Oculopharyngeal 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 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

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 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 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 weakness 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.