Ullrich congenital muscular dystrophy

Mendelian MONDO:0000355 Pathograph 22 Congenital muscular dystrophy Collagen 6-related myopathy

Ullrich congenital muscular dystrophy is an early-onset collagen-related congenital muscular dystrophy caused by pathogenic variants in COL6A1, COL6A2, COL6A3, or COL12A1. Disruption of collagen VI or collagen XII extracellular-matrix structure in skeletal muscle causes congenital hypotonia and generalized muscle weakness with proximal joint contractures, distal joint hyperlaxity, progressive scoliosis, loss of ambulation, elevated creatine kinase, myopathic muscle pathology, and childhood respiratory insufficiency.

Ask OpenScientist

Ask a research question about Ullrich congenital muscular dystrophy. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Mappings
1
Definitions
2
Inheritance
6
Pathophys.
1
Histopath.
31
Phenotypes
22
Pathograph
4
Genes
4
Treatments
4
Subtypes
9
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0000355 Ullrich congenital muscular dystrophy
skos:exactMatch Orphanet ORPHA:75840
Orphanet ORPHA:75840 lists MONDO:0000355 as an exact cross-reference for Ullrich congenital muscular dystrophy.
📘

Definitions

1
Orphanet UCMD definition
A congenital muscular dystrophy with weakness, hypotonia, proximal joint contractures, distal joint hyperlaxity, loss of ambulation, and childhood respiratory insufficiency.
OTHER
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"A form of congenital muscular dystrophy characterized by congenital weakness, hypotonia, proximal joint contractures, marked hyperlaxity of the distal joints, with a loss of ambulation (if achieved) and uniform respiratory insufficiency during childhood."
Orphanet defines the core UCMD clinical pattern.
👪

Inheritance

2
Autosomal dominant inheritance HP:0000006
UCMD can be caused by autosomal dominant, often de novo, collagen gene variants.
Autosomal dominant inheritance
Show evidence (2 references)
ORPHA:75840 SUPPORT Other
"Autosomal dominant"
Orphanet records autosomal dominant inheritance for UCMD.
PMID:24938411 SUPPORT Human Clinical
"It is known to occur through either recessive or dominant genetic mechanism"
Review evidence supports both dominant and recessive mechanisms.
Autosomal recessive inheritance HP:0000007
UCMD can also result from biallelic loss-of-function or compound heterozygous collagen gene variants.
Autosomal recessive inheritance
Show evidence (2 references)
ORPHA:75840 SUPPORT Other
"Autosomal recessive"
Orphanet records autosomal recessive inheritance for UCMD.
PMID:21280092 SUPPORT Human Clinical
"recessively-acting loss-of-function mutations."
Patient genomic evidence supports recessive loss-of-function UCMD mechanisms.
◆

Subtypes

4
Ullrich congenital muscular dystrophy 1A (COL6A1-related) MONDO:0009681
COL6A1-related UCMD subtype corresponding to OMIM:254090.
Show evidence (2 references)
ORPHA:75840 SUPPORT Other
"COL6A1 | collagen type VI alpha 1 chain | hgnc:2211 | Disease-causing germline mutation(s) in"
Orphanet identifies COL6A1 as a UCMD disease gene.
ORPHA:75840 SUPPORT Other
"OMIM:254090 | Broader"
Orphanet lists the OMIM cross-reference corresponding to the COL6A1 subtype.
Ullrich congenital muscular dystrophy 1B (COL6A2-related) MONDO:0958235
COL6A2-related UCMD subtype corresponding to OMIM:620727.
Show evidence (2 references)
ORPHA:75840 SUPPORT Other
"COL6A2 | collagen type VI alpha 2 chain | hgnc:2212 | Disease-causing germline mutation(s) in"
Orphanet identifies COL6A2 as a UCMD disease gene.
ORPHA:75840 SUPPORT Other
"OMIM:620727 | Broader"
Orphanet lists the OMIM cross-reference corresponding to the COL6A2 subtype.
Ullrich congenital muscular dystrophy 1C (COL6A3-related) MONDO:0958236
COL6A3-related UCMD subtype corresponding to OMIM:620728.
Show evidence (2 references)
ORPHA:75840 SUPPORT Other
"COL6A3 | collagen type VI alpha 3 chain | hgnc:2213 | Disease-causing germline mutation(s) in"
Orphanet identifies COL6A3 as a UCMD disease gene.
PMID:11992252 SUPPORT Human Clinical
"Mutations in COL6A3 are described in UCMD for the first time"
Human family data support COL6A3-related UCMD.
Ullrich congenital muscular dystrophy 2 (COL12A1-related) MONDO:0014654
COL12A1-related UCMD or EDS-myopathy overlap subtype corresponding to OMIM:616470.
Show evidence (2 references)
ORPHA:75840 SUPPORT Other
"COL12A1 | collagen type XII alpha 1 chain | hgnc:2188 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet identifies COL12A1 loss-of-function variants as disease-causing in UCMD.
PMID:24334604 SUPPORT Human Clinical
"a homozygous recessive loss of function mutation and a de novo dominant mutation in collagen XII (COL12A1)"
Human and mouse evidence supports COL12A1-related muscle/connective tissue overlap disease.
⚙

