In neurology clinic, your next patient is a five year old boy who was referred by his pediatrician because of an abnormal gait. He was adopted from another country about a year ago, and his adopting parents have noticed that he is clumsy when he runs where he falls often. He runs on his tiptoes, which has occurred since they started taking care of him. Otherwise, he has no other problems. He is doing well in kindergarten despite his language difficulty. His teacher notes that he has trouble getting up from a sitting position at school. His parents deny that he has chronic fevers, leg pain, weight loss, seizures, skin rash, urinary or bowel incontinence, or frequent colds.
His past medical history, developmental history, family history, and birth history are unknown. His immunizations are up-to-date and his PPD this year has been negative.
Exam: His vital signs are normal. His height, weight and head circumference are at the 50th percentile. He is alert, active, shy, well-nourished and slim in no distress. His skin shows no neurocutaneous stigmata. His head is normocephalic and atraumatic. His pupils are equal, round, reactive to light. No nystagmus is evident. His fundi are normal with sharp disk margins. His TMs are clear. His throat is normal with a uvula midline. His lungs, heart, and abdomen are normal. His back shows no sacral dimples.
Neurologic exam: A standard cranial nerve exam reveals no deficits. His strength is +4/5 in his deltoids, knee flexors and extensors; +5/5 in his biceps and triceps. His calves are visibly enlarged with a firm, rubbery feeling. He gets up to a standing position using a Gowers' maneuver. No dysdiadochokinesia. Negative Romberg sign. Sensation to light touch is intact. His reflexes are +2/4 in his biceps, triceps, brachioradialis, patella and ankle. His plantar reflex is downgoing (negative Babinski sign). No clonus is elicited. Normal anal wink and abdominal reflexes are present. His gait is best described as a wide based waddling. When running, he tends to run on his toes. He is unable to jump.
You have a suspicion of what he might have, and send off some blood tests and make an arrangement for a muscle biopsy to be performed.
Muscular dystrophy is a term used to describe a primary myopathy that is genetically acquired, is progressive, and is characterized by death and degeneration of various muscle fibers during different periods of the disease. The word dystrophy means abnormal growth, being derived from the Greek word, trophy, meaning nourishment. Therefore, muscular dystrophy can be thought of as an abnormal growth of muscle (1). Although there are many different types of muscular dystrophies, the most well known of them is Duchenne muscular dystrophy (DMD), which is the most common type of muscular dystrophy occurring in childhood.
The inheritance pattern for DMD muscular dystrophy is X-linked recessive. Therefore only males express the disease, with females being carriers. If a female were a carrier, then according to Mendelian genetics, she would have a 50% chance of having an affected son, and a 50% chance of having a daughter who is a carrier. Although family history is usually positive, there is a high rate of spontaneous mutations; about one-third of all cases of DMD are sporadic or new mutations (2).
There are several different types of muscular dystrophies, each with different modes of inheritance, chromosome gene locations and products, and presentations. The types of muscular dystrophy and modes of inheritance are listed below:
1. Duchenne muscular dystrophy (X-linked recessive)
2. Becker muscular dystrophy (X-linked recessive)
3. Myotonic dystrophy (autosomal dominant-expansion of unstable CTG trinucleotide DNA sequence) and congenital myotonic dystrophy (maternally transmitted)
4. Congenital muscular dystrophy (autosomal recessive)
5. Limb girdle muscular dystrophy (autosomal dominant or recessive)
6. Facioscapulohumeral dystrophy (autosomal dominant)
7. Emery-Dreifuss muscular dystrophy (X-linked recessive)
The incidence of Duchenne and Becker muscular dystrophy is 1 in 3,500 male births. Myotonic dystrophy is the most common dystrophy presenting in adulthood, with an incidence in all age groups being 13.5 per 100,000. The incidences of the other types of muscular dystrophies including facioscapulohumeral dystrophy, limb-girdle dystrophy, and congenital muscular dystrophy, are less common then the other muscular dystrophies (2).
When someone mentions muscular dystrophy, we think of Duchenne muscular dystrophy (DMD) since this is the most common of the muscular dystrophies. Therefore, this chapter will focus on the clinical presentation and diagnosis of DMD. The underlying problem in DMD is abnormal or absent dystrophin production. In normal individuals, there is very little dystrophin; however, in DMD patients, this protein is absent or nonfunctional. Although it is known that dystrophin is a cytoskeletal protein, the exact mechanism whereby the absence of this protein leads to muscle degeneration and necrosis is not clear. Dystrophin is transcribed from a gene located in the Xp21 locus. About 70% of cases are due to a gene deletion, 5-10% are due to gene duplications, and the remaining 20-25% are due to point mutations (3).
