muscular dystrophy

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Definition

Muscular dystrophy is the name for a group of inherited disorders in which strength and muscle bulk gradually decline. Nine types of muscular dystrophies are generally recognized.

Description

The muscular dystrophies include:

• Duchenne muscular dystrophy (DMD): DMD affects young boys, causing progressive muscle weakness, usually beginning in the legs. It is the most severe form of muscular dystrophy. DMD occurs in about 1 in 3,500 male births, and affects approximately 8,000 boys and young men in the United States. A milder form occurs in very few female carriers.
• Becker muscular dystrophy (BMD): BMD affects older boys and young men, following a milder course than DMD. BMD occurs in about 1 in 30,000 male births.
• Emery-Dreifuss muscular dystrophy (EDMD): EDMD affects young boys, causing contractures and weakness in the calves, weakness in the shoulders and upper arms, and problems in the way electrical impulses travel through the heart to make it beat (heart conduction defects). Fewer than 300 cases of EDMD have been identified.
• Limb-girdle muscular dystrophy (LGMD): LGMD begins in late childhood to early adulthood and affects both men and women, causing weakness in the muscles around the hips and shoulders. It is the most variable of the muscular dystrophies, and there are several different forms of the disease now recognized. Many people with suspected LGMD have probably been misdiagnosed in the past, and therefore the prevalence of the disease is difficult to estimate. The number of people affected in the United States may be in the low thousands.
• Facioscapulohumeral muscular dystrophy (FSH): FSH, also known as Landouzy-Dejerine disease, begins in late childhood to early adulthood and affects both men and women, causing weakness in the muscles of the face, shoulders, and upper arms. The hips and legs may also be affected. FSH occurs in about 1 out of every 20,000 people, and affects approximately 13,000 people in the United States.
• Myotonic dystrophy: also known as Steinert's disease, affects both men and women, causing generalized weakness first seen in the face, feet, and hands. It is accompanied by the inability to relax the affected muscles (myotonia). Symptoms may begin from birth through adulthood. It is the most common form of muscular dystrophy, affecting more than 30,000 people in the United States.
• Oculopharyngeal muscular dystrophy (OPMD): OPMD affects adults of both sexes, causing weakness in the eye muscles and throat. It is most common among French Canadian families in Quebec, and in Spanish-American families in the southwestern United States.
• Distal muscular dystrophy (DD): DD begins in middle age or later, causing weakness in the muscles of the feet and hands. It is most common in Sweden, and rare in other parts of the world.
• Congenital muscular dystrophy (CMD): CMD is present from birth, results in generalized weakness, and usually progresses slowly. A subtype, called Fukuyama CMD, also involves mental retardation. Both are rare; Fukuyama CMD is more common in Japan.

— Richard Robinson

1. Any of a group of progressive muscle disorders caused by a defect in one or more genes that control muscle function and characterized by gradual irreversible wasting of skeletal muscle.
2. Duchenne's muscular dystrophy.

Definition

Muscular dystrophies (MD) are inherited disorders characterized by progressive weakness and degeneration of the skeletal or voluntary muscles which control movement, without a central or peripheral nerve abnormality. The muscles of the heart and other involuntary muscles are also affected in some forms of MD, and a few forms involve other organs as well. The major forms of muscular dystrophy include myotonic, Duchenne, Becker, limb-girdle, facioscapulohumeral, congenital, oculopharyngeal, distal, Emery-Dreifuss and Fukuyama muscular dystrophy.

Description

The commonest form of these inherited disorders is the Duchenne muscular dystrophy (DMD). The disorder was originally described in the mid-nineteenth century by the English physician Edward Meryon. At a meeting of the Royal Medical and Chirurgical Society in 1851, and later published in the transactions of the society, he described in detail the clinical presentation of Duchenne muscular dystrophy, beginning in early childhood with progressive muscle wasting and weakness and leading to death in late adolescence. Furthermore, his detailed histological studies led him to conclude that the muscle membrane or sarcolemma was broken down and destroyed.

Duchenne muscular dystrophy will usually produce symptoms between the ages of three and seven in young boys. It begins with a weakness in the pelvic area first and then progresses to the shoulder muscles. As the disorder escalates, the muscles enlarge although the muscle tissue is weak. The heart muscle will also enlarge, creating problems with the heartbeat that can be detected on an electrocardiogram. In most cases, the affected child has a waddling walk, often falls, has difficulty rising from a sitting position, has a difficult time climbing stairs, is unable to fully extend the arms and legs, and may develop scoliosis (an abnormally curved spine). In most cases, children with DMD are confined to a wheel chair between the ages of ten and twelve.

Most people with Becker muscular dystrophy (BMD) first experience difficulties between the ages of five and fifteen years, although onset in the third or fourth decade or even later can occur. By definition, patients with BMD are able to walk beyond age fifteen, while patients with DMD are typically in a wheelchair by the age of twelve. Patients with BMD have a reduced life expectancy, but most survive into the fourth or fifth decade. Mental retardation may occur in BMD, but it is not as common as in DMD. Cardiac (heart muscle) involvement occurs in BMD and may result in heart failure.

Myotonic muscular dystrophy (MMD) affects the muscles in the hands and feet. Limb-girdle muscular dystrophy (LGMD) begins late in childhood affecting mainly the muscles of the shoulders and hips. Facioscapulohumeral muscular dystrophy (FSHD) affects only the muscles of the upper arms, face and shoulder girdle. Landouzy-Dejerine muscular dystrophy (LDMD), which is transmitted by an autosomal dominant gene, affects the face, shoulder and lower leg muscles.

Other disorders related to muscular dystrophy include Steinert's disease, Thomsen's disease, and Pompe's disease. Steinert's disease affects both males and females, causing the muscles to be unable to relax after contracting, while Thomsen's disease causes a stiffness of the legs, hands and eyelids. Pompe's disease, which is a glycogen storage disease, affects the liver, heart, nerves and muscles.

Demographics

United States

The incidence of muscular dystrophy varies, depending on the specific type. Duchenne muscular dystrophy is the most common condition. It is inherited on the X chromosome, primarily affects boys, and is the most severe type of the disease. Although women with the defective gene are carriers, they usually show no symptoms. DMD has an inheritance pattern of 1 case per 3,500 live male births, and one-third of cases are due to spontaneous new mutations.

Becker muscular dystrophy is the second most common form, with an incidence of 1 case per 30,000 live male births. Like DMD, BMD is linked to the X chromosome. Other types of MD are rare. Limb-girdle muscular dystrophy includes several different illnesses, which can be inherited by both males and females, as can facioscapulohumeral muscular dystrophy.

