Muscular Dystrophy

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 a 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 a very small number of female carriers.
• Becker muscular dystrophy (BMD). BMD affects older boys and young men, following a milder course than DMD. BMD occurs in about one in 30,000 male births.
• Emery-Dreifuss muscular dystrophy (EDMD). EDMD can appear as an autosomal dominant or recessive form of dystrophy. Thus, both young boys and girls can be affected. It causes 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 and also the muscles of the arms and legs. It is the most variable of the muscular dystrophies, and there are several different forms of the condition now recognized. Many people with suspected LGMD have probably been misdiagnosed in the past, and therefore the prevalence of the condition is difficult to estimate. The highest prevalence of LGMD is in a small mountainous Basque province in northern Spain, where the condition affects 69 persons per million.
• Facioscapulohumeral muscular dystrophy (FSH). FSH, also known as Landouzy-Dejerine condition, 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 one out of every 20,000 people, and affects approximately 13,000 people in the United States.
• Myotonic dystrophy. This is also known as Steinert's disease and affects both men and women, causing generalized weakness first seen in the face, feet, and hands. Other systems of the body can also be affected. 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 genders, 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 is a group of rare muscle diseases that have in common weakness and wasting of the distal (farthest from the center) muscles of the forearms, hands, lower legs, and feet. In general, the DDs are less severe, progress more slowly, and involve fewer muscles than the other dystrophies. DD usually 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 a rare group of muscular dystrophies that have in common the presence of muscle weakness at birth (congenital). Biopsies of muscles from persons affected with CMD are abnormal. CMD results in generalized weakness, and usually progresses slowly. A subtype, called Fukuyama CMD, also involves mental retardation and lissencephaly. It is more common in Japan.

The muscular dystrophies are genetic conditions, meaning they are caused by alterations 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 conditions to occur, both copies must be altered. Such conditions are called autosomal recessive conditions. Some forms of LGMD, OPMD and DD exhibit this pattern of inheritance, as does CMD. Persons with only one altered copy, called carriers, will not have the condition, but may pass the altered gene on to their children. When two carriers have children, the chances of having a child with the condition is one in four for each pregnancy.

Other conditions occur when only one altered gene copy is present. Such conditions are called autosomal dominant conditions. 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 condition has a child with someone not affected, the chances of having an affected child are one in two. Autosomal dominant conditions tend to be variable in their symptoms even among members of the same family.

Because of chromosomal differences between the genders, 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 altered, he will have the condition that alteration causes. Such conditions are said to be X-linked. X-linked conditions include DMD, BMD, and EDMD. Women are not usually affected by X-linked conditions, since they will likely have one unaltered copy between the two chromosomes. Some female carriers of DMD have a mild form of the condition, probably because their one unaltered gene copy is shut down in some of their cells.

Women carriers of X-linked conditions have a one in two chance of passing the altered gene on to each child born. Daughters who inherit the altered gene will be carriers. A son born without the altered gene will be free of the condition and cannot pass it on to his children. A son born with the altered gene will have the condition. He will pass the altered 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 alterations 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.

Causes And Symptoms

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

Duchenne muscular dystrophy

A boy with Duchenne muscular dystrophy usually begins to show symptoms before ever entering school, making walking difficult and causing balance problems. Most boys begin to walk three to six months later than expected and have difficulty running. Later on, a 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 enlarge with fibrous tissue rather than with muscle, and feel firm and rubbery; this condition gives DMD one of its alternate names, pseudohypertrophic muscular dystrophy. He 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. This is called equinus and further decreases balance. Frequent falls 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 of the spine).

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.

Among males with DMD, the incidence of cardiomyopathy (weakness of the heart muscle), increases steadily in teenage years. Almost all affected men have cardiomyopathy after 18 years of age. It has also been shown that carrier females are at increased risk for cardiomyopathy and should also be screened.

About one-third of males 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.

Becker muscular dystrophy

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 occur later for a 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. Cardiomyopathy occurs more commonly in BMD. Problems may include irregular heart beats (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.

Emery-Dreifuss muscular dystrophy

This type of muscular dystrophy usually begins in early childhood, often with contractures preceding muscle weakness. Weakness initially affects the shoulder and upper arm, 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.

Limb-girdle muscular dystrophy

While there are several genes that cause the various types of LGMD, two major clinical forms of LGMD are currently recognized. A severe childhood form is similar in appearance to DMD, but is inherited as an autosomal recessive trait. Symptoms of adultonset 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. Life-span may be somewhat shortened. Autosomal dominant forms usually occur later in life and progress in a relatively slow manner.

Facioscapulohumeral muscular dystrophy

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 condition is named for the regions of the body most severely affected by the condition: muscles of the face (facio-), shoulders (scapulo-), and upper arms (humeral). Hips and legs may be affected as well. More than half of children with FSH may develop partial or complete sensorineural 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. Persons with FSH may not be able to wrinkle their foreheads. 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. Persons with myotonic dystrophy have difficulty relaxing their 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, mental deficiency, 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 some people with this type of dystrophy within 20 years of onset, although most do not require a wheelchair even late in life. The condition is extremely variable. Some individuals show profound weak-ness as newborns (congenital myotonic dystrophy), others show mental retardation in childhood, many show characteristic facial features and muscle wasting in adulthood, while the most mildly affected individuals show only cataracts in middle age with no other symptoms.

Oculopharyngeal muscular dystrophy

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.

Distal muscular dystrophy

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. From that point, symptoms slowly progress and the condition usually does not affect life span.

Congenital muscular dystrophy

CMD is marked by severe muscle weakness from birth, with infants displaying "floppiness" (very poor muscle tone). They often have trouble moving their limbs or head against gravity. Mental function is normal but some are never able to walk. They may 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.

Diagnosis

The 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, although no family history will be evident in the event of new mutations. With autosomal recessive inheritance, a family history may also be negative for muscular dystrophy.

Lab tests may include:

• 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). This electrical test is used to examine the response of the muscles to stimulation. Decreased response is seen in muscular dystrophy. Other characteristic changes are seen in muscular dystrophy.
• Genetic tests. Several of the muscular dystrophies can be positively identified by testing for the presence of the altered gene involved. Accurate genetic tests are available for DMD, BMD, DM, several forms of LGMD, and EDMD. Genetic testing for some of these conditions in future pregnancies of an affected individual or parents of an affected individual can be performed before birth through amniocentesis or chorionic villus sampling. Prenatal testing can only be undertaken after the diagnosis in an affected individual has been genetically confirmed and the couple has been counseled regarding the risks of recurrence.
• Other specific tests as necessary. For EDMD, DMD 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 performed by someone familiar with the range of conditions. There are exceptions, however. Even with a muscle biopsy, it may be difficult to distinguish between FSH and another muscle condition, 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 genetic test may be needed to accurately distinguish them. The muscular dystrophies may be confused with conditions involving the motor neurons, such as spinal muscular atrophy; conditions of the neuromuscular junction, such as myasthenia gravis; and other muscle conditions, as all involve generalized weakness of varying distribution.

