| 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 (pqac-00000003, pqac-00000004, pqac-00000007) |
| 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 (pqac-00000003, pqac-00000007) |
| 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 (pqac-00000002, pqac-00000004) |
| 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 (pqac-00000000, pqac-00000003, pqac-00000014) |
| 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 (pqac-00000004, pqac-00000007, pqac-00000014) |
| 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 (pqac-00000018, pqac-00000014) |
| 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 (pqac-00000008, pqac-00000014, pqac-00000015) |
| 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 (pqac-00000003, pqac-00000016) |
| 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 (pqac-00000005, pqac-00000017) |
| 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 (pqac-00000003, pqac-00000005, pqac-00000007) |
| 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 (pqac-00000004, pqac-00000005) |
| 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 (pqac-00000003, pqac-00000017) |
| 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 (pqac-00000002, pqac-00000001, pqac-00000005) |
| 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 (pqac-00000001, pqac-00000005) |
| 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 (pqac-00000003, pqac-00000005) |
| 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 (pqac-00000004) |
| 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 (pqac-00000003, pqac-00000016) |
| 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 (pqac-00000002) |
| 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 (pqac-00000003, pqac-00000008) |
| 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 (pqac-00000005, pqac-00000017) |
| 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 (pqac-00000013, pqac-00000015) |
| 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 (pqac-00000008, pqac-00000011) |
| 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 (pqac-00000014, pqac-00000001) |
| 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 (pqac-00000011, pqac-00000012) |
| 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 (pqac-00000008, pqac-00000011) |
| 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 (pqac-00000008) |
| 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 (pqac-00000010, pqac-00000013) |
| 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 (pqac-00000010, pqac-00000015) |
| 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 (pqac-00000008) |
| 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 (pqac-00000001) |
| 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 (pqac-00000017) |
| 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 (pqac-00000017) |
| 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 (pqac-00000007, pqac-00000001) |
| 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 (pqac-00000016, pqac-00000017) |
| 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 (pqac-00000018) |
| 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 (pqac-00000018) |
| 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 (pqac-00000017) |
| 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 (pqac-00000005, pqac-00000018) |
| 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 (pqac-00000018) |
| 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 (pqac-00000018) |
| 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 (pqac-00000002, pqac-00000005) |
| 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 (pqac-00000003, pqac-00000008) |
| 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 (pqac-00000012, pqac-00000011) |
| 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 (pqac-00000020) |
| 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 (pqac-00000008) |
| 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 (pqac-00000018, pqac-00000004) |
| 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 (pqac-00000020) |
| 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 (pqac-00000019) |
| 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 (pqac-00000021) |
| 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 (pqac-00000000) |
| 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 (pqac-00000008, pqac-00000011) |
| 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 (pqac-00000010, pqac-00000015) |
| 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 (pqac-00000009) |
| 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 (pqac-00000008, pqac-00000018) |
| 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 (pqac-00000008) |
| 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 (pqac-00000002, pqac-00000021) |


*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.*