One of the most challenging tasks faced by physicians is the management of a child with a chronic, progressive disease. In this article we shall review a major cause of chronic, progressive illness in childhood - the muscular dystrophies. The discussion will include a description of the clinical courses of these varied disease entities. We shall also review the etiologic theories that have been proposed and discuss the limited therapies that are available.
Dystrophies are myopathies characterized by progressive degeneration and weakness, which conventionally have a hereditary basis. Myopathies are primary diseases of striated muscle in which there are apparent biochemical, morphologic, or neurophysiologic changes;1 these aberrations may appear in combination or singly.
Since pseudohypertrophic muscular paralysis was first described by Duchenne in 1868,2 researchers have greatly expanded the concept of dystrophies and their continuum of severity. Since precise pathophysiologic mechanisms have yet to be determined, a classification must be based on clinical and genetic data. The classification in Table 1 includes the common muscular dystrophies. The usefulness of many classifications has been obscured by a plethora of eponyms; often the eponyms lead to unnecessary confusion in classification. Table 2 lists some common eponyms.
COMMON MUSCULAR DYSTROPHIES
COMMONLY USED TERMS EMPLOYED TO DESCRIBE THE MUSCULAR DYSTROPHIES
The muscular dystrophies share common areas in the processes of clinical and laboratory diagnosis.
Evaluation of weakness. Clinically, the hallmark of the' dystrophies is muscle weakness, with a propensity for the proximal muscles of the legs to be affected first and most severely. Gowers' maneuver best demonstrates this weakness pattern. In Gowers' maneuver, the patient rises from the floor by "pushing off" (Figure 1). The trunk becomes erect after the patient braces the arms against the front of the thighs. This maneuver is necessitated by weakness of the proximal thigh muscles, especially the gluteus maximus.
Figure 1. This patient pushes off the floor, demonstrating the sequence of movements during Gowers' maneuver. After pushing off, the patient rapidly places his hands on his thigh and pushes himself to the upright position. (From Swaiman, K. F., and Wright, F. S. [eds. J. The Practice of Pediatric Neurology. 1975, chapter 37. Courtesy of the C. V. Mosby Company, publisher, St. Louis.)
The waddling gait is yet another manifestation of hip-girdle weakness; it results from an abrupt transfer of weight from side to side.
Functional classification. In all the dystrophies, the physician will be aided by a sound conception of the progression of the disease. Duchenne's muscular dystrophy (DMD) has been classified in terms of functional capacity3 (Table 3). The intensity of the physician's intervention, especially in the treatment of any intercurrent illness, may depend on the patient's functional capacity.
Creatine Phosphokinase. Serum enzyme activity has been used for the diagnosis of muscle disease since 1949.4 Serum aldolase activity was the first enzyme found to be increased in DMD. Numerous other serum enzymes manifest increased activity in the presence of some muscle diseases. These enzymes include creatine Phosphokinase (CPK), glutamic oxaloacetic transaminase (GOT), and lactic dehydrogenase (LDH). The serum activities of these enzymes are greatly increased in DMD, less in limb-girdle dystrophy and facioscapulohumeral dystrophy.5'8 Occasionally, elevation of activity is noted in cerebrovascular disease,9 hypothyroidism,10 severe anoxia, and gross muscle trauma.
CPK is found primarily in skeletal muscle, smooth muscle, thyroid tissue, and brain.11 There is little or no CPK activity in liver or red blood cells. CPK activity determinations have been found to be very helpful in the differentiation of myopathic processes from neurogenic processes and in determining whether or not "muscle" enzymes are increased as a result of muscle involvement. CPK enzyme studies have distinct advantages over the study of other enzymes because hemolysis or liver impairment does not increase CPK activity. Only rarely is CPK activity increased in the presence of neurogenic muscle disease. In the presence of increased serum CPK activity, the diagnosis of a neurogenic muscular disease should be made only if there is the presence of characteristic electromyographic findings and histologic changes.
Serum CPK activity is significantly higher in newborns than in older children or adults. Activity declines rapidly during the first four days and reaches expected childhood levels by the age of six to 10 weeks. This increase suggests the need for postponing screening studies of CPK activity for DMD until several weeks after delivery.12
Studies of CPK isoenzymes reveal that there is a significant difference in the MB isoenzyme* activity among patients with DMD and those with other myopathies, including Becker's dystrophy, limb-girdle dystrophy, myotonic dystrophy, facioscapulohumeral dystrophy, and noninflammatory late-onset myopathies. MB isoenzyme abnormalities do not correlate with evidence of cardiomyopathy ; indeed, MB isoenzymes are increased early in the course of DMD, while cardiac abnormality is more common late in the disease.13
The mechanism by which muscle enzymes enter the circulation is unknown. Injury to the sarcolemmal membrane may lead to exit of the enzymes into the blood.
In recent years, CPK activity has also been utilized to detect the carrier state in female siblings of patients or sisters of known carriers of DMD.
Pathology. The muscle biopsy is an indispensable tool in confirming the diagnosis of dystrophy.
