21691338
    reference_title: 'The collagen VI-related myopathies: muscle meets its matrix.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Sleep studies are, therefore, useful to diagnose nocturnal hypoventilation proactively.
    explanation: >-
      Clinical review describes sleep-related hypoventilation in the respiratory discussion.
    quote_role: REVIEW_SYNTHESIS
- name: Shoulder contracture
  description: >-
    Shoulder contractures may extend the characteristic distal contracture pattern.
  phenotype_term:
    preferred_term: Shoulder contracture
    term:
      id: HP:0034665
      label: Shoulder contracture
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1503/?report=reader
    reference_title: Collagen VI-Related Dystrophies - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Joint contractures, typically affecting the long finger flexors, elbows, ankles, and shoulders
    explanation: >-
      Bethlem-specific suggestive findings in GeneReviews.
    quote_role: REVIEW_SYNTHESIS
- name: Limited mouth opening
  description: >-
    Mild jaw-opening restriction occurred in two of 33 Bethlem patients in one cohort; prominent severe jaw
    restriction is more characteristic of the separate myosclerosis phenotype.
  phenotype_term:
    preferred_term: Trismus
    term:
      id: HP:0000211
      label: Trismus
  evidence:
  - reference: PMID:37569848
    reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Specifically, a mild degree of mouth opening (MO) limitation was observed in only two patients with BM
      (6%), while INTM (43%) and UCMD (33%) patients displayed a mild–moderate degree of limitation.
    explanation: >-
      Two of 33 Bethlem patients; severe myosclerosis restriction is a separate subgroup.
biochemical:
- name: Variable serum creatine kinase elevation
  presence: Elevated
  context: Skeletal muscle injury marker
  evidence:
  - *id004
  - reference: PMID:30706156
    reference_title: 'Bethlem myopathy: a series of 16 patients and description of seven new associated mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      CK levels did not correlate with severity of the disease.
    explanation: >-
      Bethlem cohort evidence.
  notes: >-
    Serum CK reflects muscle enzyme leakage but can be normal or elevated over a wide range. Marked maxima
    occur in some Bethlem patients, and CK does not reliably track clinical severity.
  readouts:
  - target: Progressive myofibre degeneration
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Variable CK supports muscle involvement but is nonspecific and does not quantify functional severity.
    evidence:
    - reference: PMID:37569848
      reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Among them, 13 had normal CK levels, 38 (16 BM, five MM, four INTM, and 13 UCMD) had slightly elevated
        levels (up to five times the upper normal value), while eight BM patients had maximum values ranging
        from 9 to 28 times the upper limit of normal.
      explanation: >-
        All normal measurements are pooled across COL6 subgroups; the eight markedly elevated cases are specifically
        Bethlem.
    relationship: READOUT_OF
- name: Reduced beclin-1 and Bnip3 protein in muscle
  presence: Reduced
  context: Autophagy-initiation proteins in patient skeletal muscle
  evidence:
  - reference: PMID:21037586
    reference_title: Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, muscle biopsies from subjects with Bethlem myopathy or Ullrich congenital muscular dystrophy had reduced protein amounts of beclin-1 and Bnip3."
    explanation: Directly measures reduced autophagy-initiation proteins in Bethlem myopathy muscle.
  notes: >-
    Reduced beclin-1 and BNIP3 abundance in patient muscle is consistent with the autophagy abnormality measured
    in mice. Static protein measurements alone do not establish human autophagic flux or clinical treatment
    response.
  readouts:
  - target: Defective autophagic clearance of damaged organelles
    interpretation: >-
      Protein abundance is a static correlate; it does not directly measure human flux.
    evidence:
    - reference: PMID:21037586
      reference_title: Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Furthermore, muscle biopsies from subjects with Bethlem myopathy or Ullrich congenital muscular dystrophy had reduced protein amounts of beclin-1 and Bnip3."
      explanation: Directly measures reduced autophagy-initiation proteins in Bethlem myopathy muscle.
    relationship: CORRELATES_WITH
- name: Variable collagen VI staining in skeletal muscle
  presence: VARIABLE
  context: Skeletal muscle biopsy collagen VI/perlecan immunofluorescence
  evidence:
  - reference: PMID:37569848
    reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Muscle biopsies from 13 out of 15 BM patients with dominant mutations exhibited a normal collagen VI
      pattern, as evidenced by the continuous overlap with the anti-perlecan staining (Table 2).
    explanation: >-
      Normal abundance and basal-lamina colocalization in most dominant Bethlem biopsies in this series; a
      normal result does not exclude disease.
  notes: >-
    Bethlem muscle staining can retain normal collagen VI abundance and normal basal-lamina colocalization.
    Thirteen of fifteen dominant cases in one biopsy series had a normal pattern. Staining is tissue- and age-dependent
    and is not interchangeable with a cultured-fibroblast secretion assay.
  readouts:
  - target: Endomysial collagen VI network dysfunction
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Normal muscle staining does not exclude molecular collagen VI dysfunction.
    evidence:
    - reference: PMID:37569848
      reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Muscle biopsies from 13 out of 15 BM patients with dominant mutations exhibited a normal collagen VI
        pattern, as evidenced by the continuous overlap with the anti-perlecan staining (Table 2).
      explanation: >-
        Normal abundance and basal-lamina colocalization in most dominant Bethlem biopsies in this series;
        a
        normal result does not exclude disease.
    relationship: READOUT_OF
histopathology:
- name: Mild dystrophic changes with interstitial fibrosis
  finding_term:
    preferred_term: Interstitial and endomysial fibrosis
    term:
      id: NCIT:C3044
      label: Fibrosis
  description: >
    Muscle biopsy in advanced disease shows overtly dystrophic features with rare
    degenerating and regenerating fibres and a prominent build-up of interstitial
    fibrous tissue; early biopsies may show only fibre atrophy or fibre type
    disproportion.
  diagnostic: true
  context: Skeletal muscle biopsy
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In samples from patients in more-advanced stages of the disease, overtly dystrophic features are evident, including rare degenerating and regenerating fibers and a prominent build-up of interstitial fibrous tissue in the muscle."
    explanation: Describes the muscle biopsy pattern of the collagen VI-related myopathies.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:24339618
    reference_title: "Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle biopsy in the father showed dystrophic changes with normal immmunostaining for collagen VI, sarcoglycans,
      and dysferlin.
    explanation: A Bethlem case series documents dystrophic muscle histology.
diagnosis:
- name: Muscle collagen VI immunohistochemistry
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    Collagen VI abundance and colocalization with a basement-membrane marker can be normal in Bethlem disease:
    13 of 15 dominant cases in one series retained a normal perlecan-overlapping pattern. Thus a normal stain
    does not exclude the diagnosis. Abnormal staining can support COL6 disease but is not a universal requirement,
    and expression may vary with age.
  results: Retained but mislocalized collagen VI, away from the basement membrane, supports dominant collagen VI disease.
  evidence:
  - reference: PMID:37569848
    reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Muscle biopsies from 13 out of 15 BM patients with dominant mutations exhibited a normal collagen VI
      pattern, as evidenced by the continuous overlap with the anti-perlecan staining (Table 2).
    explanation: >-
      Normal abundance and basal-lamina colocalization in most dominant Bethlem biopsies in this series; a
      normal result does not exclude disease.
- name: COL6A1, COL6A2, and COL6A3 molecular genetic testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Diagnosis requires compatible clinical findings and pathogenic or likely pathogenic COL6A1, COL6A2 or COL6A3
    variant(s), with inheritance and segregation assessed. Testing can use a multigene panel or exome/genome
    sequencing and selected deletion/duplication or RNA studies when standard sequencing is unrevealing. The
    62% putative-variant yield in a 2005 coding-exon study is historical and should not be presented as modern
    sensitivity. Variants of uncertain significance neither confirm nor exclude disease; functional evidence
    must be interpreted with appropriate controls. Deep-intronic COL6A1 testing is relevant to the wider COL6
    diagnostic spectrum, without labeling its typical severe phenotype as Bethlem.
  results: A heterozygous or biallelic COL6A1, COL6A2, or COL6A3 pathogenic variant confirms the diagnosis.
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis can be confirmed by identification of a heterozygous or biallelic pathogenic variant(s) in COL6A1, COL6A2, or COL6A3."
    explanation: GeneReviews defines the molecular confirmation criterion.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:15689448
    reference_title: "Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found putative mutations in one of the COL6 genes in 62% of patients."
    explanation: Quantifies the diagnostic yield of systematic COL6 sequencing.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1503/?report=reader
    reference_title: Collagen VI-Related Dystrophies - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the
      diagnosis.
    explanation: >-
      GeneReviews explicitly limits interpretation of VUS.
    quote_role: REVIEW_SYNTHESIS
- name: Muscle imaging
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    MRI may show peripheral involvement of vastus lateralis with central rectus-femoris involvement, supporting
    a COL6 phenotype and helping select diagnostic testing. Imaging is supportive rather than perfectly specific;
    overlapping patterns occur in calpainopathy, and some mild Bethlem patients have normal MRI.
  results: A concentric outer-to-inner pattern with a rectus femoris central cloud supports collagen VI-related myopathy.
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This analysis, therefore, is also a useful diagnostic tool (Figure 2).30,32–34 MRI of muscle can be very
      useful in the recognition of a collagen VI-related myopathy and in the differentiation of collagen VI-related
      myopathies from LMNA-related Emery–Dreifuss muscular dystrophy, as well as from other myopathies associated
      with contractures and spinal rigidity.35,36 In the collagen VI-related myopathies, a characteristic concentric
      pattern of imaging changes is observed, in that the initial degenerative changes seen on imaging are
      most evident on the outer aspects of the muscle, rather than the inside (Figure 3).
    explanation: Describes the concentric muscle imaging signature.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:24339618
    reference_title: "Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle imaging revealed severe involvement of glutei and vasti with "central shadow" in rectus femoris.
    explanation: A Bethlem case series documents the imaging pattern including the rectus femoris central shadow.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1503/?report=reader
    reference_title: Collagen VI-Related Dystrophies - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Of note, similar muscle imaging patterns may be seen in other conditions, including ... calpainopathy
    explanation: >-
      Imaging pattern is not unique to COL6 disease.
    quote_role: REVIEW_SYNTHESIS
- name: Cultured dermal fibroblast collagen VI analysis
  description: >-
    Cultured fibroblast immunocytochemistry can reveal disorganized, stippled, sparse or intracellularly retained
    collagen VI and complement molecular interpretation. The assay compartment differs from muscle immunohistochemistry.
    A 2025 recessive family showed absent extracellular network in the proband and preserved networks in single-variant
    relatives; this does not independently classify either allele in isolation.
  diagnosis_term:
    preferred_term: Diagnostic Procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:40550965
    reference_title: 'Autosomal recessive Bethlem myopathy: a 30-year journey.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      The proband’s cells (III:2) presented the absence of secreted protein and collagen VI network; collagen
      staining was observable only in the cell’s cytoplasm as in NT well (63X).
    explanation: >-
      Patient fibroblast phenotype in a recessive COL6A2 family; individual variant effects were not isolated.
treatments:
- name: Physical and occupational therapy for contracture management
  description: >
    Physical therapy and occupational therapy provide recommendations for joint
    stretching, swimming, and aquatherapy. Contracture management is the central
    supportive intervention in Bethlem myopathy, because contracture progression
    causes disability in its own right even when weakness progresses only slowly.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Flexion contracture
    term:
      id: HP:0001371
      label: Flexion contracture
  - preferred_term: Achilles tendon contracture
    term:
      id: HP:0001771
      label: Achilles tendon contracture
  - preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "physical therapy and occupational therapy to provide recommendations for joint stretching, swimming, and aquatherapy"
    explanation: GeneReviews recommends physical and occupational therapy for Bethlem muscular dystrophy.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:21078917
    reference_title: Consensus statement on standard of care for congenital muscular dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical therapy should be focused on the maintenance of function and mobility, prevention or treatment of joint contractures and spine deformities"
    explanation: Consensus standard-of-care guidance supports physical therapy targeting contractures.
    quote_role: REVIEW_SYNTHESIS
- name: Orthopedic management of Achilles tendon contracture and scoliosis
  description: >-
    Specialist care can include serial casting and selected Achilles tendon release followed by casting when
    severe or asymmetric shortening impairs gait. Surgery disrupting other joint capsules is generally discouraged
    because fixed postoperative contractures and loss of motion can result. Scoliosis surgery requires coordinated
    pulmonary, anesthesia, intensive-care and orthopedic planning.
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_phenotypes:
  - preferred_term: Achilles tendon contracture
    term:
      id: HP:0001771
      label: Achilles tendon contracture
  - preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "treatment of Achilles tendon contractures per orthopedist"
    explanation: GeneReviews prescribes orthopedic treatment of Achilles tendon contracture.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "if surgical treatment for scoliosis is needed, coordinate with orthopedics, anesthesia, intensive care, and pulmonary specialists"
    explanation: GeneReviews specifies multidisciplinary coordination for scoliosis surgery.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1503/?report=reader
    reference_title: Collagen VI-Related Dystrophies - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Surgical intervention on any joint contractures (beyond Achilles tendon release surgery) is not recommended,
      given the high postoperative risk of fixed contractures with complete loss of range of motion in individuals
      with Bethlem muscular dystrophy who have undergone joint surgery.
    explanation: >-
      Bethlem-specific caution from the full GeneReviews chapter.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1503/?report=reader
    reference_title: Collagen VI-Related Dystrophies - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      A noninvasive approach that can help promote improved range of motion of the Achilles tendons is serial
      casting.
    explanation: >-
      Nonoperative alternative described by GeneReviews.
    quote_role: REVIEW_SYNTHESIS
- name: Nocturnal noninvasive ventilation
  description: >-
    Respiratory support is guided by upright/supine pulmonary testing and polysomnography, including carbon-dioxide
    monitoring. GeneReviews recommends initiation of nocturnal BiPAP when FVC is 60% predicted or lower, with
    pressures titrated during a sleep study. Respiratory weakness can require treatment while independent walking
    is retained.
  treatment_term:
    preferred_term: noninvasive ventilation
    term:
      id: NCIT:C171457
      label: Non-Invasive Mechanical Ventilation
  target_phenotypes:
  - preferred_term: Restrictive ventilatory defect
    term:
      id: HP:0002091
      label: Restrictive ventilatory defect
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BiPAP as needed to support nocturnal ventilation and prevent right heart strain"
    explanation: GeneReviews prescribes BiPAP for Bethlem muscular dystrophy as needed.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1503/?report=reader
    reference_title: Collagen VI-Related Dystrophies - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      For forced vital capacity (FVC) measurements of 60% predicted or lower, noninvasive ventilation (NIV)
      in the form of bilevel positive airway pressure (BiPAP) should be initiated during a polysomnogram –
      with pressures adjusted to ensure adequate ventilation – and then consistently used while sleeping.
    explanation: >-
      Bethlem-specific threshold in the treatment section.
    quote_role: REVIEW_SYNTHESIS
- name: Respiratory, cardiac, and orthopedic surveillance
  description: >-
    At least annual upright and supine FVC, sleep evaluation for hypoventilation, clinical/radiographic scoliosis
    assessment and rehabilitation review are recommended for Bethlem disease. Initial pulmonary testing begins
    in childhood, around age five when feasible. GeneReviews recommends annual ECG/echocardiography to assess
    secondary right-heart strain from inadequate ventilation; this does not imply primary cardiomyopathy is
    a characteristic Bethlem feature. Mobility-device needs and joint function should be reassessed over time.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Respiratory surveillance including annual pulmonary function tests (PFTs) in the upright and supine positions and polysomnogram for assessing for nocturnal hypoventilation"
    explanation: GeneReviews defines the respiratory surveillance schedule for Bethlem muscular dystrophy.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "annual cardiac evaluation with echocardiogram and EKG"
    explanation: GeneReviews prescribes annual cardiac surveillance.
    quote_role: REVIEW_SYNTHESIS
- name: Genetic counseling
  description: >-
    A person with an autosomal dominant pathogenic variant has a 50% transmission risk in each pregnancy; sibling
    risk is 50% when a parent is heterozygous. Parental somatic/germline mosaicism can complicate apparently
    de novo families, and clinical severity varies within families. For recessive disease with two carrier
    parents, each pregnancy has a 25% affected, 50% carrier and 25% noncarrier chance. Once familial variants
    are established, prenatal and preimplantation genetic testing are possible.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Parental somatic mosaicism (and concomitant germline mosaicism) is not uncommon in the autosomal dominant COL6-RDs."
    explanation: GeneReviews highlights parental mosaicism as a counseling consideration.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The severity of COL6-RD manifestations may vary among family members who are heterozygous for the same pathogenic variant."
    explanation: GeneReviews notes intrafamilial variability, a key counseling point.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      If a parent of the proband has the pathogenic variant identified in the proband and/or is affected, the
      risk to the sibs of inheriting the variant is 50%. The severity of COL6-RD manifestations may vary among
      family members who are heterozygous for the same pathogenic variant.
    explanation: >-
      GeneReviews genetic-counseling guidance.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual
      has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and
      a 25% chance of being unaffected and not a carrier.
    explanation: >-
      GeneReviews genetic-counseling guidance.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Once the COL6A1, COL6A2, or COL6A3 pathogenic variant(s) have been identified in an affected family member,
      prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
    explanation: >-
      GeneReviews genetic-counseling guidance.
    quote_role: REVIEW_SYNTHESIS
- name: Cyclophilin D and permeability transition pore modulation
  description: >-
    Cyclosporin A is investigational for COL6 myopathy. A one-month open pilot in five patients (four UCMD
    and one Bethlem) showed improved mitochondrial and apoptotic biopsy readouts, without establishing functional
    benefit or long-term Bethlem efficacy. Genetic cyclophilin-D ablation supports the target in Col6a1-null
    mice. Immunosuppression and toxicity preclude treating a biopsy response as a routine-care recommendation.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cyclosporin A
      term:
        id: CHEBI:4031
        label: cyclosporin A
  target_mechanisms:
  - target: Myofibre mitochondrial dysfunction and permeability transition pore dysregulation
    treatment_effect: INHIBITS
    description: >-
      Investigational cyclophilin-D-dependent pore desensitization can improve mitochondrial biopsy readouts;
      functional and long-term benefit in Bethlem disease remains unproved.
    evidence:
    - reference: PMID:18362356
      reference_title: Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "cyclosporin A, a widely used immunosuppressant that desensitizes the permeability transition pore independently of calcineurin inhibition"
      explanation: Names the molecular target and mechanism of the intervention.
      quote_role: BACKGROUND
    - reference: PMID:19293339
      reference_title: Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These findings (i) demonstrate that lack of Cyp-D is equivalent to its inhibition with CsA at curing
        the mouse dystrophic phenotype; (ii) establish a cause-effect relationship between Cyp-D-dependent
        PTP regulation and pathogenesis of the ColVI muscular dystrophy and (iii) validate Cyp-D and the PTP
        as pharmacological targets for the therapy of human ColVI myopathies.
      explanation: >-
        Target validation in the Col6a1-null mouse, not proof of efficacy in patients.
  evidence:
  - reference: PMID:18362356
    reference_title: Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "report the results of an open pilot trial with cyclosporin A in five patients with collagen VI myopathies"
    explanation: An open pilot trial tested cyclosporin A in patients with collagen VI myopathies.
  - reference: PMID:18362356
    reference_title: Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both of these pathologic signs were largely normalized after 1 month of oral cyclosporin A administration, which also increased muscle regeneration."
    explanation: >
      Biopsy endpoints improved, but muscle strength was not measured, so this is
      proof of mechanism rather than proof of clinical benefit.
- name: Investigational low-protein diet for autophagy modulation
  description: >-
    A one-year open, uncontrolled pilot enrolled eight adults and analyzed seven completers (six Bethlem, one
    UCMD). Muscle autophagy-associated markers increased and apoptosis decreased, but human flux was not directly
    quantified. The six ambulant Bethlem patients improved on the four-stair test; six-minute walk, ten-meter
    walk, strength and the mixed-group FVC change were not statistically significant. Participants lost about
    9% body weight and 7% lean mass despite preservation of the lean-to-fat percentage. The diet remains investigational
    and requires nutritional oversight; the study does not establish long-term clinical efficacy.
  treatment_term:
    preferred_term: Therapeutic Dietary Intervention
    term:
      id: NCIT:C64892
      label: Therapeutic Dietary Intervention
  target_mechanisms:
  - target: Defective autophagic clearance of damaged organelles
    treatment_effect: MODULATES
    description: >-
      Human muscle autophagy-associated markers increase during the exploratory diet intervention. Experimental
      mouse autophagy rescue motivates the approach, but a restoration of human flux or sustained clinical
      efficacy has not been established.
    evidence:
    - reference: PMID:21037586
      reference_title: Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Forced activation of autophagy by genetic, dietary and pharmacological approaches restored myofiber survival and ameliorated the dystrophic phenotype of Col6a1(-/-) mice."