Pathophysiology

6
Collagen VI and XII gene defects
Germline variants in COL6A1, COL6A2, COL6A3, or COL12A1 impair collagen VI or collagen XII matrix proteins that normally contribute structural support in skeletal-muscle extracellular matrix.
COL6A1 link COL6A2 link COL6A3 link COL12A1 link
extracellular matrix structural constituent link ↓ DECREASED
extracellular matrix link
Downstream
Collagen extracellular matrix deficiency Collagen gene defects reduce, mislocalize, or dysfunctionally assemble collagen VI/XII matrix.
Show evidence (2 references)
PMID:24938411 SUPPORT Human Clinical
"UCMD) is caused by mutations in either COL6A1, COL6A2 or COL6A3 gene"
Review evidence supports COL6 gene defects as UCMD causes.
PMID:24334604 SUPPORT Human Clinical
"dominant mutation in collagen XII (COL12A1)"
Human evidence supports COL12A1 mutation in the muscle/connective tissue overlap spectrum.
Collagen extracellular matrix deficiency
Collagen VI-related UCMD involves decreased, absent, or dysfunctional collagen VI in the extracellular matrix; COL12A1 disease similarly disrupts muscle/connective tissue matrix mechanics.
extracellular matrix organization link ⚠ ABNORMAL
extracellular matrix link
Downstream
Myofiber connective tissue pathology Matrix deficiency produces abnormal muscle connective tissue and muscle-fiber pathology.
Mitochondrion-mediated myofiber apoptosis and impaired autophagy Collagen matrix deficiency promotes downstream mitochondrial permeability transition, myofiber apoptosis, and impaired autophagy.
Joint contractures and distal hyperlaxity Matrix defects in muscle and connective tissue produce the characteristic mixed contracture/hyperlaxity pattern.
Respiratory muscle involvement Progressive skeletal-muscle involvement affects respiratory muscles and respiratory function.
Show evidence (3 references)
PMID:21280092 SUPPORT Human Clinical
"Underlying these conditions is a decrease, absence or dysfunction of the extracellular matrix protein collagen VI."
Full-text review and patient study supports collagen VI ECM deficiency or dysfunction as the core mechanism.
PMID:21280092 SUPPORT In Vitro
"revealed a complete absence of collagen VI immunoreactivity"
Patient fibroblast staining supports absent collagen VI matrix deposition in severe UCMD.
PMID:24334604 SUPPORT Model Organism
"indicating a role for a matrix-based passive force-transducing elastic element in the generation of the weakness."
Mouse Col12a1 inactivation supports matrix-based muscle-force dysfunction.
Mitochondrion-mediated myofiber apoptosis and impaired autophagy
Collagen VI-related UCMD includes downstream mitochondrial permeability transition pore dysregulation, mitochondrial dysfunction, increased myofiber apoptosis, and impaired autophagy, providing the mechanistic rationale for cyclosporin A and related cyclophilin D / mPTP-modulating trials.
skeletal muscle cell link
mitochondrion-mediated myofiber apoptosis link ↑ INCREASED impaired autophagy link ↓ DECREASED
mitochondrion link
Downstream
Myofiber connective tissue pathology Mitochondrial dysfunction, apoptosis, and impaired autophagy contribute to downstream muscle-fiber pathology.
Generalized muscle weakness Myofiber apoptosis and impaired cellular quality control contribute to skeletal muscle weakness.
Show evidence (2 references)
PMID:24938411 SUPPORT Human Clinical
"clinical trials based on the theory of mitochondrion-mediated myofiber apoptosis or impaired autophagy."
Review evidence identifies mitochondrion-mediated myofiber apoptosis and impaired autophagy as the theory behind UCMD clinical trials.
PMID:18362356 SUPPORT Human Clinical
"mitochondrial dysfunction and increased frequency of apoptosis, as determined in"
Open pilot trial evidence supports mitochondrial dysfunction and increased apoptosis in collagen VI myopathy patient muscle biopsies.
Myofiber connective tissue pathology
Skeletal-muscle pathology includes prominent interstitial and endomysial fibrosis/connective tissue with increased muscle-fiber diameter variability and abnormal muscle-fiber morphology.
skeletal muscle cell link
extracellular matrix organization link ⚠ ABNORMAL
Downstream
Generalized muscle weakness Myofiber and muscle-connective tissue pathology contributes to generalized weakness.
Elevated circulating creatine kinase concentration Muscle involvement produces a dystrophic biochemical injury marker.
Show evidence (2 references)
PMID:24938411 SUPPORT Human Clinical
"Muscle pathology is characterised by prominent interstitial fibrosis"
Review evidence supports interstitial fibrosis as a muscle pathology feature.
ORPHA:75840 SUPPORT Other
"HP:0100297 | Increased endomysial connective tissue | Very frequent (99-80%)"
Orphanet records increased endomysial connective tissue as very frequent.
Joint contractures and distal hyperlaxity
UCMD combines proximal joint contractures with marked distal hyperlaxity, reflecting connective-tissue matrix involvement around joints and muscle.
Downstream
Flexion contracture Proximal contractures manifest as flexion contractures.
Wrist hypermobility Distal hyperlaxity manifests as wrist hypermobility.
Increased laxity of fingers Distal hyperlaxity manifests as finger joint laxity.
Show evidence (1 reference)
PMID:24938411 SUPPORT Human Clinical
"distal hyperlaxity, proximal joint contractures"
Review evidence supports the characteristic mixed joint phenotype.
Respiratory muscle involvement
Progressive skeletal-muscle disease involves respiratory muscles, including diaphragmatic weakness, with childhood respiratory insufficiency or failure.
skeletal muscle cell link
Downstream
Respiratory failure Respiratory muscle involvement causes respiratory insufficiency or failure.
Show evidence (2 references)
ORPHA:75840 SUPPORT Other
"HP:0009113 | Diaphragmatic weakness | Frequent (79-30%)"
Orphanet records diaphragmatic weakness as frequent.
PMID:24938411 SUPPORT Human Clinical
"rapid decline in respiratory function by 10"
Review evidence supports progressive childhood respiratory decline.
✶

Histopathology

1
Interstitial and endomysial fibrosis
Muscle biopsy can show prominent interstitial fibrosis and increased endomysial connective tissue with relatively limited necrosis and regeneration.
Show evidence (2 references)
PMID:24938411 SUPPORT Human Clinical
"prominent interstitial fibrosis disproportionate to the relative paucity of necrotic and regenerating fibres."
Review evidence supports the UCMD muscle-biopsy pattern.
ORPHA:75840 SUPPORT Other
"HP:0100297 | Increased endomysial connective tissue | Very frequent (99-80%)"
Orphanet records increased endomysial connective tissue as very frequent.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Ullrich congenital muscular dystrophy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

31
Eye 1
Esotropia FREQUENT Esotropia (HP:0000565)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0000565 | Esotropia | Frequent (79-30%)"
Orphanet records this phenotype and frequency.
Head and Neck 2
Micrognathia FREQUENT Micrognathia (HP:0000347)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0000347 | Micrognathia | Frequent (79-30%)"
Orphanet records this phenotype and frequency.
Short neck FREQUENT Short neck (HP:0000470)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0000470 | Short neck | Frequent (79-30%)"
Orphanet records this phenotype and frequency.
Metabolism 1
Elevated circulating creatine kinase concentration VERY_FREQUENT Elevated circulating creatine kinase concentration (HP:0003236)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0003236 | Elevated circulating creatine kinase concentration | Very frequent (99-80%)"
Orphanet records this phenotype and frequency.
Musculoskeletal 9
Generalized hypotonia FREQUENT Generalized hypotonia (HP:0001290)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0001290 | Generalized hypotonia | Frequent (79-30%)"
Orphanet records this phenotype and frequency.
Muscle weakness FREQUENT Muscle weakness (HP:0001324)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0001324 | Muscle weakness | Frequent (79-30%)"
Orphanet records this phenotype and frequency.
Flexion contracture VERY_FREQUENT Flexion contracture (HP:0001371)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0001371 | Flexion contracture | Very frequent (99-80%)"
Orphanet records this phenotype and frequency.
Frequent falls FREQUENT Frequent falls (HP:0002359)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0002359 | Frequent falls | Frequent (79-30%)"
Orphanet records this phenotype and frequency.
Scoliosis FREQUENT Scoliosis (HP:0002650)
Show evidence (2 references)
ORPHA:75840 SUPPORT Other
"HP:0002650 | Scoliosis | Frequent (79-30%)"
Orphanet records this phenotype and frequency.
PMID:24938411 SUPPORT Human Clinical
"early-onset, rapidly progressive scoliosis."
Review evidence supports progressive scoliosis in UCMD.
Kyphosis VERY_FREQUENT Kyphosis (HP:0002808)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0002808 | Kyphosis | Very frequent (99-80%)"
Orphanet records this phenotype and frequency.
Spinal rigidity VERY_FREQUENT Spinal rigidity (HP:0003306)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0003306 | Spinal rigidity | Very frequent (99-80%)"
Orphanet records this phenotype and frequency.
Generalized muscle weakness VERY_FREQUENT Generalized muscle weakness (HP:0003324)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0003324 | Generalized muscle weakness | Very frequent (99-80%)"
Orphanet records this phenotype and frequency.
Generalized amyotrophy FREQUENT Generalized amyotrophy (HP:0003700)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0003700 | Generalized amyotrophy | Frequent (79-30%)"
Orphanet records this phenotype and frequency.
Respiratory 1
Respiratory failure FREQUENT Respiratory failure (HP:0002878)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0002878 | Respiratory failure | Frequent (79-30%)"
Orphanet records this phenotype and frequency.
Other 17
Abnormal palate morphology VERY_FREQUENT Abnormal palate morphology (HP:0000174)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0000174 | Abnormal palate morphology | Very frequent (99-80%)"
Orphanet records this phenotype and frequency.
Torticollis FREQUENT Torticollis (HP:0000473)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0000473 | Torticollis | Frequent (79-30%)"
Orphanet records this phenotype and frequency.
Adducted thumb FREQUENT Adducted thumb (HP:0001181)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0001181 | Adducted thumb | Frequent (79-30%)"
Orphanet records this phenotype and frequency.
Slender finger FREQUENT Slender finger (HP:0001238)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0001238 | Slender finger | Frequent (79-30%)"
Orphanet records this phenotype and frequency.
Decreased fetal movement FREQUENT Decreased fetal movement (HP:0001558)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0001558 | Decreased fetal movement | Frequent (79-30%)"
Orphanet records this phenotype and frequency.
Hip dislocation FREQUENT Hip dislocation (HP:0002827)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0002827 | Hip dislocation | Frequent (79-30%)"
Orphanet records this phenotype and frequency.
Elbow flexion contracture FREQUENT Elbow flexion contracture (HP:0002987)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0002987 | Elbow flexion contracture | Frequent (79-30%)"
Orphanet records this phenotype and frequency.
EMG myopathic abnormalities VERY_FREQUENT EMG: myopathic abnormalities (HP:0003458)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0003458 | EMG: myopathic abnormalities | Very frequent (99-80%)"
Orphanet records this phenotype and frequency.
Increased variability in muscle fiber diameter VERY_FREQUENT Increased variability in muscle fiber diameter (HP:0003557)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0003557 | Increased variability in muscle fiber diameter | Very frequent (99-80%)"
Orphanet records this phenotype and frequency.
Abnormal muscle fiber morphology VERY_FREQUENT Abnormal muscle fiber morphology (HP:0004303)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0004303 | Abnormal muscle fiber morphology | Very frequent (99-80%)"
Orphanet records this phenotype and frequency.
Wrist hypermobility VERY_FREQUENT Wrist hypermobility (HP:0005072)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0005072 | Hyperextensibility at wrists | Very frequent (99-80%)"
Orphanet records this phenotype and frequency.
Increased laxity of fingers VERY_FREQUENT Increased laxity of fingers (HP:0006149)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0006149 | Increased laxity of fingers | Very frequent (99-80%)"
Orphanet records this phenotype and frequency.
Knee flexion contracture FREQUENT Knee flexion contracture (HP:0006380)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0006380 | Knee flexion contracture | Frequent (79-30%)"
Orphanet records this phenotype and frequency.
Pes valgus FREQUENT Pes valgus (HP:0008081)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0008081 | Pes valgus | Frequent (79-30%)"
Orphanet records this phenotype and frequency.
Diaphragmatic weakness FREQUENT Diaphragmatic weakness (HP:0009113)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0009113 | Diaphragmatic weakness | Frequent (79-30%)"
Orphanet records this phenotype and frequency.
Long toe FREQUENT Long toe (HP:0010511)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0010511 | Long toe | Frequent (79-30%)"
Orphanet records this phenotype and frequency.
Increased endomysial connective tissue VERY_FREQUENT Increased endomysial connective tissue (HP:0100297)
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0100297 | Increased endomysial connective tissue | Very frequent (99-80%)"
Orphanet records this phenotype and frequency.
🧬