Prenatal diagnosis (testing of the baby while in the womb) can be performed for those types of muscular dystrophy where the specific disease-causing gene alteration has been identified in a previously affected family member. Prenatal diagnosis can be accomplished by utilizing DNA extracted from tissue obtained by chorionic villus sampling or amniocentesis.

Treatment

Drugs

There are no cures for any of the muscular dystrophies. Prednisone, a corticosteroid, has been shown to delay the progression of DMD somewhat, for reasons that are still unclear. Some have reported improvement in strength and function in people treated with a single dose. Improvement begins within ten days and plateaus after three months. Long-term benefit has not been demonstrated. Prednisone is also prescribed for BMD, though no controlled studies have tested its benefit. A study is under way in the use of gentamicin, an antibiotic that may slow down the symptoms of DMD in a small number of cases. No other drugs are currently known to have an effect on the course of any other muscular dystrophy.

Treatment of muscular dystrophy is mainly directed at preventing the complications of weakness, including decreased mobility and dexterity, contractures, scoliosis, heart alterations, 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 children with 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, non-strenuous exercise helps maintain general good health. Strenuous exercise is usually not recommended, since it may further damage muscles.

Surgery

When contractures become more pronounced, tenotomy surgery may be performed. In this operation, the tendon of a contracted 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 boys with 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 an 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 patients 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

An 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 been shown to be of particular value 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 directly into the stomach to provide nutrition.

Cardiac care

The arrhythmias of EDMD and BMD may be treatable with antiarrhythmic drugs. A pacemaker may be implanted if these do not provide adequate control. Heart transplants are increasingly common for men with BMD. A complete cardiac evaluation is recommended at least once in all carrier females of DMD and EDMD.

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 via 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 the past decade. 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. Myoblast transfer is under investigation but remains experimental.

Gene therapy introduces good copies of the altered gene into muscle cells. The goal is to allow the existing muscle cells to use the new gene to produce the protein it cannot make with its abnormal gene. Problems with gene therapy research 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 an affected muscle. Researchers are preparing for the first gene therapy trial for LGMD in the United States. The goal will be to replace the missing sarcoglycan gene(s).

Genetic counseling

Individuals with muscular dystrophy and their families may benefit from genetic counseling for information on the condition and recurrence risks for future pregnancies.

Prognosis

The expected lifespan for a male with DMD has increased significantly in the past two decades. Most young men will 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 is becoming clear that several of the dystrophies are not uniform disorders, but rather symptom groups caused by different genes.

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

Health care team roles

A pediatrician or family physician often make an initial diagnosis of muscular dystrophy. Pathologists and geneticists evaluate materials collected for testing. Physical therapists may provide supportive services. Braces and other assistive devices may be manufactured by orthotists and others with specialty training. Computer engineers have devised equipment for improving communications. Counselors and nurses provide support to people with muscular dystrophy and their families.

Prevention

There is 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.

KEY TERMS

Amniocentesis— A procedure in which a needle is inserted through a pregnant woman's abdomen and into her uterus to withdraw a small sample of the fluid that surrounds the fetus (amniotic fluid) for the purposes of analysis.

Autosomal dominant— Conditions that occur when a person inherits only one abnormal copy of a gene.

Autosomal recessive— Conditions that occur when a person inherits two abnormal copies of a gene, one from each parent.

Becker muscular dystrophy (BMD)— A type of muscular dystrophy that affects older boys and men, and usually follows a milder course than DMD.

Chorionic villus sampling— A medical procedure done during weeks 10-12 of a pregnancy. A needle is inserted into the placenta and a small amount of fetal tissue is withdrawn for analysis.

Contractures— A permanent shortening (as of muscle, tendon, or scar tissue) producing deformity or distortion.

Distal muscular dystrophy (DD)— A form of muscular dystrophy that usually begins in middle age or later, causing weakness in the muscles of the feet and hands.

Duchenne muscular dystrophy (DMD)— The most severe form of muscular dystrophy, DMD usually affects young boys and causes progressive muscle weakness, usually beginning in the legs.

Dystrophin— A protein that helps muscle tissue repair itself. Both DMD and BMD are caused by abnormalities in the gene that instructs the body how to make this protein.

Facioscapulohumeral muscular dystrophy (FSH)— This form of muscular dystrophy, also known as Landouzy-Dejerine condition, 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.

Limb-girdle muscular dystrophy (LGMD)— This form of muscular dystrophy begins in late childhood to early adulthood and affects both men and women, causing weakness in the muscles around the hips and shoulders.

Myotonic dystrophy— This type of muscular 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).

Oculopharyngeal muscular dystrophy (OPMD)— This type of muscular dystrophy affects adults of both sexes, causing weakness in the eye muscles and throat.

Resources

BOOKS

Adams, Raymond D, Maurice Victor, and Allan H. Ropper. Adam's & Victor's Principles of Neurology, 6th ed. New York, McGraw Hill, 1997.

Barohn, Richard J. "Muscular dystrophies." In Cecil Textbook of Medicine, 21st ed., edited by Lee Goldman, and J. Claude Bennett. Philadelphia: W.B. Saunders, (2000): 2206-2210.

Fukuyama, Y., Makiko Osawa, and Kayoko Saito. Congenital Muscular Dystrophies. New York: Elsevier Science, 1997.

Sarnat, Harvey B. "Muscular dystrophies." In Nelson Textbook of Pediatrics, 16th ed.. Edited by Richard E. Behrman et al. Philadelphia: Saunders, (2000): 1212.

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

PERIODICALS

Cornu, C., F. Goubel, and M. Fardeau. "Muscle and Joint Elastic Properties During Elbow Flexion in Duchenne Muscular Dystrophy." Journal of Physiology 533, pt. 2 (2001): 605-616.

Kalra, V. "Muscular dystrophies." Indian Journal of Pediatrics 67, no. 12 (2000): 923-928.

Kazakov, V. "Why Did the Heated Discussion Arise Between Erb and Landouzy-Dejerine Concerning the Priority in Describing the Facio-Scapulo-Humeral Muscular Dystrophy and What is the Main Reason for This Famous Discussion?" Neuromuscular Disorders 11, no. 4 (2001): 421-434.

