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 <www.clinicaltrials.org>.

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. [email protected]. <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. [email protected]. <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. [email protected]. <http://www.parentprojectmd.org>.

Francisco de Paula Careta

Iuri Drumond Louro, MD, PhD