International

The incidence of muscular dystrophies internationally is similar to that of the United States, however some types are especially frequent in certain populations and are rare elsewhere. For example, autosomal dominant distal muscular dystrophy occurs more often in Scandinavia than elsewhere, Fukuyama muscular dystrophy in Japan, oculopharyngeal muscular dystrophy in French Canada, and several autosomal recessive LGMD in communities in Brazil, North America, and the Middle East.

Causes and symptoms

All types of muscular dystrophy are inherited. They are caused by a defect in one or more of the genes that control muscle structure and function. Some types are inherited as a dominant gene abnormality, while others are inherited as a recessive gene abnormality or an X-linked recessive gene abnormality. In an X-linked recessive gene abnormality, the gene is on the X chromosome, one of the pair of chromosomes that determine a person's sex.

Both DMD and BMD are inherited X-linked recessive diseases affecting primarily skeletal muscle and the myocardium (heart muscle). Dystrophin, a large protein that stabilizes the plasma membrane during muscle contractions, is absent in DMD and reduced in BMD. This results in an unstable muscle cell membrane and impaired function in the cell. Muscle fibers continually deteriorate and regenerate until the capacity for repair is no longer sufficient. Muscle fiber tissue is eventually replaced by fat and connective tissue. The abnormal gene for DMD and BMD is on the short arm of the X chromosome at position Xp21.

Two types of MMD are well recognized: noncongenital (NC-MMD, not present at birth) and congenital (CMMD, present at birth). In MMD, a DNA sequence within the gene on chromosome 19q 13.3, is repeated many times, leading to an enlarged, unstable area of the chromosome. Called a triplet repeat mutation, the flawed gene grows by sudden leaps when transmitted from generation to generation, causing the disease to occur at a younger age and in a more severe form (a phenomenon called anticipation). C-MMD patients have been shown to have substantially more repeats than those found in NC-MMD patients.

In FSHD, the abnormal gene is known to be near the end of chromosome 4. Exact DNA testing for diagnostic purposes is not yet available except in some cases, a detailed genetic analysis of a particular family can be accomplished.

Genetic studies with LGMD have identified one form linked to chromosome 15q, another form to chromosome 2p, and two more severe forms to 13ql2 and 17ql2-q21.

Symptoms can first appear during early childhood or late in adult life, depending on the type of muscular dystrophy.

• Duchenne muscular dystrophy—Symptoms usually begin between ages two and four. Because of a progressive weakening of leg muscles, the child falls frequently and has difficulty getting up from the ground. The child also has trouble walking or running normally. By age 12, most patients are unable to walk and are limited to a wheelchair. As the illness progresses, there also is an abnormal curvature of the spine.
• Becker muscular dystrophy—Symptoms are similar to those of DMD, but they are milder and begin later, usually between ages five and fifteen.
• Myotonic muscular dystrophy—Muscle myotonia may develop soon after birth or begin as late as early adulthood, and especially affects the hands, wrists and tongue. There also is wasting and weakening of facial muscles, neck muscles, and muscles of the wrists, fingers and ankles. Involvement of the tongue and throat muscles causes speech problems and difficulty swallowing. If the diaphragm and chest muscle also are involved, there may be breathing problems.
• Limb-girdle muscular dystrophy—Symptoms begin in late childhood or early adulthood. They include progressive muscle weakness in the shoulders and hips, together with breathing problems (if the diaphragm is involved). If illness also affects the heart muscle, there may be heart failure or abnormal heart rhythms.
• Facioscapulohumeral muscular dystrophy—Symptoms may begin during infancy, late childhood, or early adulthood. Usually, the first sign is facial weakness with difficulty smiling, whistling and closing the eyes. Later, there is difficulty raising the arms or flexing the wrists and/or ankles.

Diagnosis

The diagnosis of muscular dystrophy is made with a physical examination and diagnostic testing by the child's physician. During the examination, the child's physician obtains a complete prenatal and birth history and asks if other family members are known to have MD. In addition to a clinical history and a physical exam, others exams may be suggested:

• Serum creatine kinase—Measurement of serum (a blood component) concentration of creatine kinase is a simple and inexpensive diagnostic test for severe forms of dystrophy known to be associated with high concentrations of creatine in the blood. In DMD, serum creatine kinase values are raised from birth, and testing in newborns for early diagnosis could reduce the possibility of further affected boys in a family and improve medical assistance before the onset of symptoms.
• Electromyography—This test is important in the establishment of the myopathic (muscle disease not caused by nerve dysfunction) nature of the disease and for the exclusion of neurogenic (from the nerves) causes of weakness, including peripheral nerve disorders. Because electromyography is an invasive technique involving a needle stick, it is becoming less favored in the investigation of children, but it still has an important role in the diagnosis of adult disease.
• Muscle histology—The one unifying feature of the dystrophies is their similar muscle histological (in the tissues) findings, such as variation in muscle fiber size, muscle fiber death, invasion by macrophages (a versatile immune cell), and ultimately, replacement by fat and connective tissue. This picture is aggravated in the more severe forms of dystrophy, such as Duchenne type. However, in FSHD and LGMD, inflammatory changes in tissues are often the main features.
• Immunohistochemistry and mutation analysis—In some muscular dystrophies, certain proteins are deficient in muscle tissue. Immunohistochemistry involves methods of detecting the presence of these specific proteins in muscle cells or tissues. A diagnosis can be made when these protein deficiencies are identified. Analysis of genetic mutations associated with muscular dystrophies is also important for genetic counseling and prenatal diagnosis.

Treatment team

There are many professionals available to help the child with muscular dystrophy, depending on the patient's needs. These include physicians, orthopedic surgeons (bone specialists), physical therapists, orthotists (specialists on equipment to maintain posture and mobility), occupational therapists, dietitians, nurses, social workers, psychologists, teachers, religious advisers, staff from the Muscular Dystrophy Association, parents, and other persons with MD.

Physical therapy involves a program of stretching exercises to maintain muscle length and the flexibility of joints. Physical therapists also work with orthotists. Night splints, calipers, swivel walkers, and braces are some of the aids employed. Physical therapists are the main professionals involved in teaching parents the appropriate exercises and in making sure that any mobility aids are comfortable. Both physical therapy and hydrotherapy (water therapy) contribute significantly to mobility and respiratory function.

Treatment

Although there is no known cure for muscular dystrophy, exercise and physical therapy are recommended to maintain mobility for as long as possible. Corticosteroid drugs and gene therapies are being studied to help relieve the symptoms.

Specific treatment for muscular dystrophy is determined by the child's physician based on age, overall health, medical history, extent of the condition, type of condition, child's tolerance for specific medications, procedures or therapies.