Duchenne muscular dystrophy usually presents insidiously and after several years of age. The first sign is usually a delay in learning to walk. Normal children usually start walking on the average about 12 months of age; however, in DMD, 56% start walking at 18 months of age, and about 25% learn how to walk after 2 years of age. An inability to run properly is a hallmark sign and appears to be present in almost all cases. Other early signs are a waddling gait, walking unsteadily with frequent falling, walking on toes, and difficulty at climbing stairs. Almost all patients show signs of this disease by 5 years of age, although occasionally, this disease can present as late as 8 to 9 years of age. Another early sign is pseudohypertrophy of the calf muscles. The calf muscles feel firm or woody, in addition to being enlarged. The pseudohypertrophy is due to excessive amounts of adipose and connective tissue secondary to muscle necrosis and destruction from the lack of dystrophin. Despite its size, the muscles are weak. In addition to the calves, other muscles where pseudohypertrophy can be present are masseters, deltoids, serratus anterior, and quadriceps. In general, the pattern of muscle weakness is lower extremities and proximal muscles first, and upper extremities and distal muscles later. This pattern of muscle weakness leads to several clinical symptoms. One is the waddling gait that is seen, which is due to weakness of the gluteus medius and minimus muscles. Another is the lumbar lordosis during walking, which is caused by weakness in the gluteus maximus muscle. Because of an imbalance between the plantar and dorsiflexors, these patients also walk on their toes. After age 4 to 5 years, the Gowers' maneuver can be observed. A positive sign is seen when a child climbs up on his thighs in order to extend his hips and push up his trunk when going from a sitting to standing position. This is due to weakness of the knee and hip extensors. By age 4 years, there is weakness of the pectoral girdle muscles in that the child slides through the examiner's arms when grasped around the chest and is pulled up. Winging of the scapulae can be seen later. Although there is no pain, sometimes children will complain of muscle cramping and stiffness, especially in the calves (4).
The muscle disease is progressive and these patients are usually wheelchair bound before 13 years of age. After the loss in ambulation, equinovarus deformities of the feet and scoliosis develop rapidly. Weakness of the intercostal muscles causes a progressive restrictive respiratory disease to occur leading to nocturnal hypoventilation in the late teens to early 20s. Later, respiratory failure occurs, requiring ventilator support. Patients start to become symptomatic from progressive cardiomyopathies around their teen years, although EKG changes are seen in the early stages of the disease.
Not only does this disease affect muscle, but the central nervous system as well. About 30% of affected boys have lower intelligence quotients, especially in the verbal subtests, although boys having normal intelligence have been reported. Also emotional problems appear higher than in other disorders. The exact mechanism for the lower intelligence and emotional problems is not known; although it is known that dystrophin is normally located in the cortical synapses, and its absence might account for the CNS abnormalities. Seizures and visual and hearing problems are not present in DMD (5).
A similar entity to DMD is Becker muscular dystrophy. This type of muscular dystrophy is also due to mutation of the dystrophin gene, but instead of having a nonfunctional or absent protein product, the dystrophin itself is defective but still partially active. Therefore, these patients have milder forms of muscle weakness, and they usually present later compared to DMD. Progression is also much slower, and these patients may be ambulatory until 16 years of age or older. Cardiac problems may be severe. About 15% of patients younger than 16 years have clinically significant cardiomyopathy, and about 75% of individuals have that problem after age 40 years. Affected patients may live into late adulthood, compared to patients with DMD who die much earlier (2).
Myotonic muscular dystrophy is not due to dystrophin but to an abnormal protein kinase due to an expansion of an unstable trinucleotide repeat in chromosome 9. This disease is characterized by an older age of onset, facial weakness and greater distal muscle weakness, cardiac muscle involvement leading to arrhythmias, cataracts, and endocrine problems (such as diabetes, testicular atrophy, and menstrual irregularities).
Another type of myotonic muscular dystrophy, congenital myotonic dystrophy, is transmitted maternally and is manifested by marked hypotonia in the infant, leading to early death usually due to respiratory insufficiency. If this type of dystrophy is suspected, the mother should be tested for myotonia (2). Congenital muscular dystrophy presents with hypotonia and weakness at birth. There may also be joint contractures, respiratory and swallowing difficulties.
