CHAPTER 102

Muscular Dystrophies and Related Disorders

Muscular dystrophies are a group of inherited muscle disorders in which one or more genes needed for normal muscle function are defective, leading to muscle weakness (see page 540) of varying severity. Other inherited muscle disorders include congenital myopathies, periodic paralysis, and glycogen storage diseases. Glycogen storage diseases are a group of rare inherited disorders in which muscles cannot metabolize sugars normally (see page 1834), so they build up large stores of glycogen (a starch that is formed from sugars).

Duchenne and Becker Muscular Dystrophies

Duchenne muscular dystrophy and Becker muscular dystrophy cause weakness in the muscles closest to the torso.

These dystrophies are caused by defects in genes responsible for muscle function, which lead to muscle weakness that develops during childhood or adolescence.

Both dystrophies are characterized by physical weakness.

The diagnosis is based on the results of tests done on samples of blood and a sample of muscle tissue.

Physical therapy and sometimes prednisone or surgery provides some help.

These dystrophies are the most common muscular dystrophies and nearly always occur in boys. On average, 1 of 3,000 boys born has Duchenne muscular dystrophy, whereas on average 1 of 30,000 boys born has Becker muscular dystrophy.

The gene defect that causes Duchenne muscular dystrophy is different from the gene defect that causes Becker muscular dystrophy, but both defects involve the same gene. The gene for either of these traits is recessive and is carried on the X chromosome. Therefore, although a female can carry the defective gene, she will not develop the disease because the normal gene on one X chromosome compensates for the gene defect on the other X chromosome. However, any male who receives the defective gene will have the disease because he has only one X chromosome (see page 13).

Boys with Duchenne muscular dystrophy lack almost totally the muscle protein dystrophin, which is important for maintaining the structure of muscle cells. Boys with Becker muscular dystrophy produce dystrophin, but because the protein structure is altered, the dystrophin does not function properly.

Symptoms

In boys with Duchenne muscular dystrophy, the first symptoms are developmental delay (particularly a delay in starting to walk); difficulty walking, running, jumping, or climbing stairs; and falling. Starting between the ages of 2 years and 3 years, the gait becomes waddling, and the child has difficulty rising from the floor.

Weakness in the shoulder muscles usually follows and gets steadily worse. As the muscles weaken they also enlarge, but the abnormal muscle tissue is not strong. In boys with Duchenne muscular dystrophy, the heart muscle also gradually enlarges and weakens, causing problems with the heartbeat, which are detected by an electrocardiogram. About 33% of affected boys have mild, nonprogressive (that is, will not become worse) intellectual impairment that affects mostly verbal ability.

In boys with Duchenne muscular dystrophy, the arm and leg muscles usually contract around the joints, so that the elbows and knees cannot fully extend. Eventually, an abnormally curved spine (scoliosis) develops. By age 12, most children with the disease are confined to a wheelchair. Increasing weakness of the respiratory muscles also makes them susceptible to pneumonia and other illnesses, and most die by the age of 20.

In boys with Becker muscular dystrophy, weakness is less severe and first appears a little later, at about age 12. The pattern of weakness resembles that of Duchenne muscular dystrophy. However, very few adolescents become confined to a wheelchair. Most people survive into their 30s or 40s.

Diagnosis

Doctors suspect muscular dystrophy when a young boy becomes weak and grows weaker. An enzyme (creatine kinase) leaks out of muscle cells, causing levels of creatine kinase in the blood to be abnormally high. However, high blood levels of creatine kinase do not necessarily mean that a person has muscular dystrophy because other muscle diseases may also cause elevated levels of this enzyme. Duchenne muscular dystrophy is diagnosed when blood tests show the gene for the protein dystrophin to be absent or abnormal and when a muscle biopsy (removal of a piece of muscle tissue for examination under a microscope) shows extremely low levels of dystrophin in the muscle. Under the microscope, the muscle generally shows dead tissue and abnormally large muscle fibers. In the late stages of Duchenne muscular dystrophy, fat and other tissues replace the dead muscle tissue. Similarly, Becker muscular dystrophy is diagnosed when blood tests show the gene for the protein dystrophin to be abnormal and a muscle biopsy shows low levels of dystrophin in the muscle, but not as low as in Duchenne muscular dystrophy.

Other tests to support the diagnosis include electrical studies of muscle function (electromyography) and nerve conduction studies (see page 636).