Although it is not our purpose to discuss the intricacies of biopsying muscle, a few pitfalls are noteworthy. The information received from study of biopsy material will in large part depend on the biopsy site. A severely involved muscle will show only fibrosis, and the diagnosis will be obscured. An uninvolved muscle may show no abnormalities. It is best to choose a muscle that is mildly weak, so that the typical changes of the diseases can be best discerned. Biopsy of previous electromyography sites must be avoided.
Adequate processing of tissue is critical. Much artifact and shrinkage can occur during conventional formalin fixation.
A useful report of muscle biopsy examination should include the information given in Table 4.14
Electromyography. Electromyography (EMG) is also part of the diagnostic procedure in suspected cases of dystrophy. The EMG findings are typical of myopathies. There are numerous low -voltage, polyphasic potentials. The interference pattern is normal, but muscle action potentials are of reduced amplitude and duration. Occasional fibrillation potentials and myotonic potentials may occur in DMD. Nerve conduction studies are normal.
Dubowitz has cautioned that "all that waddles is not dystrophy."15 The waddling gait is a result of pelvic girdle weakness. Several diseases cause this symptom complex and must be considered.
Polymyositis, an inflammatory disease of muscle, manifests an anatomic distribution of involvement, CPK and aldolase activity, and an EMG pattern that are frequently associated with dystrophies; however, the muscle biopsy shows typical inflammatory changes that are absent in the dystrophies.
The congenital myopathies (e.g., central core disease, nemaline myopathy, and myotubular myopathy) may also present with pelvic girdle weakness. Enzyme activities and EMG results are often normal. Muscle biopsy is necessary to establish the diagnosis.
Anterior horn cell disease, such as that in Kugelberg-Welander syndrome, usually begins with proximal weakness similar to that in DMD and other dystrophies. EMG and muscle biopsy are necessary to establish a definitive diagnosis at the earliest possible time.
REPORT OF MUSCLE BIOPSY EXAMINATION
Late infantile acid maltase deficiency, a form of glycogenosis, may also present with weakness and elevated CPK activity. Cardiac involvement is not prominent. The EMG pattern is myopathic, with pseudomyotonic discharges. At the inception of the disease, the finding of increased muscle glycogen content may be the only clue to the diagnosis.
DISCUSSION OF INDIVIDUAL DYSTROPHIES
Duchenne's Muscular Dystrophy Clinical manifestations. The signs and symptoms of DMD are dependent on the age of the child at presentation. It is often difficult to make a diagnosis on clinical grounds before the age of two years because the patient is usually asymptomatic. The history may reveal subtle abnormalities, such as delayed acquisition of motor milestones.
Although' serum enzyme activities are often the highest in the early stage of the disease, it is at this stage that the diagnosis is most often overlooked. It may be several years before the more overt manifestations of DMD become apparent.
As the disease progresses, CPK activity eventually declines as muscle mass decreases, but it usually remains high while the patient is ambulatory.
The clinical symptoms and signs become more apparent after age two. The child begins to develop difficulty in rising from the floor and in climbing stairs (Figure 1). Repeated falling episodes and leg cramps may also be complaints. Muscle weakness is manifested by alteration in posture and gait, including exaggerated lumbar lordosis, toe-walking, a waddling gait, and Gowers' sign. Muscle prominence is often evident in the calves, but occasionally there is involvement of the deltoid, infraspinous, and quadriceps muscles (Figure 2). The pseudohypertrophy is the result of replacement of muscle bulk with connective tissue and fat.
Figure 2. This patient has Duchenne's muscular dystrophy and associated massive hypertrophy of the gastrocnemius muscles. There is obvious discrepancy between the mass of the deltoid muscles and the other muscles of the upper arm. (From Swaiman. K. F., and Wright. F. S. (eds. J. The Practice of Pediatric Neurology, 1975. chapter 37. Courtesy of the C. V. Mosby Company, publisher. St. Louis.)
The patellar tendon reflexes disappear early, whereas the Achilles tendon reflex is preserved until late in the course of the disease. Atrophy is evident in the peroneal and anterior tibial muscles. Eventually, the muscles of the pectoral girdle also atrophy.