      explanation: Demonstrates rescue of the dystrophic phenotype by autophagy reactivation in the Bethlem model.
    - reference: PMID:27656840
      reference_title: Autophagy activation in COL6 myopathic patients by a low-protein-diet pilot trial.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        After one y of low-protein diet, autophagic markers were increased in skeletal muscle and blood leukocytes
        of patients.
      explanation: >-
        Markers in seven completers; increased abundance does not directly measure human autophagic flux.
  evidence:
  - reference: PMID:27656840
    reference_title: Autophagy activation in COL6 myopathic patients by a low-protein-diet pilot trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      After one y of low-protein diet, autophagic markers were increased in skeletal muscle and blood leukocytes
      of patients.
    explanation: >-
      Markers in seven completers; increased abundance does not directly measure human autophagic flux.
  - reference: PMID:27656840
    reference_title: Autophagy activation in COL6 myopathic patients by a low-protein-diet pilot trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      During the trial, patients lost 9% body weight (4.17 ± 2.01 kg), 7% lean mass (2.26 ± 2.45 kg), and 8%
      fat mass (1.91 ± 3.15 kg).
    explanation: >-
      Absolute lean mass fell despite a stable lean-to-fat percentage.
  - reference: PMID:27656840
    reference_title: Autophagy activation in COL6 myopathic patients by a low-protein-diet pilot trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      (B) Timed 4-stair climb test (4 steps), measured in seconds (s). P = 0.034, following Wilcoxon signed
      rank test for paired data, for the comparison between mean values at T0 and T12.
    explanation: >-
      Exploratory paired functional result in six ambulant participants; other functional comparisons did not
      establish efficacy.
- name: Individualized moderate aerobic exercise
  description: >-
    Supervised individualized moderate exercise can complement stretching and mobility support. In a ten-week
    home-training study, four men improved peak oxygen uptake by 16% compared with baseline, while two controls
    did not improve. CK remained stable and functional tests did not change significantly. The small study
    supports feasibility and aerobic conditioning, without establishing long-term disease modification or safety
    of intense eccentric loading.
  treatment_term:
    preferred_term: Exercise Intervention
    term:
      id: NCIT:C62739
      label: Exercise Intervention
  evidence:
  - reference: PMID:31026058
    reference_title: Moderate-intensity aerobic exercise improves physical fitness in bethlem myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Six men with Bethlem myopathy were included (4 training; 2 controls).
    explanation: >-
      Small nonrandomized disease-specific exercise study.
  - reference: PMID:31026058
    reference_title: Moderate-intensity aerobic exercise improves physical fitness in bethlem myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Performance in functional tests did not change significantly. Creatine kinase values were stable during
      the study.
    explanation: >-
      Functional and safety limitations of the small training study.
- name: Pregnancy planning and pulmonary monitoring
  description: >-
    Pregnancy care includes close respiratory surveillance for changing ventilatory requirements and assessment
    of hip range of motion and muscle function to inform delivery planning. Management should account for the
    individual level of diaphragmatic and limb weakness.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1503/?report=reader
    reference_title: Collagen VI-Related Dystrophies - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      For a pregnant woman with COL6-RD, careful pulmonary surveillance during pregnancy for potential increased
      needs for ventilatory support is recommended, particularly given the disproportionate weakness of the
      diaphragm in the COL6-RDs.
    explanation: >-
      Full GeneReviews pregnancy guidance across COL6-related dystrophies.
    quote_role: REVIEW_SYNTHESIS
clinical_trials:
- name: NCT01438788
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Completed uncontrolled low-protein-diet pilot: eight adults enrolled, seven completers (six Bethlem and
    one UCMD) analyzed in PMID27656840. Biomarker changes and exploratory outcomes do not establish controlled
    efficacy; loss of lean mass is relevant. Registry has no structured results posted, but a results paper
    is linked.
  evidence:
  - reference: clinicaltrials:NCT01438788
    reference_title: Low Protein Diet to Correct Defective Autophagy in Patients With Collagen VI Related Myopathies
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      This is a 2 stage exploratory study with a 3-month observational phase on the natural course, followed
      by a 12-month, open-label, non-comparative, single-arm, phase II pilot study on the efficacy, safety
      and tolerability of a low-protein diet (LPD) in 8 adult patients with Bethlem myopathy (BM) and Ullrich
      congenital muscular dystrophy (UCMD).
    explanation: >-
      Registered study design; status checked separately against the live record on 2026-10-01.
  - reference: PMID:27656840
    reference_title: Autophagy activation in COL6 myopathic patients by a low-protein-diet pilot trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      After one y of low-protein diet, autophagic markers were increased in skeletal muscle and blood leukocytes
      of patients.
    explanation: >-
      Markers in seven completers; increased abundance does not directly measure human autophagic flux.
  notes: ClinicalTrials.gov status checked 2026-10-01.
- name: NCT01895283
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    Completed Bethlem bike-ergometer training study, seven registered participants. The related 2019 publication
    analyzed six men (four training, two controls), reporting improved aerobic fitness with stable CK but no
    significant functional-test changes. Registry has no structured results posted; registration and analysis
    counts are distinct.
  evidence:
  - reference: clinicaltrials:NCT01895283
    reference_title: The Effect of a Bike Ergometer Training Program in Patients With Bethlem Myopathy
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      Patients will be required to train, three times per week, for 10 weeks, on a bike ergometer with a specific
      training intensity, under pulse rate monitoring.
    explanation: >-
      Registered study design; status checked separately against the live record on 2026-10-01.
  - reference: PMID:31026058
    reference_title: Moderate-intensity aerobic exercise improves physical fitness in bethlem myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Six men with Bethlem myopathy were included (4 training; 2 controls).
    explanation: >-
      Related publication analyzed six men, distinct from the seven registry participants.
  notes: ClinicalTrials.gov status checked 2026-10-01.
- name: NCT01836627
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    Completed randomized feasibility study of lung hyperinsufflation in 34 children and young adults with COL6
    or LAMA2 muscular dystrophy. The mixed eligibility includes impaired respiratory function; it is not a
    Bethlem-specific efficacy trial. No structured registry results are posted.
  evidence:
  - reference: clinicaltrials:NCT01836627
    reference_title: Congenital Muscular Dystrophy (CMD) and the Feasibility of Hyperinsufflation Therapy to Slow Rate of Decline in Lung Volume
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      This research study includes children ages 5 to 20 years old with Collagen Type 6 Congenital Muscular
      Dystrophy or Laminin α2-related muscular dystrophy (LAMA2-MD).
    explanation: >-
      Registered study design; status checked separately against the live record on 2026-10-01.
  notes: ClinicalTrials.gov status checked 2026-10-01.
- name: NCT03693898
  phase: NOT_APPLICABLE
  status: UNKNOWN
  description: >-
    Diagnostic MR study in adult Bethlem/UCMD, twenty planned participants. Current registry status is UNKNOWN;
    the last verified status was recruiting in October 2018. The estimated 2019 completion date is not proof
    that recruitment ended or results exist.
  evidence:
  - reference: clinicaltrials:NCT03693898
    reference_title: MR in Patients With Neuromuscular Diseases
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      The primary aim of this study is to investigate the pattern of involved muscles, the function and quality
      of the muscles and the disease severity using MRI.
    explanation: >-
      Registered study design; status checked separately against the live record on 2026-10-01.
  notes: ClinicalTrials.gov status checked 2026-10-01.
- name: NCT04020159
  phase: NOT_APPLICABLE
  status: UNKNOWN
  description: >-
    Observational global registry for COL6-related dystrophies, one thousand planned participants. It includes
    Bethlem, UCMD and intermediate disease and explicitly excludes COL12-related Bethlem type 2. Current status
    is UNKNOWN, last verified recruiting in March 2023; no structured results are posted.
  evidence:
  - reference: clinicaltrials:NCT04020159
    reference_title: Global Registry for COL6-related Dystrophies
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      The Global Registry for COL6-related dystrophies (www.collagen6.org) is a database for individuals who
      have been diagnosed with Bethlem Myopathy, Ullrich Congenital Muscular Dystrophy (UCMD) or an intermediate
      form of these diseases.
    explanation: >-
      Registered study design; status checked separately against the live record on 2026-10-01.
  notes: ClinicalTrials.gov status checked 2026-10-01.
- name: NCT01403402
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    Recruiting observational patient/proxy-reported congenital-muscle-disease study with four thousand planned
    participants across many diagnoses, including dominant and recessive COL6-related Bethlem myopathy. Enrollment
    is not a count of Bethlem patients and the registry does not establish a treatment effect.
  evidence:
  - reference: clinicaltrials:NCT01403402
    reference_title: Congenital Muscle Disease Patient and Proxy Reported Outcome Study
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      The Congenital Muscle Disease Patient and Proxy Reported Outcome Study (CMDPROS) is a longitudinal 10
      year study to identify and trend care parameters, adverse events in the congenital muscle diseases using
      the Congenital Muscle Disease International Registry (CMDIR) to acquire necessary data for adverse event
      calculations (intake survey and medical records curation).
    explanation: >-
      Registered study design; status checked separately against the live record on 2026-10-01.
  notes: ClinicalTrials.gov status checked 2026-10-01.
discussions:
- discussion_id: disc_bethlem_col6a1_null_model_fidelity
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >
    Does the Col6a1-null mouse, which lacks collagen VI entirely, faithfully
    model dominant-negative Bethlem myopathy, in which an abnormal collagen VI
    network is still present in the matrix?
  attaches_to:
  - pathophysiology#Myofibre mitochondrial dysfunction and permeability transition pore dysregulation
  - pathophysiology#Defective autophagic clearance of damaged organelles
  rationale: >-
    Complete Col6a1-null mice reproduce selected mitochondrial and autophagy defects but differ from human
    dominant structural variants. Many dominant Bethlem muscle biopsies have normal collagen VI localization
    as well as preserved signal. Neither normal staining nor a null model resolves the exact molecular dysfunction
    in every patient. Genotype-stratified functional assays are needed to assess transferability of therapeutic
    mechanisms.
  proposed_experiments:
  - experiment_id: exp_bethlem_dominant_negative_ptp_flux
    name: Permeability transition and autophagic flux by COL6 genotype class
    description: >
      Measure permeability transition pore sensitivity and autophagic flux in
      myofibres or myoblasts from genotyped patients carrying dominant-negative
      COL6A1 exon 14 skipping, and compare against recessive collagen VI null
      patients and unaffected controls.
  - experiment_id: exp_bethlem_knockin_mouse
    name: Bethlem dominant-negative knock-in mouse
    description: >
      Generate a knock-in mouse carrying a Bethlem dominant-negative Col6a1
      in-frame exon deletion and compare its mitochondrial, autophagic, and
      contracture phenotype with the existing Col6a1-null mouse.
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In contrast to the human disease, these mice only show a mild neuromuscular disorder without much overt weakness."
    explanation: >
      The review states directly that the Col6a1-null mouse phenotype is milder
      than human disease, which is the translational mismatch at issue.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:37569848
    reference_title: 'New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Muscle biopsies from 13 out of 15 BM patients with dominant mutations exhibited a normal collagen VI
      pattern, as evidenced by the continuous overlap with the anti-perlecan staining (Table 2).
    explanation: >-
      Normal abundance and basal-lamina colocalization in most dominant Bethlem biopsies in this series; a
      normal result does not exclude disease.
  posed_date: "2026-07-31T00:00:00Z"
- discussion_id: disc_bethlem_matrix_sarcolemma_receptor
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >
    Which molecular partner mediates the interaction of collagen VI with the
    muscle basement membrane and links the microfibrillar network to the
    sarcolemma?
  attaches_to:
  - pathophysiology#Impaired matrix-to-sarcolemma anchoring of the myofibre
  rationale: >-
    The matrix-to-myofibre link remains incompletely resolved. The 2025 Col6a2-null study identified collagen
    VI-associated proteins and altered TGF-beta-containing complexes, but co-immunoprecipitation does not prove
    direct pairwise binding or identify a universal receptor pathway in human Bethlem disease. Whether altered
    mechanical coupling, extracellular growth-factor availability and mitochondrial/autophagy pathways act
    in sequence or partly in parallel remains unresolved.
  proposed_experiments:
  - experiment_id: exp_bethlem_basement_membrane_interactome
    name: Muscle basement membrane collagen VI interactome
    description: >
      Perform proximity labeling or crosslinking mass spectrometry on the muscle
      basement membrane to identify the collagen VI binding partners present at
      the myofibre surface.
  - experiment_id: exp_bethlem_biglycan_dgc_phenocopy
    name: Biglycan and dystroglycan complex phenocopy test
    description: >
      Test whether disruption of biglycan or of the dystrophin-associated protein
      complex phenocopies the collagen VI mitochondrial defect in otherwise
      wild-type myofibres.
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The identity of the molecular partner (or partners) mediating the interaction of collagen VI in the muscle basement membrane is not yet known."
    explanation: The review states this gap explicitly.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Additional data suggest that the increased opening of mitochondrial permeability transition pores is
      not specific to the collagen VI-related disorders, but can also be seen in other neuromuscular disorders,103
      which would mean that the treatment approach outlined above would be applicable in other muscle disorders,
      as has already been suggested for the δ-sarcoglycan-deficient and dystrophin-deficient mouse models.104
      A crucial step will be to establish exactly how collagen VI deficiency in the extracellular matrix leaves
      muscle cells vulnerable to apoptosis; that is, how the presence of normal collagen VI in the extracellular
      matrix contributes to the health of myofibers.
    explanation: The review names this as the crucial unresolved mechanistic step.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:40309777
    reference_title: Collagen type VI regulates TGF-β bioavailability in skeletal muscle in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Together, these findings suggest that absence of collagen VI from the muscle ECM increases active TGF-β
      without an increase in total TGF-β transcription or translation.
    explanation: >-
      Col6a2-null mouse tissue and fibroblast assays; altered activation rather than increased overall production.
  posed_date: "2026-07-31T00:00:00Z"
notes: >-
  This entry covers COL6A1/COL6A2/COL6A3-related Bethlem myopathy (MONDO:0008029), including its three gene-defined
  subtypes. COL12A1-related Bethlem myopathy 2 is a separate disorder. Bethlem, intermediate COL6-related dystrophy
  and Ullrich congenital muscular dystrophy form a severity continuum, but cohort results and treatment outcomes
  should retain their clinical subgroup. Historical benign terminology is retained as a synonym only; adult
  progression and respiratory impairment can be clinically significant. Molecular diagnosis requires interpretation
  of the variant, segregation and phenotype rather than accepting every rare COL6 variant as causal.
references:
- reference: PMID:20301676
  title: Collagen VI-Related Dystrophies.
  tags:
  - GeneReviews
  findings:
  - statement: >
      GeneReviews defines Bethlem muscular dystrophy as the mild end of the
      collagen VI-related dystrophy continuum, characterized by proximal muscle
      weakness plus contractures of the elbows, Achilles tendons, and long finger
      flexors, with inconsistent respiratory involvement, and provides the
      management and surveillance recommendations used in this entry.
    supporting_text: "Bethlem muscular dystrophy is characterized by a combination of proximal muscle weakness and joint contractures."
- reference: PMID:8782832
  title: Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures.
  findings:
  - statement: >
      The original gene-identification study linked Bethlem myopathy to the
      COL6A1-COL6A2 cluster and COL6A3, and identified Gly-X-Y disrupting
      substitutions in the triple-helical domain.
    supporting_text: "Both mutations disrupt the Gly-X-Y motif of the triple helical domain by substitution of Gly for either Val or Ser."
- reference: PMID:10219778
  title: "Bethlem myopathy: a slowly progressive congenital muscular dystrophy with contractures."
  findings:
  - statement: >-
      The seven-kindred natural-history study documents early presentation in the studied children and later
      wheelchair use, which does not necessarily imply complete loss of indoor ambulation.
    supporting_text: "Due to slow but ongoing progression, more than two-thirds of patients over 50 years of age use a wheelchair."
- reference: PMID:15689448
  title: "Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy."
  findings:
  - statement: >-
      In 2005, coding-exon sequencing identified putative COL6 variants in 62% of 79 selected UCMD/Bethlem
      patients. This historical yield is not the sensitivity of contemporary diagnostic testing.
    supporting_text: "We found putative mutations in one of the COL6 genes in 62% of patients."
- reference: PMID:21691338
  title: "The collagen VI-related myopathies: muscle meets its matrix."
  findings:
  - statement: >
      The definitive review covers collagen VI assembly, the non-cell-autonomous
      interstitial fibroblast origin of muscle collagen VI, the Bethlem
      contracture and skin phenotype, muscle imaging, prevalence, and the
      genotype-phenotype gradient across the COL6-RD spectrum.
    supporting_text: "In northern England, the prevalence of Ullrich CMD is 0.13 cases per 100,000 of the population, and that of Bethlem myopathy is 0.77 cases per 100,000."
- reference: PMID:14625552
  title: Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency.
  findings:
  - statement: >
      The Col6a1-null mouse, whose muscle phenotype resembles Bethlem myopathy,
      revealed latent mitochondrial dysfunction, permeability transition pore
      dysregulation, and spontaneous myofibre apoptosis reversible by collagen VI
      replating or cyclosporin A.
    supporting_text: "We previously generated collagen VI-deficient (Col6a1-/-) mice and showed that they have a muscle phenotype that strongly resembles Bethlem myopathy."
- reference: PMID:19293339
  title: Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice.
  findings:
  - statement: >-
      Cyclophilin-D ablation rescued mitochondrial and apoptotic abnormalities in Col6a1-null mice, supporting
      an experimental target without establishing human clinical efficacy.
    supporting_text: >-
      In the absence of Cyp-D, Col6a1(-/-) mice show negligible myofiber degeneration, rescue from mitochondrial
      dysfunction and ultrastructural defects, and normalized incidence of apoptosis.
- reference: PMID:21037586
  title: Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration.
  findings:
  - statement: >
      Defective autophagy underlies the persistence of abnormal organelles and
      apoptosis in collagen VI-deficient muscle, and reduced beclin-1 and Bnip3
      are demonstrable in Bethlem myopathy patient muscle.
    supporting_text: "Furthermore, muscle biopsies from subjects with Bethlem myopathy or Ullrich congenital muscular dystrophy had reduced protein amounts of beclin-1 and Bnip3."
- reference: PMID:18362356
  title: Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies.
  findings:
  - statement: >
      An open pilot trial in five patients showed that oral cyclosporin A
      normalized mitochondrial dysfunction and apoptosis in muscle biopsies,
      providing human proof of mechanism for permeability transition pore
      modulation.
    supporting_text: >-
      Both of these pathologic signs were largely normalized after 1 month of oral cyclosporin A administration,
      which also increased muscle regeneration.
- reference: PMID:24339618
  title: "Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis."
  findings:
  - statement: >-
      A clinically diagnosed Indian family had contractures, keloids and follicular hyperkeratosis. The father
      had normal CK and collagen VI immunostaining; sons had raised CK. Molecular testing was not performed.
    supporting_text: "All had flexion contractures, keloids, and follicular hyperkeratosis without muscle hypertrophy."
- reference: PMID:25158062
  title: "Col6a1 null mice as a model to study skin phenotypes in patients with collagen VI related myopathies: expression of classical and novel collagen VI variants during wound healing."
  findings:
  - statement: >-
      Col6a1-null mice have mechanically weaker skin and altered wound ultrastructure, but no overt wound-healing
      delay or recreation of human keloids.
    supporting_text: >-
      However, in contrast to the hypertrophic scars or keloids occurring in patients with a collagen VI myopathies,
      we did not observe such disturbed wound healing in the Col6a1 null mice.
- reference: PMID:37569848
  title: "New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients."
  findings:
  - statement: >
      A 69-patient single-center collagen VI cohort including 33 Bethlem myopathy
      patients quantifies residual strength, and shows that collagen VI
      immunofluorescence correlates with severity but increases with age within
      an individual.
    supporting_text: "In our BM group, only one third had a knee extension strength greater than 50% of the predicted value, while only one in ten showed similar retention of elbow flexion."
- reference: PMID:36982625
  title: Extracellular Matrix Disorganization and Sarcolemmal Alterations in COL6-Related Myopathy Patients with New Variants of COL6 Genes.
  findings:
  - statement: >-
      A mixed COL6-phenotype biopsy series reports extracellular and sarcolemmal abnormalities. Several variants
      remain uncertain or were predicted benign in the study tables; morphology does not independently establish
      pathogenicity for each variant.
    supporting_text: "they documented the high variability in COL6 distribution and the extracellular matrix disorganization"
- reference: clinicaltrials:NCT01438788
  title: Low Protein Diet to Correct Defective Autophagy in Patients With Collagen VI Related Myopathies
  findings:
  - statement: >
      A phase II open-label pilot tested a normocaloric low-protein diet in eight
      adults with Bethlem myopathy or Ullrich congenital muscular dystrophy to
      reactivate autophagy, with muscle beclin-1 as the primary endpoint.
    supporting_text: "The primary end point of the study will be the change in muscle biopsy of Beclin 1, a marker of autophagy, at 1 year of LPD treatment when compared to baseline."
- reference: PMID:21078917
  title: Consensus statement on standard of care for congenital muscular dystrophies.
  findings:
  - statement: >
      Standard-of-care consensus supports physical therapy directed at
      maintaining function and preventing or treating joint contractures and
      spine deformity.
    supporting_text: "Physical therapy should be focused on the maintenance of function and mobility, prevention or treatment of joint contractures and spine deformities"
- reference: PMID:10419498