Families with members who have either Duchenne or Becker muscular dystrophy are advised to consult a genetic counselor for help in evaluating the risk of passing the muscular dystrophy trait on to their children. In families with a history of these disorders, doctors can perform prenatal tests on the fetus to determine if the child is likely to be affected.

Treatment

Neither Duchenne nor Becker muscular dystrophy can be cured. Physical therapy, exercise, and sometimes wearing braces help prevent the muscles from contracting permanently around joints. Sometimes surgery is needed to release tight, painful muscles. Boys need fewer calories because they are less active. They should avoid overeating.

Prednisone, a corticosteroid, taken by mouth daily, may temporarily improve strength. However, long-term use causes many side effects (see box on page 568), so it is not given to every child with muscular dystrophy. Use of prednisone is generally reserved for people whose muscle weakness has severely interfered with the normal activities of daily living. Creatine, a supplement taken by mouth, has recently been shown to improve strength. Gene therapy that would enable muscles to produce dystrophin and thereby relieve the weakness is under investigation but so far has not proved successful.

Other Forms of Muscular Dystrophy

Several uncommon forms of muscular dystrophy, all inherited, also cause progressive muscle weakness.

Emery-Dreifuss dystrophy is transmitted in various ways. Only males are affected, but females may be carriers of the gene that causes the disorder. Muscles become weak and waste away (atrophy) any time before age 20 years. The most affected muscles are those of the upper arms, lower legs, and heart. An affected heart commonly causes premature death. Heart pacemakers may help prolong life.

Facioscapulohumeral (Landouzy-Dejerine) muscular dystrophy is transmitted by an autosomal dominant gene. Therefore, a single abnormal gene is sufficient to cause the disorder, and the disorder can appear in either males or females. Symptoms usually begin between the ages of 7 and 20. The facial and shoulder muscles are always affected, so that a child has difficulty whistling, closing the eyes tightly, or raising the arms. Some people with the disease also develop a footdrop (the foot flops down). The weakness is rarely severe, and people who have Landouzy-Dejerine muscular dystrophy have a normal life expectancy.

Limb-girdle muscular dystrophies can be transmitted in various ways. They cause weakness in the muscles of either the pelvis (Leyden-Möbius muscular dystrophy) or the shoulder (Erb’s muscular dystrophy). Males and females are affected equally. These inherited disorders often begin in early childhood but may not begin until adulthood. They rarely cause serious weakness.

Mitochondrial myopathies are muscle disorders inherited through faulty genes in mitochondria (the energy factories of cells, which carry their own genes). Because sperm do not contribute mitochondria during fertilization, all mitochondrial genes come from the mother (see page 11). Therefore, although they are equally likely to occur in males and females, these disorders can never be inherited from the father. These rare disorders sometimes cause increasing weakness in one or a few muscle groups, such as the eye muscles (ophthalmoplegia), and may affect other organs, such as the heart or brain. One mitochondrial myopathy is called Kearns-Sayre syndrome.

Diagnosis and Treatment

Diagnosis usually requires removing a sample of the weak muscle tissue for biopsy and either examining it under a microscope or performing chemical tests on it. Specific treatments are not available, but gene therapy is under investigation.

MYOTONIC MYOPATHIES

Myotonic myopathies are muscular dystrophies in which the muscles are not able to relax normally after contraction. Muscle weakness and spasms may also occur.

Myotonia congenita (Thomsen’s disease) is a rare autosomal dominant disorder (only one affected parent is needed to pass the trait on to offspring) that affects males and females. Symptoms usually start in infancy. The hands, legs, and eyelids become very stiff because of an inability to relax the muscles. Muscle weakness, however, is usually minimal. The diagnosis is made from the child’s characteristic appearance, inability to relax the grip of the hand rapidly after closing the hand, and prolonged contraction after the doctor taps a muscle. An electromyogram (a test in which electrical impulses from muscles are recorded—see page 636) is needed to confirm the diagnosis. Myotonia congenita is treated with phenytoin, quinine, procainamide, or mexiletine to relieve muscle stiffness and cramping; however, each of these drugs has undesirable side effects. Regular exercise may be beneficial. People with myotonia congenita have a normal life expectancy.