Contractures that limit dorsiflexion of the foot, extension of the hip, and extension of the knees and elbows are inevitable. The progression of the disease is insidious but unrelenting. The child has increasing difficulty with walking; by the age of 12, most patients are confined to a wheelchair. The patient's repertoire of fine motor skills is gradually depleted as a result of loss of muscle mass and progressive weakness. Muscles of the neck and face may be affected in the terminal stages of the disease. The patients frequently the with pneumonia before their 20th year. Virtually all patients are dead by age 32. 1ß The development of marked kyphoscoliosis usually compromises pulmonary function and results in susceptibility to pneumonia. In one series, death resulted from pneumonia in 75 per cent of patients.17
Another common complication in dystrophic diseases is cardiomyopathy. In one series of 19 patients, 84 per cent had demonstrable cardiac disease at autopsy.18 Published data have set the incidence of cardiac involvement in DMD as high as 95 per cent. Chronic heart failure may occur in 50 per cent of affected patients. 17-19
An unexplained tendency for patients with DMD to be of borderline or dull-normal intellect (IQ between 70 and 75) has been reported.20 Postmortem neuropathologic studies demonstrate the presence of heterotopias,* pachygyria,** distortion of cortical architecture, and low brain weight.21
Other clinical manifestations of dystrophic heart disease include tachycardias, arrhythmias, T-wave changes, and abnormal Q waves. The abnormalities in the QRS pattern include tall right precordial R waves, increased R:S amplitude ratios, and deep limb lead and lateral precordial Q waves.22
Other intercurrent problems may involve the gastrointestinal tract because of smooth-muscle dysfunction. Megacolon, volvulus, cramping abdominal pain, and malabsorption have been described.23
DMD is occasionally transmitted as an autosomal recessive trait with resultant disease in both sexes.24 Serum CPK activity may be increased in both parents, signifying the presence of the carrier state. The autosomal recessive form tends to progress slowly, but the clinical characteristics are much the same as in X-linked, early-onset DMD.
Biochemistry. The underlying biochemical abnormalities of DMD are not known. Many abnormalities have been detected; they almost assuredly represent secondary effects.
Protein changes, in the form of loss of enzymes from muscle sarcoplasm into the circulation, have already been discussed. This phenomenon is important because it allows utilization of serum enzyme activity for diagnostic purposes.
Studies of calcium uptake and adenosine triphosphatase (ATPase) activity performed on fragmented sarcoplasmic reticulum of DMD patients demonstrate decreased initial and total calcium uptake. Although ATPase activity is decreased, muscle efficiency appears to be normal.25
Abnormalities in DMD also include a substrate-specific endogenous protein kinase alteration in which a specific protein in the red cell membrane is phosphorylated to a greater degree in patients and carriers than in normal persons.26*27
ATPase activity in DMD red cell membranes is less inhibited by ouabain than in normals in studies utilizing assay systems with high or low salt content. Epinephrine and cyclic AMP increase total ATPase activity in all samples, and epinephrine causes ouabain sensitivity to appear in previously insensitive DMD red cell membranes.28
Other studies of red cell membranes from DMD patients have revealed reduced deformability, as measured by a negative pressure required to aspirate an erythrocyte into a micropipette with an internal diameter of 1-2 /xm.29
Polyribosomal* studies of DMD muscle demonstrate marked increase in capability of collagen formation over control tissues. If soluble enzymes from normal patients are added to an in vitro DMD reaction system, the rate of collagen synthesis is restored to normal. It appears that a substance or substances in the soluble fraction from muscle of normal persons inhibit the development of abnormal amounts of connective tissue in patients with DMD.30"32
Further polyribosomal studies of in vitro radioactive amino acid incorporation revealed a significant increase in specific activity of the total polyribosome fraction. Increased specific activity was found in 42 of the 63 carriers, and histologic changes compatible with dystrophy were present in eight carriers.33
Several areas of study in energy metabolism have also delineated abnormalities. The oxidation of palmitate by muscle mitochondria is markedly reduced in the familial form of DMD but not in muscle from sporadic cases. There is also a reduced rate of oxidation in known female carriers.34
Other studies demonstrate greater than expected conversion of radioactive glucose to fructose in both DMD patients and known female carriers. Associated studies demonstrate an alteration in muscle hexokinase isozyme U1** which probably underlies the increased conversion.35
An increase in sphingomyelin in red cell membranes from patients with DMD has also been reported.36
Biochemical abnormalities in DMD are summarized in Table 5.
SUMMARY OF BiOCHEMICAL ABNORMALITIES IN DUCHENNE'S MUSCULAR DYSTROPHY
Pathology. The histologic changes in DMD are generally indistinguishable from those in the other dystrophies.
Gross alterations in the appearance of the muscle include decreased muscle mass, prominent pink or yellowish-pink color, and excessive connective tissue and fat.
Light microscopic examination reveals loss of fibers and necrosis with accompanying phagocytosis (Figure 3). A report of findings in 21 patients with DMD stresses the following abnormalities: increased variability of muscle fiber size, clusters of basophilic fibers with vesicular nuclei, generalized fibrosis, focal areas of necrosis and phagocytosis, an increase in type HC fibers, and a decrease in type HB fibers.37*
A large number of electron microscopic abnormalities have been reported. They substantiate the high degree of phagocytic activity associated with degeneration and fiber regeneration; the latter is indicated by ribosomal aggregation. 3^*
Pathophysiology. A review of the theories that attempt to explain the cause of DMD serves to illustrate the areas that have intrigued investigators and also highlight ignorance of the basic pathogenic mechanism.39
Figure 3. Gastrocnemius of five-year-old boy with Duchenne's muscular dystrophy. The cross-section demonstrates a variation in fiber size, hypertrophic fibers, degenerating fibers, increased perimysial connective tissue, increased lipid deposition, and small dark-staining regenerating fibers (H and E. x330). (Courtesy of Dr. Stephen A. Smith. From Swaiman. K. F.. and Wright. F. S. (eds.) The Practice of Pediatric Neurology. 1975. chapter 37. Courtesy of the C. V. Mosby Company, publisher, St Louis.)
