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Definitions

1

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 Other

"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

2

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 Other

"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

Autosomal recessive Bethlem myopathy has also been reported, including the myosclerosis phenotype caused by a homozygous COL6A2 nonsense variant.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:20301676 SUPPORT Other

"although autosomal recessive inheritance has also been reported"

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

PMID:21691338 SUPPORT Other

"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"

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

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Subtypes

3

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

COL6A1 hgnc:2211

COL6A1-related Bethlem myopathy corresponding to OMIM:158810. In-frame skipping of COL6A1 exon 14 is the single most common Bethlem mutation type.

Show evidence (2 references)

PMID:8782832 SUPPORT Human Clinical

"Sequence analysis in four families reveals a mutation in COL6A1 in one"

Family sequencing identified a COL6A1 mutation in Bethlem myopathy.

PMID:21691338 SUPPORT Other

"exon-14-skipping mutations are the single most common mutation type seen in patients with Bethlem myopathy"

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

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

COL6A2 hgnc:2212

COL6A2-related Bethlem myopathy corresponding to OMIM:620725, including the recessive myosclerosis phenotype.

Show evidence (1 reference)

PMID:8782832 SUPPORT Human Clinical

"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

"whereas one family shows linkage to markers on chromosome 2q37 close to COL6A3"

Linkage evidence supports a COL6A3-related Bethlem myopathy subtype.

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Discussions and Knowledge Gaps

2

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

Nearly all of the mitochondrial permeability-transition and autophagy mechanism is derived from the Col6a1-null mouse, a complete-null model whose muscle phenotype is milder than the human disease. Most Bethlem myopathy is caused by dominant-negative variants in which collagen VI immunoreactivity is preserved but mislocalized away from the basement membrane, a molecularly different state from complete absence. Whether a mislocalized network produces the same degree of mitochondrial and autophagic failure as no network at all is not established, and it bears directly on how much of the cyclophilin D therapeutic rationale transfers to dominant Bethlem myopathy.

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 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:21691338 SUPPORT Other

"In patients with dominant mutations in particular, muscle immunohistochemistry will show a considerable amount of collagen VI immunoreactivity in the extracellular matrix, but the normal localization of collagen VI in the basement membrane is lost."

Establishes that dominant Bethlem muscle retains a mislocalized collagen VI network rather than lacking collagen VI, unlike the null mouse.

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 anchoring step is the mechanistic bridge between the extracellular collagen VI defect and the intracellular mitochondrial and apoptotic phenotype, yet the receptor or matrix partner that transmits the signal is unidentified. Collagen IV and an indirect biglycan to dystrophin-associated-protein-complex route have been proposed but not established. Without it, the causal chain from matrix to mitochondrion rests mainly on the reversibility of the defect when collagen VI-deficient myofibres are replated onto collagen VI.

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 (2 references)

PMID:21691338 SUPPORT 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 Other

"A crucial step will be to establish exactly how collagen VI deficiency in the extracellular matrix leaves muscle cells vulnerable to apoptosis"

The review names this as the crucial unresolved mechanistic step.

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Pathophysiology

11

Collagen VI alpha-chain gene defects

Germline pathogenic variants in COL6A1, COL6A2, or COL6A3 alter the collagen VI alpha chains. In Bethlem myopathy these are typically dominant-negative lesions: in-frame skipping of COL6A1 exon 14, or glycine substitutions that disrupt the Gly-X-Y repeat of the N-terminal triple-helical domain. Mutant chains are still competent to enter the monomer, so the defect is transmitted into the assembled protein rather than simply reducing dosage.

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

extracellular matrix structural constituent GO:0005201 ⚠ ABNORMAL

Downstream

Defective collagen VI microfibril assembly and secretion Mutant alpha chains are incorporated into collagen VI monomers and subvert the downstream dimer, tetramer, and microfibril assembly steps.

Show evidence (2 references)

PMID:15689448 SUPPORT Human Clinical

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

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.

Defective collagen VI microfibril assembly and secretion

Collagen VI is assembled intracellularly from one each of the alpha 1, alpha 2, and alpha 3 chains into a triple-helical monomer, then into antiparallel dimers and staggered tetramers, which are secreted and associate end to end into the characteristic beaded microfibrils. Because a mutant chain can be incorporated at the monomer step, only a minority of tetramers are normal, giving a strong dominant-negative effect. Milder lesions such as COL6A1 exon 14 skipping have a more limited dominant-negative effect and therefore shift the phenotype toward the Bethlem end of the spectrum.

protein secretion GO:0009306 ⚠ ABNORMAL

extracellular matrix GO:0031012

Downstream

Endomysial collagen VI microfibrillar network deficiency Failure of tetramer assembly and microfibril formation leaves a deficient or dysfunctional collagen VI network in the tissue matrix.

Show evidence (2 references)

PMID:21691338 SUPPORT Other

"These tetramers are secreted into the extracellular space, where they associate in an end-to-end fashion to form characteristic"

Describes the extracellular tetramer-to-microfibril assembly step that collagen VI variants disrupt.

PMID:21691338 SUPPORT Other

"exon-14-skipping mutations are the single most common mutation type seen in patients with Bethlem myopathy"

Links the assembly lesion with the mildest dominant-negative effect to the Bethlem phenotype.

Endomysial collagen VI microfibrillar network deficiency

Collagen VI forms a microfibrillar network that is particularly prominent in the endomysium of skeletal muscle, where it is produced not by the myofibre itself but by the resident interstitial fibroblast, making the collagen VI-related myopathies non-cell-autonomous muscle disorders. In dominant Bethlem myopathy the total amount of collagen VI immunoreactivity in muscle is often preserved or only mildly reduced, but the normal localization of collagen VI at the basement membrane is lost, indicating that the retained protein is not a functionally normal interactive microfibrillar network.

muscle interstitial fibroblast CL:0000057

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 collagen VI deficiency and abnormal wound healing The same collagen VI network defect is expressed in skin, producing the characteristic follicular and scarring phenotype.

Show evidence (4 references)

PMID:18362356 SUPPORT Human Clinical

"an extracellular matrix protein forming a microfibrillar network that is particularly prominent in the endomysium of skeletal muscle"

Locates the collagen VI network in the endomysial matrix of skeletal muscle.

PMID:21691338 SUPPORT Other

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

Identifies the interstitial fibroblast as the source of muscle collagen VI, establishing the non-cell-autonomous mechanism.

PMID:21691338 SUPPORT Other

"In patients with dominant mutations in particular, muscle immunohistochemistry will show a considerable amount of collagen VI immunoreactivity in the extracellular matrix, but the normal localization of collagen VI in the basement membrane is lost."

Explains why dominant Bethlem muscle can retain collagen VI signal while the network is functionally abnormal.

+ 1 more reference

Impaired matrix-to-sarcolemma anchoring of the myofibre

Microfibrillar collagen VI is thought to bridge cells with the surrounding extracellular matrix, and may be linked indirectly to muscle cell surface receptors through biglycan and the dystrophin-associated protein complex. Collagen VI-deficient cells show decreased adherence to their surroundings. Loss of this anchoring both degrades force transmission and removes the matrix attachment signals that normally protect cells from apoptosis.

skeletal muscle fiber CL:0008002

cell-matrix adhesion GO:0007160 ↓ DECREASED

Downstream

Myofibre mitochondrial dysfunction and permeability transition pore dysregulation Loss of matrix anchoring renders muscle mitochondria latently dysfunctional and sensitizes the permeability transition pore; plating collagen VI-deficient myofibres back onto collagen VI reverses the defect.

Progressive myofibre degeneration and endomysial fibrosis 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 Human Clinical

"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 Other

"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 In Vitro

"Work in cell cultures has shown that collagen VI-deficient cells exhibit decreased adherence to their surroundings"

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

Collagen VI-deficient muscle shows ultrastructural alterations of mitochondria and sarcoplasmic reticulum and a latent mitochondrial dysfunction that is unmasked by oligomycin, producing mitochondrial depolarization, calcium deregulation, and apoptosis through inappropriate opening of the cyclophilin D-dependent permeability transition pore. The defect is reversible: it is corrected by replating myofibres on collagen VI, by cyclosporin A, and by genetic ablation of cyclophilin D. The same mitochondrial dysfunction and increased apoptosis are demonstrable in muscle biopsies from patients with collagen VI myopathies.

skeletal muscle fiber CL:0008002

mitochondrion GO:0005739

Downstream

Defective autophagic clearance of damaged organelles Damaged mitochondria accumulate because the autophagic machinery that should remove them is not adequately induced.

