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Bethlem myopathy
Affected individuals typically experience slowly progressive muscle weakness, particularly in the limb muscles, and develop contractures, affecting mobility. Symptoms often begin in childhood and can vary in severity.
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Overview
Bethlem myopathy is a rare, inherited neuromuscular disorder primarily affecting skeletal muscles and connective tissues [PMID:31535492]. It is characterised by slowly progressive muscle weakness and the development of contractures, which are conditions where joints become permanently stiff and bent, commonly affecting the elbows, ankles, and neck. While it is present from birth, symptoms may become noticeable at various ages, often in early childhood or adolescence.
This condition is part of a spectrum of disorders caused by changes in collagen type VI, a crucial protein for muscle and connective tissue function. Although rare, its recognition is important for appropriate management and genetic counselling. The severity of Bethlem myopathy can vary significantly among individuals, even within the same family [PMID:20301323].
Symptoms & clinical features
Individuals with Bethlem myopathy typically experience muscle weakness that progresses slowly over time. This weakness often begins in the proximal muscles, those closer to the body's centre, such as the hips and shoulders, but can also affect distal muscles (further from the centre), like those in the hands and feet. Early signs may include difficulty with activities such as running, climbing stairs, or lifting objects.
A hallmark feature of Bethlem myopathy is the presence of contractures, which are joint stiffness or limited range of motion, often present from birth or developing in early childhood. Common sites for contractures include the elbows, knees, ankles, and spine. In some cases, skin findings such as soft, velvety skin, easy bruising, or the development of keloid scars (raised scars) may also be observed [PMID:31535492]. Respiratory weakness is uncommon but can sometimes occur in more severe cases.
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Affected organs
The primary organs affected in Bethlem myopathy are the skeletal muscles, which are responsible for movement. These muscles gradually weaken over time. Connective tissues, which provide support and structure throughout the body, are also affected, leading to joint contractures. The skin, a type of connective tissue, can show characteristic changes in some individuals.
Less commonly, the respiratory muscles may be involved, potentially leading to breathing difficulties, particularly during sleep or with infections. The heart is generally not directly affected in Bethlem myopathy, which is a distinguishing feature from some other muscle disorders.
Risks & severity
The risks and severity of Bethlem myopathy can vary greatly. Some individuals experience mild weakness and relatively stable contractures, allowing them to maintain independent mobility well into adulthood. Others may have more significant muscle weakness and contractures that progress more rapidly, leading to a greater reliance on mobility aids.
The age of onset also varies; some individuals show signs in infancy with torticollis (twisted neck) or delayed motor milestones, while others only develop noticeable symptoms in adolescence or adulthood. While the condition is progressive, it usually advances slowly, and most affected individuals have a normal life expectancy. Respiratory complications are rare but represent a more severe aspect when present.
Genetic causes
Bethlem myopathy is caused by genetic changes (mutations) in one of three genes: COL6A1, COL6A2, or COL6A3. These genes provide instructions for making components of type VI collagen, a crucial protein that forms intricate networks within the extracellular matrix [PMID:20301323]. The extracellular matrix is the complex network of molecules surrounding and supporting cells, particularly important in skeletal muscle and connective tissues.
Type VI collagen plays a vital role in maintaining the structural integrity and elasticity of muscle fibres and connective tissues, as well as helping with cell signalling. Pathogenic variants in any of these genes disrupt the normal production or function of type VI collagen. This disruption compromises the structural support of muscle cells, making them more susceptible to damage and leading to the progressive muscle weakness and contractures observed in Bethlem myopathy.
- COL6A1 collagen type VI alpha 1 chain
- COL6A2 collagen type VI alpha 2 chainThe COL6A2 gene provides instructions for making a key component of type VI collagen, a crucial protein for structural support in muscles and connective tissues.
- COL6A3 collagen type VI alpha 3 chain
Inheritance pattern
Bethlem myopathy is typically inherited in an autosomal dominant pattern. This means that a person only needs one copy of an altered COL6A1, COL6A2, or COL6A3 gene to develop the condition. If a parent has Bethlem myopathy, there is a 50% chance that each of their children will also inherit the condition.
In some cases, Bethlem myopathy can occur due to a new (de novo) genetic change in an individual, meaning neither parent has the condition. While autosomal dominant inheritance is the most common pattern, rarer forms of collagen VI-related disorders exist with autosomal recessive inheritance, though Bethlem myopathy generally refers to the dominant form.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
The diagnosis of Bethlem myopathy is often suspected based on the characteristic clinical features, such as progressive muscle weakness and joint contractures. A physical examination by a neurologist or clinical geneticist will assess muscle strength, joint mobility, and look for any distinctive skin findings.