Drug therapies

In children with Duchenne muscular dystrophy, corticosteroids (such as prednisone) may be prescribed to temporarily delay progression of their illness; however, some patients cannot tolerate this medication because of side effects. Powerful medications that suppress the immune system have been reported to help some patients, but their use is controversial. In patients with MMD, myotonia (abnormally long muscular contractions) may be treated with medications such as carbamazepine or phenytoin.

Gene therapy

With advances in molecular biology techniques, another method of treatment currently under intense investigation is somatic gene therapy. The idea is to introduce healthy immature cells into affected muscles, which would fuse and stimulate production of enough dystrophin to reverse the degeneration already taking place. Although this has been achieved successfully in mice, the benefit may not translate into humans. The mice cannot demonstrate muscle strength, and the laboratory-raised mice were not able to mount a rejection response that may occur in humans.

Other therapies

The orthopedic problems in children with MD lead to progressive weakness with walking difficulties, soft-tissue contractures, and spinal deformities. The role of the orthopedic surgeon is to correct deformities and help maintain the child's ambulatory status for as long as possible. The modalities available to obtain these goals include: functional testing; physical therapy; use of orthoses (specialized aids); fracture management; soft tissue, bone, and spinal surgeries; use of a wheelchair when indicated; and genetic and/or psychological testing.

Recovery and rehabilitation

To date, there is no known treatment, medicine, or surgery that will cure MD, or stop the muscles from weakening. The goal of treatment is to prevent deformity and allow the child to function as independently as possible at home and in the community.

Physical therapy

In general, patients are given supportive care, together with leg braces and physical therapy to maximize their ability to function in daily life. Stretching limbs to avoid tightened tendons and muscles is particularly important. When tightness of tendons develops (called contractures), surgery can be performed. When chest muscles are involved, respiratory therapy may be used to delay the onset of breathing problems. In addition, people with MD are given age-appropriate dietary therapy to help them avoid obesity. Obesity is especially harmful to patients with MD because it places additional strain on their already weak muscles. Unfortunately, many MD patients are at a high risk of obesity because their limited physical activity prevents them from exercising.

Wheelchair prescription

If the person with MD becomes nonambulatory, wheelchair mobility is essential. The wheelchair should complement the patient's lifestyle, providing comfort, safety, and functionality. Special attention should be given to the frame, seat, backrest, front rigging, rear wheels, and casters because of the functional weakness and contractures in the upper and lower extremities of patients with limb-girdle dystrophy. An accessible home and work environment and personal or public transportation with safe restraint systems for the wheelchair are also important.

Additional resources

Specific planning for vocational needs and desires may be coordinated with therapists. Resources within the community, such as the Parks and Recreation Department for activity programs, may be explored. Educational institutions, from public schools to community colleges and universities, have resources that may be used. Adaptive physical education program and Disabled Student Services generally are available for persons with MD.

Clinical trials

There are numerous open clinical trials for MD:

• An open-label pilot study of Oxatomide in steroid-naive DMD, sponsored by Cooperative International Neuromuscular Research Group;
• An open-label pilot study of Coenzyme Q10 in steroid-treated DMD, sponsored by Cooperative International Neuromuscular Research Group;
• Study of Inherited Neurological Disorders, sponsored by National Institute of Neurological Disorders and Stroke (NINDS);
• Study of Albuterol and Oxandrolone in Patients With FSHD, sponsored by the Food and Drug Administration Office of Orphan Products Development.

Updated information on clinical trials is available at the National Institutes of Health website for clinical trials at .

Prognosis

The prognosis varies according to the type of MD and its progression. Some patients have only mild symptoms with a normal lifespan, whereas others have severe symptoms and die at a young age. For example, children with DMD often die before age 18 because of respiratory failure, heart failure, pneumonia or other problems. In persons with BMD, death tends to occur later. Some examples of complications associated with MD that lead to permanent, progressive disability are:

• deformities, such as scoliosis and joint contractures
• decreased mobility
• decreased ability to perform daily self-care tasks, such as bathing and dressing
• mental impairment (varies)
• cardiomyopathy (weakened heart muscle)
• respiratory failure

Special concerns

Genetic counseling is an important aspect of the care and evaluation of patients with DMD and BMD and their family members. A minority of female carriers have MD symptoms, but even in these symptomatic patients, correct diagnosis requires appropriate testing. In families in which an affected male has a known deletion or duplication of the dystrophin gene, testing for carrier status is performed accurately by testing possible carriers for the same mutation, the absence of which would exclude them as a carrier.

Resources

BOOKS

Parker, James N., and Philip M. Parker. The 2002 Official Patient's Sourcebook on Muscular Dystrophy. San Diego: Icon Group International, 2002.

Siegel, Irwin M. Muscular Dystrophy in Children: A Guide for Families. Gardena, CA: Scb Distributors, 1999.

Thompson, Charlotte. Raising a Child with a Neuromuscular Disorder: A Guide for Parents, Grandparents, Friends, and Professionals New York: Oxford Press, 1999.

Wolfson, Penny. Moonrise: One Family, Genetic Identity, and Muscular Dystrophy. New York: St. Martin's Press, 2003.

PERIODICALS

Emery, A. "The muscular dystrophies." The Lancet 359 (February 2002): 687–695.

OTHER

"Facts About Duchenne and Becker Muscular Dystrophies (DMD and BMD)" Muscular Dystrophy Association. (March 20, 2004). http://www.mdausa.org/publications/fa-dmdbmd.html.

"NINDS Muscular Dystrophy (MD) Information Page"

National Institute of Neurological Disorders and Stroke. (March 20, 2004). http://www.ninds.nih.gov/health_and_medical/disorders/md.htm.

ORGANIZATIONS

Muscular Dystrophy Association. 3300 East Sunrise Drive, Tucson, AZ 85718-3208. (520) 529-2000 or (800) 572-1717; Fax: (520) 529-5300. mda@mdausa.org. http://www.mdausa.org/.

Muscular Dystrophy Family Foundation. 2330 North Meridien Street, Indianapolis, IN 46208. (317) 923-6333 or (800) 544-1213; Fax: (317) 923-6334. mdff@mdff.org. http://www.mdff.org/.

Parent Project for Muscular Dystrophy Research. 1012 North University Blvd., Middletown, OH 45042. (413) 424-0696 or (800) 714-KIDS (5437); Fax: (513) 425-9907. ParentProject@aol.com. http://www.parentprojectmd.org.

Francisco de Paula Careta

Iuri Drumond Louro, MD, PhD

A group of muscle diseases that are hereditary and characterized by progressive muscle weakness and wasting.