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

"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

Skeletal muscle lacking collagen VI has impaired autophagic flux, with reduced induction of beclin-1 and Bnip3 and failure to form autophagosomes after starvation, so abnormal organelles persist. Muscle biopsies from patients with Bethlem myopathy and Ullrich congenital muscular dystrophy show the same reduction of beclin-1 and Bnip3 protein, and forced activation of autophagy rescues myofibre survival in the mouse model.

skeletal muscle fiber CL:0008002

autophagy GO:0006914 ↓ DECREASED

mitochondrion GO:0005739

Downstream

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

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

Collagen VI-deficient muscle shows spontaneous apoptosis of muscle fibres, the convergent effector step of the matrix, mitochondrial, and autophagy defects, and the target of cyclophilin D-directed therapy.

skeletal muscle fiber CL:0008002

apoptotic process GO:0006915 ↑ INCREASED

Downstream

Progressive myofibre degeneration and endomysial fibrosis 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

"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 and endomysial fibrosis

The muscle in Bethlem myopathy shows a slowly progressive dystrophic process with degenerating and regenerating fibres, variability in fibre diameter, and a prominent build-up of interstitial and endomysial fibrous tissue, manifesting clinically as proximal-predominant weakness with mildly elevated creatine kinase and myopathic electromyography.

skeletal muscle fiber CL:0008002

extracellular matrix organization GO:0030198 ⚠ ABNORMAL

Downstream

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

Muscle weakness

Neonatal hypotonia

Decreased fetal movement

Motor delay

Elevated circulating creatine kinase concentration

EMG: myopathic abnormalities

Increased endomysial connective tissue

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.

Show evidence (2 references)

PMID:21691338 SUPPORT Other

"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.

Tendon and periarticular connective tissue involvement

Collagen VI is expressed pericellularly around tendon fibroblasts, and its deficiency produces a tendinopathy that contributes both to the small-joint laxity seen in young children and to the later contractures. The resulting distal contracture pattern, involving the long finger flexors, elbows, and Achilles tendons, is the clinical signature that distinguishes Bethlem myopathy from a limb-girdle pattern of weakness. On dorsiflexion of the wrist, contracture of the long finger flexors prevents complete finger extension, the Bethlem sign.

tendon fibroblast CL:0000057

extracellular matrix GO:0031012

Downstream

Achilles tendon contracture

Elbow flexion contracture

Flexion contracture of finger

Flexion contracture

Spinal rigidity

Scoliosis

Kyphosis

Torticollis

Joint hypermobility

Show evidence (3 references)

PMID:20301676 SUPPORT Other

"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 Other

"On dorsiflexion of the wrist, contractures of the long finger flexors prevent complete finger extension"

Describes the Bethlem sign produced by long finger flexor contracture.

PMID:21691338 SUPPORT Other

"at this early age display distal joint hyperlaxity rather than contractures"

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

Dermal collagen VI deficiency and abnormal wound healing

Collagen VI is a component of the dermal matrix, and its deficiency or dysfunction produces the characteristic connective-tissue skin phenotype of the collagen VI-related myopathies: prominent keratosis pilaris (follicular hyperkeratosis) over the extensor surfaces, a propensity to abnormal keloid or atrophic ("cigarette paper") scarring, and soft velvety palmar skin. This dermatological signature is one of the features that separates Bethlem myopathy from other proximal myopathies at the bedside.

dermal fibroblast CL:0000057

extracellular matrix organization GO:0030198 ⚠ ABNORMAL

Downstream

Follicular hyperkeratosis

Keratosis pilaris

Keloids

Atrophic scars

Soft skin

Show evidence (3 references)

PMID:21691338 SUPPORT Other

"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"

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.

PMID:25158062 SUPPORT Model Organism

"often also display skin abnormalities, like formation of keloids or"

Confirms the skin phenotype in collagen VI-related myopathy and motivates the Col6a1-null skin model.

Restrictive respiratory involvement

Respiratory involvement is not a consistent feature of Bethlem myopathy, in marked contrast to Ullrich congenital muscular dystrophy where early severe respiratory insufficiency is universal. Nevertheless individuals with Bethlem myopathy carry an increased risk of restrictive lung disease and nocturnal hypoventilation, which justifies proactive respiratory surveillance.

skeletal muscle fiber CL:0008002

Downstream

Restrictive ventilatory defect

Show evidence (2 references)

PMID:20301676 SUPPORT Other

"Respiratory involvement is not a consistent feature."

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

PMID:21691338 SUPPORT Other

"Patients with Bethlem myopathy have an increased risk of restrictive lung disease, with the possibility of resulting respiratory insufficiency"

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

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Histopathology

1

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 Other

"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 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"

A Bethlem case series documents dystrophic muscle histology.

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Pathograph

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Phenotypes

25

Integument 3

Keratosis pilaris FREQUENT HP:0032152

Show evidence (1 reference)

PMID:21691338 SUPPORT Other

"The most notable manifestations are prominent keratosis pilaris of the extensor surfaces of the arms and legs, giving the skin a rough appearance"

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

Keloids FREQUENT 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 Other

"the propensity for abnormal (keloid or atrophic) scar formation"

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

Atrophic scars HP:0001075

Show evidence (1 reference)

PMID:21691338 SUPPORT Other

"the propensity for abnormal (keloid or atrophic) scar formation"

The review records atrophic as well as keloid scarring.

Limbs 1

Flexion contracture of finger VERY_FREQUENT HP:0012785

Course: PROGRESSIVE

Show evidence (2 references)

PMID:20301676 SUPPORT Other

"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 Other

"On dorsiflexion of the wrist, contractures of the long finger flexors prevent complete finger extension"

Describes the clinical manoeuvre that elicits the Bethlem sign.

Metabolism 1

Elevated circulating creatine kinase concentration HP:0003236

Severity: MILD

Show evidence (1 reference)

PMID:24339618 SUPPORT Human Clinical

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

A Bethlem family series documents mild creatine kinase elevation.

Musculoskeletal 8

Proximal muscle weakness VERY_FREQUENT HP:0003701

Course: PROGRESSIVE

Show evidence (2 references)

PMID:20301676 SUPPORT Other

"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

"contractures of multiple joints in addition to generalized muscular weakness and wasting"

The original description records generalized weakness and wasting.

Flexion contracture VERY_FREQUENT 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 OCCASIONAL HP:0003306

Show evidence (1 reference)

PMID:21691338 SUPPORT Other

"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 Other

"annual clinical and radiographic assessment of scoliosis"

GeneReviews prescribes annual scoliosis surveillance for Bethlem muscular dystrophy.

Kyphosis OCCASIONAL HP:0002808

Show evidence (1 reference)

PMID:21691338 SUPPORT Other

"affecting the elbows, knees, spine (kyphoscoliosis) and neck (torticollis)"

The review records kyphoscoliosis in the collagen VI-related myopathies; the quoted sentence describes the Ullrich end of the spectrum, so this is partial support for the milder Bethlem phenotype.

Joint hypermobility HP:0001382

Show evidence (2 references)

PMID:21691338 SUPPORT Other

"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"

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

Nervous System 1

Motor delay HP:0001270

Show evidence (1 reference)

PMID:20301676 SUPPORT Other

"Hypotonia and delayed motor milestones occur in early childhood"

GeneReviews records delayed motor milestones in Bethlem muscular dystrophy.

Respiratory 1

Restrictive ventilatory defect OCCASIONAL HP:0002091

Show evidence (2 references)

PMID:21691338 SUPPORT Other

"Patients with Bethlem myopathy have an increased risk of restrictive lung disease, with the possibility of resulting respiratory insufficiency"

The review supports restrictive lung disease risk in Bethlem myopathy.

PMID:20301676 SUPPORT Other

"Respiratory involvement is not a consistent feature."

GeneReviews qualifies the frequency, supporting an OCCASIONAL rather than frequent band.