Lanza, G. A., A. D. Russo, V. Giglio, L. De Luca, L. Messano, C. Santini, E. Ricci, A. Damiani, G. Fumagalli, G. De Martino, F. Mangiola, and F. Bellocci. "Impairment of Cardiac Autonomic Function in Patients with Duchenne Muscular Dystrophy: Relationship to Myocardial and Respiratory Function." American Heart Journal 141, no. 5 (2001): 808-812.

Mendell, J. R. "Congenital Muscular Dystrophy: Searching for a Definition After 98 Years." Neurology 56, no. 8 (2001): 993-994.

Vlak, M., E. van der Kooi, and C. Angelini. "Correlation of Clinical Function and Muscle CT Scan Images in Limb-Girdle Muscular Dystrophy." Neurological Science 21, 5 Suppl. (2000): S975-S977.

ORGANIZATIONS

American Academy of Neurology, 1080 Montreal Avenue, St. Paul, Minnesota 55116. (651) 695-1940. Fax: (651) 695-2791. 〈http://www.aan.com/〉. [email protected].

American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, IL 60007-1098. (847) 434-4000. Fax: (847) 434-8000. 〈http://www.aap.org/default.htm〉. [email protected].

American Academy of Physical Medicine and Rehabilitation, One IBM Plaza, Suite 2500, Chicago, IL 60611-3604. (312) 464-9700. Fax: (312) 464-0227. 〈http://www.aapmr.org/consumers/public/amputations.htm〉. [email protected].

Muscular Dystrophy Association—USA, National Headquarters, 3300 E. Sunrise Drive, Tucson, AZ 85718. (800) 572-1717. 〈http://www.mdausa.org/〉. [email protected].

OTHER

FacioScapuloHumeral Muscular Dystrophy Society. 〈http://www.fshsociety.org/〉.

Muscular Dystrophy Association of Canada. 〈http://www.mdac.ca/〉.

National Institute of Neurological Disorders and Stroke. 〈http://www.ninds.nih.gov/health_and_medical/disorders/md.htm〉.

National Library of Medicine. 〈http://www.nlm.nih.gov/medlineplus/musculardystrophy.html〉.

Parent Project Muscular Dystrophy. 〈http://www.parentdmd.org/〉.

University of Kansas Medical Center. 〈http://www.kumc.edu/gec/support/muscular.html〉.

West Virginia University. 〈http://www.wvhealth.wvu.edu/clinical/neurological/muscular.htm〉.

Muscular Dystrophy

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.

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. Current theory holds 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. Although the genetic region responsible for it has been localized on its chromosome, the identity and function of the gene or genes involved had not been determined as of 1997.
• 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 his 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 aren't 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 will be carriers. A son born without the disease gene will be free of the disease and cannot pass it on to his children. A son born with the defect will have 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 pre-schooler. The legs are affected first, making walking difficult and causing balance problems. Most patients 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. He 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 occur 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 a half-dozen 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.

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:

• 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). This electrical test 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 genetic test 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

There are no cures for any of the muscular dystrophies. Prednisone, a corticosteroid, has been shown to delay the progression of DMD somewhat, for reasons that are still unclear. Prednisone is also prescribed for BMD, though no controlled studies have tested its benefit. A related drug, deflazacort, appears to have similar benefits with fewer side effects. It is available and is prescribed in Canada and Mexico, but is unavailable in the United States. Albuterol, an adrenergic agonist, has shown some promise for FSH in small trials; larger trials are scheduled for 1998. No other drugs are currently known to have an effect on the course of any other muscular dystrophy.

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 patients 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 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 longterm 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 the past decade. 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. Modifications in the technique may change that in the future.

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 are beginning human trials in 1998.

Prognosis

The expected lifespan for a male with DMD has increased significantly in the past two decades. Most young men will 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 is becoming 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

There is 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.

Resources

ORGANIZATIONS

Muscular Dystrophy Association. 3300 East Sunrise Drive, Tucson, AZ 85718. (800) 572-1717. 〈http://www.mdausa.org〉.

KEY TERMS

Autosomal dominant— Diseases that occur when a person inherits only one flawed copy of the gene.

Autosomal recessive— Diseases that occur when a person inherits two flawed copies of a gene—one from each parent.

Becker muscular dystrophy (BMD)— A type of muscular dystrophy that affects older boys and men, and usually follows a milder course than DMD.

Contractures— A permanent shortening (as of muscle, tendon, or scar tissue) producing deformity or distortion.

Distal muscular dystrophy (DD)— A form of muscular dystrophy that usually begins in middle age or later, causing weakness in the muscles of the feet and hands.

Duchenne muscular dystrophy (DMD)— The most severe form of muscular dystrophy, DMD usually affects young boys and causes progressive muscle weakness, usually beginning in the legs.

Dystrophin— A protein that helps muscle tissue repair itself. Both DMD and BMD are caused by flaws in the gene that instructs the body how to make this protein.

Facioscapulohumeral muscular dystrophy (FSH)— This form of muscular dystrophy, 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.

Limb-girdle muscular dystrophy (LGMD)— This form of muscular dystrophy begins in late childhood to early adulthood and affects both men and women, causing weakness in the muscles around the hips and shoulders.

Myotonic dystrophy— This type of muscular 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).

Oculopharyngeal muscular dystrophy (OPMD)— This type of muscular dystrophy affects adults of both sexes, causing weakness in the eye muscles and throat.

Muscular dystrophy

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 a severe form of muscular dystrophy. 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 a very small number of female carriers.
• Becker muscular dystrophy (BMD): BMD affects older boys and young men, following a milder course than DMD. It occurs in about one in 30,000 male births.
• Emery-Dreifuss muscular dystrophy (EDMD): EDMD affects both males and females because it can be inherited as an autosomal dominant or recessive disorder. Symptoms include 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 reported in the medical literature.
• 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, and weakness in the limbs. It is the most variable of the muscular dystrophies, and there are several different forms of the condition now recognized. Many people with suspected LGMD have probably been misdiagnosed in the past, and therefore, the prevalence of the condition is difficult to estimate. The highest prevalence of LGMD is in a small mountainous Basque province in northern Spain, where the condition affects 69 persons per million.
• Facioscapulohumeral muscular dystrophy (FSH): FSH, also known as Landouzy-Dejerine condition, 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 one out of every 20,000 people, and affects approximately 13,000 people in the United States.
• Myotonic dystrophy: Also known as Steinert's disease, it 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 is a group of rare muscle diseases that have weakness and wasting of the distal (farthest from the center) muscles of the fore-arms, hands, lower legs, and feet in common. In general, the DDs are less severe, progress more slowly, and involve fewer muscles than the other dystrophies. DD usually 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 a rare group of muscular dystrophies that have in common the presence of muscle weakness at birth (congenital), and abnormal muscle biopsies. CMD results in generalized weakness, and usually progresses slowly. A sub-type, called Fukuyama CMD, also involves mental retardation and is more common in Japan.