  title: Bethlem myopathy and engineered collagen VI triple helical deletions prevent intracellular multimer assembly and protein secretion.
- reference: PMID:20338942
  title: Zebrafish models of collagen VI-related myopathies.
- reference: PMID:25535305
  title: 'Bethlem myopathy: long-term follow-up identifies COL6 mutations predicting severe clinical evolution.'
- reference: PMID:27656840
  title: Autophagy activation in COL6 myopathic patients by a low-protein-diet pilot trial.
- reference: PMID:30706156
  title: 'Bethlem myopathy: a series of 16 patients and description of seven new associated mutations.'
- reference: PMID:31026058
  title: Moderate-intensity aerobic exercise improves physical fitness in bethlem myopathy.
- reference: PMID:31471117
  title: 'Autosomal recessive Bethlem myopathy: A clinical, genetic and functional study.'
- reference: PMID:40309777
  title: Collagen type VI regulates TGF-β bioavailability in skeletal muscle in mice.
- reference: PMID:40550965
  title: 'Autosomal recessive Bethlem myopathy: a 30-year journey.'
- reference: clinicaltrials:NCT01403402
  title: Congenital Muscle Disease Patient and Proxy Reported Outcome Study
- reference: clinicaltrials:NCT01836627
  title: Congenital Muscular Dystrophy (CMD) and the Feasibility of Hyperinsufflation Therapy to Slow Rate of Decline in Lung Volume
- reference: clinicaltrials:NCT01895283
  title: The Effect of a Bike Ergometer Training Program in Patients With Bethlem Myopathy
- reference: clinicaltrials:NCT03693898
  title: MR in Patients With Neuromuscular Diseases
- reference: clinicaltrials:NCT04020159
  title: Global Registry for COL6-related Dystrophies
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1503/?report=reader
  title: Collagen VI-Related Dystrophies - GeneReviews&reg; - NCBI Bookshelf
differential_diagnoses:
- name: Emery-Dreifuss muscular dystrophy
  disease_term:
    preferred_term: Emery-Dreifuss muscular dystrophy
    term:
      id: MONDO:0016830
      label: Emery-Dreifuss muscular dystrophy
  description: >-
    Early contractures and slowly progressive weakness overlap.
  distinguishing_features:
  - Primary cardiac involvement is a major discriminator for Emery-Dreifuss disease, whereas cardiac review in Bethlem focuses on secondary consequences of hypoventilation.
  evidence:
  - reference: PMID:21691338
    reference_title: 'The collagen VI-related myopathies: muscle meets its matrix.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The presence of cardiac involvement clearly favors the presence of an Emery–Dreifuss muscular dystrophy,
      as primary cardiac involvement is not seen in the collagen VI-related myopathies.
    explanation: >-
      Clinical differential diagnosis in the COL6 review.
    quote_role: REVIEW_SYNTHESIS
- name: Recessive calpainopathy
  description: >-
    The recessive CAPN3-related limb-girdle muscular dystrophy can resemble Bethlem disease through limb-girdle
    weakness and contractures. The source discusses calpainopathy more broadly; this term specifically represents
    its recessive form.
  distinguishing_features:
  - Periscapular and biceps atrophy may suggest calpainopathy; muscle MRI patterns can overlap, so molecular diagnosis is needed.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1503/?report=reader
    reference_title: Collagen VI-Related Dystrophies - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Of note, similar muscle imaging patterns may be seen in other conditions, including ... calpainopathy
    explanation: >-
      Imaging differential caveat.
    quote_role: REVIEW_SYNTHESIS
  disease_term:
    preferred_term: autosomal recessive limb-girdle muscular dystrophy type 2A
    term:
      id: MONDO:0009675
      label: autosomal recessive limb-girdle muscular dystrophy type 2A
- name: COL12A1-related myopathy
  disease_term:
    preferred_term: Bethlem myopathy 2
    term:
      id: MONDO:0034022
      label: Bethlem myopathy 2
  description: >-
    A genetically distinct myopathy/connective-tissue disorder can share hypotonia, laxity and contractures.
  distinguishing_features:
  - COL12A1-related disease lies outside the COL6A1/COL6A2/COL6A3 Bethlem definition and is distinguished molecularly. Its overlapping connective-tissue features should not be treated as evidence for a COL6 variant.
  evidence:
  - reference: PMID:40309777
    reference_title: Collagen type VI regulates TGF-β bioavailability in skeletal muscle in mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Mild and non-progressive muscle weakness is common in genetic connective tissue diseases — for example,
      Marfan’s syndrome due to FBN1 pathogenic variants (4), osteogenesis imperfecta due to COL1A1 pathogenic
      variants (5), and Ehlers-Danlos/myopathy overlap due to COL12A1 pathogenic variants (6).
    explanation: >-
      Background clinical distinction in the mechanistic study introduction.
    quote_role: BACKGROUND
- name: Ullrich congenital muscular dystrophy
  disease_term:
    preferred_term: Ullrich congenital muscular dystrophy
    term:
      id: MONDO:0000355
      label: Ullrich congenital muscular dystrophy
  description: >-
    An allelic COL6-related dystrophy with overlapping matrix disease.
  distinguishing_features:
  - More severe congenital weakness, earlier loss of walking and earlier ventilatory dependence distinguish UCMD; intermediate phenotypes lie between UCMD and adult-ambulant Bethlem disease.
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      UCMD is characterized by congenital weakness, hypotonia, proximal joint contractures, and striking hyperlaxity
      of distal joints.
    explanation: >-
      GeneReviews clinical distinction.
    quote_role: REVIEW_SYNTHESIS
experimental_models:
- name: COL6A1 exon-14-skipping patient fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Skin fibroblasts from the patient carrying the studied COL6A1 splice-donor allele
  description: >-
    Mutant chains entered monomers but not dimers/tetramers, and mutant-containing molecules were not secreted.
    Normal collagen VI production was approximately halved. The engineered alpha3-chain deletion also studied
    in SaOS-2 cells was a separate construct, not this patient allele.
  modeled_mechanisms:
  - target: Defective intracellular collagen VI assembly
    relationship: RECAPITULATES
    model_scale: CELLULAR
    limitations: >-
      One structurally characterized splice allele; consequences need not match all dominant COL6 variants.
    evidence:
    - reference: PMID:10419498
      reference_title: Bethlem myopathy and engineered collagen VI triple helical deletions prevent intracellular multimer assembly and protein secretion.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        The mutant alpha1(VI) chains associated intracellularly with alpha2(VI) and alpha3(VI) to form disulfide-bonded
        monomers, but further assembly into dimers and tetramers was prevented, and molecules containing the
        mutant chain were not secreted.
      explanation: >-
        Direct assembly/secretion study of one patient exon-14-skipping allele, not a universal mechanism for
        all COL6 variants.
  - target: Impaired collagen VI secretion
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: >-
      Secretion was measured for one patient splice allele; the result does not establish secretion failure
      for all dominant COL6 variants.
    evidence:
    - reference: PMID:10419498
      reference_title: Bethlem myopathy and engineered collagen VI triple helical deletions prevent intracellular multimer assembly and protein secretion.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        The mutant alpha1(VI) chains associated intracellularly with alpha2(VI) and alpha3(VI) to form disulfide-bonded
        monomers, but further assembly into dimers and tetramers was prevented, and molecules containing the
        mutant chain were not secreted.
      explanation: >-
        Direct assembly/secretion study of one patient exon-14-skipping allele, not a universal mechanism for
        all COL6 variants.
  evidence:
  - reference: PMID:10419498
    reference_title: Bethlem myopathy and engineered collagen VI triple helical deletions prevent intracellular multimer assembly and protein secretion.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      The mutant alpha1(VI) chains associated intracellularly with alpha2(VI) and alpha3(VI) to form disulfide-bonded
      monomers, but further assembly into dimers and tetramers was prevented, and molecules containing the
      mutant chain were not secreted.
    explanation: >-
      Direct assembly/secretion study of one patient exon-14-skipping allele, not a universal mechanism for
      all COL6 variants.
- name: Recessive COL6A2 patient fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Proband skin fibroblasts and single-variant relatives from the 2025 family
  description: >-
    Ascorbate-treated proband cells retained collagen VI intracellularly without the secreted network seen
    in the mother and unaffected brother. Segregation and the paired-variant cell phenotype support the family
    interpretation; each initially uncertain missense variant was not tested in isolation.
  modeled_mechanisms:
  - target: Impaired collagen VI secretion
    relationship: RECAPITULATES
    model_scale: CELLULAR
    limitations: >-
      One compound-heterozygous family; no isolated-allele functional dissection.
    evidence:
    - reference: PMID:40550965
      reference_title: 'Autosomal recessive Bethlem myopathy: a 30-year journey.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        The proband’s cells (III:2) presented the absence of secreted protein and collagen VI network; collagen
        staining was observable only in the cell’s cytoplasm as in NT well (63X).
      explanation: >-
        Patient fibroblast phenotype in a recessive COL6A2 family; individual variant effects were not isolated.
  evidence:
  - reference: PMID:40550965
    reference_title: 'Autosomal recessive Bethlem myopathy: a 30-year journey.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      The proband’s cells (III:2) presented the absence of secreted protein and collagen VI network; collagen
      staining was observable only in the cell’s cytoplasm as in NT well (63X).
    explanation: >-
      Patient fibroblast phenotype in a recessive COL6A2 family; individual variant effects were not isolated.
- name: Col6a2-null fibroblast TGF-beta reporter system
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Mouse skeletal-muscle fibroblasts; HEK293 reporter cells
  description: >-
    Conditioned medium from null mouse fibroblasts increased SMAD-responsive luciferase activity in the reporter.
    This measures extracellular bioactive ligand and does not prove that total ligand synthesis rises, that
    every candidate protein binds directly, or that TGF-beta inhibition benefits patients.
  modeled_mechanisms:
  - target: Dysregulated extracellular TGF-beta bioavailability
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: >-
      Mouse fibroblast-conditioned medium was tested in a human HEK293 SMAD reporter; this assay does not measure
      TGF-beta activity in patient muscle or establish benefit from inhibiting it.
    evidence:
    - reference: PMID:40309777
      reference_title: Collagen type VI regulates TGF-β bioavailability in skeletal muscle in mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        These experiments showed a marked increase in TGF-β activity in Col6a2–/–-derived conditioned medium
        compared with controls (Figure 6C).
      explanation: >-
        Mouse muscle-fibroblast conditioned medium measured with a human HEK293 luciferase reporter.
  evidence:
  - reference: PMID:40309777
    reference_title: Collagen type VI regulates TGF-β bioavailability in skeletal muscle in mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      These experiments showed a marked increase in TGF-β activity in Col6a2–/–-derived conditioned medium
      compared with controls (Figure 6C).
    explanation: >-
      Mouse muscle-fibroblast conditioned medium measured with a human HEK293 luciferase reporter.
animal_models:
- name: Col6a1-null mouse
  species: Mus musculus
  genotype: Col6a1 homozygous knockout
  description: >-
    This mild myopathic model supports mitochondrial, apoptotic and autophagy mechanisms, but a complete chain
    null differs from most dominant Bethlem alleles. Its skin is mechanically weaker with altered wound ultrastructure,
    yet pathological keloid-like scarring and overt wound-healing disturbance were not reproduced.
  modeled_mechanisms:
  - target: Myofibre mitochondrial dysfunction and permeability transition pore dysregulation
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: >-
      Complete Col6a1 loss differs from most dominant structural Bethlem alleles; rescue of this mouse phenotype
      does not establish treatment efficacy in patients.
    evidence:
    - reference: PMID:14625552
      reference_title: Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Here we show that Col6a1-/- muscles have a loss of contractile strength associated with ultrastructural
        alterations of sarcoplasmic reticulum (SR) and mitochondria and spontaneous apoptosis.
      explanation: >-
        Primary knockout-mouse muscle findings.
  - target: Defective autophagic clearance of damaged organelles
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: >-
      Complete Col6a1 loss differs from most dominant structural Bethlem alleles; rescue of this mouse phenotype
      does not establish treatment efficacy in patients.
    evidence:
    - reference: PMID:21037586
      reference_title: Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Skeletal muscles of collagen VI-knockout (Col6a1(-/-)) mice had impaired autophagic flux, which matched the lower induction of beclin-1 and BCL-2/adenovirus E1B-interacting protein-3 (Bnip3) and the lack of autophagosomes after starvation."
      explanation: Demonstrates the autophagy machinery defect in collagen VI-deficient muscle.
  - target: Dermal extracellular matrix dysfunction
    relationship: PARTIALLY_RECAPITULATES
    model_scale: TISSUE
    limitations: >-
      Complete Col6a1 loss differs from dominant structural alleles. Mechanical skin weakness and altered ultrastructure
      occurred without reproducing pathological human scarring.
    evidence:
    - reference: PMID:25158062
      reference_title: 'Col6a1 null mice as a model to study skin phenotypes in patients with collagen VI related myopathies: expression of classical and novel collagen VI variants during wound healing.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Interestingly, we detected a decreased tensile strength of the skin and an altered collagen fibril
        and basement membrane architecture in Col6a1 null mice, the latter being features that are also found
        in collagen VI myopathy patients.
      explanation: >-
        Direct mechanical and morphological mouse skin findings.
  - target: Abnormal cutaneous scarring
    relationship: FAILS_TO_RECAPITULATE
    model_scale: TISSUE
    limitations: >-
      The reported mouse wounds did not develop the pathological scarring characteristic of some patients.
    evidence:
    - reference: PMID:25158062
      reference_title: 'Col6a1 null mice as a model to study skin phenotypes in patients with collagen VI related myopathies: expression of classical and novel collagen VI variants during wound healing.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        However, in contrast to the hypertrophic scars or keloids occurring in patients with a collagen VI
        myopathies, we did not observe such disturbed wound healing in the Col6a1 null mice.
      explanation: >-
        Explicit model failure to reproduce pathological human scarring.
  evidence:
  - reference: PMID:14625552
    reference_title: Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Here we show that Col6a1-/- muscles have a loss of contractile strength associated with ultrastructural
      alterations of sarcoplasmic reticulum (SR) and mitochondria and spontaneous apoptosis.
    explanation: >-
      Primary knockout-mouse muscle findings.
  - reference: PMID:25158062
    reference_title: 'Col6a1 null mice as a model to study skin phenotypes in patients with collagen VI related myopathies: expression of classical and novel collagen VI variants during wound healing.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Interestingly, we detected a decreased tensile strength of the skin and an altered collagen fibril and
      basement membrane architecture in Col6a1 null mice, the latter being features that are also found in
      collagen VI myopathy patients.
    explanation: >-
      Direct mechanical and morphological mouse skin findings.
  - reference: PMID:25158062
    reference_title: 'Col6a1 null mice as a model to study skin phenotypes in patients with collagen VI related myopathies: expression of classical and novel collagen VI variants during wound healing.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      However, in contrast to the hypertrophic scars or keloids occurring in patients with a collagen VI myopathies,
      we did not observe such disturbed wound healing in the Col6a1 null mice.
    explanation: >-
      Explicit model failure to reproduce pathological human scarring.
- name: Col6a1-null cyclophilin-D-deficient mouse
  species: Mus musculus
  genotype: Col6a1 knockout with Ppif/Cyp-D ablation
  description: >-
    Removing cyclophilin D genetically rescues mitochondrial, ultrastructural and apoptotic abnormalities in
    the null model, supporting a permeability-transition mechanism. It does not establish long-term clinical
    efficacy or immunosuppressant safety in Bethlem disease.
  modeled_mechanisms:
  - target: Myofibre mitochondrial dysfunction and permeability transition pore dysregulation
    relationship: PERTURBS
    model_scale: CELLULAR
    limitations: >-
      Lifelong genetic loss of cyclophilin D in a complete Col6a1-null background does not establish the efficacy
      or safety of pharmacological inhibition in human Bethlem myopathy.
    evidence:
    - reference: PMID:19293339
      reference_title: Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        In the absence of Cyp-D, Col6a1(-/-) mice show negligible myofiber degeneration, rescue from mitochondrial
        dysfunction and ultrastructural defects, and normalized incidence of apoptosis.
      explanation: >-
        Genetic rescue in double-mutant mice; not a patient therapy trial.
  - target: Myofibre apoptosis
    relationship: PERTURBS
    model_scale: CELLULAR
    limitations: >-
      Lifelong genetic loss of cyclophilin D in a complete Col6a1-null background does not establish the efficacy
      or safety of pharmacological inhibition in human Bethlem myopathy.
    evidence:
    - reference: PMID:19293339
      reference_title: Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        In the absence of Cyp-D, Col6a1(-/-) mice show negligible myofiber degeneration, rescue from mitochondrial
        dysfunction and ultrastructural defects, and normalized incidence of apoptosis.
      explanation: >-
        Genetic rescue in double-mutant mice; not a patient therapy trial.
  evidence:
  - reference: PMID:19293339
    reference_title: Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      In the absence of Cyp-D, Col6a1(-/-) mice show negligible myofiber degeneration, rescue from mitochondrial
      dysfunction and ultrastructural defects, and normalized incidence of apoptosis.
    explanation: >-
      Genetic rescue in double-mutant mice; not a patient therapy trial.
- name: Bethlem-like col6a1 exon-13 morphant zebrafish
  species: Danio rerio
  genotype: Morpholino-induced in-frame col6a1 exon 13 skipping
  description: >-
    Transient exon-13 skipping, analogous to human COL6A1 exon 14, caused mild delayed motor and myotendinous/organellar
    abnormalities. The more severe exon-9 model was used for cyclosporin testing; its partial motor rescue
    cannot be claimed as a result in the mild arm. Morpholino embryos do not establish adult progression.
  modeled_mechanisms:
  - target: Progressive myofibre degeneration
    relationship: PARTIALLY_RECAPITULATES
    model_scale: TISSUE
    limitations: >-
      Transient developmental structural and motor phenotype, not adult longitudinal disease.
    evidence:
    - reference: PMID:20338942
      reference_title: Zebrafish models of collagen VI-related myopathies.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        In all, the functional, morphologic and structural changes caused by col6a1 morpholinos are consistent
        with a mild, Bethlem-like phenotype (exon 13 morpholino) and with a severe, UCMD-like phenotype (exon
        9 morpholino).
      explanation: >-
        Distinct transient zebrafish models; exon 13 is the Bethlem-like arm.
  evidence:
  - reference: PMID:20338942
    reference_title: Zebrafish models of collagen VI-related myopathies.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      In all, the functional, morphologic and structural changes caused by col6a1 morpholinos are consistent
      with a mild, Bethlem-like phenotype (exon 13 morpholino) and with a severe, UCMD-like phenotype (exon
      9 morpholino).
    explanation: >-
      Distinct transient zebrafish models; exon 13 is the Bethlem-like arm.
  - reference: PMID:20338942
    reference_title: Zebrafish models of collagen VI-related myopathies.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Because we were most interested in generating and studying a model of UCMD, for the remaining analysis
      we focused on the exon 9 morphant embryos.
    explanation: >-
      Bounds the subsequent drug experiments to the severe model.
- name: Col6a2-null mouse
  species: Mus musculus
  genotype: Col6a2 homozygous deletion; Ltbp4 p.Cys1260Ser cross used for intervention
  description: >-
    The model develops weakness before overt fibrosis and abnormal matrix mechanics, with increased resting
    but disturbed post-injury TGF-beta activity. Disease was milder than human COL6 dystrophy and did not clearly
    progress through 60 weeks. An Ltbp4 binding-defective cross did not rescue strength, histology or physiology;
    no clinical treatment effect follows from this pathway finding.
  modeled_mechanisms:
  - target: Dysregulated extracellular TGF-beta bioavailability
    relationship: PARTIALLY_RECAPITULATES
    model_scale: TISSUE
    limitations: >-
      The mouse disease was mild and did not clearly progress through 60 weeks; weakness preceded overt fibrosis.
      The Ltbp4 intervention failed to rescue disease, so pathway involvement alone does not validate a treatment
      target.
    evidence:
    - reference: PMID:40309777
      reference_title: Collagen type VI regulates TGF-β bioavailability in skeletal muscle in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Together, these findings suggest that absence of collagen VI from the muscle ECM increases active TGF-β
        without an increase in total TGF-β transcription or translation.
      explanation: >-
        Col6a2-null mouse tissue and fibroblast assays; altered activation rather than increased overall production.
  - target: Endomysial fibrosis
    relationship: PARTIALLY_RECAPITULATES
    model_scale: TISSUE
    limitations: >-
      The mouse disease was mild and did not clearly progress through 60 weeks; weakness preceded overt fibrosis.
      The Ltbp4 intervention failed to rescue disease, so pathway involvement alone does not validate a treatment
      target.
    evidence:
    - reference: PMID:40309777
      reference_title: Collagen type VI regulates TGF-β bioavailability in skeletal muscle in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        We found a marked increase in endomysial fibrillar collagen content based on the Sirius red staining
        and hydroxyproline content of gastrocnemius muscle of 25-week-old or older Col6a2–/– mice (Figure 4,
        A and B, and Supplemental Figure 4).
      explanation: >-
        Direct tissue evidence of endomysial fibrosis in older Col6a2-null mice; weakness was already present
        before overt fibrosis.
  evidence:
  - reference: PMID:40309777
    reference_title: Collagen type VI regulates TGF-β bioavailability in skeletal muscle in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Together, these findings suggest that absence of collagen VI from the muscle ECM increases active TGF-β
      without an increase in total TGF-β transcription or translation.
    explanation: >-
      Col6a2-null mouse tissue and fibroblast assays; altered activation rather than increased overall production.
  - reference: PMID:40309777
    reference_title: Collagen type VI regulates TGF-β bioavailability in skeletal muscle in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Crossing the Col6a2–/– mice with the Ltbp4c/s mice failed to improve muscle strength, histology, or physiological
      parameters (Figure 8).
    explanation: >-
      Negative genetic intervention prevents treating pathway association as validated therapeutic rescue.
  - reference: PMID:40309777
    reference_title: Collagen type VI regulates TGF-β bioavailability in skeletal muscle in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      We found a marked increase in endomysial fibrillar collagen content based on the Sirius red staining
      and hydroxyproline content of gastrocnemius muscle of 25-week-old or older Col6a2–/– mice (Figure 4,
      A and B, and Supplemental Figure 4).
    explanation: >-
      Direct tissue evidence of endomysial fibrosis in older Col6a2-null mice; weakness was already present
      before overt fibrosis.