Other 10

Achilles tendon contracture VERY_FREQUENT HP:0001771

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:20301676 SUPPORT Other

"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 VERY_FREQUENT HP:0002987

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:20301676 SUPPORT Other

"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.

Torticollis FREQUENT HP:0000473

Show evidence (1 reference)

PMID:21691338 SUPPORT Other

"affected babies might exhibit hypotonia, foot deformities and torticollis (which has been noted in up to 50% of patients)"

The review gives torticollis in up to 50% of Bethlem infants, supporting a FREQUENT band.

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"

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

Loss of ambulation HP:0002505

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:10219778 SUPPORT Human Clinical

"more than two-thirds of patients over 50 years of age use a wheelchair"

The natural-history cohort quantifies late loss of independent ambulation.

EMG: myopathic abnormalities HP:0003458

Show evidence (1 reference)

PMID:24339618 SUPPORT Human Clinical

"electromyography revealed myopathic features"

A Bethlem family series documents myopathic electromyography.

Increased endomysial connective tissue HP:0100297

Show evidence (1 reference)

PMID:21691338 SUPPORT Other

"a prominent build-up of interstitial fibrous tissue in the muscle"

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 Other

"often just showing evidence of fiber atrophy or even fiber type disproportion without overt dystrophic features"

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

Follicular hyperkeratosis FREQUENT 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.

Soft skin HP:0000977

Show evidence (1 reference)

PMID:21691338 SUPPORT Other

"a particularly soft and velvety texture to the palmar skin of the hands and feet"

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

🧬

Genetic Associations

3

COL6A1 (Causative)

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

Show evidence (2 references)

PMID:15689448 SUPPORT Human Clinical

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

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"

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

COL6A2 (Causative)

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

Show evidence (2 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 Other

"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"

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

COL6A3 (Causative)

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

Show evidence (2 references)

PMID:8782832 SUPPORT Human Clinical

"whereas one family shows linkage to markers on chromosome 2q37 close to COL6A3"

Linkage in a Bethlem kindred implicates the COL6A3 locus.

PMID:15689448 SUPPORT Human Clinical

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

Systematic COL6 sequencing detects causal variants in a majority of UCMD/Bethlem patients, with the remainder genetically unexplained.

💊

Medical Actions

7

Physical and occupational therapy for contracture management

Action: Physical Therapy NCIT:C15302

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 Other

"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 Other

"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

Achilles tendon contractures are treated per orthopedist, and scoliosis is treated per orthopedics. GeneReviews advises that if surgical treatment for scoliosis is needed, it should be coordinated with orthopedics, anesthesia, intensive care, and pulmonary specialists, because respiratory reserve may be reduced.

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

Show evidence (2 references)

PMID:20301676 SUPPORT Other

"treatment of Achilles tendon contractures per orthopedist"

GeneReviews prescribes orthopedic treatment of Achilles tendon contracture.

PMID:20301676 SUPPORT Other

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

GeneReviews specifies multidisciplinary coordination for scoliosis surgery.

Nocturnal noninvasive ventilation

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

BiPAP is used as needed to support nocturnal ventilation and prevent right heart strain. Because respiratory involvement is inconsistent in Bethlem myopathy, ventilation is guided by surveillance rather than applied routinely.

Target Phenotypes: Restrictive ventilatory defect HP:0002091

Show evidence (1 reference)

PMID:20301676 SUPPORT Other

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

GeneReviews prescribes BiPAP for Bethlem muscular dystrophy as needed.

Respiratory, cardiac, and orthopedic surveillance

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

Surveillance for Bethlem muscular dystrophy comprises annual pulmonary function tests in the upright and supine positions with polysomnography for nocturnal hypoventilation, annual clinical and radiographic assessment of scoliosis, annual cardiac evaluation with echocardiogram and EKG, and annual physical and occupational therapy assessment.

Show evidence (2 references)

PMID:20301676 SUPPORT Other

"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 Other

"annual cardiac evaluation with echocardiogram and EKG"

GeneReviews prescribes annual cardiac surveillance.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Counseling covers the usual autosomal dominant inheritance with 50% sibling risk when a parent carries the variant, the possibility of autosomal recessive inheritance, marked intrafamilial variability in severity among heterozygotes, and the fact that parental somatic and germline mosaicism is not uncommon in the dominant collagen VI-related dystrophies.

Show evidence (2 references)

PMID:20301676 SUPPORT Other

"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 Other

"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.

Cyclophilin D and permeability transition pore modulation

Action: Pharmacotherapy NCIT:C15986

Agent: cyclosporin A CHEBI:4031

Cyclosporin A desensitizes the mitochondrial permeability transition pore independently of calcineurin inhibition, and in an open pilot trial in five patients with collagen VI myopathies it normalized muscle-biopsy mitochondrial dysfunction and apoptosis and increased muscle regeneration. Genetic ablation of cyclophilin D reproduces the rescue in Col6a1-null mice, validating the target. This remains investigational rather than established care, and long-term immunosuppression carries infection risk.

Mechanism Target:

INHIBITS Myofibre mitochondrial dysfunction and permeability transition pore dysregulation — Cyclosporin A binds cyclophilin D and desensitizes the mitochondrial permeability transition pore, acting on the pathogenic mechanism downstream of the collagen VI genetic lesion.

Show evidence (2 references)

PMID:18362356 SUPPORT Human Clinical

"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

"validate Cyp-D and the PTP as pharmacological targets for the therapy of human ColVI myopathies"

Genetic validation of cyclophilin D and the permeability transition pore as therapeutic targets.

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.

Autophagy reactivation

Action: Therapeutic Dietary Intervention NCIT:C64892

Forced activation of autophagy by genetic, dietary, and pharmacological approaches restored myofibre survival and ameliorated the dystrophic phenotype of Col6a1-null mice, identifying autophagy reactivation as a candidate therapeutic strategy. This is preclinical only.

Mechanism Target:

ACTIVATES Defective autophagic clearance of damaged organelles — Autophagy reactivation restores clearance of the damaged organelles that accumulate in collagen VI-deficient muscle.

Show evidence (1 reference)

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.

Show evidence (2 references)

PMID:21037586 SUPPORT Model Organism

"These findings indicate that defective activation of the autophagic machinery is pathogenic in some congenital muscular dystrophies."

The rescue evidence for autophagy reactivation is preclinical; the human translation is a single small uncontrolled pilot.

clinicaltrials:NCT01438788 SUPPORT Human Clinical

"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)"

An eight-patient uncontrolled phase II pilot translated the autophagy hypothesis into a normocaloric low-protein diet intervention including Bethlem myopathy patients.

🔬

Biochemical Markers

3

Mildly elevated serum creatine kinase (Elevated)

Context: Skeletal muscle injury marker

Show evidence (1 reference)

PMID:24339618 SUPPORT Human Clinical

"Creatinine kinase was mildly elevated"

A Bethlem family series documents mild creatine kinase elevation.

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

Context: Autophagy-initiation proteins in patient skeletal 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.

Preserved or mildly reduced collagen VI in fibroblasts (Normal or mildly reduced)

Context: Cultured dermal fibroblast collagen VI expression

Show evidence (4 references)

PMID:21691338 SUPPORT Other

"Cultures of dermal fibroblasts from patients with collagen VI mutations often display changes of the collagen VI matrix, ranging from absence to abnormal formation."

Patient fibroblast collagen VI ranges from absent to merely abnormally formed across the spectrum, the milder end of which corresponds to Bethlem myopathy.

PMID:24339618 SUPPORT Human Clinical

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

A genetically consistent Bethlem family shows dystrophic muscle with normal collagen VI immunostaining.

PMID:37569848 SUPPORT Human Clinical

"The immunofluorescence analysis of collagen VI in 55 biopsies from 37 patients confirmed the correlation between collagen VI defects and the severity of the clinical phenotype."

Collagen VI immunofluorescence intensity tracks phenotype severity across the spectrum, so the mild Bethlem end shows the least collagen VI defect.