Genetic profile

The muscular dystrophies are genetic conditions, meaning they are caused by alterations 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 conditions to occur, both copies must be altered. Such conditions are called autosomal recessive conditions. Some forms of LGMD and DD exhibit this pattern of inheritance, as does CMD. A person with only one altered copy, called a carrier, will not have the condition, but may pass the altered gene on to his children. When two carriers have children, the chances of having a child with the condition is one in four for each pregnancy.

Other conditions occur when only one altered gene copy is present. Such conditions are called autosomal dominant conditions. DM, FSH, and OPMD exhibit this pattern of inheritance, as do some forms of DD and LGMD. When a person affected by the condition 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 altered, he will have the condition that alteration causes. Such conditions are said to be X-linked. X-linked conditions include DMD, BMD, and EDMD. Women are not usually affected by X-linked conditions, since they will likely have one unaltered copy between the two chromosomes. Some female carriers of DMD have a mild form of the condition, probably because their one unaltered gene copy is shut down in some of their cells.

Women carriers of X-linked conditions have a one in two chance of passing the altered gene on to each child born. Daughters who inherit the altered gene will be carriers. A son born without the altered gene will be free of the condition and cannot pass it on to his children. A son born with the altered gene will have the condition. He will pass the altered 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 alterations 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.

Several of the muscular dystrophies, including DMD, BMD, CMD, and most forms of LGMD, are due to alterations in the genes for a complex of muscle proteins. This complex spans the muscle cell membrane (a thin sheath that surrounds each muscle cell) to unite a fibrous network on the interior of the cell with a fibrous network on the outside. Theory holds 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. Alterations in the proteins of the complex lead to deterioration of the muscle during normal contraction and relaxation cycles. Symptoms of these conditions set in as the muscle gradually exhausts its ability to repair itself.

Both DMD and BMD are caused by alterations in the gene for the protein called dystrophin. The alteration 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 age of onset between the two conditions. Differences among the other muscular dystrophies in terms of the muscles involved and the ages of onset are less easily explained.

A number of genes have been found to cause LGMD. A majority of the more severe autosomal recessive types of LGMD with childhood-onset are caused by alterations in the genes responsible for making proteins called sarcoglycans. The sarcoglycans are a complex of proteins that are normally located in the muscle cell membrane along with dystrophin. Loss of these proteins causes the muscle cell membrane to lose some of its shock absorber qualities. The genes responsible include LGMD2D on chromosome 17, which codes for the alpha-sarcoglycan protein; LGMD2E on chromosome 4, which codes for the beta-sarcoglycan protein; LGMD2C on chromosome 13, which codes for the gamma-sarcoglycan protein; and LGMD2F on chromosome 5, which codes for the delta-sarcoglycan protein. Some cases of autosomal recessive LGMD are caused by an alteration in a gene, LGMD2A, on chromosome 15, which codes for a muscle enzyme, calpain 3. The relationship between this alteration and the symptoms of the condition is unclear. Alterations in a gene called LGMD2B on chromosome 2 that codes for the dysferlin protein, is also responsible for a minority of autosomal recessive LGMD cases. The exact role of dysferlin is not known. Finally, alterations in the LGMD2G gene on chromosome 17 which codes for a protein, telethonin, is responsible for autosomal recessive LGMD in two reported families. The exact role of telethonin is not known. Some families with autosomal recessive LGMD are not accounted for by alterations in any of the above mentioned genes, indicating that there are as yet undiscovered genes which can cause LGMD. The autosomal dominant LGMD genes have mostly been described in single families. These types of LGMD are considered quite rare.

The genes causing these types of LGMD, their chromosomal location, and the proteins they code for (when known) are listed below:

• LGMD1A (chromosome 5): myotilin
• LGMD1B (chromosome 1): laminin
• LGMD1C (chromosome 3): caveolin
• LGMD1D (chromosome 6)
• LGMD1E (chromosome 7)
• COL6A1 (chromosome 21): collagen VI alpha 1
• COL6A2 (chromosome 21): collagen VI alpha 2
• COL6A3 (chromosome 2): collagen VI alpha 3

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

• EDMD is due to a alteration 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 caused by alterations in a gene on chromosome 19 for an enzyme called myotonin protein kinase that may control the flow of charged particles within muscle cells. This gene alteration is called a triple repeat, meaning it contains extra triplets of DNA code. It is possible that this alteration 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 altered with a triple repeat. The function of the affected protein may involve translation of genetic messages in a cell's nucleus.
• The gene(s) for FSH is located on the long arm of chromosome 4 at gene location 4q35. Nearly all cases of FSH are associated with a deletion (missing piece) of genetic material in this region. Researchers are investigating the molecular connection of this deletion and FSH. It is not yet certain whether the deleted material contains an active gene or changes the regulation or activity of a nearby FSH gene. A small number of FSH cases are not linked to chromosome 4. Their linkage to any other chromosome or genetic feature is under investigation.
• The gene(s) responsible for DD have not yet been found.
• About 50% of individuals with CMD have their condition as a result of deficiency in a protein called merosin, which is made by a gene called laminin. The merosin protein usually lies outside muscle cells and links them to the surrounding tissue. When merosin is not produced, the muscle fibers degenerate soon after birth. A second gene called integrin is responsible for CMD in a few individuals but alterations in this gene are a rare cause of CMD. The gene responsible for Fukuyama CMD is FCMD and it is responsible for making a protein called fukutin whose function is not clear.

Signs and 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.

DUCHENNE MUSCULAR DYSTROPHY (DMD) A boy with Duchenne muscular dystrophy usually begins to show symptoms as a pre-schooler. The legs are affected first, making walking difficult and causing balance problems. Most patients walk three to six months later than expected and have difficulty running. Later on, a 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 enlarge, 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. He 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, and further decreases balance. 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.

Among males with DMD, the incidence of cardiomyopathy (weakness of the heart muscle), increases steadily in teenage years. Almost all patients have cardiomyopathy after 18 years of age. It has also been shown that carrier females are at increased risk for cardiomyopathy and should also be screened.