Genetic Associations

4
COL6A1 (Causative)
Show evidence (2 references)
ORPHA:75840 SUPPORT Other
"COL6A1 | collagen type VI alpha 1 chain | hgnc:2211 | Disease-causing germline mutation(s) in"
Orphanet asserts disease-causing COL6A1 germline mutations in UCMD.
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 study supports collagen VI genes as causes of UCMD.
COL6A2 (Causative)
Show evidence (2 references)
ORPHA:75840 SUPPORT Other
"COL6A2 | collagen type VI alpha 2 chain | hgnc:2212 | Disease-causing germline mutation(s) in"
Orphanet asserts disease-causing COL6A2 germline mutations in UCMD.
PMID:21280092 SUPPORT Human Clinical
"large genomic deletions on chromosome 21q22.3 as a novel type of mutation underlying recessively inherited UCMD"
Human genomic evidence supports COL6A2-region deletion mechanisms in recessive UCMD.
COL6A3 (Causative)
Show evidence (2 references)
ORPHA:75840 SUPPORT Other
"COL6A3 | collagen type VI alpha 3 chain | hgnc:2213 | Disease-causing germline mutation(s) in"
Orphanet asserts disease-causing COL6A3 germline mutations in UCMD.
PMID:11992252 SUPPORT Human Clinical
"the patient had a nonsense mutation, R2342X, causing absence of collagen VI in muscle and fibroblasts"
Human family evidence links COL6A3 mutation to absent collagen VI and severe UCMD.
COL12A1 (Causative)
Show evidence (2 references)
ORPHA:75840 SUPPORT Other
"COL12A1 | collagen type XII alpha 1 chain | hgnc:2188 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet asserts disease-causing COL12A1 loss-of-function mutations in UCMD.
PMID:24334604 SUPPORT Human Clinical
"COL12A1) as underlying a novel overlap syndrome involving muscle and connective tissue."
Human and mouse evidence supports COL12A1 as a cause of muscle/connective tissue overlap disease.
💊

Treatments

4
Multidisciplinary supportive care
Action: supportive care MAXO:0000950
Current care is supportive and addresses joint contractures, respiratory failure, scoliosis, mobility, and related complications.
Target Phenotypes: Flexion contracture ↗ Respiratory failure ↗ Scoliosis ↗
Show evidence (2 references)
PMID:24938411 SUPPORT Human Clinical
"treatment for patients is supportive for symptoms such as joint contractures, respiratory failure and scoliosis."
Review evidence identifies supportive care as current treatment.
PMID:21078917 SUPPORT Other
"the multidisciplinary team should include a palliative care specialist early to improve the quality of life."
Consensus care guidance supports multidisciplinary supportive management for congenital muscular dystrophy.
Cyclosporin A mitochondrial permeability transition modulation
Action: Pharmacotherapy NCIT:C15986
Agent: cyclosporin A ↗
Cyclosporin A has been evaluated in an open pilot trial for collagen VI myopathies as a downstream disease-modifying therapy that desensitizes the mitochondrial permeability transition pore, with short-term normalization of muscle-biopsy mitochondrial dysfunction and apoptosis markers. This remains preliminary pharmacotherapy rather than established standard care.
Mechanism Target:
INHIBITS Mitochondrion-mediated myofiber apoptosis and impaired autophagy — Cyclosporin A desensitizes the mitochondrial permeability transition pore, targeting the downstream mitochondrial apoptosis mechanism.
Show evidence (1 reference)
PMID:18362356 SUPPORT Human Clinical
"cyclosporin A, a widely used immunosuppressant that desensitizes the"
The pilot trial abstract states that cyclosporin A normalized mitochondrial alterations in patient-derived disease context.
Show evidence (1 reference)
PMID:18362356 SUPPORT Human Clinical
"report the results of an open pilot trial with cyclosporin A in five patients"
Open pilot trial evidence supports cyclosporin A as a pharmacologic intervention tested in collagen VI myopathies.
Noninvasive ventilation
Action: noninvasive ventilation MAXO:0000506
Nocturnal noninvasive ventilatory support is used when collagen VI-related myopathy causes progressive respiratory insufficiency or failure.
Target Phenotypes: Respiratory failure ↗
Show evidence (1 reference)
PMID:24271325 SUPPORT Human Clinical
"Nocturnal non-invasive ventilation was initiated in patients with Ullrich congenital muscular dystrophy by 11.3 years"
Human natural-history data directly support noninvasive ventilation use in UCMD.
Physical therapy
Action: physical therapy MAXO:0000011
Physical therapy and stretching are supportive interventions for weakness, mobility limitation, and contracture management.
Target Phenotypes: Muscle weakness ↗ Flexion contracture ↗
Show evidence (1 reference)
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 care guidance supports physical therapy for function, mobility, contractures, and spine deformities.
🔬