The muscular dystrophies are primary diseases of the muscle cells characterized by progressive degeneration and replacement by fibrous tissue, resulting in progressive muscle weakness. In some types of muscular dystrophies, the disease appears to be restricted to the skeletal muscles alone (facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy), and in others skeletal-muscle involvement is a part of a more generalized process, with abnormalities in other organ systems as well (Duchenne's muscular dystrophy, myotonic dystrophy). These features as well as the differing patterns of inheritance indicate that the various muscular dystrophies are different diseases with different genetic and biochemical abnormalities underlying them.

The gene for the Duchenne and the Becker muscular dystrophy has been identified. This gene produces the muscle protein dystrophin, which is absent in Duchenne's dystrophy and qualitatively altered in Becker's dystrophy. Although the gene for myotonic dystrophy has not been identified, it has been found to be closely linked to genetic markers on chromosome 19. See also Human genetics; Muscle proteins.

Duchenne's muscular dystrophy is the most rapidly progressive form of muscular dystrophy. It affects boys before the age of 4, and is characterized initially by progressive weakness of the hip muscles with difficulty in rising from the floor or chair and in climbing stairs. This is accompanied by enlargement of the calf muscles, which are infiltrated by fat and fibrous tissue (pseudohypertrophy). Weakness of the muscles of the upper arms and shoulder muscles follows.

Becker's muscular dystrophy is also characterized by calf pseudohypertrophy but is much more slowly progressive.

Myotonic dystrophy is very slowly progressive and affects the muscles of the face, neck, and hands. It usually begins in early adulthood. In addition to progressive weakness and wasting of the affected muscles, these individuals also exhibit myotonia, that is, a delayed relaxation of a muscle after forceful contraction. Mental retardation, frontal balding, cataracts, and gonadal degeneration are common.

Treatment remains largely symptomatic. See also Muscular system disorders.

A group of genetically transmitted diseases characterized by progressive atrophy of symmetric groups of skeletal muscles without evidence of involvement or degeneration of neural tissue. In all forms of muscular dystrophy there is an insidious loss of strength with increasing disability and deformity. Serum creatine phosphokinase is increased in affected individuals and acts as a diagnostic aid. Diagnosis is confirmed by muscle biopsy, electromyography, and genetic pedigree.

Definition

Muscular dystrophy is the name for a group of inherited disorders in which strength and muscle bulk gradually decline. Nine types of muscular dystrophies are generally recognized.

Description

The muscular dystrophies include:

• Duchenne muscular dystrophy (DMD), which affects young boys, causing progressive muscle weakness, usually beginning in the legs. It is the most severe form of muscular dystrophy.
• Becker muscular dystrophy (BMD), which affects older boys and young men, following a milder course than DMD
• Emery-Dreifuss muscular dystrophy (EDMD), which affects young boys, causing contractures and weakness in the calves, weakness in the shoulders and upper arms, and problems in the way electrical impulses travel through the heart to make it beat (heart conduction defects). Female carriers of EDMD are at risk for heart block.
• Limb-girdle muscular dystrophy (LGMD), which begins in late childhood to early adulthood and affects both men and women, causing weakness in the muscles around the hips and shoulders. It is the most variable of the muscular dystrophies, and there are as of 2004 several different forms of the disease recognized. Many people with suspected LGMD have probably been misdiagnosed in the past; therefore, the prevalence of the disease is difficult to estimate.
• Facioscapulohumeral muscular dystrophy (FSH), also known as Landouzy-Dejerine disease, which begins in late childhood to early adulthood and affects both men and women, causing weakness in the muscles of the face, shoulders, and upper arms. The hips and legs may also be affected.
• Myotonic dystrophy, also known as Steinert's disease, which affects both men and women, causing generalized weakness first seen in the face, feet, and hands. It is accompanied by the inability to relax the affected muscles (myotonia). Symptoms may begin any time from birth through adulthood.
• Oculopharyngeal muscular dystrophy (OPMD), which affects adults of both sexes, causing weakness in the eye muscles and throat
• Distal muscular dystrophy (DD), which begins in middle age or later, causing weakness in the muscles of the feet and hands
• Congenital muscular dystrophy (CMD), which is present from birth, results in generalized weakness, and usually progresses slowly. A subtype, called Fukuyama CMD, also involves mental retardation. Both are rare.

Demographics

DMD occurs in about one in 3,500 male births and affects approximately 8,000 boys and young men in the United States. A milder form occurs in very few female carriers.

BMD occurs in about one in 30,000 male births.

Fewer than 300 cases of EDMD have been identified.

The number of people affected with LGMD in the United States may be in the low thousands.

FSH occurs in about one out of every 20,000 people and affects approximately 13,000 people in the United States.

Myotonic dystrophy is the most common form of muscular dystrophy, affecting more than 30,000 people in the United States.

OPMD is most common among French Canadian families in Quebec and in Spanish-American families in the southwestern United States.

DD is most common in Sweden and rare in other parts of the world.

Fukuyama CMD is most common in Japan.

Causes and Symptoms

Causes

Several of the muscular dystrophies, including DMD, BMD, CMD, and most forms of LGMD, are due to defects in the genes for a complex of muscle proteins. This complex spans the muscle cell membrane to unite a fibrous network on the interior of the cell with a fibrous network on the outside. As of 2004 the theory was that by linking these two networks, the complex acts as a "shock absorber," redistributing and evening out the forces generated by contraction of the muscle, thereby preventing rupture of the muscle membrane. Defects in the proteins of the complex lead to deterioration of the muscle. Symptoms of these diseases set in as the muscle gradually exhausts its ability to repair itself. Both DMD and BMD are caused by flaws in the gene for the protein called dystrophin. The flaw leading to DMD prevents the formation of any dystrophin, while that of BMD allows some protein to be made, accounting for the differences in severity and onset between the two diseases. Differences among the other diseases in the muscles involved and the ages of onset are less easily explained.

The causes of the other muscular dystrophies are not as well understood:

• One form of LGMD is caused by defects in the gene for a muscle enzyme, calpain. The relationship between this defect and the symptoms of the disease is unclear.
• EDMD is due to a defect in the gene for a protein called emerin, which is found in the membrane of a cell's nucleus, but whose exact function is unknown.
• Myotonic dystrophy is linked to gene defects for a protein that may control the flow of charged particles within muscle cells. This gene defect is called a triple repeat, meaning it contains extra triplets of DNA code. It is possible that this mutation affects nearby genes as well, and that the widespread symptoms of myotonic dystrophy are due to a range of genetic disruptions.
• The gene for OPMD appears to also be mutated with a triple repeat. The function of the affected protein may involve translation of genetic messages in a cell's nucleus.
• The cause of FSH is unknown. The genetic region responsible for it has been localized on its chromosome, however.
• The gene responsible for DD has not yet been found.