+ 1 more reference

🔬

Diagnosis

3

Muscle collagen VI immunohistochemistry

In dominant collagen VI disease, muscle immunohistochemistry retains considerable collagen VI signal in the extracellular matrix but loses the normal collagen VI localization at the basement membrane, which is best revealed by double staining with a basement membrane marker. A normal overall collagen VI stain therefore does not exclude Bethlem myopathy, unlike the frankly absent collagen VI of recessive Ullrich disease.

diagnostic procedure NCIT:C18020

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

Show evidence (3 references)

PMID:21691338 SUPPORT Other

"In patients with dominant mutations in particular, muscle immunohistochemistry will show a considerable amount of collagen VI immunoreactivity in the extracellular matrix, but the normal localization of collagen VI in the basement membrane is lost."

Describes the immunohistochemical signature of dominant collagen VI disease.

PMID:24339618 SUPPORT Human Clinical

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

Illustrates that collagen VI immunostaining can be normal in genetically consistent Bethlem myopathy.

PMID:36982625 SUPPORT Human Clinical

"The combined use of these different technologies is pivotal in the diagnosis of COL6 patients."

Histological, immunological, and ultrastructural methods are complementary and jointly needed to validate COL6 variants.

COL6A1, COL6A2, and COL6A3 molecular genetic testing

Molecular confirmation is by identification of a heterozygous or biallelic pathogenic variant in COL6A1, COL6A2, or COL6A3. Systematic sequencing of all 107 coding exons of the three genes identifies a putative mutation in about 62% of patients across the UCMD/Bethlem spectrum, so a negative result does not exclude the diagnosis.

genetic testing NCIT:C15709

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

Show evidence (2 references)

PMID:20301676 SUPPORT Other

"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.

Muscle imaging

Muscle MRI or ultrasound shows a characteristic concentric pattern with the earliest degenerative change on the outer aspects of the muscle, plus a central zone of altered signal in rectus femoris (the central cloud or central shadow), which helps distinguish collagen VI disease from LMNA-related Emery-Dreifuss muscular dystrophy and from limb-girdle muscular dystrophy.

diagnostic procedure NCIT:C18020

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

Show evidence (2 references)

PMID:21691338 SUPPORT Other

"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"

Describes the concentric muscle imaging signature.

PMID:24339618 SUPPORT Human Clinical

"Muscle imaging revealed severe involvement of glutei and vasti with"

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

📈

Progression

3

Early childhood onset

Age: Birth to 2 years

Nearly all affected children show weakness or contractures within the first two years of life, sometimes preceded by diminished fetal movements and neonatal hypotonia; early congenital contractures are dynamic and often remit during childhood.

Show evidence (2 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.

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 Other

"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 Other

"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

Weakness progresses slowly; more than two thirds of individuals older than 50 years remain ambulatory indoors but rely on supportive means outdoors, and a substantial proportion use a wheelchair.

Show evidence (3 references)

PMID:20301676 SUPPORT Other

"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.

📊

Prevalence

1

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 Other

"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.

🔬

Clinical Trials

1

NCT01438788 PHASE_II COMPLETED

A normocaloric low-protein diet in eight adults with Bethlem myopathy or Ullrich congenital muscular dystrophy, designed to reactivate autophagy, with change in muscle-biopsy beclin-1 at one year as the primary endpoint. This is the direct human translation of the Col6a1-null autophagy rescue.

Target Phenotypes: Muscle weakness HP:0001324

Show evidence (2 references)

clinicaltrials:NCT01438788 SUPPORT Human Clinical

"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."

Defines the autophagy-marker primary endpoint of the trial.

clinicaltrials:NCT01438788 SUPPORT Human Clinical

"reactivation of autophagy with a low-protein diet or treatment with cyclosporine A, the mitochondrial PTP inhibitor, cured Co6a1-/- mice"

States the preclinical rationale linking this trial to both the autophagy and mitochondrial permeability transition arms of the mechanism.