The areas of investigation and hypothetical conjecture include (1) intrinsic abnormality within the muscle fiber, (2) neurogenic abnormality, and (3) vascular abnormality.
Intrinsic muscle abnormality. For decades it has been thought that DMD is a result of intrinsic muscle disease.40 The demonstration of numerous biochemical abnormalities, coupled with the knowledge that genetic diseases are transmitted primarily by the induced production of abnormal proteins, strengthens hypotheses that implicate the muscle or the muscle membrane. Permeability of muscle membrane is suggested by abnormal serum enzyme patterns in patients and carriers and the presence of fibrin by-products in sera of patients. Membrane abnormalities have also been demonstrated in studies of sarcotubular membranes in which there are limitations in transport, abnormalities of red blood cell membrane shape with scanning microscopic techniques, increased phosphorylation of specific red cell membrane proteins, and abnormalities of red cell membrane sodium potassiumATPase activity.
Increased rates of collagen formation and amino acid uptake by ribosomes from DMD muscle also strengthen the likelihood of the intrinsic muscle hypothesis.
Neurogenic basis. Some investigators have postulated a primary neurogenic process in DMD. This theory is based on the observation that there is a decreased number of functioning motor units in DMD, although surviving motor units are normal. This led to the concept of the "sick motor neuron."41 The concept has been criticized because conclusions were drawn from studies of muscles usually not affected until late in the disease.42
Vascular basis. Another theory is suggested by the production of histologic lesions of DMD by arterial embolization in combination with 5-hydroxtryptamine (serotonin).43 The resultant ischemia is proposed as the predominant factor in the disease process.
These studies and the observation that patients with DMD have defective uptake of serotonin by platelets44 have led to enthusiastic investigations of serotonin and its analogues. Imipramine, coupled with serotonin injection, was noted to cause a proximal myopathy in experimental animals.45 It is known that Imipramine blocks the uptake of biogenic amines by platelets and also increases cyclic AMP concentration by inhibiting phosphodiesterase.
It is clear, however, that our knowledge must be expanded before any of these hypotheses can be confirmed.
Genetics. DMD is transmitted as an X-linked recessive trait; that is, a mother transmits the disease to her sons and the carrier state to her daughters through an abnormal X chromosome. Consequently, 50 per cent of the female carrier's daughters will be carriers and 50 per cent of her sons will be affected.
The incidence of DMD is one in 3,000 to 8,000 male births.46 In the absence of any definitive therapy, genetic counseling remains a major technique in managing the disease.
An axiom of genetic counseling is to confirm the diagnosis in the index case. Serum enzyme determinations, muscle biopsy, and EMG are the most helpful diagnostic tests. In the presence of normal CPK activity, the diagnosis of DMD must be questioned.
At least 20 per cent of known carriers may have a normal CPK.24
A diagnosis of DMD carries with it drastic implications for the patient and much agony for the family. A single CPK estimation should not be the basis for launching into diagnostic revelations to the parents or potential carriers. CPK determinations performed in 10 definite carriers revealed normal activity on at least one occasion in all 10. In fact, two carriers had consistently normal results on 12 separate occasions.47 Normal enzyme activities should not deter the clinician from further investigation of a suspected carrier. If available, the red cell membrane protein kinase studies48 or the muscle ribosomal studies49 described in the biochemistry section could be employed.
Muscle biopsy for morphologic studies may be of value,50·51 but EMG and the clinical examination have not been very helpful in determining carrier status.52
Therapy. There are several aspects of therapy that can be considered individually.
Patient and family knowledge. The physician should painstakingly explain the signs, symptoms, and usual course of DMD to the parents. They should be told that the child will be confined to a wheelchair sometime between ages 10 and 12 years. It should be stressed that the child will be capable of continued participation in most school activities and many customary social activities. There should be frank interchange of information concerned with etiology of symptoms, treatment, and eventual course. It is best that the child not be included in the discussions of expected disability and life expectancy.
The genetic pattern - usually X-linked recessive in DMD - should be carefully explained. One-third or more patients do not have a family history of the condition; these cases are thought to arise from mutations. The possibility of detecting the carrier state in female siblings of the mother and affected children in classic DMD should be made clear. The parents should be told that there is no technique of prenatal diagnosis; however, prenatal determination of sex allows for abortion of a male fetus.
It should be stressed that the carrier state cannot be uniformly detected with certainty. Although females can be determined to be carriers in the presence of abnormal studies, they cannot be assured that they are not carriers if results of all studies are normal.
Weakness. There is no convincing evidence that medication or a combination of medications will retard the inevitable degeneration of muscle. In one report, 14 patients with DMD were treated with prednisone for up to 28 months. Thirteen improved; eight maintained their improvement for the 28 months' duration of the study. There was no associated change in CPK activity.53 Nevertheless, many other studies of corticosteroids and androgens have not resulted in curtailment of the relentless course of the disease.