Genetics and Patterns of Inheritance

The muscular dystrophies are genetic diseases, meaning they are caused by defects in genes. Genes, which are linked together on chromosomes, have two functions. They code for the production of proteins, and they are the material of inheritance. Parents pass along genes to their children, providing them with a complete set of instructions for making their own proteins.

Because both parents contribute genetic material to their offspring, each child carries two copies of almost every gene, one from each parent. For some diseases to occur, both copies must be flawed. Such diseases are called autosomal recessive diseases. Some forms of LGMD and DD exhibit this pattern of inheritance, as does CMD. A person with only one flawed copy, called a carrier, will not have the disease but may pass the flawed gene on to children. When two carriers have children, the chances of having a child with the disease is one in four for each pregnancy.

Other diseases occur when only one flawed gene copy is present. Such diseases are called autosomal dominant diseases. Other forms of LGMD exhibit this pattern of inheritance, as do DM, FSH, OPMD, and some forms of DD. When a person affected by the disease has a child with someone not affected, the chances of having an affected child is one in two.

Because of chromosomal differences between the sexes, some genes are not present in two copies. The chromosomes that determine whether a person is male or female are called the X and Y chromosomes. A person with two X chromosomes is female, while a person with one X and one Y is male. While the X chromosome carries many genes, the Y chromosome carries almost none. Therefore, a male has only one copy of each gene on the X chromosome, and if it is flawed, he will have the disease that defect causes. Such diseases are said to be X-linked. X-linked diseases include DMD, BMD, and EDMD. Women are not usually affected by X-linked diseases, since they will likely have one unaffected copy between the two chromosomes. Some female carriers of DMD suffer a mild form of the disease, probably because their one unaffected gene copy is shut down in some of their cells.

Women carriers of X-linked diseases have a one-in-two chance of passing the flawed gene on to each child born. Daughters who inherit the disease gene are carriers. A son born without the disease gene is free of the disease and cannot pass it on to his children. A son born with the defect has the disease. He will pass the flawed gene on to each of his daughters, who will then be carriers, but to none of his sons (because they inherit his Y chromosome).

Not all genetic flaws are inherited. As many as one-third of the cases of DMD are due to new mutations that arise during egg formation in the mother. New mutations are less common in other forms of muscular dystrophy.

Symptoms

All of the muscular dystrophies are marked by muscle weakness as the major symptom. The distribution of symptoms, age of onset, and progression differ significantly. Pain is sometimes a symptom of each, usually due to the effects of weakness on joint position.

DMD. A boy with Duchenne muscular dystrophy usually begins to show symptoms as a preschooler. The legs are affected first, making walking difficult and causing balance problems. Most affected persons walk three to six months later than expected and have difficulty running. Later on, the boy with DMD will push his hands against his knees to rise to a standing position, to compensate for leg weakness. About the same time, his calves will begin to swell, though with fibrous tissue rather than with muscle and feel firm and rubbery; this condition gives DMD one of its alternate names, pseudohypertrophic muscular dystrophy. The boy will widen his stance to maintain balance and walk with a waddling gait to advance his weakened legs. Contractures (permanent muscle tightening) usually begin by age five or six, most severely in the calf muscles. This pulls the foot down and back, forcing the boy to walk on tip-toes, called equinus, and further decreases balance. Frequent falls and broken bones are common beginning at this age. Climbing stairs and rising unaided may become impossible by age nine or ten, and most boys use a wheelchair for mobility by the age of 12. Weakening of the trunk muscles around this age often leads to scoliosis (a side-to-side spine curvature) and kyphosis (a front-to-back curvature).

The most serious weakness of DMD is weakness of the diaphragm, the sheet of muscles at the top of the abdomen that perform the main work of breathing and coughing. Diaphragm weakness leads to reduced energy and stamina and increased lung infection because of the inability to cough effectively. Young men with DMD often live into their twenties and beyond, provided they have mechanical ventilation assistance and good respiratory hygiene.

About one third of boys with DMD experience specific learning disabilities, including trouble learning by ear rather than by sight and trouble paying attention to long lists of instructions. Individualized educational programs usually compensate well for these disabilities.

BMD. The symptoms of BMD usually appear in late childhood to early adulthood. Though the progression of symptoms may parallel that of DMD, the symptoms are usually milder, and the course more variable. The same pattern of leg weakness, unsteadiness, and contractures occurs later for the young man with BMD, often allowing independent walking into the twenties or early thirties. Scoliosis may occur but is usually milder and progresses more slowly. Heart muscle disease (cardiomyopathy) occurs more commonly in BMD. Problems may include irregular heartbeats (arrhythmias) and congestive heart failure. Symptoms may include fatigue, shortness of breath, chest pain, and dizziness. Respiratory weakness also occurs and may lead to the need for mechanical ventilation.

EDMD. This type of muscular dystrophy usually begins in early childhood, often with contractures preceding muscle weakness. Weakness affects the shoulder and upper arm originally, along with the calf muscles, leading to foot-drop. Most men with EDMD survive into middle age, although a defect in the heart's rhythm (heart block) may be fatal if not treated with a pacemaker.

LGMD. While there are at least six genes that cause the various types of LGMD, two major clinical forms of LGMD are usually recognized. A severe childhood form is similar in appearance to DMD but is inherited as an autosomal recessive trait. Symptoms of adult-onset LGMD usually appear in a person's teens or twenties and are marked by progressive weakness and wasting of the muscles closest to the trunk. Contractures may occur, and the ability to walk is usually lost about 20 years after onset. Some people with LGMD develop respiratory weakness that requires use of a ventilator. Lifespan may be somewhat shortened. (Autosomal dominant forms usually occur later in life and progress relatively slowly.)

FSH. FSH varies in its severity and age of onset, even among members of the same family. Symptoms most commonly begin in the teens or early twenties, though infant or childhood onset is possible. Symptoms tend to be more severe in those with earlier onset. The disease is named for the regions of the body most severely affected by the disease: muscles of the face (facio-), shoulders (scapulo-), and upper arms (humeral). Hips and legs may be affected as well. Children with FSH often develop partial or complete deafness.

The first symptom noticed is often difficulty lifting objects above the shoulders. The weakness may be greater on one side than the other. Shoulder weakness also causes the shoulder blades to jut backward, called scapular winging. Muscles in the upper arm often lose bulk sooner than those of the forearm, giving a "Popeye" appearance to the arms. Facial weakness may lead to loss of facial expression, difficulty closing the eyes completely, and inability to drink through a straw, blow up a balloon, or whistle. A person with FSH may not develop strong facial wrinkles. Contracture of the calf muscles may cause foot-drop, leading to frequent tripping over curbs or rough spots. People with earlier onset often require a wheelchair for mobility, while those with later onset rarely do.

