Limb-girdle muscular dystrophy (LGMD) encompasses a diverse group of hereditary degenerative muscle disorders characterized by weakness and deterioration of the proximal skeletal muscles.
Description
The term limb-girdle muscular dystrophy is used to describe a group of muscular dystrophies that cause a muscle deterioration that primarily affects the voluntary muscles around the limb girdle. The muscles of the limb girdle include those around the shoulders and hips. As the disease develops, the distal muscles of the limbs can become affected. Most individuals' muscles of the heart are not affected, but exceptions can occur. There are at least 15 different LGMDs, each having a different range of symptoms. Each of the muscular dystrophies results in an absent, deficient, or abnormal protein that is required for normal structure and function of the muscles. It can be difficult to differentiate LGMD from other muscular dystrophies and muscle disorders that can also result in a weakness in the limb girdle.
Genetic profile
Each type of limb-girdle muscular dystrophy is caused by changes in a different type of gene that produces a protein normally involved in the functioning of the skeletal muscles. Each gene is found at a specific location on a chromosome. Every person inherits two copies of gene, one from their mother and one from their father. Each type of gene produces a specific type of protein. A change (mutation) in a gene can cause it to produce an abnormal protein, an increased or decreased amount of normal protein, or to stop producing protein altogether. Abnormal or decreased amounts of skeletal muscle proteins can affect the development or functioning of the muscle cells, causing the symptoms of LGMD. Most forms of LGMD are autosomal recessive, although some rare forms are autosomal dominant.
An autosomal recessive form of LGMD is caused by a change in both genes of a pair. One of the changed genes is inherited from the egg cell of the mother and one is inherited from the sperm cell of the father. Parents who have a child with an autosomal recessive form of LGMD are called carriers, since they each possess one changed LGMD gene and one unchanged LGMD gene. Carriers do not have any symptoms as they have only one unchanged gene, which produces enough normal protein to prevent the symptoms of LGMD. Each child born to parents who are both carriers for the same type of LGMD has a 25% chance of having LGMD, a 50% chance of being a carrier, and a 25% chance of being neither a carrier nor affected with LGMD. Parents who are each a carrier for a different type of LGMD are not at increased risk for having children affected with LGMD.
The autosomal dominant forms of LGMD are caused by a change in only one gene of a pair. This changed gene is inherited from either the mother or the father. If the changed gene is inherited, each child born to a carrier of LGMD has a 50% chance of inheriting the condition. Sometimes the change occurs spontaneously when the egg and sperm come together to form the first cell of the baby. In this case, other relatives, such as siblings, are probably not at increased risk for inheriting LGMD. People with an autosomal dominant form of LGMD have a 50% chance of passing the condition on to their children. Some people who possess an autosomal dominant LGMD gene change do not have any symptoms.
Demographics
The incidence of LGMD is difficult to estimate as it can have a wide variety of symptoms. The rate of incidence of LGMD is one in 14,500–123,000 people, and is found equally in men and women. LGMD is also difficult to differentiate from other muscular disorders. Some forms of LGMD are found more commonly in people of a certain ethnic background.
Signs and symptoms
Each type of LGMD has a different range of symptoms. The symptoms can even vary between individuals with the same type of LGMD. The age of onset of symptoms can occur from infancy to adulthood. The most common symptom of LGMD is muscle weakness and deterioration and involves the muscles around the hips and shoulders. The disorder progresses at a different rate in each person. Although individuals with an onset of the disorder in adulthood may have a slower progression and milder symptoms, the exact progression and extent of muscle deterioration cannot be predicted,.
The first noticeable symptom of LGMD is often a waddling gait due to weakness of the hip and leg muscles. Difficulties in rising from a chair or toilet seat and difficulties in climbing stairs are common. Eventually, walking may become impossible and lead to resorting to a wheelchair or scooter for locomotion. Enlargement or a decrease in size of the calf muscles can also be seen. Some individuals with LGMD also experience contractures and muscle cramps. The limited mobility associated with LGMD can result in muscle soreness and joint pain.
Lifting heavy objects, holding the arms outstretched, and reaching over the head can become impossible for people affected with LGMD because of weaknesses in the shoulder muscles. Some individuals with LGMD may eventually have difficulties swallowing and feeding themselves. Sometimes the back muscles can become weakened and result in scoliosis (curvature of the spine).
TABLE 1 Genetic causes of the limb-girdle muscular dystrophies
*Each tupe of sarcoglycanopathy can result from a gene change that results in complete absence sarcoglycan protein or decreased amounts of sarcoglycan protein
LGMD can occasionally result in a weakening of the heart muscles and/or the respiratory muscles. Some people may experience a weakening of the heart muscles (cardiomyopathy). Others may develop a conduction defect, an abnormality in the electrical system of the heart that regulates the heartbeat. A weakening of the muscles necessary for respiration can cause breathing difficulties. LGMD does not affect the brain and the ability to reason and think. Individuals with LGMD also do maintain normal bladder and bowel control and sexual functioning.
Diagnosis
No single test can diagnose LGMD. A diagnosis is based on clinical symptoms, physical examinations, and a variety of tests. The physician will first take a medical history to establish the type of symptoms experienced and the pattern of muscle weakness. Questions will usually be asked about the family history to see whether other relatives have similar symptoms.