Confirmation of the diagnosis primarily relies on genetic testing. DNA sequencing of the COL6A1, COL6A2, and COL6A3 genes can identify the specific pathogenic variant causing the condition. In the UK, genetic testing for Bethlem myopathy is typically accessed through the NHS Genomic Medicine Service, often following a referral from a specialist clinic. The relevant NHS R-codes for muscular dystrophy panels may include these genes.
Management & lifestyle
While there is no cure for Bethlem myopathy, management focuses on alleviating symptoms, maintaining function, and improving quality of life. This often involves a multidisciplinary team approach including neurologists, physiotherapists, occupational therapists, and genetic counsellors.
Physiotherapy and occupational therapy are crucial for managing contractures and maintaining muscle strength and flexibility. Stretching exercises, splinting, and sometimes orthotic devices can help manage joint stiffness. Regular monitoring of muscular strength and respiratory function is important. Genetic counselling is recommended for affected individuals and their families to understand the inheritance pattern, reproductive risks, and implications for other family members. Research into new therapeutic strategies is ongoing.
UK care pathway
In the UK, suspected cases of Bethlem myopathy are typically referred by a GP or other specialist to a clinical genetics service or a specialist neuromuscular centre. These services are part of the NHS Genomic Medicine Service (GMS).
Within the GMS, genetic testing is carried out based on nationally approved testing directories (e.g., those specified by NHS England's National Genomic Test Directory). A genetic counsellor will provide support and information to individuals and families throughout the diagnostic process and beyond.
Frequently asked questions
Is Bethlem myopathy always inherited?
Bethlem myopathy is usually inherited in an autosomal dominant pattern, meaning it runs in families. However, it can also arise spontaneously in an individual due to a new genetic change, meaning neither parent may carry the altered gene.
How does Bethlem myopathy affect daily life?
The impact varies. Some individuals live with mild symptoms and maintain independence, while others may experience more significant muscle weakness and joint stiffness that affects mobility, requiring support for daily activities and potentially mobility aids.
Can Bethlem myopathy be cured?
Currently, there is no cure for Bethlem myopathy. However, management focuses on treating symptoms and improving quality of life through physiotherapy, occupational therapy, and other supportive measures. Research into new treatments is ongoing.
What is the difference between Bethlem myopathy and Ullrich congenital muscular dystrophy?
Both conditions are caused by changes in the same genes (COL6A1, COL6A2, COL6A3). Bethlem myopathy is generally a milder, slowly progressive form, while Ullrich congenital muscular dystrophy is more severe, often presenting earlier with greater muscle weakness and contractures.
Are there any specific exercises to help with Bethlem myopathy?
Physiotherapy plays a key role in managing Bethlem myopathy. Specific exercises, including stretches to address contractures and gentle strengthening, are often recommended. An individualised exercise plan should be developed in consultation with a physiotherapist experienced in neuromuscular conditions.
References
- Di Martino A, Cescon M, D'Agostino C. Collagen VI in the Musculoskeletal System. International journal of molecular sciences. 2023. PMID: 36982167
- Abbonante V, Malara A, Chrisam M. Lack of COL6/collagen VI causes megakaryocyte dysfunction by impairing autophagy and inducing apoptosis. Autophagy. 2023. PMID: 35857791
- Butterfield RJ, Foley AR, Dastgir J. Position of glycine substitutions in the triple helix of COL6A1, COL6A2, and COL6A3 is correlated with severity and mode of inheritance in collagen VI myopathies. Human mutation. 2013. PMID: 24038877
- Sframeli M, Sarkozy A, Bertoli M. Congenital muscular dystrophies in the UK population: Clinical and molecular spectrum of a large cohort diagnosed over a 12-year period. Neuromuscular disorders : NMD. 2017. PMID: 28688748
- Hu C, Shi Y, Zhao L. Clinical, Pathologic, and Genetic Spectrum of Collagen VI-Related Disorder in China-A Retrospective Observational Multicenter Study. Human mutation. 2024. PMID: 40225934
- Jfri A, Alajmi A. Spontaneous Keloids: A Literature Review. Dermatology (Basel, Switzerland). 2018. PMID: 30114700
- Fortunato F, Fiocco L, Margutti A. Landscape Analysis of COL6A1, COL6A2, and COL6A3 Pathogenic Variants in a Large Italian Cohort Presenting with Collagen VI-Related Myopathies: A Nationwide Report. Biomolecules. 2025. PMID: 41154655
- de Souza PVS, Bortholin T, Pinheiro JRS. Collagen type VI-related myopathy. Practical neurology. 2017. PMID: 28578317