{ }

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 mild end of the collagen VI-related dystrophy
  (COL6-RD) spectrum, whose severe end is Ullrich congenital muscular dystrophy.
  It is caused by pathogenic variants in COL6A1, COL6A2, or COL6A3 and is
  usually autosomal dominant, although recessive forms are described. Defective
  assembly and secretion of the collagen VI microfibrillar network in the
  endomysial extracellular matrix impairs matrix-to-sarcolemma anchoring of the
  myofibre and leaves muscle mitochondria vulnerable to inappropriate
  permeability-transition-pore opening, with defective autophagic clearance of
  damaged organelles and increased myofibre apoptosis. The signature clinical
  combination is slowly progressive proximal weakness together with striking
  distal joint contractures of the long finger flexors, elbows, and Achilles
  tendons, accompanied by connective-tissue skin findings such as follicular
  hyperkeratosis (keratosis pilaris) and abnormal keloid or atrophic scarring.
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: OTHER
    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.
  - 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: OTHER
    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.
  - 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: >
    Autosomal recessive Bethlem myopathy has also been reported, including the
    myosclerosis phenotype caused by a homozygous COL6A2 nonsense variant.
  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: OTHER
    snippet: "although autosomal recessive inheritance has also been reported"
    explanation: GeneReviews records that recessive inheritance also occurs in Bethlem muscular dystrophy.
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "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"
    explanation: The review documents a recessive (myosclerosis) form of Bethlem myopathy caused by a homozygous COL6A2 nonsense variant.
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 corresponding to OMIM:158810. In-frame
    skipping of COL6A1 exon 14 is the single most common Bethlem mutation type.
  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"
    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: OTHER
    snippet: "exon-14-skipping mutations are the single most common mutation type seen in patients with Bethlem myopathy"
    explanation: The review identifies COL6A1 exon 14 skipping as the most common Bethlem mutation type.
- 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 corresponding to OMIM:620725, including the
    recessive myosclerosis phenotype.
  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: "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: "whereas one family shows linkage to markers on chromosome 2q37 close to COL6A3"
    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: OTHER
    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.
progression:
- phase: Early childhood onset
  age_range: Birth to 2 years
  notes: >
    Nearly all affected children show weakness or contractures within the first
    two years of life, sometimes preceded by diminished fetal movements and
    neonatal hypotonia; early congenital contractures are dynamic and often
    remit during childhood.
  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.
- 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: OTHER
    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.
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    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.
- phase: Slow adult progression with late mobility loss
  age_range: Fourth decade onward
  notes: >
    Weakness progresses slowly; more than two thirds of individuals older than
    50 years remain ambulatory indoors but rely on supportive means outdoors,
    and a substantial proportion use a wheelchair.
  evidence:
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: OTHER
    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.
  - 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.
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. Dominant-negative variants,
    especially in-frame skipping of exon 14 and glycine substitutions in the
    Gly-X-Y motif of the N-terminal triple-helical domain, are the classic
    Bethlem lesions.
  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: "Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy"
    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"
    explanation: The original study identified a COL6A1 mutation segregating in a Bethlem kindred.
- name: COL6A2
  gene_term:
    preferred_term: COL6A2
    term:
      id: hgnc:2212
      label: COL6A2
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >
    COL6A2 encodes the collagen VI alpha 2 chain. Dominant glycine substitutions
    disrupting the Gly-X-Y motif cause classic Bethlem myopathy, and a
    homozygous nonsense variant truncating the C2 domain causes the recessive
    myosclerosis form.
  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: OTHER
    snippet: "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"
    explanation: The review documents recessive COL6A2 disease at the Bethlem end of the spectrum.
- 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 collagen VI alpha 3 chain, whose large alternatively
    spliced N-terminal globular domain means that variants in alternatively
    spliced regions can have milder, Bethlem-range consequences.
  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: "whereas one family shows linkage to markers on chromosome 2q37 close to COL6A3"
    explanation: Linkage in a Bethlem kindred implicates the COL6A3 locus.
  - 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: Systematic COL6 sequencing detects causal variants in a majority of UCMD/Bethlem patients, with the remainder genetically unexplained.
pathophysiology:
- name: Collagen VI alpha-chain gene defects
  biological_scale: MOLECULAR
  description: >
    Germline pathogenic variants in COL6A1, COL6A2, or COL6A3 alter the collagen
    VI alpha chains. In Bethlem myopathy these are typically dominant-negative
    lesions: in-frame skipping of COL6A1 exon 14, or glycine substitutions that
    disrupt the Gly-X-Y repeat of the N-terminal triple-helical domain. Mutant
    chains are still competent to enter the monomer, so the defect is
    transmitted into the assembled protein rather than simply reducing dosage.
  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: "Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy"
    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.
  downstream:
  - target: Defective collagen VI microfibril assembly and secretion
    description: >
      Mutant alpha chains are incorporated into collagen VI monomers and
      subvert the downstream dimer, tetramer, and microfibril assembly steps.
    causal_link_type: DIRECT
- name: Defective collagen VI microfibril assembly and secretion
  biological_scale: MOLECULAR
  description: >
    Collagen VI is assembled intracellularly from one each of the alpha 1, alpha
    2, and alpha 3 chains into a triple-helical monomer, then into antiparallel
    dimers and staggered tetramers, which are secreted and associate end to end
    into the characteristic beaded microfibrils. Because a mutant chain can be
    incorporated at the monomer step, only a minority of tetramers are normal,
    giving a strong dominant-negative effect. Milder lesions such as COL6A1 exon
    14 skipping have a more limited dominant-negative effect and therefore shift
    the phenotype toward the Bethlem end of the spectrum.
  biological_processes:
  - preferred_term: protein secretion
    modifier: ABNORMAL
    term:
      id: GO:0009306
      label: protein secretion
  locations:
  - preferred_term: extracellular matrix
    term:
      id: GO:0031012
      label: extracellular matrix
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These tetramers are secreted into the extracellular space, where they associate in an end-to-end fashion to form characteristic"
    explanation: Describes the extracellular tetramer-to-microfibril assembly step that collagen VI variants disrupt.
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "exon-14-skipping mutations are the single most common mutation type seen in patients with Bethlem myopathy"
    explanation: Links the assembly lesion with the mildest dominant-negative effect to the Bethlem phenotype.
  downstream:
  - target: Endomysial collagen VI microfibrillar network deficiency
    description: >
      Failure of tetramer assembly and microfibril formation leaves a deficient
      or dysfunctional collagen VI network in the tissue matrix.
    causal_link_type: DIRECT
- name: Endomysial collagen VI microfibrillar network deficiency
  biological_scale: TISSUE
  description: >
    Collagen VI forms a microfibrillar network that is particularly prominent in
    the endomysium of skeletal muscle, where it is produced not by the myofibre
    itself but by the resident interstitial fibroblast, making the collagen
    VI-related myopathies non-cell-autonomous muscle disorders. In dominant
    Bethlem myopathy the total amount of collagen VI immunoreactivity in muscle
    is often preserved or only mildly reduced, but the normal localization of
    collagen VI at the basement membrane is lost, indicating that the retained
    protein is not a functionally normal interactive microfibrillar network.
  cell_types:
  - preferred_term: muscle interstitial fibroblast
    term:
      id: CL:0000057
      label: 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:18362356
    reference_title: Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an extracellular matrix protein forming a microfibrillar network that is particularly prominent in the endomysium of skeletal muscle"
    explanation: Locates the collagen VI network in the endomysial matrix of skeletal muscle.
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In muscle, the cell of origin for collagen VI is the interstitial fibroblast."
    explanation: Identifies the interstitial fibroblast as the source of muscle collagen VI, establishing the non-cell-autonomous mechanism.
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In patients with dominant mutations in particular, muscle immunohistochemistry will show a considerable amount of collagen VI immunoreactivity in the extracellular matrix, but the normal localization of collagen VI in the basement membrane is lost."
    explanation: Explains why dominant Bethlem muscle can retain collagen VI signal while the network is functionally abnormal.
  - 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: HUMAN_CLINICAL
    snippet: "they documented the high variability in COL6 distribution and the extracellular matrix disorganization"
    explanation: >
      A 15-patient COL6 cohort directly documents variable collagen VI
      distribution and extracellular matrix disorganization in patient muscle.
  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: DIRECT
  - 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: DIRECT
  - target: Dermal collagen VI deficiency and abnormal wound healing
    description: >
      The same collagen VI network defect is expressed in skin, producing the
      characteristic follicular and scarring phenotype.
    causal_link_type: DIRECT
- name: Impaired matrix-to-sarcolemma anchoring of the myofibre
  biological_scale: CELLULAR
  description: >
    Microfibrillar collagen VI is thought to bridge cells with the surrounding
    extracellular matrix, and may be linked indirectly to muscle cell surface
    receptors through biglycan and the dystrophin-associated protein complex.
    Collagen VI-deficient cells show decreased adherence to their surroundings.
    Loss of this anchoring both degrades force transmission and removes the
    matrix attachment signals that normally protect cells from apoptosis.
  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: HUMAN_CLINICAL
    snippet: "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.
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "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.
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Work in cell cultures has shown that collagen VI-deficient cells exhibit decreased adherence to their surroundings"
    explanation: Cell-culture data support reduced matrix adherence, although the precise myofibre receptor remains unidentified.
  - 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: HUMAN_CLINICAL
    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.
  downstream:
  - target: Myofibre mitochondrial dysfunction and permeability transition pore dysregulation
    description: >
      Loss of matrix anchoring renders muscle mitochondria latently dysfunctional
      and sensitizes the permeability transition pore; plating collagen
      VI-deficient myofibres back onto collagen VI reverses the defect.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Progressive myofibre degeneration and endomysial fibrosis
    description: >
      Defective matrix-based force transmission contributes directly to loss of
      contractile strength and to the dystrophic muscle process.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Myofibre mitochondrial dysfunction and permeability transition pore dysregulation
  biological_scale: CELLULAR
  description: >
    Collagen VI-deficient muscle shows ultrastructural alterations of
    mitochondria and sarcoplasmic reticulum and a latent mitochondrial
    dysfunction that is unmasked by oligomycin, producing mitochondrial
    depolarization, calcium deregulation, and apoptosis through inappropriate
    opening of the cyclophilin D-dependent permeability transition pore. The
    defect is reversible: it is corrected by replating myofibres on collagen VI,
    by cyclosporin A, and by genetic ablation of cyclophilin D. The same
    mitochondrial dysfunction and increased apoptosis are demonstrable in muscle
    biopsies from patients with collagen VI myopathies.
  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: "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: Defective autophagic clearance of damaged organelles
    description: >
      Damaged mitochondria accumulate because the autophagic machinery that
      should remove them is not adequately induced.
    causal_link_type: DIRECT
  - 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: >
    Skeletal muscle lacking collagen VI has impaired autophagic flux, with
    reduced induction of beclin-1 and Bnip3 and failure to form autophagosomes
    after starvation, so abnormal organelles persist. Muscle biopsies from
    patients with Bethlem myopathy and Ullrich congenital muscular dystrophy show
    the same reduction of beclin-1 and Bnip3 protein, and forced activation of
    autophagy rescues myofibre survival in the mouse model.
  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
- name: Myofibre apoptosis
  biological_scale: CELLULAR
  description: >
    Collagen VI-deficient muscle shows spontaneous apoptosis of muscle fibres,
    the convergent effector step of the matrix, mitochondrial, and autophagy
    defects, and the target of cyclophilin D-directed therapy.
  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: "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 and endomysial fibrosis
    description: >
      Cumulative loss of individual muscle fibres drives the slowly progressive
      dystrophic process.
    causal_link_type: DIRECT
- name: Progressive myofibre degeneration and endomysial fibrosis
  biological_scale: TISSUE
  description: >
    The muscle in Bethlem myopathy shows a slowly progressive dystrophic process
    with degenerating and regenerating fibres, variability in fibre diameter, and
    a prominent build-up of interstitial and endomysial fibrous tissue,