Biochemical Markers

2
Elevated serum creatine kinase (Elevated)
Context: Skeletal muscle injury marker
Show evidence (1 reference)
ORPHA:75840 SUPPORT Other
"HP:0003236 | Elevated circulating creatine kinase concentration | Very frequent (99-80%)"
Orphanet records elevated circulating creatine kinase as very frequent.
Reduced collagen VI matrix deposition (Reduced)
Context: Patient fibroblast or muscle collagen VI assessment
Show evidence (1 reference)
PMID:21280092 SUPPORT In Vitro
"revealed a complete absence of collagen VI immunoreactivity"
Patient fibroblast staining supports absent collagen VI matrix deposition.
{ }

Source YAML

click to show 
name: Ullrich congenital muscular dystrophy
category: Mendelian
creation_date: "2026-05-09T14:11:05Z"
updated_date: "2026-05-09T23:19:24Z"
synonyms:
- UCMD
- Ullrich scleroatonic muscular dystrophy
description: >
  Ullrich congenital muscular dystrophy is an early-onset collagen-related
  congenital muscular dystrophy caused by pathogenic variants in COL6A1,
  COL6A2, COL6A3, or COL12A1. Disruption of collagen VI or collagen XII
  extracellular-matrix structure in skeletal muscle causes congenital hypotonia
  and generalized muscle weakness with proximal joint contractures, distal joint
  hyperlaxity, progressive scoliosis, loss of ambulation, elevated creatine
  kinase, myopathic muscle pathology, and childhood respiratory insufficiency.
disease_term:
  preferred_term: Ullrich congenital muscular dystrophy
  term:
    id: MONDO:0000355
    label: Ullrich congenital muscular dystrophy
parents:
- Congenital muscular dystrophy
- Collagen 6-related myopathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0000355
      label: Ullrich congenital muscular dystrophy
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:75840
    mapping_justification: >
      Orphanet ORPHA:75840 lists MONDO:0000355 as an exact cross-reference for
      Ullrich congenital muscular dystrophy.
external_assertions:
- name: Orphanet Ullrich congenital muscular dystrophy record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:75840
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=75840
  description: >
    Orphanet's ORPHA:75840 structured record for Ullrich congenital muscular
    dystrophy includes the exact MONDO cross-reference, autosomal dominant and
    autosomal recessive inheritance, neonatal/infancy onset, prevalence rows,
    COL12A1 and COL6A1/COL6A2/COL6A3 disease-gene assertions, and HPO phenotype
    rows used in this entry.
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0000355 | Exact"
    explanation: Orphanet maps ORPHA:75840 exactly to the MONDO identifier used by this entry.
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:254090 | Broader"
    explanation: Orphanet lists OMIM:254090 among broader subtype-level cross-references.
definitions:
- name: Orphanet UCMD definition
  definition_type: OTHER
  description: >
    A congenital muscular dystrophy with weakness, hypotonia, proximal joint
    contractures, distal joint hyperlaxity, loss of ambulation, and childhood
    respiratory insufficiency.
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A form of congenital muscular dystrophy characterized by congenital weakness, hypotonia, proximal joint contractures, marked hyperlaxity of the distal joints, with a loss of ambulation (if achieved) and uniform respiratory insufficiency during childhood."
    explanation: Orphanet defines the core UCMD clinical pattern.
inheritance:
- name: Autosomal dominant inheritance
  description: UCMD can be caused by autosomal dominant, often de novo, collagen gene variants.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Orphanet records autosomal dominant inheritance for UCMD.
  - reference: PMID:24938411
    reference_title: "Ullrich congenital muscular dystrophy: clinicopathological features, natural history and pathomechanism(s)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is known to occur through either recessive or dominant genetic mechanism"
    explanation: Review evidence supports both dominant and recessive mechanisms.
- name: Autosomal recessive inheritance
  description: UCMD can also result from biallelic loss-of-function or compound heterozygous collagen gene variants.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance for UCMD.
  - reference: PMID:21280092
    reference_title: "Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recessively-acting loss-of-function mutations."
    explanation: Patient genomic evidence supports recessive loss-of-function UCMD mechanisms.
has_subtypes:
- name: UCMD1A
  display_name: Ullrich congenital muscular dystrophy 1A (COL6A1-related)
  subtype_term:
    preferred_term: Ullrich congenital muscular dystrophy 1A
    term:
      id: MONDO:0009681
      label: Ullrich congenital muscular dystrophy 1A
  description: COL6A1-related UCMD subtype corresponding to OMIM:254090.
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "COL6A1 | collagen type VI alpha 1 chain | hgnc:2211 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies COL6A1 as a UCMD disease gene.
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:254090 | Broader"
    explanation: Orphanet lists the OMIM cross-reference corresponding to the COL6A1 subtype.
- name: UCMD1B
  display_name: Ullrich congenital muscular dystrophy 1B (COL6A2-related)
  subtype_term:
    preferred_term: Ullrich congenital muscular dystrophy 1B
    term:
      id: MONDO:0958235
      label: Ullrich congenital muscular dystrophy 1B
  description: COL6A2-related UCMD subtype corresponding to OMIM:620727.
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "COL6A2 | collagen type VI alpha 2 chain | hgnc:2212 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies COL6A2 as a UCMD disease gene.
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:620727 | Broader"
    explanation: Orphanet lists the OMIM cross-reference corresponding to the COL6A2 subtype.
- name: UCMD1C
  display_name: Ullrich congenital muscular dystrophy 1C (COL6A3-related)
  subtype_term:
    preferred_term: Ullrich congenital muscular dystrophy 1C
    term:
      id: MONDO:0958236
      label: Ullrich congenital muscular dystrophy 1C
  description: COL6A3-related UCMD subtype corresponding to OMIM:620728.
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "COL6A3 | collagen type VI alpha 3 chain | hgnc:2213 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies COL6A3 as a UCMD disease gene.
  - reference: PMID:11992252
    reference_title: Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in COL6A3 are described in UCMD for the first time"
    explanation: Human family data support COL6A3-related UCMD.
- name: UCMD2
  display_name: Ullrich congenital muscular dystrophy 2 (COL12A1-related)
  subtype_term:
    preferred_term: Ullrich congenital muscular dystrophy 2
    term:
      id: MONDO:0014654
      label: Ullrich congenital muscular dystrophy 2
  description: COL12A1-related UCMD or EDS-myopathy overlap subtype corresponding to OMIM:616470.
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "COL12A1 | collagen type XII alpha 1 chain | hgnc:2188 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet identifies COL12A1 loss-of-function variants as disease-causing in UCMD.
  - reference: PMID:24334604
    reference_title: Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndrome in humans and mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a homozygous recessive loss of function mutation and a de novo dominant mutation in collagen XII (COL12A1)"
    explanation: Human and mouse evidence supports COL12A1-related muscle/connective tissue overlap disease.
prevalence:
- population: Europe
  percentage: 1-9 per 1,000,000
  notes: Orphanet records UCMD point prevalence of 1-9 per 1,000,000 in Europe.
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 1 000 000 | Europe | Point prevalence | ORPHANET"
    explanation: Orphanet provides the European point-prevalence band.
progression:
- phase: Neonatal or infancy onset
  age_range: Neonatal period to infancy
  notes: >
    Weakness and hypotonia begin congenitally, neonatally, or in infancy.
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Neonatal"
    explanation: Orphanet records neonatal onset.
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Infancy"
    explanation: Orphanet records infancy onset.
- phase: Progressive childhood motor and respiratory decline
  age_range: Childhood to adolescence
  notes: >
    Natural history includes loss of ambulation, rapidly progressive scoliosis,
    and decline in respiratory function during childhood.
  evidence:
  - reference: PMID:24938411
    reference_title: "Ullrich congenital muscular dystrophy: clinicopathological features, natural history and pathomechanism(s)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "loss of ambulation by early teenage years, rapid decline in respiratory function by 10"
    explanation: Review evidence supports progressive motor and respiratory decline.
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; pathogenic variants can cause
    UCMD through dominant-negative or recessive collagen VI mechanisms.
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "COL6A1 | collagen type VI alpha 1 chain | hgnc:2211 | Disease-causing germline mutation(s) in"
    explanation: Orphanet asserts disease-causing COL6A1 germline mutations in UCMD.
  - 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 study supports collagen VI genes as causes of UCMD.
- 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 and recessive
    variants can disrupt collagen VI assembly, secretion, or matrix deposition.
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "COL6A2 | collagen type VI alpha 2 chain | hgnc:2212 | Disease-causing germline mutation(s) in"
    explanation: Orphanet asserts disease-causing COL6A2 germline mutations in UCMD.
  - reference: PMID:21280092
    reference_title: "Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "large genomic deletions on chromosome 21q22.3 as a novel type of mutation underlying recessively inherited UCMD"
    explanation: Human genomic evidence supports COL6A2-region deletion mechanisms in recessive UCMD.
- 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; pathogenic variants can
    reduce or abolish collagen VI in muscle and fibroblasts and produce UCMD
    across a severity spectrum.
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "COL6A3 | collagen type VI alpha 3 chain | hgnc:2213 | Disease-causing germline mutation(s) in"
    explanation: Orphanet asserts disease-causing COL6A3 germline mutations in UCMD.