It is necessary for the doctor to establish whether the weakness is due to problems with the muscles or due to a problem with the nerves that control the muscles. Sometimes this can be accomplished through a physical examination. Electromyography testing is often performed to establish whether the weakness is in the nerves or the muscles. During electromyography, a needle electrode is inserted into the muscle and measurements are taken of the electrical activity of the muscle in response to stimulation by the nerves.
A blood test that measures the amount of creatine kinase is often performed. Creatine kinase is an enzyme that is produced by damaged muscles. High levels of creatine kinase suggest that the muscle is being destroyed, but the high levels cannot indicate the cause of the damage. The most common causes of increased creatine kinase levels are muscular dystrophy and muscle inflammation.
A muscle biopsy will often be performed if LGMD is suspected. During the muscle biopsy, a small amount of muscle is surgically removed. The muscle sample is examined to check for changes that are characteristic of muscular dystrophies. The amount and type of muscle proteins present in the sample can sometimes help to confirm a diagnosis of LGMD and can sometimes indicate the type of LGMD.
Ultimately, a diagnosis can be difficult to make as there are many types of LGMD and a wide range of symptoms. It can also be difficult to differentiate LGMD from other muscular dystrophies that have similar symptoms, such as Becker and Duchenne muscular dystrophies. Anyone suspected of having LGMD should, therefore, consider undergoing testing for other types of muscular dystrophies.
DNA testing for some forms of LGMD is now available through clinical and commercial laboratories. DNA testing is complicated by the many genes and the types of gene mutations (changes) that can cause LGMD. Some research laboratories are looking for the gene mutations that cause LGMD and may detect the gene mutation or mutations responsible for LGMD in a particular individual. DNA testing may be performed on a sample of blood cells or a sample of muscle cells. If an autosomal dominant gene mutation is detected in someone with LGMD, then both of the individual's parents can be tested to see if the gene mutation was inherited. If the gene mutation was inherited, siblings can be tested to see if they have inherited the mutated gene. If autosomal recessive gene mutations are detected, relatives, such as siblings, can be tested to see if they are carriers.
TABLE 2 Frequency of limb-girdle muscular dystrophy
Prenatal testing for LGMD is only available if DNA testing has detected an autosomal dominant LGMD gene mutation in one parent or an autosomal recessive gene mutation in both parents. Cells for prenatal testing are obtained through an amniocentesis or chorionic villus sampling (CVS). These cells are analyzed for the LGMD gene mutation or mutations that were found in one or both parents.
Treatment and management
Physical therapy and exercises can often help keep the muscles and joints mobile and prevent contractures. Muscle and joint pain can be treated through exercise, warm baths, and pain medications. Surgical treatment of complications, such as a curved spine, may be necessary. Breathing exercises can sometimes help if breathing becomes difficult. If breathing independently becomes impossible, a portable mechanical ventilator can be used. A wheelchair or scooter can help when a person can no longer walk. Medications are often prescribed for cardiomyopathies and heart conduction defects. A device such as a pacemaker that creates normal contractions of the heart muscle may be necessary for some people with heart muscle abnormalities.
Gene therapy may one day cure or improve LGMD. Gene therapy introduces unchanged copies of a LGMD gene into the muscle cells. The goal of therapy is for the normal LGMD gene to produce normal protein that will allow the muscle cells to function normally. Gene therapy clinical trials are still in their infancy. It will take quite a few years, however, for gene therapy to become a viable way to treat LGMD.
TABLE 3 Symptoms of the limb-girdle muscular dystrophies
Type
Age of Onset
Early Symptoms
Late Symptoms
*Includes alpha, beta, gamma and delta sarcoglycanopathies that result in complete absence of a sarcoglycan protein
**Includes alpha, beta, gamma and delta sarcoglycanopathies that result in decreased amounts of a sarcoglycan protein
Floppy muscles in infancy; Proximal muscle weakness; Contractures
2/3 of patents are wheelchair dependent by age 50
Prognosis
The prognosis of LGMD varies tremendously. Most people with LGMD, however, do not have severe symptoms and most experience a normal life expectancy. Cardiac and respiratory difficulties can, however, decrease the lifespan.
PERIODICALS
Bushby, K. "Making Sense of the Limb-girdle Muscular Dystrophies." Brain 122 (1999): 1403–1420.
Kirschner, J, and C. G. Bonnemann. "The Congenital and Limb-girdle Muscular Dystrophies: Sharpening the Focus, Blurring the Boundaries." Arch Neurol 61, no. 2 (2004): 189–199.
Laval, S. H., and K. M. Bushby. "Limb-girdle Muscular Dystrophies—From Genetics to Molecular Pathology." Neuropathology and Applied Neurobiology 30 (2004): 91–105.
Zatz, M., M. Vainzof, and M. R. Passos-Bueno. "Limb-girdle Muscular Dystrophy: One Gene with Different Phenotypes, One Phenotype with Different Genes." Current Opinion in Neurology 13, no. 5 (October 2000): 511–517.
ORGANIZATIONS
Muscular Dystrophy Association. 3300 East Sunrise Dr., Tucson, AZ 85718. (520) 529-2000 or (800) 572-1717. <http://www.mdausa.org/>.
Muscular Dystrophy Association Canada. 2345 Yonge St., Suite 900, Toronto, ONT M4P 2E5, Canada. (416) 488-2699. E-mail: info@mdac.ca. (April 21, 2005.) <http://www.mdac.ca/>.
