Bethlem myopathy is a rare disease affecting the skeletal muscles and connective tissue. The disease is characterized by slowly progressive muscle weakness and joint stiffness (contractures). It most often affects the fingers, wrists, elbows, and ankles. Signs and symptoms may begin before birth (with decreased fetal movements), shortly after birth (with low muscle tone or torticollis), in early childhood (with delayed motor skills, muscle weakness, and contractures), or in adulthood (with weakness, Achilles tendon, or finger contractures). Due to the disease's progression, most people with Bethlem myopathy over age 50 require mobility aids (such as a cane, crutches, or wheelchair) for outdoor mobility. Rarely, severe muscle weakness may lead to respiratory difficulties in later life.

Bethlem myopathy is caused by mutations (changes) in the COL6A1, COL6A2, or COL6A3genes. Most cases are inherited in an autosomal dominant manner, but in rare cases the disease is autosomal recessive. The diagnosis is based on clinical examination and laboratory tests, but genetic testing may confirm the diagnosis. Treatment depends on individual symptoms but routinely involves physical therapy. Surgery to correct joint contractures may be needed.

COL6A1, COL6A2, or COL6A3 genes. These genes each provide instructions for making one component of a protein called type VI collagen. This protein plays an important role in the muscles, particularly skeletal muscles. Type VI collagen makes up part of the extracellular matrix, an intricate lattice that forms in the space between cells and provides structural support to the muscles.

Mutations in the type VI collagen genes result in the formation of abnormal type VI collagen or reduced amounts of type VI collagen. This decrease in amounts of normal type VI collagen disrupts the extracellular matrix surrounding muscle cells, which leads to the progressive muscle weakness and other signs and symptoms of Bethlem myopathy.

Normal Function

The COL6A1 gene provides instructions for making one component of type VI collagen, which is a flexible protein found in the space that surrounds cells. Specifically, the protein produced from the COL6A1 gene is the alpha(α)1(VI) chain of type VI collagen. This chain combines with chains produced from other genes to produce a complete type VI collagen molecule.

Collagens are found in the extracellular matrix, which is an intricate lattice that forms in the space between cells and provides structural support. Type VI collagen is located in the extracellular matrix surrounding cells that make up the muscles used for movement (skeletal muscle cells) and cells that make up connective tissue, which provides strength and flexibility to structures throughout the body, including skin and joints. The extracellular matrix is necessary for cell stability and growth. Research suggests that type VI collagen links basement membranes, which are thin, sheet-like structures that are part of the extracellular matrix, to nearby cells.

Health Conditions Related to Genetic Changes

Collagen VI-related dystrophy

Variants (also known as mutations) in the COL6A1 gene have been found to cause some cases of collagen VI-related dystrophy, which is a group of disorders that vary in severity but generally result in muscle weakness and joint deformities called contractures. These variants often change single protein building blocks (amino acids) in the α1(VI) chain. The most frequently affected amino acid is glycine; changes to this building block disrupt the structure of the α1(VI) chain. Other variants can also disrupt the structure of the α1(VI) chain.

Variants in the COL6A1 gene affect type VI collagen in different ways. Some variants lead to altered α1(VI) chains that can be incorporated into the mature type VI collagen molecule, although they disrupt the molecule's structure and function. Other variants result in an altered chain that cannot be incorporated at all. Still other variants prevent the production of any functional α1(VI) chain, which impedes formation of type VI collagen. All of these COL6A1 gene variants lead to a reduction or absence of functional collagen VI molecules. While it is difficult to predict the severity of collagen VI-related dystrophy based on the type of variant, in general, lower amounts of type VI collagen lead to more severe signs and symptoms that begin earlier in life.

Changes in α1(VI) chain structure or production lead to an unstable extracellular matrix that is no longer attached to cells through the basement membrane. As a result, the stability of muscle cells and connective tissue progressively declines, which leads to the muscle weakness, contractures, and other signs and symptoms of collagen VI-related dystrophy.