  - reference: PMID:11992252
    reference_title: Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patient had a nonsense mutation, R2342X, causing absence of collagen VI in muscle and fibroblasts"
    explanation: Human family evidence links COL6A3 mutation to absent collagen VI and severe UCMD.
- name: COL12A1
  gene_term:
    preferred_term: COL12A1
    term:
      id: hgnc:2188
      label: COL12A1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >
    COL12A1 encodes collagen XII. Recessive loss-of-function and de novo
    dominant variants cause a muscle/connective tissue overlap syndrome within
    the UCMD spectrum.
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "COL12A1 | collagen type XII alpha 1 chain | hgnc:2188 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet asserts disease-causing COL12A1 loss-of-function mutations in UCMD.
  - reference: PMID:24334604
    reference_title: Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndrome in humans and mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "COL12A1) as underlying a novel overlap syndrome involving muscle and connective tissue."
    explanation: Human and mouse evidence supports COL12A1 as a cause of muscle/connective tissue overlap disease.
pathophysiology:
- name: Collagen VI and XII gene defects
  description: >
    Germline variants in COL6A1, COL6A2, COL6A3, or COL12A1 impair collagen VI
    or collagen XII matrix proteins that normally contribute structural support
    in skeletal-muscle extracellular matrix.
  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
  - preferred_term: COL12A1
    term:
      id: hgnc:2188
      label: COL12A1
  molecular_functions:
  - preferred_term: extracellular matrix structural constituent
    modifier: DECREASED
    term:
      id: GO:0005201
      label: extracellular matrix structural constituent
  locations:
  - preferred_term: extracellular matrix
    term:
      id: GO:0031012
      label: extracellular matrix
  evidence:
  - reference: PMID:24938411
    reference_title: "Ullrich congenital muscular dystrophy: clinicopathological features, natural history and pathomechanism(s)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "UCMD) is caused by mutations in either COL6A1, COL6A2 or COL6A3 gene"
    explanation: Review evidence supports COL6 gene defects as UCMD causes.
  - reference: PMID:24334604
    reference_title: Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndrome in humans and mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dominant mutation in collagen XII (COL12A1)"
    explanation: Human evidence supports COL12A1 mutation in the muscle/connective tissue overlap spectrum.
  downstream:
  - target: Collagen extracellular matrix deficiency
    description: Collagen gene defects reduce, mislocalize, or dysfunctionally assemble collagen VI/XII matrix.
    causal_link_type: DIRECT
- name: Collagen extracellular matrix deficiency
  description: >
    Collagen VI-related UCMD involves decreased, absent, or dysfunctional
    collagen VI in the extracellular matrix; COL12A1 disease similarly disrupts
    muscle/connective tissue matrix mechanics.
  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:21280092
    reference_title: "Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Underlying these conditions is a decrease, absence or dysfunction of the extracellular matrix protein collagen VI."
    explanation: Full-text review and patient study supports collagen VI ECM deficiency or dysfunction as the core mechanism.
  - reference: PMID:21280092
    reference_title: "Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "revealed a complete absence of collagen VI immunoreactivity"
    explanation: Patient fibroblast staining supports absent collagen VI matrix deposition in severe UCMD.
  - reference: PMID:24334604
    reference_title: Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndrome in humans and mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "indicating a role for a matrix-based passive force-transducing elastic element in the generation of the weakness."
    explanation: Mouse Col12a1 inactivation supports matrix-based muscle-force dysfunction.
  downstream:
  - target: Myofiber connective tissue pathology
    description: Matrix deficiency produces abnormal muscle connective tissue and muscle-fiber pathology.
    causal_link_type: DIRECT
  - target: Mitochondrion-mediated myofiber apoptosis and impaired autophagy
    description: Collagen matrix deficiency promotes downstream mitochondrial permeability transition, myofiber apoptosis, and impaired autophagy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Joint contractures and distal hyperlaxity
    description: Matrix defects in muscle and connective tissue produce the characteristic mixed contracture/hyperlaxity pattern.
    causal_link_type: DIRECT
  - target: Respiratory muscle involvement
    description: Progressive skeletal-muscle involvement affects respiratory muscles and respiratory function.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Mitochondrion-mediated myofiber apoptosis and impaired autophagy
  description: >
    Collagen VI-related UCMD includes downstream mitochondrial permeability
    transition pore dysregulation, mitochondrial dysfunction, increased myofiber
    apoptosis, and impaired autophagy, providing the mechanistic rationale for
    cyclosporin A and related cyclophilin D / mPTP-modulating trials.
  cell_types:
  - preferred_term: skeletal muscle cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  biological_processes:
  - preferred_term: mitochondrion-mediated myofiber apoptosis
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  - preferred_term: impaired autophagy
    modifier: DECREASED
    term:
      id: GO:0006914
      label: autophagy
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:24938411
    reference_title: "Ullrich congenital muscular dystrophy: clinicopathological features, natural history and pathomechanism(s)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      clinical trials based on the theory of mitochondrion-mediated myofiber apoptosis
      or impaired autophagy.
    explanation: Review evidence identifies mitochondrion-mediated myofiber apoptosis and impaired autophagy as the theory behind UCMD clinical trials.
  - 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: "mitochondrial dysfunction and increased frequency of apoptosis, as determined in"
    explanation: Open pilot trial evidence supports mitochondrial dysfunction and increased apoptosis in collagen VI myopathy patient muscle biopsies.
  downstream:
  - target: Myofiber connective tissue pathology
    description: Mitochondrial dysfunction, apoptosis, and impaired autophagy contribute to downstream muscle-fiber pathology.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Generalized muscle weakness
    description: Myofiber apoptosis and impaired cellular quality control contribute to skeletal muscle weakness.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Myofiber connective tissue pathology
  description: >
    Skeletal-muscle pathology includes prominent interstitial and endomysial
    fibrosis/connective tissue with increased muscle-fiber diameter variability
    and abnormal muscle-fiber morphology.
  cell_types:
  - preferred_term: skeletal muscle cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:24938411
    reference_title: "Ullrich congenital muscular dystrophy: clinicopathological features, natural history and pathomechanism(s)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle pathology is characterised by prominent interstitial fibrosis"
    explanation: Review evidence supports interstitial fibrosis as a muscle pathology feature.
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100297 | Increased endomysial connective tissue | Very frequent (99-80%)"
    explanation: Orphanet records increased endomysial connective tissue as very frequent.
  downstream:
  - target: Generalized muscle weakness
    description: Myofiber and muscle-connective tissue pathology contributes to generalized weakness.
    causal_link_type: DIRECT
  - target: Elevated circulating creatine kinase concentration
    description: Muscle involvement produces a dystrophic biochemical injury marker.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Joint contractures and distal hyperlaxity
  description: >
    UCMD combines proximal joint contractures with marked distal hyperlaxity,
    reflecting connective-tissue matrix involvement around joints and muscle.
  evidence:
  - reference: PMID:24938411
    reference_title: "Ullrich congenital muscular dystrophy: clinicopathological features, natural history and pathomechanism(s)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "distal hyperlaxity, proximal joint contractures"
    explanation: Review evidence supports the characteristic mixed joint phenotype.
  downstream:
  - target: Flexion contracture
    description: Proximal contractures manifest as flexion contractures.
    causal_link_type: DIRECT
  - target: Wrist hypermobility
    description: Distal hyperlaxity manifests as wrist hypermobility.
    causal_link_type: DIRECT
  - target: Increased laxity of fingers
    description: Distal hyperlaxity manifests as finger joint laxity.
    causal_link_type: DIRECT
- name: Respiratory muscle involvement
  description: >
    Progressive skeletal-muscle disease involves respiratory muscles, including
    diaphragmatic weakness, with childhood respiratory insufficiency or failure.
  cell_types:
  - preferred_term: skeletal muscle cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009113 | Diaphragmatic weakness | Frequent (79-30%)"
    explanation: Orphanet records diaphragmatic weakness as frequent.
  - reference: PMID:24938411
    reference_title: "Ullrich congenital muscular dystrophy: clinicopathological features, natural history and pathomechanism(s)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rapid decline in respiratory function by 10"
    explanation: Review evidence supports progressive childhood respiratory decline.
  downstream:
  - target: Respiratory failure
    description: Respiratory muscle involvement causes respiratory insufficiency or failure.
    causal_link_type: DIRECT
phenotypes:
- name: Abnormal palate morphology
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal palate morphology
    term:
      id: HP:0000174
      label: Abnormal palate morphology