It is necessary to maintain active exercise whenever possible. Children confined to bed because of surgery, injuries, or illness may not resume walking unless a physical therapy program of continued ambulation and range-of-motion exercises is maintained. Fracture of the legs should be treated with walking casts whenever feasible.54
It is reasonable to insist on three hours of daily walking to maintain strength and reduce contracture formation.55 The amount of advisable activity is governed by the avoidance of the appearance of fatigue after a night's sleep.56
Efforts must be made early to prevent overweight. As the children become less active and perhaps bored or depressed, obesity may become a serious problem. Obesity may significantly shorten the period of ambulation, contribute to scoliosis, and promote respiratory and cardiac insufficiency.
Contractures. Contractures of the Achilles tendons and of the hip flexors are commonly encountered. Contractures of the Achilles tendons can be postponed with active exercise. The use of a standing board so that constant stretch is placed on the Achilles tendon for 20 minutes twice a day is recommended.
In the presence of severe contractures, subcutaneous tenotomy is advisable. The operation is performed under local anesthesia. The patient should be ambulated the day of surgery after application of a light walking cast. Bracing is essential to success after tenotomy.
Release of flexion contractures of the hip should be effected before apof a long leg brace. Bracing of value to some patients but not to Long leg braces are utilized with a spring lock and adjustable ankle Braces should not be recomfor children who can ambureasonably well; nevertheless, should not be postponed the patient is nonambulatory most lost function will not be When daily walking time decreased to less than one hour the child requires external supwhile walking, bracing should employed.55
Scoliosis. Scoliosis is usually progressive and difficult to arrest. Wheelchairs should be fitted with a hard seat in the place of the customary sling seat.58 A tightly fitting jacket of plastic or fiberglass is usually of value.59 Both these approaches support the vertebral column in the absenses of adequate supportive muscle strength. The immobilization required for surgical procedures for scoliosis will have an overall detrimental effect to the patient and under most circumstances should be avoided.
Respiratory compromise. Pneumonia is the most common life-taking condition. Predilection to pneumonia inas the child becomes increasingly weak. Reduced vital capacity ensues because of a combination of dystrophic diaphragmatic muscle, dystrophic abdominal and chest muscles, scoliosis, and eventual episodes of pulmonary scarring and atelectasis. The utilization of postural drainage, intermittent positive-pressure techniques, and vigorous antibiotic therapy is essential.
Cardiac complications. Cardiac difficulties are frequently unimportant in the early and middle stages of DMD. Occasionally, cardiac arrhythmias are present. It is noteworthy that cardiac myopathy has been well documented by pathologic studies. As described earlier, electrocardiographic changes are often present. Congestive heart failure is the most common clinical problem and often occurs in the last stages of the disease. The conventional medical approaches to congestive heart failure are of value.
The few patients with failure during the middle stages of DMD may require digitalis derivatives and diuretics over long periods.
Anticholinergic drugs and ganglionic blocking agents should be avoided because they may decrease muscle tone. General anesthesia should be undertaken with great caution. Cardiotoxic drugs, such as halothane, should be avoided.
Emotional and behavioral abnormalities. Overt psychosis is extremely rare in DMD.60 However, many DMD patients and their families are in need of explanation and counseling because of the child's preoccupation with self and withdrawal, which is often a manifestation of depression and passivity. The frequent presence of intellectual limitation may facilitate low tolerance for frustration and promote other manifestations of emotional immaturity. The combination of a progressive condition and increasing dependency on parents and siblings is a situation that breeds manipulative behavior. Parental overprotection can promote improper interpersonal relationships, foster dependence, and obscure necessary reality testing.
Sooner or later the child understands that the disease process will continue, that there is no satisfactory therapy, and that premature death will occur. Intervention by the physician or a skilled social worker and clinical psychologist to help the parents encourage the child, decrease overprotection, and discourage withdrawal from society is necessary.
The burden of care imposed on the family by the patient as the disease progresses may result in ambivalence among siblings and sometimes in parents. The parents' reluctance to discipline handicapped children may promote jealousy and confusion in siblings.
At times, it is necessary to concentrate on supporting the mother and deal with her guilt feelings when the disease is clearly transmitted by her.
The basis of various behavior patterns must be explained to the parents and to siblings. The family must set limits on behavior that is untenable.
Excellent results can often be experienced with the use of designated conference hours, usually at the end of the day, when the physician - with or without social workers and clinical psychologists - meets with the parents and the children to help promote insight into their behavior and interrelationships.
A chronically ill child may threaten the integrity of the family. The goal of therapy should be to prevent family deterioration and to encourage the child to achieve maximal levels of development.
Late-Onset, X-Linked Muscular Dystrophy (Becker's Muscular Dystrophy)
This disease is quite similar to DMD in many ways. Pseudohypertrophy, proximal weakness, a tendency towards intellectual retardation, and cardiac abnormalities are all present in this condition. The disease is usually manifest during the second decade, but it may present during the first few years of life or as late as the third decade. The age at onset, as well as the severity of the disease, tends to be consistent within a family.16 Since the condition is X-linked, a family history that reveals maternal uncles or male siblings who are mildly affected may be the only clinical clue to differentiate this form of dystrophy from DMD.