MYOTONIC DYSTROPHY. Symptoms of myotonic dystrophy include facial weakness and a slack jaw, drooping eyelids (ptosis), and muscle wasting in the forearms and calves. A person with this dystrophy has difficulty relaxing his grasp, especially if the object is cold. Myotonic dystrophy affects heart muscle, causing arrhythmias and heart block, and the muscles of the digestive system, leading to motility disorders and constipation. Other body systems are affected as well: myotonic dystrophy may cause cataracts, retinal degeneration, low IQ, frontal balding, skin disorders, testicular atrophy, sleep apnea, and insulin resistance. An increased need or desire for sleep is common, as is diminished motivation. Severe disability affects most people with this type of dystrophy within 20 years of onset, although most do not require a wheelchair even late in life.

OPMD. OPMD usually begins in a person's thirties or forties, with weakness in the muscles controlling the eyes and throat. Symptoms include drooping eyelids, difficulty swallowing (dysphagia), and weakness progresses to other muscles of the face, neck, and occasionally the upper limbs. Swallowing difficulty may cause aspiration or the introduction of food or saliva into the airways. Pneumonia may follow.

DD. DD usually begins in the twenties or thirties with weakness in the hands, forearms, and lower legs.

Difficulty with fine movements such as typing or fastening buttons may be the first symptoms. Symptoms progress slowly, and the disease usually does not affect life span.

CMD. CMD is marked by severe muscle weakness from birth, with infants displaying "floppiness" and very little voluntary movement. Nonetheless, a child with CMD may learn to walk, either with or without some assistive device, and live into young adulthood or beyond. In contrast, children with Fukuyama CMD are rarely able to walk and have severe mental retardation. Most children with this type of CMD die in childhood.

When to Call the Doctor

A doctor should be consulted whenever muscle development is thought to be abnormal or slow.

Diagnosis

Diagnosis of muscular dystrophy involves a careful medical history and a thorough physical exam to determine the distribution of symptoms and to rule out other causes. Family history may give important clues, since all the muscular dystrophies are genetic conditions (though no family history will be evident in the event of new mutations).

Lab tests may include the following:

• Blood level of the muscle enzyme creatine kinase (CK). CK levels rise in the blood due to muscle damage and may be seen in some conditions even before symptoms appear.
• Muscle biopsy, in which a small piece of muscle tissue is removed for microscopic examination. Changes in the structure of muscle cells and presence of fibrous tissue or other aberrant structures are characteristic of different forms of muscular dystrophy. The muscle tissue can also be stained to detect the presence or absence of particular proteins, including dystrophin.
• Electromyogram (EMG). EMG is used to examine the response of the muscles to stimulation. Decreased response is seen in muscular dystrophy. Other characteristic changes are seen in DM.
• Genetic tests. Several of the muscular dystrophies can be positively identified by testing for the presence of the mutated gene involved. Accurate genetic tests are available for DMD, BMD, DM, several forms of LGMD, and EDMD.
• Other specific tests as necessary. For EDMD and BMD, for example, an electrocardiogram may be needed to test heart function, and hearing tests are performed for children with FSH.

For most forms of muscular dystrophy, accurate diagnosis is not difficult when done by someone familiar with the range of diseases. There are exceptions, however. Even with a muscle biopsy, it may be difficult to distinguish between FSH and another muscle disease, polymyositis. Childhood-onset LGMD is often mistaken for the much more common DMD, especially when it occurs in boys. BMD with an early onset appears very similar to DMD, and a muscle biopsy may be needed to accurately distinguish them. The muscular dystrophies may be confused with diseases involving the motor neurons, such as spinal muscular atrophy; diseases of the neuromuscular junction, such as myasthenia gravis; and other muscle diseases, as all involve generalized weakening of varying distribution.

Treatment

Drugs

As of 2004 there were no cures for any of the muscular dystrophies. Prednisone, a corticosteroid, has been shown to delay the progression of DMD somewhat, for reasons that as of 2004 are still unclear. Prednisone is also prescribed for BMD.

Treatment of muscular dystrophy is mainly directed at preventing the complications of weakness, including decreased mobility and dexterity, contractures, scoliosis, heart defects, and respiratory insufficiency.

Physical Therapy

Physical therapy, in particular regular stretching, is used to maintain the range of motion of affected muscles and to prevent or delay contractures. Braces are used as well, especially on the ankles and feet to prevent equinus. Full-leg braces may be used in DMD to prolong the period of independent walking. Strengthening other muscle groups to compensate for weakness may be possible if the affected muscles are few and isolated, as in the earlier stages of the milder muscular dystrophies. Regular, nonstrenuous exercise helps maintain general good health. Strenuous exercise is usually not recommended, since it may damage muscles further.

Surgery

When contractures become more pronounced, tenotomy surgery may be performed. In this operation, the tendon of the contractured muscle is cut, and the limb is braced in its normal resting position while the tendon regrows. In FSH, surgical fixation of the scapula can help compensate for shoulder weakness. For a person with OPMD, surgical lifting of the eyelids may help compensate for weakened muscular control. For a person with DM, sleep apnea may be treated surgically to maintain an open airway. Scoliosis surgery is often needed in DMD but much less often in other muscular dystrophies. Surgery is recommended at a much lower degree of curvature for DMD than for scoliosis due to other conditions, since the decline in respiratory function in DMD makes surgery at a later time dangerous. In this surgery, the vertebrae are fused together to maintain the spine in the upright position. Steel rods are inserted at the time of operation to keep the spine rigid while the bones grow together.

When any type of surgery is performed in people with muscular dystrophy, anesthesia must be carefully selected. People with MD are susceptible to a severe reaction, known as malignant hyperthermia, when given halothane anesthetic.

Occupational Therapy

The occupational therapist suggests techniques and tools to compensate for the loss of strength and dexterity. Strategies may include modifications in the home, adaptive utensils and dressing aids, compensatory movements and positioning, wheelchair accessories, or communication aids.

Nutrition

Good nutrition helps to promote general health in all the muscular dystrophies. No special diet or supplement has as of 2004 been shown to be of use in any of the conditions. The weakness in the throat muscles seen especially in OPMD and later DMD may necessitate the use of a gastrostomy tube, inserted in the stomach to provide nutrition directly.

Cardiac Care

The arrhythmias of EDMD and BMD may be treatable with antiarrhythmia drugs such as mexiletine or nifedipine. A pacemaker may be implanted if these do not provide adequate control. Heart transplants are increasingly common for men with BMD.