    manifesting clinically as proximal-predominant weakness with mildly elevated
    creatine kinase and myopathic electromyography.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  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: OTHER
    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.
  - 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: Neonatal hypotonia
    causal_link_type: DIRECT
  - target: Decreased fetal movement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Motor delay
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Elevated circulating creatine kinase concentration
    causal_link_type: DIRECT
  - target: "EMG: myopathic abnormalities"
    causal_link_type: DIRECT
  - target: Increased endomysial connective tissue
    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_KNOWN_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_KNOWN_INTERMEDIATES
- name: Tendon and periarticular connective tissue involvement
  biological_scale: TISSUE
  description: >
    Collagen VI is expressed pericellularly around tendon fibroblasts, and its
    deficiency produces a tendinopathy that contributes both to the small-joint
    laxity seen in young children and to the later contractures. The resulting
    distal contracture pattern, involving the long finger flexors, elbows, and
    Achilles tendons, is the clinical signature that distinguishes Bethlem
    myopathy from a limb-girdle pattern of weakness. On dorsiflexion of the
    wrist, contracture of the long finger flexors prevents complete finger
    extension, the Bethlem sign.
  cell_types:
  - preferred_term: tendon fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  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: OTHER
    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.
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "On dorsiflexion of the wrist, contractures of the long finger flexors prevent complete finger extension"
    explanation: Describes the Bethlem sign produced by long finger flexor contracture.
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "at this early age display distal joint hyperlaxity rather than contractures"
    explanation: Documents the early-childhood distal hyperlaxity that later converts to contracture.
  downstream:
  - target: Achilles tendon contracture
    causal_link_type: DIRECT
  - target: Elbow flexion contracture
    causal_link_type: DIRECT
  - target: Flexion contracture of finger
    causal_link_type: DIRECT
  - target: Flexion contracture
    causal_link_type: DIRECT
  - target: Spinal rigidity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Scoliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Kyphosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Torticollis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Joint hypermobility
    causal_link_type: DIRECT
- name: Dermal collagen VI deficiency and abnormal wound healing
  biological_scale: TISSUE
  description: >
    Collagen VI is a component of the dermal matrix, and its deficiency or
    dysfunction produces the characteristic connective-tissue skin phenotype of
    the collagen VI-related myopathies: prominent keratosis pilaris (follicular
    hyperkeratosis) over the extensor surfaces, a propensity to abnormal keloid
    or atrophic ("cigarette paper") scarring, and soft velvety palmar skin. This
    dermatological signature is one of the features that separates Bethlem
    myopathy from other proximal myopathies at the bedside.
  cell_types:
  - preferred_term: dermal fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  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: OTHER
    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"
    explanation: Describes the characteristic collagen VI skin phenotype.
  - 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.
  - 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
    snippet: "often also display skin abnormalities, like formation of keloids or"
    explanation: Confirms the skin phenotype in collagen VI-related myopathy and motivates the Col6a1-null skin model.
  downstream:
  - target: Follicular hyperkeratosis
    causal_link_type: DIRECT
  - target: Keratosis pilaris
    causal_link_type: DIRECT
  - target: Keloids
    causal_link_type: DIRECT
  - target: Atrophic scars
    causal_link_type: DIRECT
  - target: Soft skin
    causal_link_type: DIRECT
- name: Restrictive respiratory involvement
  biological_scale: ORGANISM
  description: >
    Respiratory involvement is not a consistent feature of Bethlem myopathy, in
    marked contrast to Ullrich congenital muscular dystrophy where early severe
    respiratory insufficiency is universal. Nevertheless individuals with Bethlem
    myopathy carry an increased risk of restrictive lung disease and nocturnal
    hypoventilation, which justifies proactive respiratory surveillance.
  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: OTHER
    snippet: "Respiratory involvement is not a consistent feature."
    explanation: GeneReviews states that respiratory involvement is inconsistent in Bethlem muscular dystrophy.
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Patients with Bethlem myopathy have an increased risk of restrictive lung disease, with the possibility of resulting respiratory insufficiency"
    explanation: Documents the increased but variable restrictive respiratory risk in Bethlem myopathy.
  downstream:
  - target: Restrictive ventilatory defect
    causal_link_type: DIRECT
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.
  frequency: VERY_FREQUENT
  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: OTHER
    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.
  - 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: "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.
  frequency: VERY_FREQUENT
  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: OTHER
    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.
- category: Musculoskeletal
  name: Elbow flexion contracture
  description: >
    Elbow contractures develop alongside the Achilles tendon contractures and are
    part of the characteristic Bethlem distribution.
  frequency: VERY_FREQUENT
  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: OTHER
    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.
- 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.
  frequency: VERY_FREQUENT
  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: OTHER
    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.
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "On dorsiflexion of the wrist, contractures of the long finger flexors prevent complete finger extension"
    explanation: Describes the clinical manoeuvre that elicits the Bethlem sign.
- category: Musculoskeletal
  name: Flexion contracture
  description: >
    Multiple joint flexion contractures are the second half of the defining
    Bethlem clinical combination.
  frequency: VERY_FREQUENT
  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.
  frequency: OCCASIONAL
  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: OTHER
    snippet: "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.
- 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: OTHER
    snippet: "annual clinical and radiographic assessment of scoliosis"
    explanation: GeneReviews prescribes annual scoliosis surveillance for Bethlem muscular dystrophy.
- category: Musculoskeletal
  name: Kyphosis
  description: >
    Spinal deformity in the collagen VI-related myopathies can include
    kyphoscoliosis.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Kyphosis
    term:
      id: HP:0002808
      label: Kyphosis
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "affecting the elbows, knees, spine (kyphoscoliosis) and neck (torticollis)"
    explanation: >
      The review records kyphoscoliosis in the collagen VI-related myopathies;
      the quoted sentence describes the Ullrich end of the spectrum, so this is
      partial support for the milder Bethlem phenotype.
- category: Musculoskeletal
  name: Torticollis
  description: >
    Torticollis is reported in infancy in up to half of individuals later
    diagnosed with Bethlem myopathy.
  frequency: FREQUENT
  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: OTHER
    snippet: "affected babies might exhibit hypotonia, foot deformities and torticollis (which has been noted in up to 50% of patients)"
    explanation: The review gives torticollis in up to 50% of Bethlem infants, supporting a FREQUENT band.
- 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: OTHER
    snippet: "at this early age display distal joint hyperlaxity rather than contractures"
    explanation: The review documents early distal hyperlaxity in Bethlem myopathy.
  - 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"
    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"
    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: OTHER
    snippet: "Hypotonia and delayed motor milestones occur in early childhood"
    explanation: GeneReviews records delayed motor milestones in Bethlem muscular dystrophy.
- category: Neuromuscular
  name: Loss of ambulation
  description: >
    Progression is slow, but more than two thirds of individuals older than 50
    years need help with ambulation and many use a wheelchair.
  phenotype_term:
    preferred_term: Loss of independent ambulation in later adult life
    term:
      id: HP:0002505
      label: Loss of ambulation
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:10219778
    reference_title: "Bethlem myopathy: a slowly progressive congenital muscular dystrophy with contractures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "more than two-thirds of patients over 50 years of age use a wheelchair"
    explanation: The natural-history cohort quantifies late loss of independent ambulation.
- category: Laboratory
  name: Elevated circulating creatine kinase concentration
  description: >
    Creatine kinase is typically only mildly elevated in Bethlem myopathy,
    consistent with the mild dystrophic process.
  phenotype_term:
    preferred_term: Mildly elevated creatine kinase
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase concentration
    severity: MILD
  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.
- 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: "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: OTHER
    snippet: "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.
- 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: OTHER
    snippet: "often just showing evidence of fiber atrophy or even fiber type disproportion without overt dystrophic features"
    explanation: The review describes early-biopsy fibre-size abnormality in collagen VI-related myopathy.
- category: Dermatologic
  name: Follicular hyperkeratosis
  description: >
    Follicular hyperkeratosis is a signature connective-tissue skin sign of
    Bethlem myopathy.
  frequency: FREQUENT
  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.
  frequency: FREQUENT
  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: OTHER
    snippet: "The most notable manifestations are prominent keratosis pilaris of the extensor surfaces of the arms and legs, giving the skin a rough appearance"
    explanation: The review names keratosis pilaris as the most notable skin manifestation.
- category: Dermatologic
  name: Keloids
  description: >
    A propensity to keloid scar formation is characteristic of the collagen
    VI-related myopathies and prominent in Bethlem myopathy.
  frequency: FREQUENT
  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: OTHER
    snippet: "the propensity for abnormal (keloid or atrophic) scar formation"
    explanation: The review documents keloid scarring as a collagen VI connective-tissue feature.
- 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: OTHER
    snippet: "the propensity for abnormal (keloid or atrophic) scar formation"
    explanation: The review records atrophic as well as keloid scarring.
- 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: OTHER
    snippet: "a particularly soft and velvety texture to the palmar skin of the hands and feet"
    explanation: The review documents the soft velvety palmar skin of collagen VI-related myopathy.
- category: Respiratory
  name: Restrictive ventilatory defect
  description: >
    Respiratory involvement is inconsistent in Bethlem myopathy, but there is an
    increased risk of restrictive lung disease and nocturnal hypoventilation.
  frequency: OCCASIONAL
  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: OTHER
    snippet: "Patients with Bethlem myopathy have an increased risk of restrictive lung disease, with the possibility of resulting respiratory insufficiency"
    explanation: The review supports restrictive lung disease risk in Bethlem myopathy.
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Respiratory involvement is not a consistent feature."
    explanation: GeneReviews qualifies the frequency, supporting an OCCASIONAL rather than frequent band.
biochemical:
- name: Mildly elevated serum creatine kinase
  presence: Elevated
  context: Skeletal muscle injury marker
  notes: >
    Creatine kinase elevation in Bethlem myopathy is characteristically mild,
    unlike the marked elevations seen in the severe dystrophinopathies.
  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"
    explanation: A Bethlem family series documents mild creatine kinase elevation.
- name: Reduced beclin-1 and Bnip3 protein in muscle
  presence: Reduced
  context: Autophagy-initiation proteins in patient skeletal muscle
  notes: >
    Reduced beclin-1 and Bnip3 protein in muscle biopsies is the human
    biochemical correlate of the defective autophagy demonstrated in the
    Col6a1-null mouse.
  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.
- name: Preserved or mildly reduced collagen VI in fibroblasts
  presence: Normal or mildly reduced
  context: Cultured dermal fibroblast collagen VI expression
  notes: >
    Unlike the absent collagen VI typical of recessive Ullrich congenital
    muscular dystrophy, most Bethlem myopathy patients have normal or only mildly
    reduced collagen VI expression in cultured fibroblasts, so a normal
    immunostain does not exclude the diagnosis.
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cultures of dermal fibroblasts from patients with collagen VI mutations often display changes of the collagen VI matrix, ranging from absence to abnormal formation."
    explanation: >
      Patient fibroblast collagen VI ranges from absent to merely abnormally
      formed across the spectrum, the milder end of which corresponds to Bethlem
      myopathy.
  - 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 genetically consistent Bethlem family shows dystrophic muscle with normal collagen VI immunostaining.
  - 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: "The immunofluorescence analysis of collagen VI in 55 biopsies from 37 patients confirmed the correlation between collagen VI defects and the severity of the clinical phenotype."
    explanation: >
      Collagen VI immunofluorescence intensity tracks phenotype severity across
      the spectrum, so the mild Bethlem end shows the least collagen VI defect.
  - 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: "biopsies from the same patient or from patients with the same mutation taken at different times showed a progressive increase in protein expression with age"
    explanation: >
      Collagen VI expression is time-dependent within an individual, which
      complicates use of immunofluorescence as a trial biomarker.
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: OTHER
    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.
  - 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"