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000174 | Abnormal palate morphology | Very frequent (99-80%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Micrognathia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000347 | Micrognathia | Frequent (79-30%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Short neck
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Short neck
    term:
      id: HP:0000470
      label: Short neck
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000470 | Short neck | Frequent (79-30%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Torticollis
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Torticollis
    term:
      id: HP:0000473
      label: Torticollis
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000473 | Torticollis | Frequent (79-30%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Esotropia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Esotropia
    term:
      id: HP:0000565
      label: Esotropia
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000565 | Esotropia | Frequent (79-30%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Adducted thumb
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Adducted thumb
    term:
      id: HP:0001181
      label: Adducted thumb
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001181 | Adducted thumb | Frequent (79-30%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Slender finger
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Slender finger
    term:
      id: HP:0001238
      label: Slender finger
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001238 | Slender finger | Frequent (79-30%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Generalized hypotonia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001290 | Generalized hypotonia | Frequent (79-30%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Muscle weakness
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001324 | Muscle weakness | Frequent (79-30%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Flexion contracture
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Flexion contracture
    term:
      id: HP:0001371
      label: Flexion contracture
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001371 | Flexion contracture | Very frequent (99-80%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Decreased fetal movement
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Decreased fetal movement
    term:
      id: HP:0001558
      label: Decreased fetal movement
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001558 | Decreased fetal movement | Frequent (79-30%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Frequent falls
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Frequent falls
    term:
      id: HP:0002359
      label: Frequent falls
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002359 | Frequent falls | Frequent (79-30%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Scoliosis
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002650 | Scoliosis | Frequent (79-30%)"
    explanation: Orphanet records this phenotype and frequency.
  - reference: PMID:24938411
    reference_title: "Ullrich congenital muscular dystrophy: clinicopathological features, natural history and pathomechanism(s)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "early-onset, rapidly progressive scoliosis."
    explanation: Review evidence supports progressive scoliosis in UCMD.
- name: Kyphosis
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Kyphosis
    term:
      id: HP:0002808
      label: Kyphosis
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002808 | Kyphosis | Very frequent (99-80%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Hip dislocation
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hip dislocation
    term:
      id: HP:0002827
      label: Hip dislocation
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002827 | Hip dislocation | Frequent (79-30%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Respiratory failure
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002878 | Respiratory failure | Frequent (79-30%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Elbow flexion contracture
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Elbow flexion contracture
    term:
      id: HP:0002987
      label: Elbow flexion contracture
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002987 | Elbow flexion contracture | Frequent (79-30%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Elevated circulating creatine kinase concentration
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase concentration
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase concentration
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003236 | Elevated circulating creatine kinase concentration | Very frequent (99-80%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Spinal rigidity
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Spinal rigidity
    term:
      id: HP:0003306
      label: Spinal rigidity
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003306 | Spinal rigidity | Very frequent (99-80%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Generalized muscle weakness
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Generalized muscle weakness
    term:
      id: HP:0003324
      label: Generalized muscle weakness
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003324 | Generalized muscle weakness | Very frequent (99-80%)"
    explanation: Orphanet records this phenotype and frequency.
- name: EMG myopathic abnormalities
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: "EMG: myopathic abnormalities"
    term:
      id: HP:0003458
      label: "EMG: myopathic abnormalities"
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003458 | EMG: myopathic abnormalities | Very frequent (99-80%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Increased variability in muscle fiber diameter
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Increased variability in muscle fiber diameter
    term:
      id: HP:0003557
      label: Increased variability in muscle fiber diameter
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003557 | Increased variability in muscle fiber diameter | Very frequent (99-80%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Generalized amyotrophy
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Generalized amyotrophy
    term:
      id: HP:0003700
      label: Generalized amyotrophy
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003700 | Generalized amyotrophy | Frequent (79-30%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Abnormal muscle fiber morphology
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal muscle fiber morphology
    term:
      id: HP:0004303
      label: Abnormal muscle fiber morphology
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004303 | Abnormal muscle fiber morphology | Very frequent (99-80%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Wrist hypermobility
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Wrist hypermobility
    term:
      id: HP:0005072
      label: Wrist hypermobility
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005072 | Hyperextensibility at wrists | Very frequent (99-80%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Increased laxity of fingers
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Increased laxity of fingers
    term:
      id: HP:0006149
      label: Increased laxity of fingers
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006149 | Increased laxity of fingers | Very frequent (99-80%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Knee flexion contracture
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Knee flexion contracture
    term:
      id: HP:0006380
      label: Knee flexion contracture
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006380 | Knee flexion contracture | Frequent (79-30%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Pes valgus
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Pes valgus
    term:
      id: HP:0008081
      label: Pes valgus
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008081 | Pes valgus | Frequent (79-30%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Diaphragmatic weakness
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Diaphragmatic weakness
    term:
      id: HP:0009113
      label: Diaphragmatic weakness
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009113 | Diaphragmatic weakness | Frequent (79-30%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Long toe
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Long toe
    term:
      id: HP:0010511
      label: Long toe
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010511 | Long toe | Frequent (79-30%)"
    explanation: Orphanet records this phenotype and frequency.
- name: Increased endomysial connective tissue
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Increased endomysial connective tissue
    term:
      id: HP:0100297
      label: Increased endomysial connective tissue
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100297 | Increased endomysial connective tissue | Very frequent (99-80%)"
    explanation: Orphanet records this phenotype and frequency.
biochemical:
- name: Elevated serum creatine kinase
  presence: Elevated
  context: Skeletal muscle injury marker
  notes: >
    Elevated circulating creatine kinase is a very frequent biochemical marker
    in UCMD and supports a dystrophic skeletal-muscle process.
  evidence:
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003236 | Elevated circulating creatine kinase concentration | Very frequent (99-80%)"
    explanation: Orphanet records elevated circulating creatine kinase as very frequent.
- name: Reduced collagen VI matrix deposition
  presence: Reduced
  context: Patient fibroblast or muscle collagen VI assessment
  notes: >
    Severe collagen VI-related UCMD can show absent or reduced collagen VI
    immunoreactivity in patient-derived cells or muscle.
  evidence:
  - reference: PMID:21280092
    reference_title: "Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "revealed a complete absence of collagen VI immunoreactivity"
    explanation: Patient fibroblast staining supports absent collagen VI matrix deposition.
histopathology:
- name: Interstitial and endomysial fibrosis
  description: >
    Muscle biopsy can show prominent interstitial fibrosis and increased
    endomysial connective tissue with relatively limited necrosis and
    regeneration.
  diagnostic: true
  context: Skeletal muscle biopsy
  evidence:
  - reference: PMID:24938411