Respiratory Care

People who develop weakness of the diaphragm or other ventilatory muscles may require a mechanical ventilator to continue breathing deeply enough. Air may be administered through a nasal mask or mouthpiece or through a tracheostomy tube, which is inserted through a surgical incision through the neck and into the windpipe. Most people with muscular dystrophy do not need a tracheostomy, although some may prefer it to continual use of a mask or mouthpiece. Supplemental oxygen is not needed. Good hygiene of the lungs is critical for health and long-term survival of a person with weakened ventilatory muscles. Assisted cough techniques provide the strength needed to clear the airways of secretions; an assisted cough machine is also available and provides excellent results.

Experimental Treatments

Two experimental procedures aiming to cure DMD have attracted a great deal of attention. In myoblast transfer, millions of immature muscle cells are injected into an affected muscle. The goal of the treatment is to promote the growth of the injected cells, replacing the defective host cells with healthy new ones. Despite continued claims to the contrary by a very few researchers, this procedure is widely judged a failure.

Gene therapy introduces good copies of the dystrophin gene into muscle cells. The goal is to allow the existing muscle cells to use the new gene to produce the dystrophin it cannot make with its flawed gene. Problems have included immune rejection of the virus used to introduce the gene, loss of gene function after several weeks, and an inability to get the gene to enough cells to make a functional difference in the affected muscle. Nonetheless, after a number of years of refining the techniques in mice, researchers began human trials in 1998. These trials are ongoing.

Prognosis

The expected life span for a male with DMD has increased significantly since the 1970s. Most young men live into their early or mid-twenties. Respiratory infections become an increasing problem as their breathing becomes weaker, and these infections are usually the cause of death.

The course of the other muscular dystrophies is more variable; expected life spans and degrees of disability are hard to predict but may be related to age of onset and initial symptoms. Prediction is made more difficult because, as new genes are discovered, it becomes clear that several of the dystrophies are not uniform disorders but rather symptom groups caused by different genes.

People with dystrophies with significant heart involvement (BMD, EDMD, Myotonic dystrophy) may nonetheless have almost normal life spans, provided that cardiac complications are monitored and treated aggressively. The respiratory involvement of BMD and LGMD similarly require careful and prompt treatment.

Prevention

As of 2004 there was no way to prevent any of the muscular dystrophies in a person who has the genes responsible for these disorders. Accurate genetic tests, including prenatal tests, are available for some of the muscular dystrophies. Results of these tests may be useful for purposes of family planning.

Nutritional Concerns

There is no known link between nutrition and the onset of muscular dystrophy.

Parental Concerns

Prospective parents with first-degree relatives (parents, siblings, or other children) who have been diagnosed with muscular dystrophy should consider including counseling in their family planning process.

Resources

Books

Barohn, Richard J. "Muscle Diseases." In Cecil Textbook ofMedicine, 22nd ed. Edited by Lee Goldman et al. Philadelphia: Saunders, 2003, pp. 2387–99.

Brown, Robert H., and Jerry R. Mendell. "Muscular Dystrophies and Other Muscle Diseases." In Harrison's Principles of Internal Medicine, 15th ed. Edited by Eugene Braunwald et al. New York: McGraw-Hill, 2001, pp. 2529–40.

Emery, Alan E. Muscular Dystrophies. Cary, NC: Oxford University Press, 2003.

Muscular Dystrophy: A Medical Dictionary, Bibliography, andAnnotated Research Guide to Internet References. San Diego, CA: Icon Health Publications, 2003.

Sarnat, Harvey B. "Muscular Dystrophies." In NelsonTextbook of Pediatrics, 17th ed. Edited by Richard E. Behrman et al. Philadelphia: Saunders, 2003, pp. 2060–9.

Periodicals

Cossu, G., and M. Sampaolesi. "New therapies for muscular dystrophy: cautious optimism." Trends in Molecular Medicine 10, no. 10 (2004): 516–20.

Rando, T. A. "Artificial sweeteners—enhancing glycosylation to treat muscular dystrophies." New England Journal of Medicine 351, no. 12 (2004): 1254–6.

Organizations

American Academy of Physical Medicine and Rehabilitation. One IBM Plaza, Suite 2500, Chicago, IL 60611–3604. Web site: www.aapmr.org/.

Muscular Dystrophy Association. National Headquarters, 3300 E. Sunrise Drive, Tucson, AZ 85718. Web site: www.mdausa.org//p

Web Sites

"Muscular Dystrophies." Merck Manual. Available online at www.merck.com/mrkshared/mmanual/section14/chapter184/184a.jsp (accessed January 7, 2005).

"Muscular Dystrophy." Milton S. Hershey Medical CenterSchool of Medicine. Available online at www.hmc.psu.edu/healthinfo/m/musculardystrophy.htm (accessed January 7, 2005).

[Article by: L. Fleming Fallon, Jr., MD, DrPH]

Muscular dystrophies (MDs) are a group of disorders that share three characteristics: They are inherited, they cause progressive weakness and muscle wasting, and the primary defect is localized to skeletal muscle, sparing the nerves. Although selected limb muscles develop some degree of weakness in all dystrophies, to distinguish among the different types, it is critical to know the mode of inheritance, the age of onset, and whether muscles other than limb muscles are also affected. For example, some dystrophies additionally affect eye and lip closure; another type affects eye movement ability, as well as swallowing and speech.

More than thirty types of MDs are now recognized. Three of the more prevalent forms—Duchenne, myotonic, and limb-girdle dystrophies—will be discussed from the standpoint of the presenting symptoms, age of onset, inheritance pattern, causative genes, and the availability of prenatal and presymptomatic molecular testing.

Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder with a worldwide occurrence of one in four thousand newborn males, with approximately one-third of the cases arising from new mutations. DMD was named after the French neurologist Duchenne de Boulogne, who described the disorder in 1861. Becker muscular dystrophy (BMD), named after Peter Becker, a German geneticist who first described it in the mid-1950s, is a disorder that is very similar to DMD but has a much milder course. In 1983 these disorders were first shown to be located on the short arm of the X chromosome. The disorders are now known to be allelic, meaning an alternate form of the DMD gene causes BMD.

Because DMD is X-linked, almost all cases occur in males. Boys with DMD are normal at birth, and their early motor milestones occur at normal times. The manifestations of DMD are frequently apparent from the time they begin to walk, due to the developing weakness of the hip-girdle and upper-leg muscles. Their gait is unsteady and clumsy, resulting in frequent falls. If running is attempted, it is slow and waddling. The calf muscles often are enlarged enough to be termed "hypertrophic," implying that these children are muscular and strong. In reality calf pseudo hypertrophy is present: When the calves are examined microscopically, the amount of muscle tissue is markedly reduced, having been replaced by fat and fibrous tissue.