There are some types of congenital muscular dystrophies, such as Fukuyama type, muscle-eye-brain disease, and Walker-Warburg syndrome, which have mental retardation, seizures, hydrocephalus, and structural brain and eye abnormalities. These are autosomal recessive (2).
Limb-girdle dystrophy is a heterogeneous disorder involving several different gene loci. It can be autosomal recessive or dominant (2).
Facioscapulohumeral muscular dystrophy usually presents in late childhood to early adolescence with facial weakness, and weakness of the scapulohumeral muscles. Deltoid muscle strength is spared. It is autosomal dominant (2).
DMD can be suspected clinically; however, there are several tests that can greatly assist in its diagnosis. Serum creatine phosphokinase (CPK or CK) is an enzyme present in muscle, and when there is damage in the muscle cells, CPK is released. Therefore, CPK is highly elevated in DMD, commonly 50 to 100 times normal values in Duchenne and Becker muscular dystrophies (15,000-35,000 IU/L). CPK is usually highest in the early stages of the disease, but then decreases with progression. CPK is not specific for muscular dystrophy. It may also be elevated in spinal muscular atrophy, normal vaginal delivery, acute hypoxic-ischemic cerebral injury, intramuscular injections, muscle trauma, and recent vigorous exercise. Other lysosomal enzymes present in muscle, such aldolase and aspartate aminotransferase are also elevated in muscular dystrophy; however, they are also nonspecific (6).
Electromyography (EMG) may identify a myopathic process, but it is not specific for muscular dystrophy and plays a minor role in its diagnosis. The EMG shows low-amplitude, short-duration polyphasic motor unit action potentials in this disease.
A specific test using molecular genetic techniques can be performed using a blood sample in which the identification of specific gene deletions or mutations is done by PCR. This has obviated the need for muscle biopsies since deletions in the Xp21 gene can be identified to confirm the presence of Duchenne and Becker muscular dystrophy in two thirds of the cases (2). The other cases that are not diagnosed by PCR can be confirmed by the dystrophin immunocytochemistry test on muscle biopsies.
Muscle biopsy is probably very helpful and specific for Duchenne and Becker muscular dystrophy, in addition to other types of muscular dystrophies. Muscle degeneration and regeneration and connective tissue proliferation are present. Staining for dystrophin and other associated proteins through specialized immunocytochemical techniques can be done. Cardiomyopathy can be screened for using chest radiographs, EKG, or echocardiography.
There is a myriad of diagnoses possible for weakness; however, the neurologist is concerned about where the lesion causing the weakness is. The problem can be in the upper motor neurons, peripheral nerves, neuromuscular junctions, or in the muscles themselves. The history and examination can point to the cause of weakness being due to the muscles, and not to other parts of the nervous system. Clues include intact ankle reflexes without clonus or hyperreflexia, no loss of sensation, and pseudohypertrophy. There are several diseases that affect muscles. Myositis is one, although the muscles are tender in this group of diseases. Although dermatomyositis can also present insidiously with a positive Gowers' maneuver, and elevated aldolase and CPK, there are also rheumatologic signs such as a heliotrope rash on the eyelids, rash on sun-exposed areas, and Gottron papules, which muscular dystrophies lack. Some types of spinal muscular atrophies (SMA), such as Werdnig-Hoffman (type 1) and type 2, can be easily differentiated from DMD because these diseases present at a much earlier age with marked hypotonia and weakness, in addition to the presence of fasciculations and a normal to slightly elevated CPK level. Type 3 SMA (or Kugelberg-Welander disease), might be confused with DMD because of its presentation later on in childhood and its pattern of muscle weakness being mainly in the proximal muscles. However, Kugelberg-Welander disease, like the other SMA's, lacks pseudohypertrophy of the calf muscles, muscle fasciculations are present, and deep tendon reflexes are absent. Another differentiating sign is the presence of minipolymyoclonus, which is a fine tremor in the outstretched hands, which is present in the SMA's but absent in the muscular dystrophies (7). Lastly, muscle immunocytochemistry for dystrophin and PCR for Xp21 gene deletions should be able to confirm the diagnosis for Duchenne and Becker muscular dystrophies.