Limb-girdle muscular dystrophy

MedlinePlus Genetics provides information about Limb-girdle muscular dystrophy

Other Names for This Gene

• alpha 1 (VI) chain (61 AA)
• CO6A1_HUMAN
• collagen alpha-1(VI) chain
• collagen type VI alpha 1
• collagen VI, alpha-1 polypeptide
• collagen, type VI, alpha 1

Genomic Location

The COL6A1 gene is found on chromosome 21.

Normal Function

The COL6A2 gene provides instructions for making one component of type VI collagen, which is a flexible protein found in the space that surrounds cells. Specifically, the protein produced from the COL6A2 gene is the alpha(α)2(VI) chain of type VI collagen. This chain combines with chains produced from other genes to produce a complete type VI collagen molecule.

Collagens are found in the extracellular matrix, which is an intricate lattice that forms in the space between cells and provides structural support. Type VI collagen is located in the extracellular matrix surrounding cells that make up the muscles used for movement (skeletal muscle cells) and cells that make up connective tissue, which provides strength and flexibility to structures throughout the body, including skin and joints. The extracellular matrix is necessary for cell stability and growth. Research suggests that type VI collagen links basement membranes, which are thin, sheet-like structures that are part of the extracellular matrix, to nearby cells.

Health Conditions Related to Genetic Changes

Collagen VI-related dystrophy

Variants (also known as mutations) in the COL6A2 gene have been found to cause some cases of collagen VI-related dystrophy, which is a group of disorders that vary in severity but generally result in muscle weakness and joint deformities called contractures. These variants often change single protein building blocks (amino acids) in the α2(VI) chain. The most frequently affected amino acid is glycine; changes to this building block disrupt the structure of the α2(VI) chain. Other variants can also disrupt the structure of the α2(VI) chain.

Variants in the COL6A2 gene affect type VI collagen in different ways. Some variants lead to altered α2(VI) chains that can be incorporated into the mature type VI collagen molecule, although they disrupt the molecule's structure and function. Other variants result in an altered chain that cannot be incorporated at all. Still other variants prevent the production of any functional α2(VI) chain, which impedes formation of type VI collagen. All of these COL6A2 gene variants lead to a reduction or absence of functional collagen VI molecules. While it is difficult to predict the severity of collagen VI-related dystrophy based on the type of variant, in general, lower amounts of type VI collagen lead to more severe signs and symptoms that begin earlier in life.

Changes in α2(VI) chain structure or production lead to an unstable extracellular matrix that is no longer attached to cells through the basement membrane. As a result, the stability of muscle cells and connective tissue progressively declines, which leads to the muscle weakness, contractures, and other signs and symptoms of collagen VI-related dystrophy.

Limb-girdle muscular dystrophy

MedlinePlus Genetics provides information about Limb-girdle muscular dystrophy

Other Names for This Gene

• CO6A2_HUMAN
• collagen alpha-2(VI) chain
• collagen type VI alpha 2
• collagen VI, alpha-2 polypeptide
• collagen, type VI, alpha 2

Genomic Location

The COL6A2 gene is found on chromosome 21.

Normal Function

The COL6A3 gene provides instructions for making one component of type VI collagen, which is a flexible protein found in the space that surrounds cells. Specifically, the protein produced from the COL6A3 gene is the alpha(α)3(VI) chain of type VI collagen. This chain combines with chains produced from other genes to produce a complete type VI collagen molecule.

Collagens are found in the extracellular matrix, which is an intricate lattice that forms in the space between cells and provides structural support. Type VI collagen is located in the extracellular matrix surrounding cells that make up the muscles used for movement (skeletal muscle cells) and cells that make up connective tissue, which provides strength and flexibility to structures throughout the body, including skin and joints. The extracellular matrix is necessary for cell stability and growth. Research suggests that type VI collagen links basement membranes, which are thin, sheet-like structures that are part of the extracellular matrix, to nearby cells.

