Limb-Girdle Muscular Dystrophy
What is LGMD?


Overview


Limb-girdle muscular dystrophy (LGMD) is a group of diseases that cause weakness and wasting of the muscles in the arms and legs.

  • The muscles most affected are those closest to the body (proximal muscles), specifically the muscles of the shoulders, upper arms, pelvic area, and thighs. Eventually, however, all skeletal muscles are affected.

    Illustration of man with LGMD.

    Limb-girdle muscular dystrophy (LGMD) is a group of diseases that cause weakness and wasting of the muscles in the arms and legs.

    The severity, age of onset, and features of LGMD vary among the many subtypes. Signs and symptoms may first appear at any age and generally worsen with time, although in some cases they remain mild. However, within each LGMD subtype, the severity, age of onset, and features demonstrate a high degree of consistency.

    In the early stages of LGMD, affected individuals may have an unusual walking gait, such as waddling or walking on the balls of their feet, and may also have difficulty running. They may need to use their arms to press themselves up from a squatting position because of their weak thigh muscles. As the condition progresses, people with LGMD eventually require wheelchair assistance.

    Muscle wasting may cause changes in posture or in the appearance of the shoulder, back, and arm. In particular, weak shoulder muscles tend to make the shoulder blades (scapulae) “stick out” from the back, a sign known as scapular winging. Affected individuals may also have an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Some develop joint stiffness (contractures) that can restrict movement in their hips, knees, ankles, or elbows. Overgrowth (hypertrophy) of the calf muscles occurs in some people with LGMD.

    Weakening of the heart muscle (cardiomyopathy) occurs in some forms of LGMD, most notably the sarcoglycanopathies (LGMD2C, LGMD2D, LGMD2E, and LGMD2F) and dysferlinopathy (LGMD2B). Some affected individuals experience mild to severe breathing problems related to the weakness of muscles needed for breathing. In some cases, the breathing problems are severe enough that affected individuals need to use a machine to help them breathe (mechanical ventilation). Death resulting from cardiopulmonary insufficiency can occur before age 30 in some subtypes.

  • LGMD can be caused by mutations in many different genes. These genes provide cells with instructions for making proteins that are involved in muscle maintenance and repair.

    Illustration of LGMD mutation

    LGMD can be caused by mutations in many different genes.

    Some of the proteins produced from these genes assemble with other proteins into larger protein complexes. These complexes maintain the physical integrity of muscle tissue and allow the muscles to contract. Other proteins participate in cell signaling, cell membrane repair, or the removal of potentially toxic wastes from muscle cells.

    Most forms of LGMD are 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 condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Autosomal recessive forms of LGMD are known as Type 2 forms, characterized by having a numeral two in their names, e.g. LGMD2B.

    Several rare forms of LGMD are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Autosomal dominant forms of LGMD are known as Type 1 forms, characterized by having a numeral one in their names, e.g. LGMD1B.

  • After carefully evaluating a patient’s medical history, the doctor will perform a thorough physical exam. If muscular dystrophy (MD) is suspected, there are a variety of laboratory tests that can be used to confirm the diagnosis. These tests may include:

    Blood tests: When blood tests are performed to test for MD, the doctors are looking for an enzyme called creatine kinase (CK). Elevated CK level is noted when there is muscle damage and is a very helpful marker for MDs.

    Electromyogram (EMG): EMG is a test that measures the muscle’s response to stimulation of its nerve supply (nerve conduction study) and examines the electrical activity of muscles (needle electrode examination). This test is very helpful in demonstrating that the weakness is due to a muscle disease rather than a nerve disease.

    Muscle biopsy: During a muscle biopsy, a small piece of muscle tissue is removed, sent to a pathology lab for specific staining, and then examined under a microscope. If MD is present, changes in the structure of muscle cells and the findings on different immunohistochemical stainings can help with the diagnosis of MDs.

    Genetic testing: Many MDs can be definitively diagnosed by testing for the mutated genes. In many instances, this is the most specific test to diagnose MDs. If clinical features and family history point to specific types of MDs, neuromuscular specialists might directly go to genetic testing and skip muscle biopsy. This approach is common in LGMDs.

  • There is currently no cure for LGMD. Care is focused on physical therapy, occupational therapy, surgery to correct musculoskeletal complications, cardiac care, and respiratory care. These treatments aim to prevent complications caused by the disease manifestation, including muscle weakness, decreased mobility, contractures, scoliosis, heart defects, and respiratory insufficiency.

    Learn more about the Myonexus treatments in development.


LGMD Subtypes

  • LGMD2E or Beta-sarcoglycanopathy is an ultra-rare, severe, debilitating condition characterized by progressive muscle fiber loss, inflammation, and muscle fiber replacement with fat and fibrotic scars, leading to continually deteriorating muscle strength and function.