📚

References & Deep Research

References

PMID:20301676

Collagen VI-Related Dystrophies.

1 finding

GeneReviews defines Bethlem muscular dystrophy as the mild end of the collagen VI-related dystrophy continuum, characterized by proximal muscle weakness plus contractures of the elbows, Achilles tendons, and long finger flexors, with inconsistent respiratory involvement, and provides the management and surveillance recommendations used in this entry.

"Bethlem muscular dystrophy is characterized by a combination of proximal muscle weakness and joint contractures."

PMID:8782832

Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures.

1 finding

The original gene-identification study linked Bethlem myopathy to the COL6A1-COL6A2 cluster and COL6A3, and identified Gly-X-Y disrupting substitutions in the triple-helical domain.

"Both mutations disrupt the Gly-X-Y motif of the triple helical domain by substitution of Gly for either Val or Ser."

PMID:10219778

Bethlem myopathy: a slowly progressive congenital muscular dystrophy with contractures.

1 finding

The seven-kindred natural-history study documents early presentation in the studied children and later wheelchair use, which does not necessarily imply complete loss of indoor ambulation.

"Due to slow but ongoing progression, more than two-thirds of patients over 50 years of age use a wheelchair."

PMID:15689448

Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy.

1 finding

In 2005, coding-exon sequencing identified putative COL6 variants in 62% of 79 selected UCMD/Bethlem patients. This historical yield is not the sensitivity of contemporary diagnostic testing.

"We found putative mutations in one of the COL6 genes in 62% of patients."

PMID:21691338

The collagen VI-related myopathies: muscle meets its matrix.

1 finding

The definitive review covers collagen VI assembly, the non-cell-autonomous interstitial fibroblast origin of muscle collagen VI, the Bethlem contracture and skin phenotype, muscle imaging, prevalence, and the genotype-phenotype gradient across the COL6-RD spectrum.

"In northern England, the prevalence of Ullrich CMD is 0.13 cases per 100,000 of the population, and that of Bethlem myopathy is 0.77 cases per 100,000."

PMID:14625552

Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency.

1 finding

The Col6a1-null mouse, whose muscle phenotype resembles Bethlem myopathy, revealed latent mitochondrial dysfunction, permeability transition pore dysregulation, and spontaneous myofibre apoptosis reversible by collagen VI replating or cyclosporin A.

"We previously generated collagen VI-deficient (Col6a1-/-) mice and showed that they have a muscle phenotype that strongly resembles Bethlem myopathy."

PMID:19293339

Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice.

1 finding

Cyclophilin-D ablation rescued mitochondrial and apoptotic abnormalities in Col6a1-null mice, supporting an experimental target without establishing human clinical efficacy.

"In the absence of Cyp-D, Col6a1(-/-) mice show negligible myofiber degeneration, rescue from mitochondrial dysfunction and ultrastructural defects, and normalized incidence of apoptosis."

PMID:21037586

Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration.

1 finding

Defective autophagy underlies the persistence of abnormal organelles and apoptosis in collagen VI-deficient muscle, and reduced beclin-1 and Bnip3 are demonstrable in Bethlem myopathy patient muscle.

"Furthermore, muscle biopsies from subjects with Bethlem myopathy or Ullrich congenital muscular dystrophy had reduced protein amounts of beclin-1 and Bnip3."

PMID:18362356

Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies.

1 finding

An open pilot trial in five patients showed that oral cyclosporin A normalized mitochondrial dysfunction and apoptosis in muscle biopsies, providing human proof of mechanism for permeability transition pore modulation.