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

BECKER MUSCULAR DYSTROPHY (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 occur 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. 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.

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

LIMB-GIRDLE MUSCULAR DYSTROPHY (LGMD) While there are several 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. Life-span may be somewhat shortened. Autosomal dominant forms usually occur later in life and progress relatively slowly.

FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY (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 condition is named for the regions of the body most severely affected by the condition: muscles of the face (facio-), shoulders (scapulo-), and upper arms (humeral). Hips and legs may be affected as well. Children with FSH may 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 be able to wrinkle thier forehead. 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 fore-arms and calves. A person with myotonic 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, mental deficiency, frontal balding, skin disorders, testicular atrophy, sleep apnea, and insulin resistance. An increased need or desire for sleep is common, as is diminished motivation. The condition is extremely variable; some individuals show profound weakness as a newborn (congenital myotonic dystrophy), others show mental retardation in childhood, many show characteristic facial features and muscle wasting in adulthood, while the most mildly affected individuals show only cataracts in middle age with no other symptoms. Individuals with a severe form of mytonic dystropy typically have severe disabilities within 20 years of onset, although most do not require a wheelchair even late in life.

OCULOPHARYNGEAL MUSCULAR DYSTROPHY (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 and difficulty swallowing (dysphagia). 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.

DISTAL MUSCULAR DYSTROPHY (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 condition usually does not affect life span.

CONGENITAL MUSCULAR DYSTROPHY (CMD) CMD is marked by severe muscle weakness from birth, with infants displaying "floppiness," very poor muscle tone, and they often have trouble moving their limbs or head against gravity. Mental function is normal but some are never able to walk. They may 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.

Diagnosis

The 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; in autosomal recessive inheritance, the family history may also be negative).

Lab tests may include:

• 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). This electrical test 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 altered gene involved. Accurate genetic tests are available for DMD, BMD, DM, several forms of LGMD, and EDMD. Genetic testing for some of these conditions in future pregnancies of an affected individual or parents of an affected individual can be done before birth through amniocentesis or chorionic villus sampling. Prenatal testing can only be undertaken after the diagnosis in the affected individual has been genetically confirmed and the couple has been counseled regarding the risks of recurrence.
• Other specific tests as necessary. For EDMD, DMD 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 conditions. There are exceptions, however. Even with a muscle biopsy, it may be difficult to distinguish between FSH and another muscle condition, 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 genetic test may be needed to accurately distinguish them. The muscular dystrophies may be confused with conditions involving the motor neurons, such as spinal muscular atrophy ; conditions of the neuromuscular junction, such as myasthenia gravis ; and other muscle conditions, as all involve generalized weakness of varying distribution.

Prenatal diagnosis (testing of the baby while in the womb) can be done for those types of muscular dystrophy where the specific disease-causing gene alteration has been identified in a previously affected family member. Prenatal diagnosis can be done utilizing DNA extracted from tissue obtained by chorionic villus sampling or amniocentesis.

Treatment and management

Drugs

There are no cures for any of the muscular dystrophies. Prednisone, a corticosteroid, has been shown to delay the progression of DMD somewhat, for reasons that are still unclear. Some have reported improvement in strength and function in patients treated with a single dose. Improvement begins within ten days and plateaus after three months. Long-term benefit has not been demonstrated. Prednisone is also prescribed for BMD, though no controlled studies have tested its benefit. A study is under way in the use of gentamicin, an antibiotic that may slow down the symptoms of DMD in a small number of cases. No other drugs are currently known to have an effect on the course of any other muscular dystrophy.

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

Physical therapy

Physical therapy, regular stretching in particular, 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 tip-toeing. Full-leg braces may be used in children with 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 boys with 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 patients 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 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. A pacemaker may be implanted if these do not provide adequate control. Heart transplants are increasingly common for men with BMD. A complete cardiac evaluation is recommended at least once in all carrier females of DMD and EDMD.

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 the past decade. 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 abnormal host cells with healthy new ones. Myoblast transfer is under investigation but remains experimental.

Gene therapy introduces unaltered copies of the altered gene into muscle cells. The goal is to allow the existing muscle cells to use the new gene to produce the protein it cannot make with its abnormal gene. Problems with gene therapy research 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. Researchers are preparing for the first gene therapy trial for LGMD in the United States. The goal will be to replace the missing sarcoglycan gene(s).

Genetic counseling

Individuals with muscular dystrophy and their families may benefit from genetic counseling for information on the condition and recurrence risks for future pregnancies.

Prognosis

The expected life span for a male with DMD has increased significantly in the past two decades. Most young men will 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 is becoming 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

There is 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.

*Each type of sarcoglycanopathy can result from a gene change that resultsin complete absence of sarcoglycan protein or decreased amounts of sarcoglycanprotein.

* Includes alpha, beta, gamma and delta sarcoglycanopathies that resultin complete absence of a sarcoglycan protein

**Includes alpha, beta, gamma and delta sarcoglycanopathies that resultin decreased amounts of a sarcoglycan protein

Resources

BOOKS

Emery, Alan. Muscular Dystrophy: The Facts. Oxford Medical Publications, 1994.

Swash, Michael, and Martin Schwartz. Neuromuscular Conditions: A Practical Approach to Diagnosis and Management, 3rd edition. Springer, 1997.

ORGANIZATIONS

Muscular Dystrophy Association. 3300 East Sunrise Dr., Tucson, AZ 85718. (520) 529-2000 or (800) 572-1717. <http://www.mdausa.org>.

Online Myotonic & Congenital Dystrophies Support Group International. 185 Unionville Road, Freedom, PA 15042. (724)775-9448 or (724)774-0261. <http://www.angelfire.com/pa2/MyotonicDystrophy/index.html>.

Nada Quercia, Msc, CCGC

Muscular dystrophy

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.

KEY TERMS

Autosomal dominant —A pattern of inheritance in which only one of the two copies of an autosomal gene must be abnormal for a genetic condition or disease to occur. An autosomal gene is a gene that is located on one of the autosomes or non-sex chromosomes. A person with an autosomal dominant disorder has a 50 percent chance of passing it to each of their offspring.

Autosomal recessive —A pattern of inheritance in which both copies of an autosomal gene must be abnormal for a genetic condition or disease to occur. An autosomal gene is a gene that is located on one of the autosomes or non-sex chromosomes. When both parents have one abnormal copy of the same gene, they have a 25 percent chance with each pregnancy that their offspring will have the disorder.

Becker muscular dystrophy (BMD) —A type of muscular dystrophy that affects older boys and men and usually follows a milder course than Duchenne muscular dystrophy.