Health Conditions Related to Genetic Changes

Collagen VI-related dystrophy

Variants (also known as mutations) in the COL6A3 gene have been found to cause some cases of collagen VI-related dystrophy, which is a group of disorders that vary in severity but generally result in muscle weakness and joint deformities called contractures. These variants often change single protein building blocks (amino acids) in the α3(VI) chain. The most frequently affected amino acid is glycine; changes to this building block disrupt the structure of the α3(VI) chain. Other variants can also disrupt the structure of the α3(VI) chain.

Variants in the COL6A3 gene affect type VI collagen in different ways. Some variants lead to altered α3(VI) chains that can be incorporated into the mature type VI collagen molecule, although they disrupt the molecule's structure and function. Other variants result in an altered chain that cannot be incorporated at all. Still other variants prevent the production of any functional α3(VI) chain, which impedes formation of type VI collagen. All of these COL6A3 gene variants lead to a reduction or absence of functional collagen VI molecules. While it is difficult to predict the severity of collagen VI-related dystrophy based on the type of variant, in general, lower amounts of type VI collagen lead to more severe signs and symptoms that begin earlier in life.

Changes in α3(VI) chain structure or production lead to an unstable extracellular matrix that is no longer attached to cells through the basement membrane. As a result, the stability of muscle cells and connective tissue progressively declines, which leads to the muscle weakness, contractures, and other signs and symptoms of collagen VI-related dystrophy.

Limb-girdle muscular dystrophy

MedlinePlus Genetics provides information about Limb-girdle muscular dystrophy

Other Names for This Gene

• CO6A3_HUMAN
• collagen alpha-3(VI) chain
• collagen type VI alpha 3
• collagen VI, alpha-3 polypeptide
• collagen, type VI, alpha 3

Genomic Location

The COL6A3 gene is found on chromosome 2.

In some cases, a person who has Bethlem myopathy inherited the mutation from one affected parent. In these cases, future children of this parent will also have a 50% chance to inherit the disease. The parent who has the disease may be so mildly affected that they didn’t know they were showing symptoms of the disease at all.

In rare cases, Bethlem myopathy is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive disease each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the disease. These individuals are known as carriers. When two carriers of a gene mutation causing Bethlem myopathy have children, for each child there is a:

• 25% chance that the child will have Bethlem myopathy
• 50% chance that the child will be a carrier of Bethlem myopathy like the parents
• 25% chance that the child will have two working copies of the gene that makes type VI collagen, so the child will not have Bethlem myopathy and will not be a carrier.

In addition to the muscle problems, some people with Bethlem myopathy have skin abnormalities. These abnormalities may include small bumps called follicular hyperkeratosis that develop around the elbows and knees or soft, velvety skin on the palms and soles. Some people may also have wounds that split open with little bleeding and widen over time to create shallow scars. Rarely, individuals with Bethlem myopathy may develop breathing problems as the disease progresses.

• Blood test measuring creatine kinase (CK) levels: these levels will typically be normal or only slightly elevated
• Skin biopsy
• Muscle MRI
• Electromyography (EMG)

Genetic testing of the COL6A1, COL6A2, and COL6A3genes can confirm the diagnosis.

Treatment for Bethlem myopathy is symptomatic and supportive. This means that treatment aims to relieve symptoms and improve quality of life. There is currently no cure for the disease, and there are no specific medications for Bethlem myopathy. In many cases, physical therapy, stretching exercises, braces, splints, and mobility aids such as a walker or wheelchair are helpful. In rare cases, surgery may be needed to help with joint contractures or scoliosis.

Bethlem myopathy is not expected to shorten a person’s lifespan. People with Bethlem myopathy have symptoms that affect them for their whole lives, including progressive muscle weakness. About 66% of people with this disease require a walker, cane, or wheelchair after the age of 50 years. In some cases, people with Bethlem myopathy may require respiratory therapy, especially at night, to help them breathe. However, life-threatening complications associated with the disease are rare.