"Both of these pathologic signs were largely normalized after 1 month of oral cyclosporin A administration, which also increased muscle regeneration."

PMID:24339618

Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis.

1 finding

A clinically diagnosed Indian family had contractures, keloids and follicular hyperkeratosis. The father had normal CK and collagen VI immunostaining; sons had raised CK. Molecular testing was not performed.

"All had flexion contractures, keloids, and follicular hyperkeratosis without muscle hypertrophy."

PMID:25158062

Col6a1 null mice as a model to study skin phenotypes in patients with collagen VI related myopathies: expression of classical and novel collagen VI variants during wound healing.

1 finding

Col6a1-null mice have mechanically weaker skin and altered wound ultrastructure, but no overt wound-healing delay or recreation of human keloids.

"However, in contrast to the hypertrophic scars or keloids occurring in patients with a collagen VI myopathies, we did not observe such disturbed wound healing in the Col6a1 null mice."

PMID:37569848

New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.

1 finding

A 69-patient single-center collagen VI cohort including 33 Bethlem myopathy patients quantifies residual strength, and shows that collagen VI immunofluorescence correlates with severity but increases with age within an individual.

"In our BM group, only one third had a knee extension strength greater than 50% of the predicted value, while only one in ten showed similar retention of elbow flexion."

PMID:36982625

Extracellular Matrix Disorganization and Sarcolemmal Alterations in COL6-Related Myopathy Patients with New Variants of COL6 Genes.

1 finding

A mixed COL6-phenotype biopsy series reports extracellular and sarcolemmal abnormalities. Several variants remain uncertain or were predicted benign in the study tables; morphology does not independently establish pathogenicity for each variant.

"they documented the high variability in COL6 distribution and the extracellular matrix disorganization"

clinicaltrials:NCT01438788

Low Protein Diet to Correct Defective Autophagy in Patients With Collagen VI Related Myopathies

1 finding

A phase II open-label pilot tested a normocaloric low-protein diet in eight adults with Bethlem myopathy or Ullrich congenital muscular dystrophy to reactivate autophagy, with muscle beclin-1 as the primary endpoint.

"The primary end point of the study will be the change in muscle biopsy of Beclin 1, a marker of autophagy, at 1 year of LPD treatment when compared to baseline."

PMID:21078917

Consensus statement on standard of care for congenital muscular dystrophies.

1 finding

Standard-of-care consensus supports physical therapy directed at maintaining function and preventing or treating joint contractures and spine deformity.

"Physical therapy should be focused on the maintenance of function and mobility, prevention or treatment of joint contractures and spine deformities"

PMID:10419498

Bethlem myopathy and engineered collagen VI triple helical deletions prevent intracellular multimer assembly and protein secretion.

No top-level findings curated for this source.

PMID:20338942

Zebrafish models of collagen VI-related myopathies.

No top-level findings curated for this source.

PMID:25535305

Bethlem myopathy: long-term follow-up identifies COL6 mutations predicting severe clinical evolution.

No top-level findings curated for this source.

PMID:27656840

Autophagy activation in COL6 myopathic patients by a low-protein-diet pilot trial.

No top-level findings curated for this source.

PMID:30706156

Bethlem myopathy: a series of 16 patients and description of seven new associated mutations.

No top-level findings curated for this source.

PMID:31026058

Moderate-intensity aerobic exercise improves physical fitness in bethlem myopathy.

No top-level findings curated for this source.

PMID:31471117

Autosomal recessive Bethlem myopathy: A clinical, genetic and functional study.

No top-level findings curated for this source.

PMID:40309777

Collagen type VI regulates TGF-β bioavailability in skeletal muscle in mice.

No top-level findings curated for this source.

PMID:40550965

Autosomal recessive Bethlem myopathy: a 30-year journey.

No top-level findings curated for this source.

clinicaltrials:NCT01403402

Congenital Muscle Disease Patient and Proxy Reported Outcome Study

No top-level findings curated for this source.

clinicaltrials:NCT01836627

Congenital Muscular Dystrophy (CMD) and the Feasibility of Hyperinsufflation Therapy to Slow Rate of Decline in Lung Volume

No top-level findings curated for this source.

clinicaltrials:NCT01895283

The Effect of a Bike Ergometer Training Program in Patients With Bethlem Myopathy

No top-level findings curated for this source.

clinicaltrials:NCT03693898

MR in Patients With Neuromuscular Diseases

No top-level findings curated for this source.

clinicaltrials:NCT04020159

Global Registry for COL6-related Dystrophies

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1503/?report=reader

Collagen VI-Related Dystrophies - GeneReviews® - NCBI Bookshelf

No top-level findings curated for this source.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Bethlem_Myopathy · 2026-08-01T00:20:42Z · View source

Created kb/disorders/Bethlem_Myopathy.yaml as a greenfield entry for MONDO:0008029, the mild end of the collagen VI-related dystrophy spectrum COL6A1/COL6A2/COL6A3, curated to be mechanistically consistent with the existing Ullrich_Congenital_Muscular_Dystrophy entry. A Named Entity Confusion preflight against the MONDO record - causal genes COL6A1/2/3, OMIMPS:158810, Orphanet:610, synonyms BTHLM1 and benign autosomal dominant myopathy - confirmed identity before any deep-research content was used. Deep research was run with falcon, the Edison Scientific provider, via just research-disorder falcon Bethlem_Myopathy, taking 608 seconds and returning 29 citations plus one artifact; the report converged on the same disease identity with no drift into Ullrich CMD or limb-girdle dystrophy, and was treated strictly as leads rather than ground truth. The GeneReviews chapter Collagen VI-Related Dystrophies, PMID:20301676, was fetched and tagged as the phenotype baseline, and every Clinical Characteristics item in its abstract is represented in the entry. Content: an 11-node single-connected-component pathograph running from COL6 alpha-chain gene defects through defective microfibril assembly and secretion, endomysial network deficiency, impaired matrix-to-sarcolemma anchoring, mitochondrial permeability transition pore dysregulation, defective autophagy, and myofibre apoptosis to degeneration and fibrosis, with parallel tendon and dermal connective-tissue arms and a restrictive respiratory arm; 24 phenotypes; three gene-defined MONDO subtypes; both inheritance modes; prevalence; three progression phases; biochemical, histopathology, and diagnosis sections; seven treatments including cyclosporin A and autophagy reactivation wired via target_mechanisms; one clinical trial NCT01438788; and two discussions, one HUMAN_MODEL_MISMATCH on Col6a1-null mouse fidelity to dominant-negative human disease and one KNOWLEDGE_GAP on the unidentified collagen VI basement-membrane binding partner. Module conformance was declared to disabled_macroautophagy#Failure of Cytoplasmic Quality Control; the aging-framed mitochondrial_dysfunction and fibrotic_response modules were considered and deliberately not declared. Validation: just validate passed covering schema plus ontology term validation, just validate-references verified 122 of 122 snippets as exact substrings of cached references, scripts/check_folded_hyphens.py reported no new folded-scalar hyphen splits, just validate-graphs was clean for this file, and pathograph connectivity was confirmed programmatically with 11 of 11 nodes in one component, no dangling targets, and no orphan phenotypes. Not verified: no ORPHA:610 structured cache record could be generated because just refresh-orphadata fails a checksum against the pinned data/orphadata/MANIFEST.yaml, so no ORPHA-sourced evidence is asserted; this limitation is recorded in the entry notes.

Falcon ▸

Bethlem Myopathy: Disease Characteristics Research Report

Edison Scientific Literature 29 citations 2026-07-31T17:06:25.282642

Bethlem Myopathy: Disease Characteristics Research Report

Scope and evidence basis. This report treats Bethlem myopathy (BM) as the mild end of the collagen-VI-related dystrophy (COL6-RD) spectrum. Evidence is primarily aggregated disease-level literature, specialist cohorts, family studies, experimental models, and ClinicalTrials.gov records—not routine EHR-derived data. Exact HPO/GO/CL/UBERON accessions should be validated against the current ontology release before database import; names below are suggested mappings.

Executive summary

Bethlem myopathy is a rare, chronic Mendelian muscle/connective-tissue disorder caused by pathogenic variants in COL6A1, COL6A2, or COL6A3. It is usually autosomal dominant but can be recessive. The characteristic combination is slowly progressive axial/proximal weakness, early distal laxity followed by contractures—particularly long finger flexors, elbows, ankles, knees, and neck—and variably abnormal skin. Ambulation is generally retained into adulthood, although meaningful weakness, wheelchair use, and restrictive respiratory disease occur in a subset. Cardiac involvement is not a usual primary feature. Open Targets recognizes all three genes as associated with MONDO:0008029 (OpenTargets Search: Bethlem myopathy-COL6A1,COL6A2,COL6A3).

No approved disease-modifying treatment exists. Current practice is multidisciplinary supportive management, especially contracture prevention, mobility preservation, respiratory surveillance, and noninvasive ventilation when indicated. Experimental approaches target defective autophagy/mitophagy, mitochondrial permeability-transition-pore dysfunction, abnormal extracellular-matrix signaling, or the causal allele.

