Collagen VI-Related Dystrophies

Written by: Dr Jeremy Steinberg – created: 3 April 2025; last modified: 8 April 2025

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Left: fatty infiltration around triceps brachialis, right: fatty infiltration along vastus lateralis and vastus medialis.
Collagen VI-Related Dystrophies
Inheritance	Autosomal dominant or autosomal recessive (depending on the subtype)
Genetics	Pathogenic variants in the COL6A1, COL6A2, or COL6A3 genes
Pathophysiology	Defects in collagen VI impair the structural integrity of the extracellular matrix, leading to muscle fiber damage, fibrosis, and progressive muscle weakness.
Classification	Phenotypic spectrum ranging from severe Ullrich congenital muscular dystrophy (UCMD) with early-onset weakness and contractures, to milder Bethlem myopathy with later onset and slower progression.
Clinical Features	Proximal muscle weakness, joint hypermobility (early), joint contractures (later), scoliosis, respiratory insufficiency in severe cases
Tests	Genetic testing of COL6A1, COL6A2, and COL6A3; muscle biopsy showing collagen VI deficiency or abnormal distribution; muscle MRI
DDX	Other congenital muscular dystrophies (e.g. LMNA-related), Ehlers-Danlos syndrome, spinal muscular atrophy
Treatment	Supportive care with physiotherapy, orthotic management, respiratory monitoring, and multidisciplinary involvement; no disease-modifying therapy currently available

Collagen VI-Related Dystrophies (COL6-RDs) are a group of inherited muscle disorders caused by mutations in the COL6A1, COL6A2, or COL6A3 genes, which encode the α1(VI), α2(VI), and α3(VI) chains of collagen VI respectively. The phenotypic spectrum ranges from the milder Bethlem muscular dystrophy (BMD) to the more severe Ullrich congenital muscular dystrophy (UCMD), with intermediate phenotypes also recognized. There are two further conditions that fall within the spectrum of COL6-RDs namely autosomal dominant limb girdle muscular dystrophy and autosomal recessive myosclerosis myopathy. The spectrum highly overlaps with myopathic Ehlers Danlos Syndrome.

Pathophysiology

Collagen VI is an essential extracellular matrix protein found in skeletal muscle, skin, tendon, cartilage, and other connective tissues. It forms a microfibrillar network that supports the structural stability of muscle fibers. Mutations in the COL6A1, COL6A2, or COL6A3 genes impair the formation and function of collagen VI, resulting in progressive myopathy. A large proportion of these are de novo.

The pathogenesis of COL6-RDs involves defective assembly of collagen VI microfibrils due to mutations in the COL6 genes. This defect compromises the stability of the extracellular matrix, resulting in muscle fiber damage and progressive muscle weakness. Additionally, impaired autophagy has been implicated in the muscle degeneration observed in these disorders

Clinical Features

The clinical spectrum includes:

• Bethlem Muscular Dystrophy (BMD): A milder phenotype, typically presenting in early childhood or later with slowly progressive proximal muscle weakness and joint contractures. Common features include finger flexor contractures, Achilles tendon tightening, and hypermobility of distal joints (particularly knees and ankles), and scoliosis. Ambulation is often preserved into adulthood. Respiratory involvement may occur, but is usually mild.

• Ullrich Congenital Muscular Dystrophy (UCMD): A more severe phenotype with congenital onset. Presents with marked hypotonia, proximal joint contractures, distal hyperlaxity (more significant than in BMD), and early respiratory insufficiency. Many individuals never achieve independent ambulation or lose ambulation in early childhood.

• Intermediate Phenotypes: Individuals may have features that fall between UCMD and BMD, such as delayed walking, moderate progression of weakness, and variable respiratory involvement.

There may be skin findings including keloid or "cigarette-paper" scarring following even slight skin traumatic injuries and follicular hyperkeratosis.

There is a wide variation in the presentation of BM, including within the same affected family. Some may present in early childhood with symptoms such as hypotonia, delayed motor milestones, and joint contractures, particularly in the fingers, wrists, elbows, and ankles. Distal joint hypermobility can be observed particularly affecting the knees. Proximal muscle weakness is slowly progressive, and respiratory involvement can occur later in life. Contractures and muscle weakness can lead to difficulties in mobility, with many patients requiring assistive devices by adulthood. In a minority of cases respiratory insufficiency occurs.

Diagnosis

Diagnosis is based on clinical features, family history, and confirmed by molecular genetic testing identifying pathogenic variants in COL6A1, COL6A2, or COL6A3.

Supportive investigations include:

• Muscle MRI showing characteristic "outside-in" fatty infiltration in the vastus lateralis and "central cloud" in the rectus femoris.
• Muscle biopsy demonstrating dystrophic changes, with reduced or absent collagen VI expression on immunohistochemistry or western blot.
• Skin fibroblast analysis may be used to assess collagen VI secretion.
• Genetic testing options include single-gene sequencing, gene panels, or exome/genome sequencing.
• Serum CK is normal or mildly elevated.

Management

Management of BM is primarily supportive and includes physical therapy to maintain mobility and prevent contractures, orthopedic interventions for severe contractures, and respiratory support if needed. Regular monitoring of respiratory function is recommended. Genetic counseling is important for affected families.

Resources

ColVI myopathies - Allamand 2011.pdf - 6.6 MB (f)

Collagen 6 - di Martino 2023.pdf - 1.45 MB (f)

Members

Collagen VI-Related Dystrophies - Members Subpage

Literature Review

Literature Review

Reviews from the last 7 years: review articles, free review articles, systematic reviews, meta-analyses, NCBI Bookshelf

Articles from all years: PubMed search, Google Scholar search.

TRIP Database: clinical publications about evidence-based medicine.

Other Wikis: Radiopaedia, Wikipedia Search, Wikipedia I Feel Lucky, Orthobullets,