    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: >
    In dominant collagen VI disease, muscle immunohistochemistry retains
    considerable collagen VI signal in the extracellular matrix but loses the
    normal collagen VI localization at the basement membrane, which is best
    revealed by double staining with a basement membrane marker. A normal
    overall collagen VI stain therefore does not exclude Bethlem myopathy,
    unlike the frankly absent collagen VI of recessive Ullrich disease.
  results: Retained but mislocalized collagen VI, away from the basement membrane, supports dominant collagen VI disease.
  evidence:
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In patients with dominant mutations in particular, muscle immunohistochemistry will show a considerable amount of collagen VI immunoreactivity in the extracellular matrix, but the normal localization of collagen VI in the basement membrane is lost."
    explanation: Describes the immunohistochemical signature of dominant collagen VI disease.
  - 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: Illustrates that collagen VI immunostaining can be normal in genetically consistent Bethlem myopathy.
  - 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: HUMAN_CLINICAL
    snippet: "The combined use of these different technologies is pivotal in the diagnosis of COL6 patients."
    explanation: >
      Histological, immunological, and ultrastructural methods are complementary
      and jointly needed to validate COL6 variants.
- name: COL6A1, COL6A2, and COL6A3 molecular genetic testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >
    Molecular confirmation is by identification of a heterozygous or biallelic
    pathogenic variant in COL6A1, COL6A2, or COL6A3. Systematic sequencing of all
    107 coding exons of the three genes identifies a putative mutation in about
    62% of patients across the UCMD/Bethlem spectrum, so a negative result does
    not exclude the diagnosis.
  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: OTHER
    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.
  - 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.
- name: Muscle imaging
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >
    Muscle MRI or ultrasound shows a characteristic concentric pattern with the
    earliest degenerative change on the outer aspects of the muscle, plus a
    central zone of altered signal in rectus femoris (the central cloud or
    central shadow), which helps distinguish collagen VI disease from
    LMNA-related Emery-Dreifuss muscular dystrophy and from limb-girdle
    muscular dystrophy.
  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: OTHER
    snippet: "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"
    explanation: Describes the concentric muscle imaging signature.
  - 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"
    explanation: A Bethlem case series documents the imaging pattern including the rectus femoris central shadow.
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: OTHER
    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.
  - reference: PMID:21078917
    reference_title: Consensus statement on standard of care for congenital muscular dystrophies.
    supports: SUPPORT
    evidence_source: OTHER
    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.
- name: Orthopedic management of Achilles tendon contracture and scoliosis
  description: >
    Achilles tendon contractures are treated per orthopedist, and scoliosis is
    treated per orthopedics. GeneReviews advises that if surgical treatment for
    scoliosis is needed, it should be coordinated with orthopedics, anesthesia,
    intensive care, and pulmonary specialists, because respiratory reserve may be
    reduced.
  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: OTHER
    snippet: "treatment of Achilles tendon contractures per orthopedist"
    explanation: GeneReviews prescribes orthopedic treatment of Achilles tendon contracture.
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: OTHER
    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.
- name: Nocturnal noninvasive ventilation
  description: >
    BiPAP is used as needed to support nocturnal ventilation and prevent right
    heart strain. Because respiratory involvement is inconsistent in Bethlem
    myopathy, ventilation is guided by surveillance rather than applied
    routinely.
  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: OTHER
    snippet: "BiPAP as needed to support nocturnal ventilation and prevent right heart strain"
    explanation: GeneReviews prescribes BiPAP for Bethlem muscular dystrophy as needed.
- name: Respiratory, cardiac, and orthopedic surveillance
  description: >
    Surveillance for Bethlem muscular dystrophy comprises annual pulmonary
    function tests in the upright and supine positions with polysomnography for
    nocturnal hypoventilation, annual clinical and radiographic assessment of
    scoliosis, annual cardiac evaluation with echocardiogram and EKG, and annual
    physical and occupational therapy assessment.
  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: OTHER
    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.
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "annual cardiac evaluation with echocardiogram and EKG"
    explanation: GeneReviews prescribes annual cardiac surveillance.
- name: Genetic counseling
  description: >
    Counseling covers the usual autosomal dominant inheritance with 50% sibling
    risk when a parent carries the variant, the possibility of autosomal
    recessive inheritance, marked intrafamilial variability in severity among
    heterozygotes, and the fact that parental somatic and germline mosaicism is
    not uncommon in the dominant collagen VI-related dystrophies.
  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: OTHER
    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.
  - reference: PMID:20301676
    reference_title: Collagen VI-Related Dystrophies.
    supports: SUPPORT
    evidence_source: OTHER
    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.
- name: Cyclophilin D and permeability transition pore modulation
  description: >
    Cyclosporin A desensitizes the mitochondrial permeability transition pore
    independently of calcineurin inhibition, and in an open pilot trial in five
    patients with collagen VI myopathies it normalized muscle-biopsy mitochondrial
    dysfunction and apoptosis and increased muscle regeneration. Genetic ablation
    of cyclophilin D reproduces the rescue in Col6a1-null mice, validating the
    target. This remains investigational rather than established care, and
    long-term immunosuppression carries infection risk.
  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: >
      Cyclosporin A binds cyclophilin D and desensitizes the mitochondrial
      permeability transition pore, acting on the pathogenic mechanism downstream
      of the collagen VI genetic lesion.
    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: "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.
    - 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: "validate Cyp-D and the PTP as pharmacological targets for the therapy of human ColVI myopathies"
      explanation: Genetic validation of cyclophilin D and the permeability transition pore as therapeutic targets.
  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: Autophagy reactivation
  description: >
    Forced activation of autophagy by genetic, dietary, and pharmacological
    approaches restored myofibre survival and ameliorated the dystrophic
    phenotype of Col6a1-null mice, identifying autophagy reactivation as a
    candidate therapeutic strategy. This is preclinical only.
  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: ACTIVATES
    description: >
      Autophagy reactivation restores clearance of the damaged organelles that
      accumulate in collagen VI-deficient 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: 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.
  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: "These findings indicate that defective activation of the autophagic machinery is pathogenic in some congenital muscular dystrophies."
    explanation: >
      The rescue evidence for autophagy reactivation is preclinical; the human
      translation is a single small uncontrolled pilot.
  - reference: clinicaltrials:NCT01438788
    reference_title: Low Protein Diet to Correct Defective Autophagy in Patients With Collagen VI Related Myopathies
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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: >
      An eight-patient uncontrolled phase II pilot translated the autophagy
      hypothesis into a normocaloric low-protein diet intervention including
      Bethlem myopathy patients.
clinical_trials:
- name: NCT01438788
  phase: PHASE_II
  status: COMPLETED
  description: >
    A normocaloric low-protein diet in eight adults with Bethlem myopathy or
    Ullrich congenital muscular dystrophy, designed to reactivate autophagy, with
    change in muscle-biopsy beclin-1 at one year as the primary endpoint. This is
    the direct human translation of the Col6a1-null autophagy rescue.
  target_phenotypes:
  - preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: clinicaltrials:NCT01438788
    reference_title: Low Protein Diet to Correct Defective Autophagy in Patients With Collagen VI Related Myopathies
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Defines the autophagy-marker primary endpoint of the trial.
  - reference: clinicaltrials:NCT01438788
    reference_title: Low Protein Diet to Correct Defective Autophagy in Patients With Collagen VI Related Myopathies
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reactivation of autophagy with a low-protein diet or treatment with cyclosporine A, the mitochondrial PTP inhibitor, cured Co6a1-/- mice"
    explanation: >
      States the preclinical rationale linking this trial to both the autophagy
      and mitochondrial permeability transition arms of the mechanism.
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: >
    Nearly all of the mitochondrial permeability-transition and autophagy
    mechanism is derived from the Col6a1-null mouse, a complete-null model whose
    muscle phenotype is milder than the human disease. Most Bethlem myopathy is
    caused by dominant-negative variants in which collagen VI immunoreactivity is
    preserved but mislocalized away from the basement membrane, a molecularly
    different state from complete absence. Whether a mislocalized network
    produces the same degree of mitochondrial and autophagic failure as no
    network at all is not established, and it bears directly on how much of the
    cyclophilin D therapeutic rationale transfers to dominant Bethlem myopathy.
  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.
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In patients with dominant mutations in particular, muscle immunohistochemistry will show a considerable amount of collagen VI immunoreactivity in the extracellular matrix, but the normal localization of collagen VI in the basement membrane is lost."
    explanation: >
      Establishes that dominant Bethlem muscle retains a mislocalized collagen VI
      network rather than lacking collagen VI, unlike the null mouse.
  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 anchoring step is the mechanistic bridge between the extracellular
    collagen VI defect and the intracellular mitochondrial and apoptotic
    phenotype, yet the receptor or matrix partner that transmits the signal is
    unidentified. Collagen IV and an indirect biglycan to
    dystrophin-associated-protein-complex route have been proposed but not
    established. Without it, the causal chain from matrix to mitochondrion rests
    mainly on the reversibility of the defect when collagen VI-deficient
    myofibres are replated onto collagen VI.
  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.
  - reference: PMID:21691338
    reference_title: "The collagen VI-related myopathies: muscle meets its matrix."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A crucial step will be to establish exactly how collagen VI deficiency in the extracellular matrix leaves muscle cells vulnerable to apoptosis"
    explanation: The review names this as the crucial unresolved mechanistic step.
  posed_date: "2026-07-31T00:00:00Z"
notes: >
  This entry scopes Bethlem myopathy as MONDO:0008029 (BTHLM1, OMIM phenotypic
  series 158810), the collagen VI form, with gene-defined MONDO subtypes Bethlem
  myopathy 1A (COL6A1), 1B (COL6A2), and 1C (COL6A3). MONDO also carries a
  separate Bethlem myopathy 2 (MONDO:0034022, OMIM:616471) caused by COL12A1
  variants; that is a distinct entity outside MONDO:0008029 and is not curated
  here. Bethlem myopathy sits at the mild end of the collagen VI-related
  dystrophy continuum whose severe end is curated separately as Ullrich
  congenital muscular dystrophy; the two entries deliberately share the same
  collagen VI matrix, mitochondrial permeability transition, and autophagy
  mechanism and are distinguished by severity, respiratory involvement, and the
  contracture-versus-hyperlaxity balance. An intermediate COL6-RD phenotype lies
  between them and is not separately curated. About 25% of patients with a
  Bethlem or mild intermediate phenotype have no identified collagen VI gene
  variant, so genetic heterogeneity remains. Orphanet ORPHA:610 corresponds to
  this entity, but a structured ORPHA cache record could not be generated during
  curation because the pinned Orphadata bulk XML checksum no longer matches
  upstream; no ORPHA-sourced evidence is asserted here.
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: >
      Natural-history analysis of seven kindreds established early-childhood
      onset and the less-benign-than-thought adult course.
    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: >
      Systematic sequencing of all 107 COL6 coding exons in 79 UCMD/Bethlem
      patients found putative mutations in 62%, supporting molecular diagnosis
      and documenting residual genetic heterogeneity.
    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: >
      Genetic inactivation of cyclophilin D rescues the Col6a1-null phenotype,
      establishing a cause-effect relationship between permeability transition
      pore opening and collagen VI myopathy.
    supporting_text: "validate Cyp-D and the PTP as pharmacological targets for the therapy of human ColVI myopathies"
- 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: "report the results of an open pilot trial with cyclosporin A in five patients"
- reference: PMID:24339618
  title: "Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis."
  findings:
  - statement: >
      A three-generation Indian family diagnosed by ENMC Bethlem Consortium
      criteria showed the full combination of proximal weakness, flexion
      contractures, keloids, and follicular hyperkeratosis with mildly elevated
      creatine kinase and normal collagen VI immunostaining.
    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: >
      Patients with collagen VI-related myopathies display keloids, cigarette
      paper scars, dry skin, striae, and keratosis pilaris, and the Col6a1-null
      mouse is a model for the skin arm of the disease.
    supporting_text: "often also display skin abnormalities, like formation of keloids or"
- 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 15-patient COL6 cohort documents extracellular matrix disorganization,
      sarcolemmal alterations, and highly variable collagen VI distribution, and
      establishes that combined histological, immunological, and ultrastructural
      methods are needed for diagnosis.
    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"