Domain	High-value entry	Suggested ontology/identifier	Evidence/notes
Disease definition	Bethlem myopathy; mild end of the collagen VI-related dystrophy/myopathy spectrum with slowly progressive muscle weakness and contractures	MONDO:0008029; OMIM:158810; suggested disease family: collagen VI-related dystrophy	Human disease-level resources and cohorts support BM as a COL6-related disorder with axial/proximal weakness, contractures, distal laxity, and possible respiratory involvement (merlini2023newclinicaland pages 1-2, bonnemann2011thecollagenvirelateda pages 1-2, zanotti2023extracellularmatrixdisorganization pages 1-2)
Synonyms	Bethlem myopathy (BM); Bethlem muscular dystrophy; collagen VI-related myopathy, Bethlem phenotype	Suggested text synonyms only	BM is used consistently in clinical and mechanistic literature; nomenclature often placed within COL6-RM/COL6-RD spectrum (merlini2023newclinicaland pages 1-2, zanotti2023extracellularmatrixdisorganization pages 1-2)
Disease evidence granularity	Aggregated disease-level knowledge plus individual-patient and cohort evidence	Suggested evidence model: disease-level + human cohort + case-level	Current understanding comes from aggregated reviews plus single-center cohorts and family reports, not EHR-derived population studies (merlini2023newclinicaland pages 14-15, bonnemann2011thecollagenvirelateda pages 1-2)
Causal genes	COL6A1, COL6A2, COL6A3	HGNC gene symbols; Open Targets disease-target support for Bethlem myopathy	Strong gene-disease association across multiple evidence sources; collagen VI microfibril defects are causal (OpenTargets Search: Bethlem myopathy-COL6A1,COL6A2,COL6A3, merlini2023newclinicaland pages 1-2, zanotti2023extracellularmatrixdisorganization pages 1-2)
Inheritance	Usually autosomal dominant; recessive forms also reported in collagen VI-related myopathy spectrum including Bethlem presentations	Suggested HPO inheritance terms: Autosomal dominant inheritance; Autosomal recessive inheritance	Foundational review describes classic AD BM; more recent genetic literature and cohorts show both dominant and recessive mechanisms in COL6 disease spectrum (bonnemann2011thecollagenvirelateda pages 1-2, zanotti2023extracellularmatrixdisorganization pages 1-2)
Representative pathogenic variant classes	Missense (including glycine substitutions in triple-helical domain), splice-site/intronic, exon-skipping, small deletions, CNVs, dominant-negative assembly-competent variants, biallelic loss-of-function alleles	Suggested sequence ontology names only: missense_variant, splice_donor_variant, intron_variant, inframe_deletion, copy_number_variant	Standard sequencing may miss intronic/CNV events; fibroblast/RNA studies help resolve splicing and secretion defects (bonnemann2011thecollagenvirelateda pages 14-15, zanotti2023extracellularmatrixdisorganization pages 1-2)
Molecular defect	Defective collagen VI assembly/secretion and extracellular microfibril network organization	Suggested GO/CC: extracellular matrix; collagen-containing extracellular matrix	Collagen VI chains assemble into monomers, dimers, tetramers, then extracellular microfibrils; mutations disrupt matrix organization and cell-matrix integrity (castagnaro2018extracellularcollagenvi pages 10-14, zanotti2023extracellularmatrixdisorganization pages 1-2, mohassel2023collagentypevi pages 1-6)
Hallmark phenotype	Axial and proximal muscle weakness	Suggested HPO: proximal muscle weakness; axial muscle weakness	Core phenotype across reviews and cohorts; BM patients remain ambulant into adulthood by definition in one 2023 cohort (merlini2023newclinicaland pages 1-2)
Hallmark phenotype	Finger flexor/interphalangeal contractures	Suggested HPO: flexion contracture of finger; camptodactyly-like term if locally used	Long finger flexor contractures are a classic clue and help distinguish from some differentials (bonnemann2011thecollagenvirelateda pages 6-7, bonnemann2011thecollagenvirelateda pages 12-14)
Hallmark phenotype	Elbow, knee, ankle, neck contractures; rigid spine in some patients	Suggested HPO: elbow contracture; knee flexion contracture; ankle contracture; neck flexion contracture; rigid spine	Contractures are often progressive and may outweigh weakness in some phenotypic variants (merlini2023newclinicaland pages 1-2, bonnemann2011thecollagenvirelateda pages 6-7, zanotti2023extracellularmatrixdisorganization pages 1-2)
Hallmark phenotype	Distal joint laxity / hyperlaxity, especially earlier in life	Suggested HPO: distal joint hypermobility	Early laxity transitioning to later contractures is part of classic natural history (bonnemann2011thecollagenvirelateda pages 1-2, bonnemann2011thecollagenvirelateda pages 6-7)
Hallmark phenotype	Skin changes	Suggested HPO terms by use-case: abnormal skin morphology; keloid tendency; follicular hyperkeratosis	Skin involvement is recognized in collagen VI disorders and can aid differential diagnosis (merlini2023newclinicaland pages 1-2, bonnemann2011thecollagenvirelateda pages 12-14)
Respiratory phenotype	Restrictive respiratory involvement; risk of nocturnal hypoventilation/respiratory insufficiency	Suggested HPO: restrictive ventilatory defect; respiratory insufficiency; sleep hypoventilation	In 2023 cohort, 45% of BM had FVC <70% predicted; restrictive pattern reported in 2023 variant cohort; monitoring is recommended (merlini2023newclinicaland pages 14-15, zanotti2023extracellularmatrixdisorganization pages 2-3, bonnemann2011thecollagenvirelateda pages 6-7)
Cardiac phenotype	Cardiac involvement uncommon/rare	Suggested HPO: cardiomyopathy only when present	Cardiac function was normal in all patients of one 2023 COL6 cohort; historical review notes only rare coincidental findings (zanotti2023extracellularmatrixdisorganization pages 2-3, bonnemann2011thecollagenvirelateda pages 6-7)
Onset / course	Prenatal-to-adult onset; often childhood or adolescence; slowly progressive; weakness may be stable/improve in puberty then worsen later	Suggested HPO onset/course labels: congenital onset; childhood onset; adult onset; progressive	Reviews and 2023 cohorts support broad onset window and slow progression; some older adults require walking aids (merlini2023newclinicaland pages 1-2, bonnemann2011thecollagenvirelateda pages 6-7)
Epidemiology	Rare disease; prevalence estimate 0.77 per 100,000 reported from Newcastle dataset	Suggested epidemiology note only	Widely cited historical prevalence estimate; contemporary global prevalence/incidence remain uncertain (bonnemann2011thecollagenvirelateda pages 1-2)
Functional statistics	In 33 BM patients, only one-third had knee extension strength >50% predicted; only one-tenth had elbow flexion >50% predicted	Suggested measurement terms only	Useful contemporary quantitative severity anchors from 2023 single-center cohort (merlini2023newclinicaland pages 1-2)
Mobility prognosis	Ambulation usually preserved into adulthood, but wheelchair use can occur	Suggested HPO: impaired ambulation; wheelchair dependence	2023 cohort reported 15% of BM patients used wheelchairs, higher than historic pre-gene-discovery series (merlini2023newclinicaland pages 14-15)
Primary anatomy affected	Skeletal muscle, especially limb-girdle/axial musculature	Suggested UBERON: skeletal muscle tissue; limb muscle; trunk muscle	BM is primarily a musculoskeletal/connective tissue disorder affecting muscle function and surrounding ECM (merlini2023newclinicaland pages 1-2, castagnaro2018extracellularcollagenvi pages 10-14)
Secondary anatomy affected	Tendons, joint capsules, fascia, diaphragm, skin	Suggested UBERON names only: tendon, joint capsule, muscle fascia, diaphragm, skin	Contractures and restrictive pulmonary disease implicate periarticular connective tissue and diaphragm/chest wall mechanics (bonnemann2011thecollagenvirelateda pages 6-7, bonnemann2011thecollagenvirelateda pages 12-14)
Relevant cell types	Muscle fibroblasts / fibroadipogenic precursor-like stromal cells; skeletal myofibers; satellite cells	Suggested CL names only: fibroblast, skeletal muscle fiber cell, satellite cell	Collagen VI is produced largely by fibroblastic interstitial cells rather than myofibers; disease is partly non-cell-autonomous and affects satellite-cell reserve (mohassel2023collagentypevi pages 38-41, mohassel2023collagentypevi pages 1-6)
Subcellular/localization	Endoplasmic reticulum (assembly), sarcolemma-ECM interface, mitochondria, autophagosome/lysosome system	Suggested GO cellular component names only	Pathophysiology spans collagen assembly, ECM anchorage, mitochondrial pore dysregulation, and autophagy/mitophagy defects (castagnaro2018extracellularcollagenvi pages 10-14, bernardi2013mitochondrialdysfunctionand pages 1-2)
Core mechanism	ECM disorganization and impaired collagen VI microfibril network compromise mechanical stability and signaling	Suggested GO: extracellular matrix organization; cell-matrix adhesion	Supported by 2023 pathology study showing ECM disorganization and sarcolemmal alterations (zanotti2023extracellularmatrixdisorganization pages 1-2, zanotti2023extracellularmatrixdisorganization pages 2-3)
Core mechanism	Mitochondrial permeability transition pore dysregulation with latent mitochondrial dysfunction and apoptosis	Suggested GO: regulation of mitochondrial membrane permeability; intrinsic apoptotic signaling pathway	Major established disease mechanism from mouse and human studies; targetable by cyclophilin/PTP inhibition (bernardi2013mitochondrialdysfunctionand pages 1-2, merlini2023newclinicaland pages 1-2)
Core mechanism	Defective autophagy/mitophagy with accumulation of dysfunctional organelles	Suggested GO: autophagy; mitophagy; macroautophagy	A central conserved mechanism across Col6-null mice and patient tissue/fibroblasts (castagnaro2018extracellularcollagenvi pages 10-14, bernardi2013mitochondrialdysfunctionand pages 1-2)
Core mechanism	AKT-mTOR pathway activation associated with impaired autophagic flux	Suggested GO/pathway names only: AKT signaling; mTOR signaling	Demonstrated in Col6a1-null fibroblasts as part of autophagy dysregulation (castagnaro2018extracellularcollagenvi pages 10-14)
Core mechanism	Reduced satellite-cell self-renewal / regeneration defects	Suggested GO: skeletal muscle satellite cell activation; muscle regeneration	Relevant downstream mechanism in collagen VI deficiency models (mohassel2023collagentypevi pages 6-10, mohassel2023collagentypevi pages 38-41)
Emerging mechanism (2023)	Altered TGF-beta bioavailability in collagen VI-deficient skeletal muscle ECM	Suggested GO/pathway name only: transforming growth factor beta signaling pathway	2023 preprint proposes early TGF-beta dysregulation as an upstream matrix-signaling defect; emerging, not yet fully settled (mohassel2023collagentypevi pages 6-10, mohassel2023collagentypevi pages 1-6)
Molecular profiling	Deep RNA profiling identified CLOCK/molecular clock signatures in collagen VI myopathy	Suggested pathway/process names only: circadian rhythm; transcriptional dysregulation	Evidence is from broader collagen VI myopathy work rather than BM-only cohorts (castagnaro2018extracellularcollagenvi pages 10-14)
Serum/lab testing	CK often normal to mildly elevated, though higher values can occur in congenital/severe cases	Suggested lab descriptor only	2023 series reported CK 2-10× in many, normal in some, and a markedly elevated congenital case (zanotti2023extracellularmatrixdisorganization pages 2-3)
Electrophysiology	EMG typically supportive of myopathy rather than diagnostic	Suggested test term only: electromyography	Specific quantitative EMG data were not well captured in retrieved evidence; use as supportive test, not defining biomarker (bonnemann2011thecollagenvirelateda pages 12-14)
Imaging	Muscle MRI pattern with perifascial fatty/connective-tissue replacement, notably rectus femoris and vastus lateralis; ultrasound 'central cloud' sign in rectus femoris	Suggested RadLex/ontology names only: muscle MRI; muscle ultrasonography	Pattern-recognition imaging supports diagnosis and differential diagnosis (bonnemann2011thecollagenvirelateda pages 12-14)
Biopsy/pathology	Variable dystrophic/myopathic changes; fiber size variability/disproportion, internal nuclei, interstitial fibrosis, relatively scarce necrosis	Suggested pathology terms only	2023 pathology cohort confirmed ECM disorganization and variable collagen VI distribution (zanotti2023extracellularmatrixdisorganization pages 1-2, zanotti2023extracellularmatrixdisorganization pages 2-3)
Protein studies	Collagen VI immunofluorescence/immunohistochemistry on muscle biopsy or fibroblasts	Suggested assay term only	Can correlate with severity, but may be near-normal in milder BM; serial biopsies may show age-related increase in expression (merlini2023newclinicaland pages 1-2, bonnemann2011thecollagenvirelateda pages 12-14)
Cellular diagnostics	Dermal fibroblast culture with collagen VI secretion/deposition analysis; RT-PCR for splicing defects	Suggested assay terms only	Especially useful when genomic sequencing is negative or variant interpretation is uncertain (bonnemann2011thecollagenvirelateda pages 14-15)
Molecular testing strategy	First-line NGS panel or exome-based testing of COL6A1/COL6A2/COL6A3; add RNA studies and CNV analysis when needed	Suggested testing stack only: gene panel, WES, RNA analysis, MLPA/SNP array/CGH	Standard sequencing misses some intronic and copy-number defects; deep intronic COL6A2 mutation detected by custom CGH with RNA confirmation (bonnemann2011thecollagenvirelateda pages 14-15)
Differential diagnosis	Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophies, other congenital muscular dystrophies/connective-tissue myopathies	Suggested MONDO/HPO names only	Finger flexor contractures plus skin features and characteristic imaging favor collagen VI disease (bonnemann2011thecollagenvirelateda pages 12-14)
Surveillance	Regular respiratory function testing, sleep studies when indicated, orthopedic/contracture/scoliosis monitoring, strength and mobility assessment	Suggested clinical care concepts only	Restrictive respiratory disease may emerge despite relatively mild limb weakness; contractures are progressive (bonnemann2011thecollagenvirelateda pages 6-7, bonnemann2011thecollagenvirelateda pages 14-15)
Supportive management	Stretching, physiotherapy, dynamic splinting, orthotics, mobility aids	Suggested NCIT-style terms: Physical Therapy; Splinting; Orthotic Device Use	Mainstay care is supportive and multidisciplinary; progression rarely fully stops (bonnemann2011thecollagenvirelateda pages 14-15)
Orthopedic interventions	Achilles tendon release/selective contracture surgery; scoliosis bracing/surgery in selected cases	Suggested NCIT-style terms: Tendon Release Surgery; Orthopedic Surgical Procedure; Spinal Bracing	Surgery may preserve ambulation in some BM patients but recurrence of contracture is common (bonnemann2011thecollagenvirelateda pages 14-15)
Respiratory management	Noninvasive ventilation when needed; pulmonary monitoring	Suggested NCIT-style terms: Noninvasive Ventilation; Pulmonary Function Test	Respiratory compromise is less severe than UCMD on average but clinically important in a substantial subset (merlini2023newclinicaland pages 14-15, bonnemann2011thecollagenvirelateda pages 6-7)
Pharmacologic/targeted management status	No approved disease-modifying therapy specific for BM	Suggested status label only	Reviews and 2023 papers still state no effective curative therapy is available; translational options are under study (merlini2023newclinicaland pages 1-2, castagnaro2018extracellularcollagenvi pages 10-14)
Experimental therapy	Cyclosporin A / cyclophilin inhibition to normalize mitochondrial dysfunction and apoptosis	Suggested NCIT-style terms: Cyclosporine; Mitochondrial Permeability Transition Pore Inhibition	Supported by human proof-of-concept and animal studies, but not established standard-of-care disease modification (merlini2023newclinicaland pages 1-2, bernardi2013mitochondrialdysfunctionand pages 1-2)
Experimental therapy	Low-protein diet to activate autophagy	Suggested NCIT-style terms: Dietary Intervention; Low Protein Diet	Phase II pilot enrolled 8 adults with collagen VI-related myopathies; aimed to increase Beclin 1/autophagy markers (NCT01438788 chunk 1)
Experimental therapy	Pterostilbene/autophagy induction; splice correction; CRISPR allele-specific editing	Suggested NCIT-style terms: Nutraceutical Therapy; Splice-Switching Therapy; CRISPR-Cas Gene Editing	Preclinical/experimental only; 2024 fibroblast CRISPR study restored extracellular collagen VI network in UCMD cells, conceptually relevant across dominant COL6 disease (castagnaro2018extracellularcollagenvi pages 10-14)
Prevention / genetic counseling	Cascade testing, reproductive counseling, prenatal diagnosis possible once familial variant/mechanism known	Suggested concepts only: genetic counseling; prenatal testing; family screening	Especially important given frequent dominant inheritance and intrafamilial variability (bonnemann2011thecollagenvirelateda pages 14-15, bonnemann2011thecollagenvirelateda pages 1-2)
Trial / registry	NCT01438788 – Low Protein Diet in Patients With Collagen VI Related Myopathies; Phase II; completed; enrollment 8	ClinicalTrials.gov: NCT01438788	Open-label pilot of normocaloric low-protein diet (0.6-0.8 g/kg/day) to reactivate autophagy (NCT01438788 chunk 1)
Trial / imaging	NCT03693898 – MR in Patients With Collagen VI Related Myopathies; recruiting/interventional diagnostic; enrollment 20	ClinicalTrials.gov: NCT03693898	MRI Dixon fat fraction plus strength testing in confirmed Bethlem/Ulrich disease (NCT03693898 chunk 1)
Trial / registry	NCT04020159 – Global Registry for COL6-related Dystrophies; observational prospective registry; target enrollment 1000	ClinicalTrials.gov: NCT04020159	Annual questionnaire-based global registry collecting genetics, motor/respiratory function, QoL, pain, imaging and hospitalization data; useful for trial readiness (NCT04020159 chunk 1)
Other relevant study	NCT01403402 – Congenital Muscle Disease Study of Patient and Family Reported Medical Information	ClinicalTrials.gov: NCT01403402	Broader congenital muscle disease registry relevant for patient-reported natural history, though not BM-specific in retrieved evidence (OpenTargets Search: Bethlem myopathy-COL6A1,COL6A2,COL6A3)
Model organism	Col6a1-null mouse	Suggested model name only	Recapitulates mild myopathic phenotype, mitochondrial dysfunction, apoptosis, defective autophagy; useful for therapy testing but milder than severe human disease (castagnaro2018extracellularcollagenvi pages 10-14, bernardi2013mitochondrialdysfunctionand pages 1-2)
Model organism	Col6a2-null mouse (2023 characterization)	Suggested model name only	Shows early postnatal atrophy/weakness, mild dystrophic changes, impaired regeneration, sarcolemmal fragility, and emerging TGF-beta dysregulation (mohassel2023collagentypevi pages 6-10, mohassel2023collagentypevi pages 1-6)
Model organism	Zebrafish col6a1 exon-targeted morphants	Suggested model name only	Exon 13 perturbation produced a milder BM-like phenotype; CsA improved motor deficits in severe UCMD-like model (telfer2010zebrafishmodelsof pages 1-2)
Cellular model	Patient dermal fibroblasts / myoblasts	Suggested model name only	Widely used for diagnostic secretion/deposition assays and mechanistic studies of autophagy and mitochondrial defects (castagnaro2018extracellularcollagenvi pages 10-14, bonnemann2011thecollagenvirelateda pages 14-15)
Gene-editing model	CRISPR-corrected patient fibroblasts restoring collagen VI microfilament network	Suggested model/intervention name only	2024 proof-of-principle in dominant COL6A1 UCMD fibroblasts supports translational feasibility of allele-targeted editing for COL6 disorders (castagnaro2018extracellularcollagenvi pages 10-14)
Knowledge gaps	Contemporary population prevalence, penetrance estimates, formal QoL datasets, and validated prognostic biomarkers remain limited for BM specifically	Suggested curation flag only	Evidence base remains dominated by specialist cohorts and mixed-spectrum COL6 studies rather than large prospective BM-only studies (merlini2023newclinicaland pages 14-15, NCT04020159 chunk 1)

Table: This compact table summarizes the most actionable Bethlem myopathy knowledge-base elements across identifiers, genes, phenotypes, mechanisms, diagnosis, management, trials, and models. It is designed for rapid curation and highlights where exact ontology IDs are suggested versus where only ontology names are appropriate.

1. Disease information

Definition and nomenclature

BM is a relatively mild, slowly progressive collagen-VI-related myopathy characterized by axial and proximal weakness, contractures, distal joint laxity, and skin manifestations. Onset can range from prenatal life to adulthood; retention of walking into adult life is often used as an operational distinction from intermediate and Ullrich phenotypes (merlini2023newclinicaland pages 1-2).

Identifiers and synonyms

MONDO: MONDO:0008029.
OMIM/MIM: 158810.
Orphanet: Bethlem myopathy is represented within Orphanet’s collagen-VI-related disease nomenclature; the exact current ORPHA accession should be verified before ingestion.
MeSH: generally indexed through Muscular Diseases, Muscular Dystrophies, and collagen type VI rather than a consistently used BM-specific descriptor.
ICD-10: no specific BM code; commonly mapped to congenital/hereditary myopathy or muscular-dystrophy categories according to local coding rules.
ICD-11: map under congenital myopathy/muscular dystrophy; a dedicated universally implemented BM code was not established in the retrieved evidence.
Synonyms: Bethlem myopathy, Bethlem muscular dystrophy, collagen VI-related myopathy—Bethlem phenotype, mild collagen VI-related dystrophy.

BM was described in 1976 as an autosomal-dominant early-onset “benign” myopathy with contractures; causal collagen-VI variants were identified during 1996–1998. “Benign” is now discouraged because respiratory and functional morbidity may be substantial (bonnemann2011thecollagenvirelateda pages 1-2).

2. Etiology, risk, and protective factors

Causal factors

The primary cause is a germline pathogenic variant in COL6A1, COL6A2, or COL6A3, genes encoding the α1(VI), α2(VI), and α3(VI) chains of collagen VI. Pathogenic mechanisms include monoallelic assembly-competent variants producing dominant-negative microfibrils and biallelic loss-of-function, splice, or structural variants that reduce or abolish collagen production. Both dominant and recessive molecular defects are established across the spectrum (OpenTargets Search: Bethlem myopathy-COL6A1,COL6A2,COL6A3, zanotti2023extracellularmatrixdisorganization pages 1-2, mohassel2023collagentypevi pages 1-6).

Genetic risk factors

Risk is determined principally by inheriting or acquiring a pathogenic COL6 allele. Relevant variant classes include glycine substitutions in the triple-helical region, missense variants, exon-skipping splice variants, nonsense/frameshift alleles, in-frame deletions, deep-intronic variants, and copy-number changes. Dominant-negative variants near the amino-terminal portion of the triple helix can interfere with assembly; biallelic null alleles generally reduce chain availability. Examples described in the literature include dominant COL6A1 p.Lys121Arg and COL6A2 p.Asp630Asn, although any individual variant requires contemporary ACMG/AMP and ClinVar review (bonnemann2011thecollagenvirelateda pages 6-7).

Variant frequencies are usually extremely low or absent in population databases because BM is rare and pathogenic alleles are family-specific. No single population allele frequency should be generalized. Variant-level gnomAD frequency, ClinVar assertions, segregation, RNA effect, and collagen secretion/deposition should be curated separately.

Environmental, lifestyle, infectious, and protective factors

There is no evidence that toxin, infection, smoking, alcohol, diet, occupation, radiation, sex, or another environmental exposure causes BM. Activity, nutrition, respiratory infection, surgery, immobilization, and weight may alter functional burden or complications but do not create the disease. No validated genetic protective allele, modifier gene, diet, medication, or exposure prevents penetrance. Apparent gene–environment effects are therefore best framed as modification of functional reserve, not causation. Avoiding prolonged immobility, maintaining safe activity, and prompt respiratory care are tertiary prevention measures, not primary protection.

3. Phenotypes

Musculoskeletal manifestations

Axial and proximal weakness: usually mild-to-moderate early, chronic and slowly progressive; pelvic-girdle, shoulder-girdle, neck, and trunk muscles are prominent. Suggested HPO: Proximal muscle weakness, Axial muscle weakness, Muscular hypotonia when present.
Contractures: long finger flexors/interphalangeal joints are particularly characteristic; elbows, Achilles tendons/ankles, knees, hips, neck, and spine may be involved. Suggested HPO: Flexion contracture of finger, Elbow flexion contracture, Knee flexion contracture, Achilles tendon contracture, Rigid spine (merlini2023newclinicaland pages 1-2, bonnemann2011thecollagenvirelateda pages 6-7).
Distal hyperlaxity: often more evident in childhood and may transition to contracture with age. Suggested HPO: Distal joint hypermobility (bonnemann2011thecollagenvirelateda pages 1-2).
Motor delay, difficulty running/climbing stairs/rising, and reduced endurance: variable; walking is usually achieved and retained into adulthood.
Scoliosis/kyphosis and rigid spine: less severe than in classic Ullrich disease but clinically relevant in some patients.
Myopathic facies/ptosis: occasional rather than defining. In one mixed 15-patient COL6 cohort, rigid spine occurred in four and myopathic face with ptosis in three (zanotti2023extracellularmatrixdisorganization pages 2-3).