Contracture —A tightening or shortening of muscles that prevents normal movement of the associated limb or other body part.

Distal muscular dystrophy (DD) —A form of muscular dystrophy that usually begins in middle age or later, causing weakness in the muscles of the feet and hands.

Duchenne muscular dystrophy (DMD) —The most severe form of muscular dystrophy, DMD usually affects young boys and causes progressive muscle weakness, usually beginning in the legs.

Dystrophin —A protein that helps muscle tissue repair itself. Both Duchenne muscular dystrophy and Becker muscular dystrophy are caused by flaws in the gene that tells the body how to make this protein.

Facioscapulohumeral muscular dystrophy (FSH) —This form of muscular dystrophy, 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.

Limb-girdle muscular dystrophy (LGMD) —A form of muscular dystrophy that begins in late childhood to early adulthood and affects both men and women. It causes weakness in the muscles around the hips and shoulders.

Myotonic dystrophy —A form of muscular dystrophy, also known as Steinert's disease, that affects both men and women. It is characterized by delay in the ability to relax muscles after forceful contraction (myotonia) and wasting of muscles, as well as other abnormalities.

Oculopharyngeal muscular dystrophy —A type of muscular dystrophy that affects adults of both sexes, causing weakness in the eye muscles and throat.

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 of Medicine, 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, and Annotated Research Guide to Internet References. San Diego, CA: Icon Health Publications, 2003.

Sarnat, Harvey B. "Muscular Dystrophies." In Nelson Textbook 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/

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 Center School of Medicine. Available online at <www.hmc.psu.edu/healthinfo/m/musculardystrophy.htm> (accessed January 7, 2005).

L. Fleming Fallon, Jr., MD, DrPH

MUSCULAR DYSTROPHY

DEFINITION

Muscular dystrophy (MD) is the name for a group of disorders in which muscle size and strength gradually decrease over time. Nine different forms of the disorder have been discovered.

DESCRIPTION

The nine different forms of muscular dystrophy are usually distinguished by the part of the body they affect. They include the following:

• Duchenne muscular dystrophy (DMD). DMD primarily affects young boys. It causes weakness in the muscles that gets worse over time. The problem usually begins in the legs and then spreads to muscles in other parts of the body. It is the severest form of MD. DMD occurs in about 1 out of every 3,500 male births. About 8,000 boys and young men in the United States have the disorder. A milder form of the disorder occurs in a very few females.
• Becker muscular dystrophy (BMD). BMD affects older boys and young men. It is a milder form of MD than DMD, which occurs in about 1 in every 30,000 male births.
• Emery-Dreifuss muscular dystrophy (EDMD). EDMD is a very rare form of MD. It affects young boys exclusively. It causes contracture (permanent tightening) and weakness of the calf muscles and weakness in the shoulders and upper arms. It can also cause problems in the electrical signals that cause the heart to beat. Fewer than 300 cases of EDMD have been seen.
• Limb-girdle muscular dystrophy (LGMD). LGMD begins in later childhood or early adulthood. It affects both men and women. It causes weakness in the muscles around the hips and shoulders. LGMD has the greatest variety of symptoms of all forms of MD. In fact, researchers think it may actually consist of other forms of the disorder. Diagnosis of LGMD is difficult, and some patients with the disorder may have been diagnosed incorrectly in the past. The number of people with LGMD in the United States is probably a few thousand.
• Facioscapulohumeral muscular dystrophy (FSH). (pronounced FAY-shee-o-SKAP-yuh-lo-HYOOM-uh-ruhl) is also known as Landouzy-Dejerine disease. It begins in later childhood or early adulthood. It affects both men and women. FSH is characterized by 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 2,000 people. About 13,000 people in the United States have the condition.
• Myotonic dystrophy. Myotonic (pronounced my-uh-TON-ik) dystrophy is also known as Steinert's disease. It affects both men and women. The disorder is usually seen first in the face, feet, and hands. It is characterized by an inability to relax the affected muscles. This condition is known as myotonia (pronounced my-uh-TO-nee-uh). Symptoms may first appear at any time between birth and adulthood. It is the most common form of MD. About 30,000 people in the United States have myotonic dystrophy.
• Oculopharyngeal muscular dystrophy (OPMD). Oculopharyngeal (pronounced OK-yuh-lo-fuh-RIN-jee-uhl) muscular dystrophy OPMD causes weakness in the eye muscles and throat. It affects adults of both sexes. 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. It causes 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 appears at birth and progresses slowly thereafter. It causes a generalized weakness in muscles throughout the body. One form of the disorder is called Fukuyama, for a district in Japan where it is relatively common. Fukuyama CMD also causes mental retardation.

Muscular Dystrophy: Words to Know

Becker muscular dystrophy (BMD):

A type of muscular dystrophy that affects older boys and men and usually follows a milder course than DMD.

Contracture:

A permanent shortening and tightening of a muscle or tendon causing a deformity.

Distal muscular dystrophy (DD):

A form of muscular dystrophy that usually begins in middle age or later, causing weakness in the muscles of the feet and hands.

Duchenne muscular dystrophy (DMD):

The severest form of muscular dystrophy, usually affecting young boys, beginning in the legs, and resulting in progressive muscle weakness.

Facioscapulohumeral muscular dystrophy (FSH):

A form of muscular dystrophy that begins in late childhood to early adulthood; affects both men and women; and causes weakness in the muscles of the face, shoulders, and upper arms.

Limb-girdle muscular dystrophy (LGMD):

A form of muscular dystrophy that begins in late childhood to early adulthood; affects both men and women; and causes weakness in the muscles around the hips and shoulders.

Myotonic dystrophy:

A form of muscular dystrophy that affects both men and women and causes generalized weakness in the face, feet, and hands.

Oculopharyngeal muscular dystrophy (OPMD):

A form of muscular dystrophy that affects adults of both sexes and causes weakness in the muscles of the eyes and throat.

CAUSES

All forms of muscular dystrophy are caused by wasting of muscle tissue. Muscle cells die, and muscles become weaker and unable to perform their normal functions. Researchers are still uncertain how this loss of muscle function takes place. They believe that cells may lose their ability to produce certain muscle proteins. Proteins are essential chemicals that occur in all cells and have many different functions. For example, they act as building blocks for cells and as enzymes. Enzymes are special kinds of proteins that control the rate at which chemical reactions take place in cells.