Sadly, there is no definitive treatment for Duchenne muscular dystrophy. Supportive care includes daily passive stretching of joint contractures, night splints, bracing if there is loss of ambulation, orthopedic surgery (including surgical tendon releases and surgery for scoliosis), and ventilatory support measures. The only medication proven to be beneficial in DMD is corticosteroids. Several studies have shown that prednisone at 0.75 mg/kg/day appears to increase muscle strength within 10 days, with its effects being maintained for at least 18 months. Because of its impressive results, patients who are older than 5 years and are ambulatory may receive steroids, with close monitoring for side effects. Another drug, deflazacort, which is a derivative of prednisolone, has also been studied because of having fewer side effects than prednisone; however this drug is not available in the United States (2). Because it is a genetic disease, genetic counseling is an important part of DMD management. Prenatal diagnosis is also possible for male fetuses using molecular genetic techniques like PCR through amniocentesis or chorionic villus sampling (8).
The prognosis for Duchenne muscular dystrophy is not good. Affected males with this progressive muscular disease become wheelchair bound before 13 years of age, are ventilator dependent in their late teens to early 20s due to respiratory failure, with death in their late 20s to 30s due to cardiac or pulmonary problems. Patients with Becker muscular dystrophy fare much better. Many remain ambulatory after age 16 years and survive through late adulthood (2). Despite the depressing nature of the muscular dystrophies, we are entering into a new age of molecular genetics, and perhaps in the near future we will have a cure for this crippling disease through gene therapy.
Questions
1. How are Duchenne and Becker muscular dystrophy inherited?
2. What protein is absent in Duchenne muscular dystrophy?
3. What is the Gowers' maneuver (or sign)?
4. What are some early signs and symptoms of Duchenne muscular dystrophy?
5. What is the average life expectancy for Duchenne muscular dystrophy? What do they die from? When do they lose ambulation?
6. By what age do almost all patients with Duchenne muscular dystrophy present with weakness?
7. Name three other organ systems, besides the musculoskeletal system, that are affected in Duchenne muscular dystrophy.
8. What is the only medication proven to improve weakness in DMD?
I would like to thank Dr. Yoshio Futatsugi for reviewing this chapter on muscular dystrophies. He has made many suggestions which is very much appreciated.
References
1. Haslam R.H.A. Part 26 - The Nervous System. In: Behrman RE, et al (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: W.B. Saunders Company, pp. 1873-1874.
2. Roland EH. Muscular Dystrophy. Pediatrics in Review 2000;21(7):233-237.
3. Emery AEH. Chapter 10 - Pathogenesis. In: Emery AEH. Duchenne Muscular Dystrophy, 2nd edition. 1993, New York: Oxford University Press, pp. 190-208.
4. Emery AEH. Chapter 3 - Clinical Features. In: Emery AEH. Duchenne Muscular Dystrophy, 2nd edition. 1993, New York: Oxford University Press, pp. 26-44.
5. Emery AEH. Chapter 6 - Involvement of Tissues Other Than Skeletal Muscle. In: Emery AEH. Duchenne Muscular Dystrophy, 2nd edition. 1993, New York: Oxford University Press, pp. 108-124.
6. Sarnat HB. Chapter 616 - Muscular Dystrophies. In: Behrman RE, et al (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: W.B. Saunders Company, pp. 1874-1875.
7. Emery AEH. Chapter 5 - Differential Diagnosis. In: Emery AEH. Duchenne Muscular Dystrophy, 2nd edition. 1993, New York: Oxford University Press, pp. 80-107.
8. Emery AEH. Chapter 11 - Prevention. In: Emery AEH. Duchenne Muscular Dystrophy, 2nd edition. 1993, New York: Oxford University Press, pp. 209-250.
Answers to questions
1. Both Duchenne and Becker muscular dystrophy are X-linked recessive.
2. Dystrophin.
3. The Gowers' maneuver is seen when a child climbs up on his thighs with his hands when going from a sitting to standing position. This is due to weakness in the knee and hip extensors.
4. Delay in walking, waddling gait, walking unsteadily with frequent falling, walking on toes, and difficulty at climbing stairs, Gowers' maneuver, and pseudohypertrophy of the calves.
5. 20 to 30 years. They die from pulmonary or cardiac problems. They lose ambulation before 13 years old.
6. 5 years.
7. Pulmonary, cardiac, and neurological (CNS).
8. Corticosteroids.