Muscle enzyme activity is rarely elevated to the same degree as in DMD. Muscle biopsy reveals subtle changes from DMD. In the Becker form, type IIB fibers are not abnormal, whereas in DMD there is a relative paucity of type IIB fibers.37 Serum CPK activity is elevated in approximately 60 per cent of women who are known carriers of Becker's muscular dystrophy.61
Virtually all therapeutic suggestions appropriate to DMD are appropriate for Becker's dystrophy. Unlike DMD patients, almost all patients with Becker's dystrophy are still walking at age 15, but many are no longer walking late in the third decade. Only 50 per cent survive to age 40.62
Congenital Muscular Dystrophy
Congenital muscular dystrophy is characterized by hypotonia and weakness of the facial and oropharyngeal muscles from birth (Figure 4). The course may be stationary, or improvement may occur; other patients may have a progressive course63 or an intermediate form.
Examination usually reveals decreased or absent deep tendon reflexes. The sensory examination usually yields normal results. Intellectual development appears to be within the normal range.
A congenital muscular dystrophy associated with hypotonia that is invariably linked to severe mental retardation and occasionally to seizures has been described in Japan.64-65
The course is a slowly progressive one. CPK serum activity is mildly increased. The EMG is mildly myopathic, and the muscle biopsy is similar to that in DMD.66 The disease appears to be inherited as an autosomal recessive trait.
The incidence of congenital muscular dystrophy is unknown. In fact, the delineation between such entities as nemaline myopathy, central core disease, myotubular myopathy, and congenital muscular dystrophy is difficult on clinical grounds alone.
Figure 4. This 16-year-old girl with congenital muscular dystrophy demonstrates the weakness of the face and extraocular muscles that frequently occurs. (From Swaiman. K, F., and Wright, F. S. [eds. ]. The Practice of Pediatric Neurology, 1975, chapter 37. Courtesy of the C. V. Mosby Company, publisher, St. Louis.)
In a recent series, congenital muscular dystrophy represented 6 per cent of the neuromuscular disorders seen in one hospital over a 10-year period.67
Limb-Girdle Muscular Dystrophy
Limb-girdle muscular dystrophy is composed of a group of dystrophies mainly confined to weakness of the pelvic girdle and/or weakness of the shoulder girdle.
The symptoms are frequently evident during the second decade and progress at a slower pace than in DMD. Early hip-girdle weakness causes difficulty in arising from the floor and climbing steps. Gowers' sign is often manifest during the examination, associated with weakness of the gluteus maximus, gluteus médius, and gluteus minimus muscles.
Figure 5. Twelve -year-oid girl with facioscapulohumeral dystrophy who is actively resisting the examiner's attempt to elevate her eyelids. Her facial expression remains impassive because of facial muscle weakness (From Swaiman. K. F.. and Wright. F. S. [eds. J. The Practice of Pediatric Neurology, 1975. chapter 37. Courtesy of the C. V. Mosby Company, publisher. St. Louis.)
Pseudohypertrophy of the gastrocnemius muscles is occasionally seen; even rarer is pseudohypertrophy of the deltoid muscles. Contractures of the Achilles tendon result in talipes equinovarus deformity. Many patients are wheelchair-bound by age 30, but the sequence of the disease differs from pedigree to pedigree.
In the few patients who manifest electrocardiographic abnormalities, low T waves and high-voltage QRS complexes in the precordial leads are seen.68
Serum enzyme activity is moderately elevated, as in Becker's dystrophy. The pathology is very similar to that described for DMD.
The inheritance pattern is autosomal recessive. A number of cases of DMD with autosomal recessive inheritance have been described;24 some girls described as having DMD may in fact suffer from the limbgirdle type.69
Facioscapulohumeral dystrophy, or Landouzy-Déjerine dystrophy, usually manifests in the second decade. The disease is heralded by weakness of the facial and scapular muscles.
Often the patient cannot close the eyes forcefully, whistle, or hold air within the oral cavity when the cheeks are tapped lightly. There are faint movements of the perioral muscles during attempts at smiling or grimacing (Figure 5). Involvement of the scapular muscles results in winging and elevation of the scapulae, associated with decreased ability to raise and extend the arms overhead. Pseudohypertrophy and contracture formation are rare.
Patients may develop weakness of the peroneal and anterior tibial muscles, with resultant foot drop. Hipgirdle weakness may also develop, and associated kyphoscoliosis and lumbar lordosis may ensue. In rare instances, facioscapulohumeral dystrophy may consist entirely of wrist and finger weakness. These patients live a normal life span and are of normal intelligence.