    reference_title: "Ullrich congenital muscular dystrophy: clinicopathological features, natural history and pathomechanism(s)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "prominent interstitial fibrosis disproportionate to the relative paucity of necrotic and regenerating fibres."
    explanation: Review evidence supports the UCMD muscle-biopsy pattern.
  - reference: ORPHA:75840
    reference_title: Ullrich congenital muscular dystrophy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100297 | Increased endomysial connective tissue | Very frequent (99-80%)"
    explanation: Orphanet records increased endomysial connective tissue as very frequent.
diagnosis:
- name: COL6A1/COL6A2/COL6A3/COL12A1 molecular genetic testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  description: >
    Molecular testing across COL6A1, COL6A2, COL6A3, and COL12A1 can confirm the
    collagen-related UCMD subtype and distinguish dominant-negative from
    recessive loss-of-function mechanisms.
  results: Pathogenic variants in COL6A1, COL6A2, COL6A3, or COL12A1 support UCMD diagnosis.
  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: "rapid direct sequence analysis of all 107 coding exons of the COL6 genes"
    explanation: Sequencing study supports molecular testing of COL6 genes in UCMD.
  - reference: PMID:21280092
    reference_title: "Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "large genomic deletions on chromosome 21q22.3 as a novel type of mutation underlying recessively inherited UCMD"
    explanation: Large-deletion evidence supports dosage-aware molecular testing.
- name: Muscle biopsy and collagen VI immunostaining
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  description: >
    Muscle biopsy and collagen VI immunostaining can demonstrate the
    interstitial fibrotic pathology and reduced or absent collagen VI matrix
    deposition in collagen VI-related UCMD.
  results: Prominent interstitial fibrosis or reduced/absent collagen VI supports UCMD in context.
  evidence:
  - reference: PMID:24938411
    reference_title: "Ullrich congenital muscular dystrophy: clinicopathological features, natural history and pathomechanism(s)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle pathology is characterised by prominent interstitial fibrosis"
    explanation: Review evidence supports muscle biopsy pathology.
  - reference: PMID:21280092
    reference_title: "Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "revealed a complete absence of collagen VI immunoreactivity"
    explanation: Patient-derived cell staining supports collagen VI immunostaining as a diagnostic adjunct.
treatments:
- name: Multidisciplinary supportive care
  description: >
    Current care is supportive and addresses joint contractures, respiratory
    failure, scoliosis, mobility, and related complications.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Flexion contracture
    term:
      id: HP:0001371
      label: Flexion contracture
  - preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  - preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:24938411
    reference_title: "Ullrich congenital muscular dystrophy: clinicopathological features, natural history and pathomechanism(s)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "treatment for patients is supportive for symptoms such as joint contractures, respiratory failure and scoliosis."
    explanation: Review evidence identifies supportive care as current treatment.
  - reference: PMID:21078917
    reference_title: Consensus statement on standard of care for congenital muscular dystrophies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the multidisciplinary team should include a palliative care specialist early to improve the quality of life."
    explanation: Consensus care guidance supports multidisciplinary supportive management for congenital muscular dystrophy.
- name: Cyclosporin A mitochondrial permeability transition modulation
  description: >
    Cyclosporin A has been evaluated in an open pilot trial for collagen VI
    myopathies as a downstream disease-modifying therapy that desensitizes the
    mitochondrial permeability transition pore, with short-term normalization of
    muscle-biopsy mitochondrial dysfunction and apoptosis markers. This remains
    preliminary pharmacotherapy rather than established standard care.
  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: Mitochondrion-mediated myofiber apoptosis and impaired autophagy
    treatment_effect: INHIBITS
    description: Cyclosporin A desensitizes the mitochondrial permeability transition pore, targeting the downstream mitochondrial apoptosis mechanism.
    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"
      explanation: The pilot trial abstract states that cyclosporin A normalized mitochondrial alterations in patient-derived disease context.
  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"
    explanation: Open pilot trial evidence supports cyclosporin A as a pharmacologic intervention tested in collagen VI myopathies.
- name: Noninvasive ventilation
  description: >
    Nocturnal noninvasive ventilatory support is used when collagen VI-related
    myopathy causes progressive respiratory insufficiency or failure.
  treatment_term:
    preferred_term: noninvasive ventilation
    term:
      id: MAXO:0000506
      label: noninvasive ventilation
  target_phenotypes:
  - preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:24271325
    reference_title: Natural history of pulmonary function in collagen VI-related myopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nocturnal non-invasive ventilation was initiated in patients with Ullrich congenital muscular dystrophy by 11.3 years"
    explanation: Human natural-history data directly support noninvasive ventilation use in UCMD.
- name: Physical therapy
  description: >
    Physical therapy and stretching are supportive interventions for weakness,
    mobility limitation, and contracture management.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  target_phenotypes:
  - preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  - preferred_term: Flexion contracture
    term:
      id: HP:0001371
      label: Flexion contracture
  evidence:
  - 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 care guidance supports physical therapy for function, mobility, contractures, and spine deformities.
notes: >
  This entry scopes UCMD broadly as the MONDO/Orphanet root disease with
  gene-defined MONDO subtypes UCMD1A, UCMD1B, UCMD1C, and UCMD2. Orphanet
  records both autosomal dominant and autosomal recessive inheritance and lists
  COL12A1 plus the three collagen VI alpha-chain genes as disease-causing.
references:
- reference: ORPHA:75840
  title: Ullrich congenital muscular dystrophy
  found_in:
  - Ullrich_Congenital_Muscular_Dystrophy-deep-research-fallback.md
  findings:
  - statement: Orphanet provides the UCMD definition, exact MONDO mapping, inheritance modes, gene assertions, prevalence rows, onset rows, and phenotype frequencies used in this entry.
    supporting_text: "MONDO:0000355 | Exact"
- reference: PMID:11992252
  title: Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy.
  found_in:
  - Ullrich_Congenital_Muscular_Dystrophy-deep-research-fallback.md
  findings:
  - statement: Human family evidence links COL6A3 mutations with severe and intermediate UCMD phenotypes and collagen VI deficiency.
    supporting_text: "Mutations in COL6A3 are described in UCMD for the first time"
- reference: PMID:15689448
  title: "Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy."
  found_in:
  - Ullrich_Congenital_Muscular_Dystrophy-deep-research-fallback.md
  findings:
  - statement: COL6A1, COL6A2, and COL6A3 sequencing evidence supports collagen VI genes as UCMD causes and molecular diagnostic targets.
    supporting_text: "Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy"
- reference: PMID:18362356
  title: Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies.
  findings:
  - statement: An open pilot trial tested oral cyclosporin A as a downstream treatment for mitochondrial dysfunction and apoptosis in collagen VI myopathies.
    supporting_text: "report the results of an open pilot trial with cyclosporin A in five patients"
- reference: PMID:21078917
  title: Consensus statement on standard of care for congenital muscular dystrophies.
  found_in:
  - Ullrich_Congenital_Muscular_Dystrophy-deep-research-fallback.md
  findings:
  - statement: Standard-of-care guidance supports multidisciplinary management and physical therapy for congenital muscular dystrophies.
    supporting_text: "Physical therapy should be focused on the maintenance of function and mobility, prevention or treatment of joint contractures and spine deformities"
- reference: PMID:21280092
  title: "Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy."
  found_in:
  - Ullrich_Congenital_Muscular_Dystrophy-deep-research-fallback.md
  findings:
  - statement: Large COL6A1/COL6A2-region deletions support recessive UCMD mechanisms and collagen VI extracellular-matrix deficiency.
    supporting_text: "Underlying these conditions is a decrease, absence or dysfunction of the extracellular matrix protein collagen VI."
- reference: PMID:24271325
  title: Natural history of pulmonary function in collagen VI-related myopathies.
  found_in:
  - Ullrich_Congenital_Muscular_Dystrophy-deep-research-fallback.md
  findings:
  - statement: Human natural-history data support respiratory decline and non-invasive ventilation use in UCMD.
    supporting_text: "Nocturnal non-invasive ventilation was initiated in patients with Ullrich congenital muscular dystrophy by 11.3 years"
- reference: PMID:24334604
  title: Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndrome in humans and mice.
  found_in:
  - Ullrich_Congenital_Muscular_Dystrophy-deep-research-fallback.md
  findings:
  - statement: COL12A1 human and mouse data support the UCMD2 muscle/connective-tissue overlap subtype and matrix-force dysfunction.
    supporting_text: "COL12A1) as underlying a novel overlap syndrome involving muscle and connective tissue."
- reference: PMID:24938411
  title: "Ullrich congenital muscular dystrophy: clinicopathological features, natural history and pathomechanism(s)."
  found_in:
  - Ullrich_Congenital_Muscular_Dystrophy-deep-research-fallback.md
  findings:
  - statement: Clinicopathological review evidence supports COL6-related pathomechanisms, natural history, muscle pathology, scoliosis, and supportive treatment framing.
    supporting_text: "treatment for patients is supportive for symptoms such as joint contractures, respiratory failure and scoliosis."
📚