Myotonic dystrophy (Steinert’s disease) is an autosomal dominant disorder affecting males and females. It is the most common muscular dystrophy among whites. Symptoms begin during adolescence or young adulthood. The disorder causes weakness and stiff muscles, especially in the hands. Drooping eyelids are also common. Symptoms can appear at any age and can range from mild to severe. People with the most severe form of the disorder have extreme muscle weakness and many other symptoms, including cataracts, small testes (in men), premature balding in the front (in men), irregular heartbeats, diabetes, and mental retardation. They usually die by age 50. Treatment with mexiletine or other drugs (for example, quinine, phenytoin, or procainamide) has been used, but these drugs do not relieve the weakness, which is the most bothersome symptom to the person. Also, each of these drugs has undesirable side effects. The only treatment for muscle weakness is supportive measures, such as ankle braces and other devices.

Congenital Myopathies

Congenital myopathies is a term used to describe a wide variety of inherited disorders of the muscles, nerves, or both, which are present at birth or infancy.

There are hundreds of congenital myopathies. The five most common types of congenital myopathy are nemaline myopathy, myotubular myopathy, central core myopathy, congenital fiber type disproportion, and multicore myopathy. Among these most common types, life span is usually normal in central core myopathy, congenital fiber type disproportion, and myotubular myopathy. However, exceptions often occur. Life span tends to be more variable in multicore myopathy and nemaline myopathy.

The diagnosis usually requires taking a sample of the weak muscle tissue for biopsy (in which a piece of tissue is removed for examination under a microscope). Specific treatments are not available, but physical therapy may help preserve function.

Periodic Paralysis

Periodic paralysis is an autosomal dominant inherited disorder (only one affected parent is needed to pass the trait on to offspring) that causes sudden attacks of weakness and paralysis. There are several forms.

Muscles do not respond normally to stimulation, usually when the blood potassium level is too low or high.

Weakness is intermittent, affecting mainly the limbs, and is often brought on by exercising or eating too much or too little carbohydrates.

The diagnosis is based on the symptoms and a check of the potassium level in the blood.

Avoiding triggers that cause attacks and taking drugs can prevent attacks effectively.

During an attack of periodic paralysis, muscles do not respond to normal nerve impulses or even to artificial stimulation with an electronic instrument. The precise form that the disorder takes varies among different families. In some families, the paralysis is related to low levels of potassium in the blood (hypokalemia). In others, the paralysis is related to high levels of potassium in the blood (hyperkalemia). In a rare form, potassium levels are normal.

Symptoms and Diagnosis

During an attack of weakness, the person remains completely awake and alert. Muscles in the eye and face are not affected. Weakness may affect only certain muscles or all four limbs.

In the hypokalemic form, attacks generally first appear before age 16 but may appear during the 20s and always by age 30. The attacks last up to 24 hours, occasionally even longer. Often, the person awakens the day after vigorous exercise with an attack of weakness. However, eating meals rich in carbohydrates (sometimes hours or even the day after) can also cause attacks. Eating carbohydrates and exercising vigorously drive sugar into cells. Potassium moves with the sugar, and the result is lowered potassium levels in the blood.

In the hyperkalemic form of the disorder, attacks often begin by age 10. The attacks last 15 minutes to 1 hour. Weakness tends to be less severe than in the hypokalemic form. Fasting, exercise, strenuous work, and exposure to cold may precipitate attacks.

A doctor’s best clue to the diagnosis is a person’s description of a typical attack. If possible, the doctor draws blood while an attack is in progress to check the level of potassium. If the levels of potassium are abnormal, doctors usually perform additional tests to be sure the abnormal levels are not from other causes. Occasionally, a doctor may give the person intravenous drugs that increase or decrease the levels of potassium in the blood to see whether an attack results.

Prevention and Treatment

Acetazolamide, a drug that alters the blood’s acidity, may prevent attacks in all types of periodic paralysis. People with the hypokalemic form can take potassium chloride in an unsweetened solution while an attack is in progress. Usually symptoms improve considerably within an hour. People with the hypokalemic form should also avoid meals rich in carbohydrates and salt and avoid alcohol or strenuous exercise.

People with the hyperkalemic form can prevent attacks by eating frequent meals rich in carbohydrates and low in potassium and by avoiding fasting, strenuous activity, and exposure to cold. If an attack is severe or persistent, drugs (such as a thiazide diuretic or inhaled albuterol) can help lower the potassium level.