Limb-girdle muscular dystrophy type 2B (LGMD2B) is one type of limb-girdle muscular dystrophy. These diseases affect the voluntary muscles, which are the muscles that are moved on purpose, such as the arms, legs, fingers, toes, and facial muscles. Specifically, LGMD2B is a slowly progressive disease that causes muscle weakness and wasting (atrophy) of the pelvic muscles and muscles of the shoulder girdle. People who are Jewish, and specifically those of Libyan Jewish descent, are more likely to have LGMD2B.

LGMD2B is caused by variations (also known mutations) in the DYSF gene. The disease is inherited in an autosomal recessive manner. Diagnosis of LGMD2B is suspected in people who have signs and symptoms of the disease, and the diagnosis can be confirmed by a muscle biopsy and genetic testing. While there are no treatments that can reverse the muscle weakness associated with the disease, supportive treatment can decrease complications.

DYSF gene. When a genetic change causes a disease, it is also known as a pathogenic variation. The DYSF gene provides instructions to make a protein called dysferlin. Dysferlin is found in the thin membrane (sarcolemma) that surrounds muscle fibers. Scientists believe dysferlin is involved in repairing muscle fibers damaged naturally through use and may also be involved in the control of muscle inflammation. When there is a pathogenic mutation in the DYSF gene, the instructions to make dysferlin are not correct, which means the protein is either not made at all or the protein that is made cannot do its job properly. Without working dysferlin, the muscles are not able to repair themselves correctly and may become inflamed too easily leading to further damage to the muscle. Over time, this leads to the muscle weakness and wasting associated with LGMD2B.

Normal Function

The DYSF gene provides instructions for making a protein called dysferlin. This protein is found in the thin membrane called the sarcolemma that surrounds muscle fibers. Dysferlin is thought to aid in repairing the sarcolemma when it becomes damaged or torn due to muscle strain. Researchers suggest that dysferlin may also be involved in the formation of new muscle fibers (regeneration) and in inflammation, but little is known about these functions.

Health Conditions Related to Genetic Changes

Limb-girdle muscular dystrophy

More than 140 mutations in the DYSF gene that can cause limb-girdle muscular dystrophy type 2B have been identified. Limb-girdle muscular dystrophy is a group of related disorders characterized by muscle weakness and wasting (atrophy), particularly in the shoulders, hips, thighs, and upper arms. Muscle problems caused by DYSF gene mutations, such as limb-girdle muscular dystrophy type 2B and others (see below), are called dysferlinopathies.

DYSF gene mutations may disrupt the function of the dysferlin protein and interfere with the muscle repair process. Studies suggest that inefficient repair of damaged muscle fibers may lead to inflammation and degeneration of muscles, resulting in muscle weakness.

Miyoshi myopathy

More than 100 mutations in the DYSF gene have been found to cause Miyoshi myopathy. This condition is a muscle disorder that is characterized by progressive weakness and atrophy of muscles that are away from the center of the body (distal muscles), particularly those in the legs. The DYSF gene mutations identified in people with Miyoshi myopathy change single amino acids in the dysferlin protein, which impairs the protein's function or results in the production of a nonfunctional protein. A common cause of the condition in people of Japanese ancestry is a mutation that replaces the amino acid tryptophan with the amino acid cysteine at position 999 in dysferlin (written Trp999Cys or W999C).

A lack of normal dysferlin leads to a reduced ability to repair damage done to the sarcolemma of muscle fibers. As a result, damage accumulates and leads to atrophy of the muscle fiber. It is unclear why the DYSF gene mutations that cause Miyoshi myopathy lead to the specific pattern of weakness and atrophy that is characteristic of this disorder.

Some researchers consider Miyoshi myopathy to be a variant of limb-girdle muscular dystrophy (see above) rather than a separate disorder because they are caused by mutations in the same gene and have overlapping signs and symptoms.

Other disorders

DYSF gene mutations also cause another dysferlinopathy called distal myopathy with anterior tibial onset. In this condition, the muscle weakness is most apparent in the muscles of the lower legs. This condition first becomes apparent in a muscle called tibialis anterior, which is located at the front of the lower leg and helps to flex the foot. Distal myopathy with anterior tibial onset later affects the muscles of the upper leg, and affected individuals eventually require wheelchair assistance.

Other Names for This Gene

• DYSF_HUMAN
• dysferlin, limb girdle muscular dystrophy 2B (autosomal recessive)
• dystrophy-associated fer-1-like 1
• fer-1-like protein 1
• FER1L1
• FLJ00175
• FLJ90168
• LGMD2B

Genomic Location

The DYSF gene is found on chromosome 2.

DYSFgene in each cell of the body. We inherit one copy of each gene from our mother and the other from our father. People who have only one changed copy of the DYSF gene are known as carriers of the disease. Carriers of LGMD2B typically do not have any signs or symptoms of the disease. When two carriers of LGMD2B have children, each child has a:

• 25% chance to have LGMD2B
• 50% chance to be a carrier of LGMD2B like each parent
• 25% chance to have inherited two working copies of the DYSF gene, so he or she is not a carrier and is not affected with the disease

The symptoms of LGMD2B typically begin in adolescence or young adulthood. The age of onset ranges from 15 to 35 years, and the legs are usually the first part of the body affected. Symptoms that may be common in other types of limb-girdle muscular dystrophy, such as heart (cardiac) and breathing (respiratory) problems, are uncommon in people with LGMD2B. The signs and symptoms of people with LGMD2B can vary, even among members of the same family.

• Electromyography (EMG)
• Creatine-kinase levels
• Muscle biopsy
• Immunoblotting to determine if the dysferlin protein is present at typical levels

Genetic testing of the DYSF gene may be ordered to confirm the diagnosis of LGMD2B and to help identify family members who are carriers of the disease.

• Weight control to avoid obesity
• Physical therapy and stretching exercises
• Use of mechanical aids such as canes, walkers, and wheelchairs

It is recommended that people with LGMD2B be provided with social and emotional support to cope with the diagnosis. Other specialists that may be recommended include a neurologist, occupational therapist, nutritionist, and genetic counselor. No currently available medications can relieve or reverse the symptoms associated with LGMD2B. However, research is ongoing to try to determine if treatments such as gene therapy may be helpful in the future.

In general, limb-girdle muscular dystrophy type 2B (LGMD2B) is a slowly progressive disease, meaning the muscle weakness slowly continues to worsen. Eventually, most people with LGMD2B require a wheelchair, but this may be years after the diagnosis. Muscle weakness affecting the heart muscles or muscles necessary for breathing is uncommon in people with LGMD2B. In rare cases, the progression of the disease may be more rapid, with people requiring a wheelchair in one or two years after symptoms begin.