Contemporary quantitative evidence shows that “mild” does not mean trivial. In a 2023 cohort of 33 BM patients, only one-third retained knee-extension strength above 50% predicted and only one-tenth retained elbow-flexion strength above 50%. Forty-five percent had FVC below 70% predicted, and 15% used wheelchairs (merlini2023newclinicaland pages 14-15, merlini2023newclinicaland pages 1-2).

Respiratory manifestations

Restrictive impairment results from respiratory-muscle/diaphragmatic weakness and chest-wall stiffness. Nocturnal hypoventilation, sleep-disordered breathing, ineffective cough, and eventual respiratory insufficiency can occur, although ventilator dependence is much less common than in Ullrich disease. Suggested HPO: Restrictive ventilatory defect, Respiratory insufficiency, Sleep hypoventilation. A 2023 mixed COL6 cohort found restrictive respiratory involvement in 6/15 patients, including two severe cases; one had obstructive sleep apnea (zanotti2023extracellularmatrixdisorganization pages 2-3). Historical expert analysis recommends pulmonary function and sleep monitoring even when limb weakness appears mild (bonnemann2011thecollagenvirelateda pages 6-7).

Skin and connective-tissue manifestations

Follicular hyperkeratosis, abnormal scarring/keloids, soft or velvety skin, and other subtle connective-tissue changes may occur. Skin findings support a COL6 diagnosis and help distinguish it from Emery–Dreifuss muscular dystrophy. Suggested HPO: Follicular hyperkeratosis, Keloids, Abnormality of skin morphology (bonnemann2011thecollagenvirelateda pages 12-14).

Laboratory and cardiac findings

Creatine kinase is often normal or mildly elevated. In a 2023 mixed cohort it was normal in three patients and commonly 2–10× elevated, with an exceptional 60× congenital case; such marked elevation should prompt careful differential diagnosis (zanotti2023extracellularmatrixdisorganization pages 2-3). EMG is usually myopathic and nonspecific. Cardiac disease is not considered a typical direct manifestation: cardiac testing was normal throughout that 2023 cohort, and historical reviews describe only rare possibly coincidental abnormalities (zanotti2023extracellularmatrixdisorganization pages 2-3, bonnemann2011thecollagenvirelateda pages 6-7).

Quality of life

Contractures impair hand use, dressing, transfers, gait, and self-care; weakness and fatigue restrict schooling, employment, recreation, and community participation; respiratory support and orthopedic procedures increase care burden. BM-specific EQ-5D, SF-36, or PROMIS datasets remain sparse. The global registry collects pain, hospitalization, mobility, respiratory, medication, imaging, and quality-of-life data, but mature published BM-specific estimates were unavailable (NCT04020159 chunk 1).

4. Genetic and molecular information

Genes and chromosomes

COL6A1 and COL6A2: chromosome 21; encode α1(VI) and α2(VI).
COL6A3: chromosome 2; encodes α3(VI).

COL6A1/A2/A3 form the canonical heterotrimer. Although COL6A4–COL6A6 encode additional collagen-VI-like chains, they are not established primary BM genes. Open Targets reports disease associations only for COL6A1/A2/A3 in BM (OpenTargets Search: Bethlem myopathy-COL6A1,COL6A2,COL6A3).

Variant interpretation

Variants must be classified individually under ACMG/AMP criteria. Important evidence includes rarity, affected-domain location, segregation, de novo status, RNA splicing, collagen-VI secretion/deposition, and microfibril morphology. Germline origin is expected; BM is not a somatic neoplasm. Germline or parental mosaicism is possible and should be considered when an apparently de novo dominant variant recurs, although its frequency is unknown.

Standard sequencing historically detected only approximately 60–65% of clinically diagnosed BM, partly because deep-intronic and copy-number variants were missed. A deep-intronic COL6A2 deletion was detected by custom CGH and shown by RNA analysis to cause monoallelic transcription, illustrating the need for complementary assays (DOI 10.1186/1471-2350-11-44).

Modifiers, epigenetics, and chromosomal abnormalities

Marked intrafamilial variability suggests genetic, developmental, and environmental modifiers, but no modifier gene is clinically validated. There is no established BM-specific epigenetic signature used diagnostically. Large deletions/CNVs involving COL6 loci can be causal, but recurrent aneuploidy, translocation, or inversion is not characteristic. Conventional karyotyping and FISH are therefore low-yield unless another chromosomal disorder is suspected.

5. Environmental information

BM has no infectious agent, zoonotic trigger, toxicant, or occupational cause. Lifestyle does not determine occurrence. Exercise should be individualized: moderate, non-eccentric aerobic activity may support conditioning, whereas overwork, pain-provoking eccentric loading, falls, and prolonged immobilization should be avoided. Vaccination against respiratory pathogens follows standard neuromuscular respiratory-risk practice but does not prevent BM itself.

6. Mechanism and pathophysiology

Upstream causal chain

A pathogenic COL6A1/A2/A3 allele alters chain quantity or structure.
In the endoplasmic reticulum, α1/α2/α3 chains normally assemble into approximately 500-kDa monomers, then disulfide-linked dimers and tetramers; secreted tetramers form extracellular beaded microfibrils.
Mutant or absent chains impair secretion, microfibril assembly, or interaction with collagens I/II, fibronectin, glycosaminoglycans, and proteoglycans.
The muscle interstitial/basement-membrane matrix becomes disorganized and mechanically/signally abnormal.
Sarcolemmal stress, dysregulated calcium handling, mitochondrial permeability-transition-pore opening, reduced ATP production, and apoptosis injure myofibers.
Defective autophagy/mitophagy fails to clear damaged mitochondria; impaired regeneration and fibrosis compound weakness and contractures (castagnaro2018extracellularcollagenvi pages 10-14, bernardi2013mitochondrialdysfunctionand pages 1-2, zanotti2023extracellularmatrixdisorganization pages 1-2).

A 2023 human pathology series directly documented heterogeneous collagen-VI distribution, extracellular-matrix disorganization, sarcolemmal alterations, internal nuclei, fiber-size variation, and interstitial fibrosis. Its abstract states that combined histological, immunological, and ultrastructural methods are “pivotal in the diagnosis of COL6 patients” (published March 2023; DOI 10.3390/ijms24065551) (zanotti2023extracellularmatrixdisorganization pages 2-3, zanotti2023extracellularmatrixdisorganization pages 1-2).

Cellular pathways

Mitochondria and apoptosis. Persistent mPTP opening promotes depolarization, swelling, impaired bioenergetics, and intrinsic apoptosis. Cyclosporin A/cyclophilin-D inhibition normalizes several defects in cells and models, supporting causality rather than mere association (telfer2010zebrafishmodelsof pages 1-2, bernardi2013mitochondrialdysfunctionand pages 1-2, merlini2023newclinicaland pages 1-2).

Autophagy/mitophagy. Reduced BECN1/Beclin-1 and BNIP3 signaling and abnormal AKT–mTOR activity diminish autophagic flux. Dysfunctional mitochondria accumulate, amplifying oxidative and apoptotic stress. Suggested GO: autophagy, mitophagy, regulation of mitochondrial membrane permeability, intrinsic apoptotic signaling (castagnaro2018extracellularcollagenvi pages 10-14).

Regeneration. Collagen VI supports satellite-cell self-renewal and regenerative niches. Deficiency reduces regenerative reserve and delays repair. Suggested cells: fibroblast/fibroadipogenic progenitor, skeletal myofiber, satellite cell; suggested GO: skeletal muscle tissue regeneration (mohassel2023collagentypevi pages 6-10, mohassel2023collagentypevi pages 38-41).

TGF-β signaling—emerging evidence. A June 2023 Col6a2-null mouse preprint proposed that collagen VI regulates TGF-β bioavailability and that matrix deficiency produces early TGF-β dysregulation. This is biologically coherent with fibrosis but remains less established than mitochondrial/autophagy mechanisms and should be annotated as preclinical/emerging (mohassel2023collagentypevi pages 6-10, mohassel2023collagentypevi pages 1-6).

Molecular profiling

Deep RNA profiling of patient and Col6a1-null muscle identified CLOCK and molecular-clock gene signatures (2016; DOI 10.1242/jcs.175927). These are research signatures, not validated biomarkers. Proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, and multi-omic BM-specific datasets remain limited. The principal reproducible biochemical abnormalities are defective collagen deposition, mitochondrial dysfunction, and altered autophagic markers.

7. Anatomical structures affected

The primary organ is skeletal muscle, especially axial, pelvic-girdle, shoulder-girdle, and proximal limb musculature; diaphragm and intercostal muscles may be affected secondarily. Tendons, fascia, joint capsules, skin, and muscle connective tissue contribute to contractures and tissue stiffness. Disease is typically bilateral and relatively symmetric, although severity between muscles varies.

Suggested mappings include UBERON: skeletal muscle tissue, diaphragm, tendon, muscle fascia, joint capsule, skin; CL: fibroblast, skeletal muscle fiber, skeletal muscle satellite cell, fibroadipogenic progenitor; GO cellular components: collagen-containing extracellular matrix, basement membrane, endoplasmic reticulum, mitochondrial inner membrane, autophagosome, lysosome.

8. Temporal development

Onset may be congenital, childhood, adolescent, or adult and is usually insidious. Congenital presentations can include hypotonia, torticollis, hip dislocation, clubfoot, or delayed milestones. Childhood may show distal laxity and modest weakness; contractures become progressively more prominent. Weakness may appear stable or improve around puberty, followed by slow deterioration from the third or fourth decade. Historical series suggest approximately two-thirds of patients older than 60 require some ambulation assistance (bonnemann2011thecollagenvirelateda pages 6-7).

BM is lifelong and generally progressive, not episodic or relapsing-remitting. There is no true spontaneous remission. Critical intervention windows include early maintenance of range of motion, timely correction of function-threatening contractures, and detection of nocturnal hypoventilation before daytime respiratory failure.

9. Inheritance and population

Classic BM is autosomal dominant, frequently with variable expressivity; recessive BM-like presentations are also established. Penetrance is high for many clearly pathogenic dominant variants but can be age-dependent and mild, so apparently unaffected adults need careful examination. Anticipation is not established. Consanguinity increases risk for biallelic disease but is irrelevant to most dominant families.

A Newcastle estimate placed prevalence at 0.77 per 100,000; modern incidence, carrier frequency, and population-specific prevalence are uncertain (bonnemann2011thecollagenvirelateda pages 1-2). There is no established sex bias or endemic geography. Founder variants may occur in individual populations, but most families have private variants. The 2024 report of a recessive COL6A2 splice variant in a consanguineous Saudi family illustrates population-specific ascertainment rather than proven increased regional prevalence.

10. Diagnostics

Clinical assessment

Suspect BM when chronic proximal/axial weakness coexists with long finger-flexor or Achilles contractures, early distal laxity, characteristic skin findings, preserved adult ambulation, and a dominant family history. Assess range of motion, MRC/quantitative strength, gait, transfers, six-minute walk where feasible, pulmonary function sitting and supine, cough strength, oximetry/capnography, and sleep symptoms.

Tests

CK: normal or mildly elevated in typical disease; marked elevation warrants broader evaluation.
EMG/NCS: myopathic EMG; nerve conduction usually normal.
Pulmonary: serial FVC, maximal inspiratory/expiratory pressures, peak cough flow, sleep oximetry/capnography or polysomnography.
Cardiac: baseline ECG/echocardiogram is reasonable, especially before anesthesia or if symptoms/family history exist, but routine progressive cardiomyopathy is not characteristic.
Muscle MRI: perifascial fatty/connective-tissue replacement, especially the rectus femoris “central shadow/central cloud” and peripheral vastus lateralis pattern. Ultrasound can show a rectus-femoris central cloud (bonnemann2011thecollagenvirelateda pages 12-14).
Biopsy: variable myopathic/dystrophic change, fiber-size disproportion, internal nuclei, fibrosis, and relatively limited necrosis. Collagen-VI immunostaining may be subtly abnormal or apparently normal in mild BM, so normal staining does not exclude disease (zanotti2023extracellularmatrixdisorganization pages 1-2, bonnemann2011thecollagenvirelateda pages 12-14).
Fibroblast assay: dermal fibroblasts can demonstrate abnormal collagen secretion/deposition; RT-PCR can reveal exon skipping or deep-intronic effects (bonnemann2011thecollagenvirelateda pages 14-15).

Genetic testing algorithm

Use a neuromuscular/congenital-myopathy panel including COL6A1, COL6A2, COL6A3, with robust CNV calling, or exome/genome sequencing.
Confirm and segregate candidate variants; determine de novo versus inherited status.
For VUS or negative sequencing with a strong phenotype, add fibroblast collagen studies and RNA sequencing/targeted RT-PCR.
Use MLPA, exon-level array/CGH, or genome sequencing for deletions, duplications, structural and deep-intronic variants.
WGS is particularly useful after nondiagnostic panel/WES because it interrogates intronic and structural variation. CMA, karyotype, FISH, mtDNA testing, and repeat-expansion testing are not routine unless the phenotype suggests another diagnosis (bonnemann2011thecollagenvirelateda pages 14-15).

Differential diagnosis

Key alternatives are Emery–Dreifuss muscular dystrophy/LMNA-related disease, LAMA2-related dystrophy, SEPN1/SELENON myopathy, RYR1-related congenital myopathy, LMNA congenital muscular dystrophy, other limb-girdle muscular dystrophies, Ehlers–Danlos/connective-tissue disorders, and myosclerosis myopathy. Long finger-flexor contractures, skin changes, collagen-VI MRI pattern, absence of significant primary cardiomyopathy, and COL6 molecular evidence favor BM (bonnemann2011thecollagenvirelateda pages 12-14).

Screening

There is no population or newborn screening program. Once a familial variant is known, cascade testing, targeted prenatal diagnosis, and preimplantation genetic testing are possible. Asymptomatic relatives require age-aware counseling because expression can be subtle.

11. Outcome and prognosis

Life expectancy is often near normal in mild BM if respiratory complications are recognized, but robust survival-rate or mortality estimates are unavailable. Most patients remain ambulant into adulthood; late walking aids or wheelchair use occur. In the 2023 cohort, wheelchair use was 15%, underscoring a broader severity range than historic pre-molecular series (merlini2023newclinicaland pages 14-15).

Major morbidity includes progressive weakness, hand and lower-limb contractures, falls, reduced endurance, scoliosis/rigid spine, pain, impaired self-care, and restrictive respiratory disease. Cardiac mortality is not typical. Prognostic factors include respiratory trajectory, severity and distribution of contractures, quantitative strength, mutation mechanism, and phenotype position within the COL6 continuum. No validated circulating prognostic biomarker exists. Collagen immunofluorescence correlates with phenotype at group level but is age-dependent and unsuitable as a stand-alone prognostic marker: serial biopsies showed increasing expression over time, an important consideration for genetic-correction trials (merlini2023newclinicaland pages 14-15, merlini2023newclinicaland pages 1-2).

12. Treatment and current applications

Standard supportive care

Physiotherapy and occupational therapy: daily gentle stretching, range-of-motion maintenance, posture, safe low-impact aerobic conditioning, energy conservation, and adaptive equipment. Suggested NCIT concepts: Physical Therapy, Occupational Therapy, Exercise Intervention.
Splints/orthoses: dynamic finger splints and ankle-foot orthoses where tolerated. Suggested NCIT: Splinting, Orthotic Device.
Orthopedic surgery: selected Achilles-tendon or other contracture release may preserve walking, but recurrence is common; scoliosis bracing is temporizing and surgery requires specialist respiratory/anesthetic planning (bonnemann2011thecollagenvirelateda pages 14-15).
Respiratory care: regular pulmonary/sleep surveillance, airway-clearance support, cough-assist when indicated, prompt infection treatment, and nocturnal noninvasive ventilation for hypoventilation. Suggested NCIT: Pulmonary Function Test, Noninvasive Ventilation.
Nutrition/pain/bone health: maintain healthy weight and adequate nutrition; treat pain and osteoporosis risk conventionally. Avoid unmonitored protein restriction.

Experimental pharmacologic and nutritional strategies

Cyclosporin A and non-immunosuppressive cyclophilin inhibitors. Human proof-of-concept and animal/cellular studies show correction of mitochondrial dysfunction and apoptosis, but immunosuppression and limited clinical efficacy evidence preclude routine disease-modifying use. NIM811 and related mPTP modulators remain preclinical (bernardi2013mitochondrialdysfunctionand pages 1-2, merlini2023newclinicaland pages 1-2).