Researchers believe that some forms of MD occur because some muscle proteins are absent or present in smaller-than-average amounts. In such cases, muscle tissue becomes weak. Other muscle proteins may be needed to repair damage in muscle tissue. If those proteins are absent, muscles that are damaged cannot be repaired. In most cases, the connection between absent muscle proteins or reduced amounts of proteins and various forms of MD is simply not yet known.

What scientists do know is that MD is almost entirely a genetic disorder. A genetic disorder is a medical problem caused by defects in a person's genes. Genes are chemical units found within cells that carry essential information telling the cell what functions it should perform. Every person gets two sets of genes, one from each parent. Under most circumstances, the two sets of genes merge to produce a normal set of instructions. A cell follows those instructions to perform a normal set of functions.

Occasionally, a person inherits faulty genes from one or both of his or her parents. In such cases, the instructions provided to a cell can be incorrect and the cell is unable to perform its normal functions.

In the case of MD, a person may receive a single faulty gene from one parent or a pair of faulty genes, one from each parent. A single faulty gene may cause no problem at all. In that case, the person is said to be a carrier. A carrier can transmit the faulty gene to his or her own children. But it will not interfere with the person's own health.

In other cases, one faulty gene is all it takes to cause some form of MD. For example, DMD, FSH, OPMD, and some forms of LGMD and DD are thought to be caused by a single faulty gene. The faulty gene may make it impossible for muscle cells to function as they should. Muscle tissues weaken, and some form of muscular dystrophy results.

Other forms of MD require the presence of two faulty genes, one from each parent. CMD and some forms of LGMD and DD are thought to be caused by this mechanism. Again, the two faulty genes carry incorrect information to a cell and the cell does not function normally. It produces faulty muscle protein, an insufficient amount of the protein, or no protein at all. Muscle tissue weakens and dies, and MD results.

SYMPTOMS

All forms of MD have one characteristic in common—muscular weakness. Other symptoms differ, however, depending on the type of MD involved.

DMD Symptoms

The first symptoms of DMD appear during preschool years. The disorder affects the legs first. A boy has trouble walking and maintaining balance. In most cases, he begins walking three to six months later than average. As his calf muscles begin to weaken, he may change the way he walks. He places his legs farther apart in order to maintain balance. Walking this way produces a waddling effect that is characteristic of DMD.

Contractures usually begin at about the age of five or six. They affect the calf muscles most severely, pulling the foot down and back. This forces a boy to walk on his tiptoes. Balance becomes more of a problem. As a result, falls and broken bones become common at this age. By the age of nine or ten, a boy with DMD might not be able to climb stairs or stand by himself. Most DMD patients have to use a wheelchair by the age of twelve.

FAULTY GENES AND MD

Sometimes faulty genes occur on the Y chromosome but not the X chromosome. Chromosomes are structures in cells that contain many genes. Women have two X chromosomes and no Y chromosomes. Men have one X chromosome and one Y chromosome. Faulty genes that occur in Y chromosomes are only present in men. This explains why some forms of muscular dystrophy affect men only. Men inherit those faulty genes, but women do not.

Muscles in other parts of the body are also weakened. When muscles in the upper body are affected, scoliosis (see scoliosis entry), or curvature of the spine, may result. The most serious problem, however, affects the muscles of the diaphragm. The diaphragm provides the in-and-out force that allows a person to breathe and to cough. As the diaphragm weakens, breathing becomes more difficult and patients will have less energy and stamina. They also become more subject to infection because they cannot cough up infectious agents that get into their lungs. Young men with DMD can live into their twenties provided they have mechanical aids to help with their breathing and good respiratory (breathing system) hygiene.

About a third of the boys with DMD also have learning disorders. These disorders can include problems with learning by ear and trouble paying attention to some tasks. Specialized educational problems can help compensate for these disorders.

BMD Symptoms

The symptoms of BMD usually appear in late childhood to early adulthood. They are similar to those of DMD, but they are usually less severe. They may also develop at a different rate and in a different pattern. For example, young men with BMD can often walk on their own into their twenties or early thirties. Scoliosis may also develop, but it is less severe and develops more slowly. One symptom that is more serious in BMD than DMD involves heart problems. These problems include irregular heartbeats and congestive heart failure. Symptoms related to heart problems include fatigue, shortness of breath, chest pain, and dizziness. Respiratory problems may also develop, requiring the use of a mechanical device to help the patient breathe.

EDMD Symptoms

EDMD usually begins in early childhood. The first symptom is likely to be contractures, which is a permanent shortening of a muscle. Muscle weakness then appears in the shoulders, upper arms, and calves. Most men with EDMD survive into middle age. As with BMD, heart problems may develop and can cause death.

LGMD Symptoms

At least two forms of LGMD occur. One develops during childhood and the other in the teens or twenties. The major symptom is weakening of muscles in the center of the body. Contractures may occur, and most people lose the ability to walk about twenty years after their disorder is diagnosed. In some people, respiratory problems may require the use of a mechanical device to assist with breathing.

FSH Symptoms

FSH varies in its severity and age of onset. Symptoms can begin anywhere from childhood to the early twenties. Symptoms tend to be more severe when the disorder appears earlier. The condition mostly affects muscles of the face, shoulders, and upper arms, although hips and legs may also be affected. Children with FSH often develop partial or complete deafness.

Symptoms of Myotonic Dystrophy

Symptoms of myotonic dystrophy include facial weakness, a slack (loose) jaw, drooping eyelids, and muscle wasting in the forearms and calves. A person with this dystrophy has difficulty letting go of an object, especially if it's cold. Myotonic dystrophy affects heart muscles, causing irregular heartbeats, and the muscles of the digestive system, leading to digestion problems and constipation.

Myotonic dystrophy can also affect other body systems. It can cause cataracts (see cataracts entry), destruction of the retina, mental retardation (see mental retardation entry), skin disorders (see skin disorders entry), wasting of the testicles, sleep problems (see insomnia entry), and diabetes-like problems (see diabetes mellitus entry). Most people with this type of dystrophy are severely disabled within twenty years of first diagnosis. They usually do not require a wheelchair, however.

Symptoms of OPMD

OPMD usually begins when a person has reached his or her thirties or forties. The disorder affects muscles controlling the eyes and throat. Symptoms include drooping eyelids and difficulty swallowing. Muscle weakness later spreads to the face, neck, and sometimes the upper limbs. Difficulty in swallowing can result in problems of the upper respiratory system. Among the most serious of these problems is pneumonia (see pneumonia entry).

Symptoms of DD

DD usually begins in the twenties or thirties. It first appears as a weakness in the hands, forearms, and lower legs. One of the first symptoms may be difficulty with fine movements, such as typing or fastening buttons. Symptoms usually progress slowly. The disorder seldom affects a person's normal life span.