As the disorder progresses, the Achilles tendons tighten, causing toe-walking, which further compromises patients' gait and balance. Stair-climbing, rising from a fall, and even walking on level ground becomes more arduous. Even if they undergo Achilles tendon lengthening surgery or use leg braces, virtually all DMD boys require a wheelchair for mobility before the age of thirteen. Weakening of the muscles of the upper extremities and neck and of the respiratory muscles occurs in parallel to that of the lower extremities, although at a slower rate. By some time in their twenties, if not before, nearly all DMD patients will die, often due to an overwhelming respiratory infection resulting in respiratory failure, cardiac arrest, or both.

The causative gene for DMD (named dystrophin) and the protein product (also named dystrophin) were identified in 1986. Dystrophin is found on the inner side of the membrane that surrounds skeletal muscle fibers (the sarcolemma). It is usually absent or severely deficient in DMD boys, and this causes the sarcolemma to weaken and develop tears, allowing excess calcium to enter the muscle fiber. This eventually leads to the death of muscle fibers, and, when a sufficient number of fibers are involved, muscle weakness results.

The dystrophin gene is the largest known human gene, encompassing two thousand kilobases (two million bases) of genomic DNA. In 55 percent to 65 percent of DMD or BMD cases, large deletions of the dystrophin gene can be found. Duplications within the gene account for about 5 percent of cases. DNA testing, available through a number of commercial laboratories in the United States, is based on the identification of these large deletions and duplications. DNA tests can confirm a diagnosis of DMD or BMD, and they can be used for accurate carrier or prenatal testing.

Myotonic Muscular Dystrophy

Myotonic muscular dystrophy (DM, or dystrophia myotonica) is the most common adult-onset muscular dystrophy, having a frequency of one per twenty thousand persons in the general population. Myotonia, the delayed relaxation of a voluntary muscle after it is contracted, and muscle weakness are the hallmarks of the disorder. For example, a person with DM using a hammer will not immediately be able to release his grip on the handle when finished. It is an autosomal dominant disorder, but there is great variability in the disorder's severity and in the number of manifestations it leads to.

A unique feature of this dystrophy is a genetic phenomenon called pleiotropy, or multisystem involvement, despite the single genetic defect. The potential involvement includes multiple organs and organ systems other than skeletal muscle, including the cardiac, respiratory, gastrointestinal, central nervous, endocrine, and dermatologic systems, as well as bone or eyes. A congenital variety occurs in which infants are born floppy, often require respiratory assistance, have extremity deformities, and are both physically and mentally retarded.

Patients often initially complain of a loss of hand strength (they have difficulty twisting off caps from bottles, for example) or of tripping while walking or climbing stairs, due to the weakness of muscles that extend the feet and toes. Weakness may progress to involve the shoulder and hip girdles and, in some cases, is severe enough to necessitate the use of a wheel-chair. Droopy eyelids, wasting of facial and neck muscles, and frontal balding frequently occur, producing atypical facial appearance.

The gene for DM is a protein kinase gene (known as DMPK) and is located on the long arm of chromosome 19. The disorder arises from a repeated sequence of three nucleotides—cytosine (C), thymine (T), and gua-nine (G)—in the gene. Individuals without DM have C-T-G repeats that contain between 5 and 37 iterations of the triplets. By contrast, repeats that are between 40 and 170 iterations long are found in the mild phenotype, repeats between 100 and 1,000 iterations are found in the "classic pheno-type," and repeats of between 500 and 3,000 are found in the congenital phenotype. A number of laboratories in the United States perform this triplet repeat assay for diagnostic, prenatal, and presymptomatic testing.

Limb-Girdle Muscular Dystrophy

Limb-girdle muscular dystrophy (LGMD) has been described both as a heterogeneous group of disorders and as a diagnosis of exclusion. Any patient who has weakness of the shoulder and hip-girdle muscles and who otherwise has been excluded from the other MDs will be diagnosed with LGMD. Using the patterns of inheritance that exist within LGMD, a classification system has been created to simplify the heterogeneity: Both autosomal dominant (LGMD1) and recessive families (LGMD2) are well recognized. The number of LGMD genes that have already been identified has further improved the classification.

The frequency of LGMD in the general population is reported to be one in twenty-five thousand. The age at onset may vary widely. In some individuals, onset is in early childhood and in others it occurs in the forties and fifties, but most commonly it occurs in the teens to early adulthood. The characteristic pattern of muscle involvement is symmetric weakness, beginning initially in the hip and shoulder girdle, but usually noticed in the hips before the shoulders. Thus slowness in running, difficulty rising from a low seat, and difficulty ascending stairs are all common complaints from affected individuals. As LGMD progresses, it will involve upper-leg and arm muscles and may eventually affect the muscles that extend the feet and wrists. Lower-extremity weakness may become severe enough to require a wheelchair.

Among the LGMD1 types, five have chromosomal linkages, but only in one is the protein product of the gene known. LGMD2 is better characterized, with nine chromosomal localizations, five with known proteins. Almost all these proteins are membrane-associated proteins (just as dystrophin is). When they are abnormal in structure or deficient in quantity, they affect the stability of the muscle membrane, resulting in the same pathological process that was described for DMD. Commercial testing in the United States is only available for some of the LGMD2 types and is performed using muscle tissue.

Treatment of the Muscular Dystrophies

As of mid-2002, gene therapy treatment of LGMD was tried in a very small number of patients. These early experiments delivered a functional gene to a very small muscle in the foot and were designed to test the long-term safety and effectiveness of the treatment. Gene therapy for DMD is much more problematic, because of the immense size of the gene and the distribution throughout the body that would be required for effective treatment. Drug treatment with prednisone or other corticosteroids is being used, although at best this provides another six to twelve months of mobility before a wheelchair becomes necessary. There are no effective treatments for myotonic dystrophy as of 2002, although research continues in many laboratories worldwide.

Bibliography

Emery, Alan E. H., ed. Neuromuscular Disorders: Clinical and Molecular Genetics. Chichester, U.K.: John Wiley & Sons, 1998.

———. Muscular Dystrophy, The Facts. Oxford, U.K.: Oxford University Press, 2000.

Hoffman, Eric P. "Muscular Dystrophy: Identification and Use of Genes for Diagnostics and Therapeutics." Archives of Pathology and Laboratory Medicine 123 (1999): 1050-1052.

Internet Resource

Muscular Dystrophy Association. http://www.mdausa.org.

—Jeffrey M. Stajich

For more information on muscular dystrophy, visit Britannica.com.

A disease in which there is a progressive wasting of muscle.

A hereditary disease in which the muscles progressively waste away. The disease can be potentially treated through gene therapy.

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