    The disease affects approximately 3.3 per million newborns without regard to sex, race, or national origin. The disease is an autosomal recessive genetic disorder, meaning the patient inherited one defective beta-sarcoglycan gene each from both parents. Patients most commonly first present with difficulty running, jumping and climbing stairs at about age 3-5 years. Patients typically become wheelchair dependent in their mid- to late-teens. Respiratory impairment occurs as the disease progresses, leading to the need for ventilator assistance. Scoliosis and joint contractures develop over time as well. Cardiac muscle involvement and decline is also fairly typical. Patients often succumb to the continuing muscle deterioration in their late 20’s to early 30’s. Currently there is no cure or treatment for LGMD2E.

  • LGMD2D or alpha-sarcoglycanopathy is an ultra-rare, severe, debilitating condition characterized by progressive muscle fibers loss, inflammation, and muscle fiber replacement with fat and fibrotic scars. LGMD2D is believed to be the most common sarcoglycanopathy, affecting approximately 3.5 per million newborns without regard to sex, race, or national origin.

    The disease is an autosomal recessive genetic disorder, meaning the patient inherited one defective alpha-sarcoglycan gene each from both parents. The usual age of onset of symptoms ranges from 3-10 years, but in some cases symptoms don’t appear until early adulthood. A marker of muscle damage (creatine kinase (CK)) is markedly elevated in these patients, with 50 to 100X normal levels not unusual. LGMD2D most often first presents with weakness of muscles in the hip, shoulder and abdomen. Subjects usually become wheelchair dependent by age 13-15. Respiratory impairment occurs as the disease progresses, leading to the need for ventilatory assistance. Scoliosis and joint contractures develop over time as well. Currently there is no cure or treatment for LGMD2D.

  • LGMD2C or gamma-sarcoglycanopathy is an ultra-rare, severe, debilitating condition characterized by progressive muscle fiber loss, inflammation, and muscle fiber replacement with fat and fibrotic scars, leading to continually deteriorating muscle strength and function.

    LGMD2C is one of the most severe muscular dystrophies, affecting approximately two per million newborns without regard to sex, race or national origin. The disease is an autosomal recessive genetic disorder, meaning the patient inherited one defective gamma-sarcoglycan gene each from both parents. The muscles most affected in LGMD2C are those surrounding the shoulder, hips and nearby muscles in the arms and legs. Symptoms of LGMD2C usually appear around 6-8 years of age and can progress to wheelchair dependence by 12-16 years of age. Enlargement of the calf muscle, tongue and heart are common, as are respiratory abnormalities. Currently there is no cure or treatment for LGMD2C.

  • LGMD2B and Myoshi Myopathy (MMD1) are slightly different clinical manifestations of a rare, severe debilitating recessive genetic disease also known as dysferlinopathy.

    The rate of progression of LGMD2B/Myoshi is fairly slow compared to most other muscular dystrophies but is also characterized by chronic progressive muscle fiber loss, inflammation, and muscle fiber replacement by fat infiltration and fibrotic scars, leading to continually deteriorating muscle strength and function. Dysferlinopathy affects approximately 8.1 per million newborns worldwide affecting both sexes, all races, and all national origins. The disease is an autosomal recessive genetic disorder, meaning the patient inherited one defective dysferlin gene each from both parents. Typically, patients present in their early 20’s with slowly progressive muscle weakness and high serum levels of a marker of muscle damage (creatine kinase (CK)). As the disease progresses, patients experience muscle weakness in both proximal and distal limbs. Approximately one-third of patients become wheelchair-dependent within 15 years of onset of symptoms and generally progressive challenges in performing activities of daily living. This type of muscular dystrophy does not affect the heart muscle. Currently there is no cure or treatment for LGMD2B.

  • LGMD2L, ANO5-related muscle disease or anoctaminopathy is an ultra-rare, often debilitating condition characterized by progressive muscle fiber loss, inflammation and muscle fiber replacement with fat and fibrotic scars, leading to continually deteriorating muscle strength and function.

    The disease affects approximately 5.5 per million newborns without regard to sex, but appears to be much more common in people of northern European descent. The disease is an autosomal recessive genetic disorder, meaning the patient inherited one defective anoctamin 5 gene each from both parents. LGMD2L is a late onset (avg age of 35, range 15-70 years) proximal lower-limb weakness with markedly elevated creatine kinase (a biomarker of muscle injury); usually 10-50 times the upper limit of normal. Joint contractures (tightening) are not a frequent feature in LGMD2L, however they can occur as a consequence of the reduced mobility of these patients. It is not infrequent that one side of the body is more severely affected than the other. The weakness and wasting of the lower limbs can lead to frequent falls, and difficulty in running, climbing stairs, and raising up from the floor. As the condition progresses, patients can also develop some weakness in their arms, resulting in difficulties with lifting heavy objects. The severity of the disease is variable from person to person and even amongst members of the same family. Currently there is no cure or treatment for LGMD2L.