Symptoms of CMD

CMD is marked by severe muscle weakness from birth. Infants with the disorder cannot control their muscles and tend to flop around. Nonetheless, children with CMD may learn to walk, with or without a supporting device, such as crutches. Many live into young adulthood and even beyond. Fukuyama CMD is a far more serious disorder, however. Children with this condition seldom learn to walk and suffer severe mental retardation. They generally die in childhood.

DIAGNOSIS

Diagnosis begins with a medical history and a complete physical examination. A medical history is important to find out if dystrophy has occurred in other family members. Since the disorder is hereditary, family patterns are helpful in diagnosing the condition. A physical examination is necessary to rule out conditions with similar symptoms.

A number of laboratory tests are available for diagnosing MD. These tests include:

• Blood levels of creatine kinase (CK; pronounced KREE-uh-teen KIE-nase). CK is an enzyme present in muscle tissue. Its production increases when muscle tissue is damaged.
• Muscle biopsy. A biopsy is a procedure by which a small sample of tissue is removed with a needle. The sample can then be studied under a microscope. Changes in muscle tissue can be observed, indicating the presence of a dystrophy.
• Electromyogram (EMG; pronounced e-LEK-tro-my-o-gram). An EMG is an electrical test to see how well muscles are functioning. If muscles do not respond normally to the test, a dystrophy may be present.
• Genetic tests. It is now possible to examine the genes present in a person's cells and identify genes that are faulty.
• Other tests for specific forms of MD. Specific tests can be conducted for certain types of MD. For example, a hearing test can be used to help diagnose FSH in children.

Most doctors with experience in dealing with MD can diagnose the disorder quite easily. In some cases, however, MD can be confused with other diseases that have similar symptoms. For example, the disorder known as myasthenia gravis (pronounced MY-uhs-THEE-nee-uh GRA-vuhs) affects the site where nerves and muscles come together. Its symptoms are somewhat similar to those of some forms of MD.

TREATMENT

There are currently no cures for any form of muscular dystrophy. A few drugs have been found that slow the progress of some forms of MD. For example, prednisone (pronounced PRED-nih-zone), a corticosteroid (pronounced kor-tih-ko-STIHR-oid), slows the progress of DMD. Generally speaking, however, drugs have a limited and uncertain value in the treatment of MD.

The primary goal of treatment programs for MD is to prevent complications. The major complications are decreased ability to move on one's own, contractures, scoliosis, heart defects, and respiratory problems.

Physical Therapy

Regular stretching exercises help prevent or delay contractures. Braces may be used to help support ankles, feet, legs, and other body parts with weakened muscles. Patients can sometimes be taught to use another set of muscles in place of muscles damaged by MD. A program of regular, light exercise can help keep muscles in good condition.

Surgery

Surgery may be necessary to correct some severe symptoms of MD. Contractures can be treated, for example, by cutting the damaged muscle. The muscle is then held in place until it grows back normally. In FSH, the shoulder blade can be braced to compensate for muscle weakness. For a person with OPMD, eyelids can be lifted by a surgical procedure to correct for drooping eyelids. Scoliosis can sometimes be corrected by back surgery. In this surgery, the vertebrae that make up the spine are fused (fixed) together. Steel rods are then inserted and attached to the vertebrae to keep the spine in a straight, stiff position.

Occupational Therapy

The purpose of occupational therapy is to help patients find ways of making up for their loss of strength and dexterity. Strategies may include changes in the home environment, learning to use special utensils and dressing aids, and use of a wheelchair and communication devices, such as hearing aids.

Nutrition

Good nutrition helps promote general health in all forms of MD. No special diet is needed or has been shown to relieve any of its symptoms, however.

Cardiac Care

EDMD and BMD may require certain kinds of treatment for heart problems. For example, drugs such as nifedipine (pronounced nie-FED-uh-peen) help maintain a regular heartbeat. An artificial pacemaker may also need to be installed in patients with an irregular heartbeat.

Respiratory Care

Weakness in diaphragm muscles can be a very serious condition that may result in a person losing the ability to breathe on his or her own. In such cases, a mechanical device may be needed to help the patient breathe. For example, air may be administered through a face mask or mouthpiece. Or a tracheotomy (pronounced TRAY-kee-OT-uh-mee) may be necessary. In a tracheotomy, a tube is inserted through a hole cut in the throat. Air can then be provided directly to the person's respiratory system.

Good lung hygiene is always necessary. Without proper care, infections of the lungs are common. Such infections can easily lead to pneumonia and even death. Patients with MD may also need to learn techniques for coughing. The normal cough reaction is usually difficult because of damaged muscles. But coughing is necessary to expel foreign particles that can cause disease and infection.

Experimental Treatments

Two experimental procedures may hold some promise for treating MD. One of these procedures is called myoblast transfer. In this procedure, millions of immature muscle cells are injected into a patient's damaged muscle. The goal of the procedure is to provide the person's body with normal, healthy cells that may be able to function in place of damaged ones. Thus far, there seems to be no evidence that this procedure is successful, although research continues in the hope of success in the future.

The second procedure is gene therapy. In gene therapy, a person with MD is injected with artificially produced genes that are correct copies of the faulty genes in their body. The hope is that the correct genes will function in cells the way the faulty genes are supposed to but don't. Gene therapy is a very difficult task complicated with many side effects. However, many researchers believe that it may be the most likely way of curing MD.

PROGNOSIS

The expected lifetime for a male with DMD has increased significantly in the past two decades. Most young men will now live into their early or mid-twenties. The main cause of death is respiratory infection.

Prognosis for other forms of MD is highly variable. It depends very much on the age at which symptoms first appear and how severe those symptoms are. People with BMD, EDMD, and myotonic dystrophy may have normal life spans. The critical issue for people with these disorders is attention to and care for heart problems that may develop.

PREVENTION

There is no way to prevent any form of MD. Some forms of the disorder can now be detected by genetic tests. Parents can have their unborn children tested for these forms of muscular dystrophy. They can then use that information for family planning purposes.

FOR MORE INFORMATION

Books

Bergman, Thomas. Precious Time: Children Living With Muscular Dystrophy (Don't Turn Away). Milwaukee, WI: Gareth Stevens, 1996.

Emery, Alan. Muscular Dystrophy: The Facts. Oxford Medical Publication, 1994.

Organizations

The Muscular Dystrophy Association. 3300 East Sunrise Drive, Tucson, AZ 85718. (520) 529–2000; (800) 572–1717. http://www.mdausa.org.