The course of the disease is commonly prolonged and insidious. Varying severity among members of one family, as well as between families, has been reported.70
Serum enzyme activity is frequently normal in the facioscapulohumeral form. Moderate elevation of CPK activity is most commonly found during the first 10 to 15 symptomatic years, but activity may then fall to normal.71
Only mild changes in muscle morphology may be seen despite severe clinical involvement. Dubowitz and Brooke37 reviewed 11 cases that showed varied fiber sizes with nests of fiber atrophy. There were also moth-eaten and whorled fibers, as well as type II predominance. In addition, inflammatory components were not unusual. Only fiber hypertrophy can differentiate this appearance from that of polymyositis.
Facioscapulohumeral dystrophy is transmitted as an autosomal dominant trait. The disease may vary in severity within affected families. As in other forms of dystrophy, confirmation of the index case and good genetic counseling are essential components of therapy.
Severe kyphoscoliosis may demand surgical intervention. Contractures resulting from anterior tibial and peroneal muscle weakness may necessitate subcutaneous Achilles tenotomy.
Disfiguration of the face because of weakness of the muscles of expression may also be corrected by reconstructive surgery including the use of grafting procedures.72
Several rare scapuloperoneal syndromes are clinically similar to facioscapulohumeral dystrophy. In fact, the absence of facial involvement may be the only sign to distinguish these conditions from facioscapulohumeral dystrophy. Generally, the condition is relatively benign, and many patients are only moderately handicapped past middle age. There appears to be both a rare Xlinked73 and a relatively common autosomal dominant pattern of inheritance.74 The X-linked form is accompanied by a high incidence of color blindness.73
Introduction. Myotonia is an easily elicited sign that is found in several disease entities. It is characterized by an abnormal persistence of induced or voluntary muscular contraction.1 The patient cannot relax quickly or rapidly release the grip on an object. Myotonia predominantly affects the limb muscles, but it may also involve the extraocular and facial muscles. It is potentiated by fatigue and cold.
The diseases in which myotonia is a major finding include myotonic dystrophy (Steinert's disease), myotonic chondrodystrophy (SchwartzJampel syndrome), paramyotonia congenita (Eulenburg's disease), and myotonia congenita (Thomsen's disease). Other diseases associated with myotonia include periodic paralysis, hypothyroidism, and polymyositis.
Clinical manifestations. Childhood form. The onset of myotonic dystrophy is usually in the second or third decade; however, the disease may present early in the first decade or well into middle age. The disease is characterized by myotonia, muscle weakness, and atrophy. Muscle groups most often affected are the facial muscles, temporalis muscles, and distal leg muscles. Progression of symptoms is insidious, and the disease rarely causes debilitation during childhood. In fact, it is often the myotonia, not the weakness, that motivates the patient to seek medical consultation. Patients complain of muscle stiffness.
Figure ß. This 1 4-year-old boy with myotonic dystrophy has a thin face with weakness of the facial muscles and flatness of facial expression The patient also manifests the common tented position of the upper lip. (From Swaiman. K. F.. and Wright. F. S. [eds. 1- The Practice of Pediatric Neurology, 1975. chapter 37. Courtesy of the C. V. Mosby Company, publisher. St. Louis.)
Examination reveals a characteristic constellation of signs and symptoms. Facial diplegia causes the face to appear dull and flat, and the mouth often sags openly (Figure 6). Atrophy of the temporal and masseter muscles causes the temples and cheeks to be hollowed. Weakness of the hand flexors and atrophy of the neck muscles cause the head to be bent forward, often with cervical kyphosis. Because of involvement of the oropharyngeal muscles, the speech pattern may be explosive, dysarthric, or nasal. Dysphagia may also be present. Subnormal intelligence of varying degrees is common.75
Weakness of the foot extensors may cause a foot drop, steppage gait, or Achilles tendon contracture. Deep tendon reflexes are initially present but diminish as the disease progresses. Myotonia may be elicited by tapping the muscle belly of the biceps muscle, thenar muscle, or tongue. Myotonia may also be facilitated by asking the patient to open and close the hands. The opening phase will be slow. However, an unusual property of myotonia is that it fatigues. As the patient performs more repetitive movements, the degree of myotonia decreases.
The EMG may be helpful because myotonia has a characteristic pattern. The usual myotonic response is a high-frequency, repetitive discharge that increases and decreases in both amplitude and frequency over a period of seconds. This pattern produces a "dive bomber" effect when the action potential is transformed into sound.
The older patient may evidence additional features of myotonic dystrophy: frontal baldness, lenticular opacities, testicular atrophy, and a variety of cardiac abnormalities.
Table 6 lists the nonneurologic manifestations of myotonic dystrophy. A few of these problems deserve additional comment.
NONNEUROLOGIC PROBLEMS OF MYOTONIC DYSTROPHY
Clinically, the most important cardiac problem is the Stokes-Adams attack. This may account for some of the unexplained sudden deaths in myotonic dystrophy7* and should be vigorously treated. Postural hypotension and syncopal episodes may be the most bothersome cardiovascular complaint. Treatment with desoxycorticosterone acetate may be helpful.
