Bethlem myopathy

Bethlem myopathy is caused by mutations (changes) in the 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.

Bethlem myopathy is typically diagnosed based on a clinical evaluation that identifies signs and symptoms typical of people with the disease. A healthcare provider may recommend additional laboratory test including:

• 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 COL6A3 __genes can confirm the diagnosis.

Bethlem myopathy is typically inherited in an autosomal dominant manner, meaning one copy of the altered gene in each cell is sufficient to cause the disease. We inherit one copy of each of our genes from our mother and the other from our father. Many cases of Bethlem myopathy result from new (de novo) mutations in the gene, meaning the mutations were not inherited from either parent. When people who have a new mutation in a gene causing Bethlem myopathy go on to have children, each of their children will have a 50% chance of inheriting the disease.

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.

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 COL6A3 __ genes. 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.

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.

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.