📚

References & Deep Research

References

15

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

Natural-history analysis of seven kindreds established early-childhood onset and the less-benign-than-thought adult course.

"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

Systematic sequencing of all 107 COL6 coding exons in 79 UCMD/Bethlem patients found putative mutations in 62%, supporting molecular diagnosis and documenting residual genetic heterogeneity.

"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

Genetic inactivation of cyclophilin D rescues the Col6a1-null phenotype, establishing a cause-effect relationship between permeability transition pore opening and collagen VI myopathy.

"validate Cyp-D and the PTP as pharmacological targets for the therapy of human ColVI myopathies"

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.

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

PMID:24339618

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

1 finding

A three-generation Indian family diagnosed by ENMC Bethlem Consortium criteria showed the full combination of proximal weakness, flexion contractures, keloids, and follicular hyperkeratosis with mildly elevated creatine kinase and normal collagen VI immunostaining.

"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

Patients with collagen VI-related myopathies display keloids, cigarette paper scars, dry skin, striae, and keratosis pilaris, and the Col6a1-null mouse is a model for the skin arm of the disease.

"often also display skin abnormalities, like formation of keloids or"

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 15-patient COL6 cohort documents extracellular matrix disorganization, sarcolemmal alterations, and highly variable collagen VI distribution, and establishes that combined histological, immunological, and ultrastructural methods are needed for diagnosis.

"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"

Deep Research

1

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

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(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.
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(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.
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Definitions

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Progression

Prevalence

Clinical Trials

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

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