Autophagy activation. A one-year pilot low-protein diet increased autophagic markers and was reported safe/tolerable in seven analyzed adults, with preserved body composition and function and reduced myofiber apoptosis. The abstract states: “These data provide evidence that a low-protein diet is able to activate autophagy and is safe and tolerable in patients with COL6 myopathies” (published November 2016; DOI 10.1080/15548627.2016.1231279). This was mechanistic proof-of-concept, not evidence for routine clinical efficacy. Pterostilbene improved pathology in Col6-deficient mice but remains preclinical.

Gene/RNA therapy. Allele-specific silencing, splice correction, and CRISPR disruption/correction are experimental. A November 2024 fibroblast study achieved 32% editing of a dominant mutant COL6A1 allele with negligible wild-type editing and restored collagen secretion and microfibril ultrastructure; it involved UCMD fibroblasts, so translation to BM and muscle in vivo remains unproven (DOI 10.3390/biom14111412).

There is no established pharmacogenomic dosing algorithm, approved gene therapy, cell therapy, ASO, or combination regimen for BM.

Clinical studies and real-world infrastructure

NCT01438788: completed Phase II, open-label low-protein-diet pilot; eight adults; 0.6–0.8 g protein/kg/day; Beclin-1/autophagy endpoint (NCT01438788 chunk 1). URL: https://clinicaltrials.gov/study/NCT01438788
NCT03693898: diagnostic MRI study, planned n=20 adults with BM/Ullrich disease; Dixon MRI fat fraction and strength testing (NCT03693898 chunk 1). URL: https://clinicaltrials.gov/study/NCT03693898
NCT04020159: prospective Global Registry for COL6-related Dystrophies, target n=1,000; annual genetics, motor, respiratory, contracture, pain, hospitalization, QoL, medication, and imaging data (NCT04020159 chunk 1). URL: https://clinicaltrials.gov/study/NCT04020159

Status labels should be rechecked live because registry records retrieved here had differing historical and aggregate status displays.

13. Prevention

Primary prevention through lifestyle or vaccination is impossible because BM is genetic. Secondary prevention consists of family recognition, cascade testing, early molecular diagnosis, and surveillance before irreversible contractures or respiratory failure. Tertiary prevention includes stretching/orthoses, fall prevention, bone health, respiratory vaccination, airway clearance, sleep assessment, and timely ventilation.

Genetic counseling should cover autosomal-dominant and recessive possibilities, variable expressivity, de novo and mosaic recurrence risk, and reproductive options. Targeted prenatal diagnosis and preimplantation genetic testing are possible once the familial pathogenic variant is established; older approaches included haplotype analysis and chorionic-villus collagen-VI staining (bonnemann2011thecollagenvirelateda pages 14-15).

14. Other species and natural disease

The causal genes are evolutionarily conserved across vertebrates. Relevant taxa include Mus musculus (NCBI Taxon 10090) and Danio rerio (7955). No well-established naturally occurring companion-animal or wildlife disease equivalent to human Bethlem myopathy was identified in the retrieved literature; veterinary breed ontology mapping is therefore not applicable. BM is not transmissible or zoonotic.

15. Model organisms and experimental systems

Mouse

Col6a1−/− mice lack collagen-VI assembly/secretion and show myopathy, abnormal mitochondria, spontaneous myofiber apoptosis, defective autophagy/mitophagy, and impaired regeneration. They are highly useful for mechanistic and drug studies but have a milder motor phenotype than severe human COL6 disease (castagnaro2018extracellularcollagenvi pages 10-14, bernardi2013mitochondrialdysfunctionand pages 1-2).

A Col6a2−/− model, characterized in 2023, showed early postnatal atrophy and weakness, fiber-size variability, central nuclei, delayed regeneration, sarcolemmal fragility, and altered TGF-β bioavailability. This supports matrix-signaling and non-cell-autonomous mechanisms; the work was initially reported as a preprint and requires appropriate evidence grading (mohassel2023collagentypevi pages 6-10, mohassel2023collagentypevi pages 1-6).

Zebrafish

Exon-specific col6a1 morphants produced severe UCMD-like disease when exon 9 was targeted and a milder BM-like phenotype with exon 13 targeting. Severe morphants had abnormal mitochondria and increased cell death; cyclosporin A improved motor function but not sarcolemmal membrane damage. The model is valuable for rapid in-vivo pharmacology but transient morpholino biology and developmental timing limit direct human extrapolation. The abstract reports that the authors generated “zebrafish models of the collagen VI myopathies” and that CsA “improved the motor deficits” in the severe model (published March 2010; DOI 10.1093/hmg/ddq126) (telfer2010zebrafishmodelsof pages 1-2).

Cellular systems

Patient dermal fibroblasts and myoblasts support collagen secretion/deposition assays, RNA studies, mitochondrial/autophagy phenotyping, and editing experiments. Col6a1-null mouse fibroblasts show impaired autophagosome clearance, defective Parkin-dependent mitophagy, AKT–mTOR activation, and increased apoptosis under nutrient stress; adhesion to purified collagen VI improves autophagic flux, demonstrating an extracellular instructive signal (castagnaro2018extracellularcollagenvi pages 10-14). Patient-derived iPSC, organoid, single-cell, and spatial models are promising but not yet mature enough for routine BM annotation.

Recent developments, expert interpretation, and evidence gaps

The strongest 2023 clinical advance was quantitative phenotyping in a 69-person COL6 cohort, including 33 BM patients. It demonstrated unexpectedly substantial strength and pulmonary deficits and age-dependent collagen-VI immunofluorescence, directly affecting endpoint and biopsy interpretation in future trials (merlini2023newclinicaland pages 14-15, merlini2023newclinicaland pages 1-2). A separate March 2023 human study identified three previously unreported variants among 14 pathogenic variants and emphasized integrating genetics with histology, immunology, and ultrastructure (zanotti2023extracellularmatrixdisorganization pages 2-3, zanotti2023extracellularmatrixdisorganization pages 1-2). Emerging 2023 work links collagen VI to TGF-β bioavailability, while 2024 CRISPR work provides allele-selective fibroblast rescue; both are translationally important but not clinical therapies.

Authoritative expert consensus is that BM should be managed as a multisystem neuromuscular/connective-tissue disorder, not dismissed as a benign contracture syndrome. Key unresolved issues are contemporary prevalence and incidence, variant-specific penetrance, validated BM-specific patient-reported outcomes, prospective respiratory trajectories, circulating biomarkers, and controlled disease-modifying trials. Most mechanistic data derive from mixed COL6 phenotypes or models; phenotype-specific extrapolation should therefore be labeled explicitly.

Selected primary/recent sources

Merlini L et al. New Clinical and Immunofluorescence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients. August 2023. DOI/URL: https://doi.org/10.3390/ijms241512474 (merlini2023newclinicaland pages 14-15, merlini2023newclinicaland pages 1-2)
Zanotti S et al. Extracellular Matrix Disorganization and Sarcolemmal Alterations in COL6-Related Myopathy Patients with New Variants of COL6 Genes. March 2023. DOI/URL: https://doi.org/10.3390/ijms24065551 (zanotti2023extracellularmatrixdisorganization pages 2-3, zanotti2023extracellularmatrixdisorganization pages 1-2)
Mohassel P et al. Collagen type VI regulates TGFβ bioavailability in skeletal muscle. June 2023 preprint. DOI/URL: https://doi.org/10.1101/2023.06.22.545964 (mohassel2023collagentypevi pages 6-10, mohassel2023collagentypevi pages 1-6)
Telfer WR et al. Zebrafish models of collagen VI-related myopathies. March 2010. DOI/URL: https://doi.org/10.1093/hmg/ddq126 (telfer2010zebrafishmodelsof pages 1-2)
Bernardi P, Bonaldo P. Mitochondrial dysfunction and defective autophagy in the pathogenesis of collagen VI muscular dystrophies. May 2013. DOI/URL: https://doi.org/10.1101/cshperspect.a011387 (bernardi2013mitochondrialdysfunctionand pages 1-2)

PMID note: PMID values were not consistently exposed in the retrieved full-text metadata. To avoid erroneous identifiers, DOI and direct registry URLs are supplied above; database curators should resolve PMIDs through Crossref/PubMed during ingestion.

References

(OpenTargets Search: Bethlem myopathy-COL6A1,COL6A2,COL6A3): Open Targets Query (Bethlem myopathy-COL6A1,COL6A2,COL6A3, 13 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(merlini2023newclinicaland pages 1-2): Luciano Merlini, Patrizia Sabatelli, Francesca Gualandi, Edoardo Redivo, Alberto Di Martino, and Cesare Faldini. New clinical and immunofluorescence data of collagen vi-related myopathy: a single center cohort of 69 patients. International Journal of Molecular Sciences, 24:12474, Aug 2023. URL: https://doi.org/10.3390/ijms241512474, doi:10.3390/ijms241512474. This article has 21 citations.
(bonnemann2011thecollagenvirelateda pages 1-2): Carsten G. Bönnemann. The collagen vi-related myopathies ullrich congenital muscular dystrophy and bethlem myopathy. Handbook of clinical neurology, 101:81-96, Jan 2011. URL: https://doi.org/10.1016/b978-0-08-045031-5.00005-0, doi:10.1016/b978-0-08-045031-5.00005-0. This article has 154 citations.
(zanotti2023extracellularmatrixdisorganization pages 1-2): Simona Zanotti, Francesca Magri, Sabrina Salani, Laura Napoli, Michela Ripolone, Dario Ronchi, Francesco Fortunato, Patrizia Ciscato, Daniele Velardo, Maria Grazia D’Angelo, Francesca Gualandi, Vincenzo Nigro, Monica Sciacco, Stefania Corti, Giacomo Pietro Comi, and Daniela Piga. Extracellular matrix disorganization and sarcolemmal alterations in col6-related myopathy patients with new variants of col6 genes. International Journal of Molecular Sciences, 24:5551, Mar 2023. URL: https://doi.org/10.3390/ijms24065551, doi:10.3390/ijms24065551. This article has 15 citations.
(merlini2023newclinicaland pages 14-15): Luciano Merlini, Patrizia Sabatelli, Francesca Gualandi, Edoardo Redivo, Alberto Di Martino, and Cesare Faldini. New clinical and immunofluorescence data of collagen vi-related myopathy: a single center cohort of 69 patients. International Journal of Molecular Sciences, 24:12474, Aug 2023. URL: https://doi.org/10.3390/ijms241512474, doi:10.3390/ijms241512474. This article has 21 citations.
(bonnemann2011thecollagenvirelateda pages 14-15): Carsten G. Bönnemann. The collagen vi-related myopathies ullrich congenital muscular dystrophy and bethlem myopathy. Handbook of clinical neurology, 101:81-96, Jan 2011. URL: https://doi.org/10.1016/b978-0-08-045031-5.00005-0, doi:10.1016/b978-0-08-045031-5.00005-0. This article has 154 citations.
(castagnaro2018extracellularcollagenvi pages 10-14): Silvia Castagnaro, Martina Chrisam, Matilde Cescon, Paola Braghetta, Paolo Grumati, and Paolo Bonaldo. Extracellular collagen vi has prosurvival and autophagy instructive properties in mouse fibroblasts. Frontiers in Physiology, Aug 2018. URL: https://doi.org/10.3389/fphys.2018.01129, doi:10.3389/fphys.2018.01129. This article has 53 citations.
(mohassel2023collagentypevi pages 1-6): Payam Mohassel, Jachinta Rooney, Yaqun Zou, Kory Johnson, Gina Norato, Hailey Hearn, Matthew A Nalls, Pomi Yun, Tracy Ogata, Sarah Silverstein, David A Sleboda, Thomas J Roberts, Daniel B Rifkin, and Carsten G Bönnemann. Collagen type vi regulates tgfβ bioavailability in skeletal muscle. bioRxiv, Jun 2023. URL: https://doi.org/10.1101/2023.06.22.545964, doi:10.1101/2023.06.22.545964. This article has 5 citations.
(bonnemann2011thecollagenvirelateda pages 6-7): Carsten G. Bönnemann. The collagen vi-related myopathies ullrich congenital muscular dystrophy and bethlem myopathy. Handbook of clinical neurology, 101:81-96, Jan 2011. URL: https://doi.org/10.1016/b978-0-08-045031-5.00005-0, doi:10.1016/b978-0-08-045031-5.00005-0. This article has 154 citations.
(bonnemann2011thecollagenvirelateda pages 12-14): Carsten G. Bönnemann. The collagen vi-related myopathies ullrich congenital muscular dystrophy and bethlem myopathy. Handbook of clinical neurology, 101:81-96, Jan 2011. URL: https://doi.org/10.1016/b978-0-08-045031-5.00005-0, doi:10.1016/b978-0-08-045031-5.00005-0. This article has 154 citations.
(zanotti2023extracellularmatrixdisorganization pages 2-3): Simona Zanotti, Francesca Magri, Sabrina Salani, Laura Napoli, Michela Ripolone, Dario Ronchi, Francesco Fortunato, Patrizia Ciscato, Daniele Velardo, Maria Grazia D’Angelo, Francesca Gualandi, Vincenzo Nigro, Monica Sciacco, Stefania Corti, Giacomo Pietro Comi, and Daniela Piga. Extracellular matrix disorganization and sarcolemmal alterations in col6-related myopathy patients with new variants of col6 genes. International Journal of Molecular Sciences, 24:5551, Mar 2023. URL: https://doi.org/10.3390/ijms24065551, doi:10.3390/ijms24065551. This article has 15 citations.
(mohassel2023collagentypevi pages 38-41): Payam Mohassel, Jachinta Rooney, Yaqun Zou, Kory Johnson, Gina Norato, Hailey Hearn, Matthew A Nalls, Pomi Yun, Tracy Ogata, Sarah Silverstein, David A Sleboda, Thomas J Roberts, Daniel B Rifkin, and Carsten G Bönnemann. Collagen type vi regulates tgfβ bioavailability in skeletal muscle. bioRxiv, Jun 2023. URL: https://doi.org/10.1101/2023.06.22.545964, doi:10.1101/2023.06.22.545964. This article has 5 citations.
(bernardi2013mitochondrialdysfunctionand pages 1-2): P. Bernardi and P. Bonaldo. Mitochondrial dysfunction and defective autophagy in the pathogenesis of collagen vi muscular dystrophies. Cold Spring Harbor perspectives in biology, 5 5:a011387, May 2013. URL: https://doi.org/10.1101/cshperspect.a011387, doi:10.1101/cshperspect.a011387. This article has 91 citations and is from a peer-reviewed journal.
(mohassel2023collagentypevi pages 6-10): Payam Mohassel, Jachinta Rooney, Yaqun Zou, Kory Johnson, Gina Norato, Hailey Hearn, Matthew A Nalls, Pomi Yun, Tracy Ogata, Sarah Silverstein, David A Sleboda, Thomas J Roberts, Daniel B Rifkin, and Carsten G Bönnemann. Collagen type vi regulates tgfβ bioavailability in skeletal muscle. bioRxiv, Jun 2023. URL: https://doi.org/10.1101/2023.06.22.545964, doi:10.1101/2023.06.22.545964. This article has 5 citations.
(NCT01438788 chunk 1): Low Protein Diet in Patients With Collagen VI Related Myopathies. Istituto Ortopedico Rizzoli. 2011. ClinicalTrials.gov Identifier: NCT01438788
(NCT03693898 chunk 1): Ruth Salim. MR in Patients With Collagen VI Related Myopathies. Ruth Salim. 2018. ClinicalTrials.gov Identifier: NCT03693898
(NCT04020159 chunk 1): Global Registry for COL6-related Dystrophies. Newcastle-upon-Tyne Hospitals NHS Trust. 2018. ClinicalTrials.gov Identifier: NCT04020159
(telfer2010zebrafishmodelsof pages 1-2): W. R. Telfer, A. Busta, Carsten G. Bönnemann, Eva L. Feldman, and James J. Dowling. Zebrafish models of collagen vi-related myopathies. Human Molecular Genetics, 19:2433-2444, Mar 2010. URL: https://doi.org/10.1093/hmg/ddq126, doi:10.1093/hmg/ddq126. This article has 127 citations and is from a domain leading peer-reviewed journal.

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Definitions

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Progression

Prevalence

Differential Diagnoses

Clinical Trials

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Bethlem Myopathy: Disease Characteristics Research Report

Executive summary

1. Disease information

Definition and nomenclature

2. Etiology, risk, and protective factors

Causal factors

Genetic risk factors

Environmental, lifestyle, infectious, and protective factors

3. Phenotypes

Musculoskeletal manifestations

Respiratory manifestations

Skin and connective-tissue manifestations

Laboratory and cardiac findings

Quality of life

4. Genetic and molecular information

Genes and chromosomes

Variant interpretation

Modifiers, epigenetics, and chromosomal abnormalities

5. Environmental information

6. Mechanism and pathophysiology

Upstream causal chain

Cellular pathways

Molecular profiling

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical assessment

Tests

Genetic testing algorithm

Differential diagnosis

Screening

11. Outcome and prognosis

12. Treatment and current applications

Standard supportive care

Experimental pharmacologic and nutritional strategies

Clinical studies and real-world infrastructure

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Mouse

Zebrafish

Cellular systems

Recent developments, expert interpretation, and evidence gaps

Selected primary/recent sources

Artifacts