References & Deep Research

References

9
ORPHA:75840
Ullrich congenital muscular dystrophy
1 finding
Orphanet provides the UCMD definition, exact MONDO mapping, inheritance modes, gene assertions, prevalence rows, onset rows, and phenotype frequencies used in this entry.
"MONDO:0000355 | Exact"
PMID:11992252
Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy.
1 finding
Human family evidence links COL6A3 mutations with severe and intermediate UCMD phenotypes and collagen VI deficiency.
"Mutations in COL6A3 are described in UCMD for the first time"
PMID:15689448
Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy.
1 finding
COL6A1, COL6A2, and COL6A3 sequencing evidence supports collagen VI genes as UCMD causes and molecular diagnostic targets.
"Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy"
PMID:18362356
Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies.
1 finding
An open pilot trial tested oral cyclosporin A as a downstream treatment for mitochondrial dysfunction and apoptosis in collagen VI myopathies.
"report the results of an open pilot trial with cyclosporin A in five patients"
PMID:21078917
Consensus statement on standard of care for congenital muscular dystrophies.
1 finding
Standard-of-care guidance supports multidisciplinary management and physical therapy for congenital muscular dystrophies.
"Physical therapy should be focused on the maintenance of function and mobility, prevention or treatment of joint contractures and spine deformities"
PMID:21280092
Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy.
1 finding
Large COL6A1/COL6A2-region deletions support recessive UCMD mechanisms and collagen VI extracellular-matrix deficiency.
"Underlying these conditions is a decrease, absence or dysfunction of the extracellular matrix protein collagen VI."
PMID:24271325
Natural history of pulmonary function in collagen VI-related myopathies.
1 finding
Human natural-history data support respiratory decline and non-invasive ventilation use in UCMD.
"Nocturnal non-invasive ventilation was initiated in patients with Ullrich congenital muscular dystrophy by 11.3 years"
PMID:24334604
Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndrome in humans and mice.
1 finding
COL12A1 human and mouse data support the UCMD2 muscle/connective-tissue overlap subtype and matrix-force dysfunction.
"COL12A1) as underlying a novel overlap syndrome involving muscle and connective tissue."
PMID:24938411
Ullrich congenital muscular dystrophy: clinicopathological features, natural history and pathomechanism(s).
1 finding
Clinicopathological review evidence supports COL6-related pathomechanisms, natural history, muscle pathology, scoliosis, and supportive treatment framing.
"treatment for patients is supportive for symptoms such as joint contractures, respiratory failure and scoliosis."

Deep Research

1
Ullrich Congenital Muscular Dystrophy Deep Research Fallback ▸

Ullrich Congenital Muscular Dystrophy Deep Research Fallback

Provider Attempts

  • 2026-05-09T14:29Z: timeout 240s just research-disorder falcon Ullrich_Congenital_Muscular_Dystrophy timed out with exit code 124 after the provider command was terminated by timeout.
  • 2026-05-09T14:33Z: timeout 240s just research-disorder openai Ullrich_Congenital_Muscular_Dystrophy timed out with exit code 124 after the provider command was terminated by timeout.

No provider-generated research artifact was available to integrate. Curation therefore proceeded from generated structured Orphanet evidence and fetched PubMed caches, without hand-editing any references_cache/*.md files.

Evidence Scope Used For Curation

  • ORPHA:75840 structured record for the definition, MONDO exact mapping, inheritance modes, prevalence, neonatal/infancy onset, COL12A1 and COL6A1/ COL6A2/COL6A3 gene assertions, and HPO phenotype-frequency rows.
  • PMID:24938411 for the core UCMD clinicopathological pattern, collagen VI ECM pathomechanism, natural-history features, muscle pathology, and supportive treatment framework.
  • PMID:11992252 for COL6A3 human variant evidence and collagen VI deficiency in muscle and fibroblasts.
  • PMID:15689448 for COL6A1/COL6A2/COL6A3 sequencing evidence, dominant and recessive inheritance, and molecular diagnostic support.
  • PMID:21280092 for large COL6A1/COL6A2-region deletion mechanisms, recessive loss-of-function disease, and collagen VI absence in patient fibroblasts.
  • PMID:24334604 for COL12A1-related muscle/connective-tissue overlap disease and extracellular-matrix force-transduction evidence.
  • PMID:21078917 for congenital muscular dystrophy standard-of-care guidance, including multidisciplinary supportive care, physical therapy, respiratory monitoring, and orthopedic/rehabilitation management.
  • PMID:24271325 for human collagen VI-related myopathy pulmonary natural history and the timing of non-invasive ventilation in UCMD.

Curation Conclusions

The curated model treats UCMD as the Orphanet/MONDO root disease with gene-defined COL6A1, COL6A2, COL6A3, and COL12A1 subtype mappings. Germline collagen VI or collagen XII defects disrupt skeletal-muscle extracellular matrix structure and mechanics, leading to collagen matrix deficiency, myofiber connective-tissue pathology, joint contractures with distal hypermobility, generalized weakness, progressive scoliosis, elevated creatine kinase, and childhood respiratory insufficiency. Current care remains supportive, with multidisciplinary management, physical therapy/orthopedic rehabilitation, and non-invasive ventilation for respiratory decline.