General anesthesia should be undertaken with great caution. These patients are particularly sensitive to respiratory depressants and may easily become hypercapnic and hypoxic. Respiratory arrest and death have been reported in patients with myotonic dystrophy following general anesthesia.77,78
Cataracts are more common in the older patient, but they may present at birth.79 Slit-lamp examination should be performed on every patient with myotonic dystrophy, as well as on family members.
Skull films may also be abnormal. The sella turcica is often small, and the paranasal sinuses may be enlarged.
Neonatal form. At the other end of the biologic spectrum is a neonatal form of myotonic dystrophy that differs significantly from the more slowly progressive childhood and adult form.80-81
Women with myotonic dystrophy develop more severe symptoms during pregnancy.82·83 There is a high rate of fetal loss due to prematurity, spontaneous abortion, and neonatal complications. Many neonates are asymptomatic; however, neonatal symptoms are not correlated with the severity of the maternal illness. The neonatal symptoms most commonly found include generalized hypotonia, weakness, pharyngeal weakness, and arthrogryposis in the legs. Decreased motility of the gastrointestinal tract, ptosis, congenital cataracts, and electrocardiographic abnormalities are present.83 Cataracts may be the only evidence of the disease.
The diagnosis of neonatal myotonic dystrophy should prompt a vigorous investigation for other affected family members.
Myotonic chondrodystrophy (Schwartz-Jampel syndrome) is a rare condition with early childhood myotonia. The main features are myotonia, muscle hypertrophy, short stature, and bone and joint abnormalities. The facies is distinctly unusual, and the child appears to be whistling.84
Biochemistry. Most laboratory tests are not useful in myotonic dystrophy. A thorough history and physical examination usually reveal the diagnosis. Serum enzymes - such as CPK, SGOT, and LDH - are normal or only minimally elevated.
The glucose tolerance curve is often flat, and many patients are overtly diabetic.85"87 An excessive increase in circulating immunoreactive insulin in response to glucose is often present in patients with myotonic dystrophy. 88 The lack of the uniform abnormality in these patients reflects the genetic heterogeneity.
Paradoxically, there is a failure of the secreted insulin to influence glucose transport in the predicted fashion. These patients may be forming insulin with reduced biologic activity, or the metabolic defect in myotonic dystrophy may cause insulin to be bound at the expense of normal glucose metabolism.
The basal metabolic rate may be reduced, and hypothyroidism has been sporadically reported.89 Accompanying the hypogonadism is a reduction in the urinary excretion of 17-ketosteroids.85 Increased catabolismi and decreased levels of serum IgG have also been reported.90,91
Pathology. Muscle biopsy is the key to confirmation of the diagnosis in myotonic dystrophy and should be performed on all suspected patients. The findings are characteristic of the disease.
The earliest changes are atrophy of type I fibers and hypertrophy of type II fibers. As the disease progresses, the disparity between fiber types lessens. Angular fibers, which are normally considered characteristic of denervation, may also occur.37
Changes in sarcolemmal nuclei are very prominent, even in the early stages. There is a proliferation of internal nuclei, and in longitudinal section these nuclei frequently appear in chains (Figure 7). Cellular responses are seen only rarely.
In advanced stages there are, in addition to the internal nuclei, an abundance of ring fibers, whorled fibers, and fibrosis.
Study of muscle from neonatal myotonic dystrophic patients reveals that the most severely affected muscles are those associated with the arthrogryposis of the legs. Pharyngeal muscles and the diaphragm are also profoundly involved. The muscles manifest immature features, including round muscle fibers with large vesicular internal nuclei, sparse myofibrils, and irregularly distributed small, round muscle fibers. There is a delay in differentiation of fiber types.
Electron microscopic studies reveal fine granular chromatin and convoluted nuclear membranes of centronuclear fibers. There are dilated transverse tubules, poorly formed Z bands, many satellite cells, and simple mitochondria. These findings suggest an arrest in fetal muscle maturation due to sarcolemmal membrane defect, which renders the muscle refractory to normal trophic influences.92
Pathophysiology. Myotonia can be demonstrated in muscle after electrical stimulation or by percussion, even in the presence of denervation; therefore, it is unlikely that a neurogenic process is primary. Because many organ systems are involved, a generalized defect that transcends muscle must be responsible. A generalized membrane defect has been postulated.93 Myotonia can be demonstrated in normal muscle fibers by decreasing the chloride content of the incubating fluid.94 Furthermore, the internalized surface membrane, in the form of the transverse tubular system, must function normally to prevent myotonia.95
Figure 7. Biopsy of anterior tibialis muscle of young patient with myotonic dystrophy. Cross-section shows increased variation of fiber size and a striking number of internally placed nuclei. In two of the fibers, sarcoplasmic pads are seen. (Courtesy of Dr. A. J. Spiro )
Membrane-bound protein kinase has been demonstrated to be decreased in both erythrocytes96 and muscle membranes97 of affected patients. Electron spin resonance spectroscopy also substantiates the presence of a membrane defect in myotonic erythrocytes.98
The nature of the membrane defect is not fully understood. The muscle membrane has a normal resting potential, but there is a marked increase in resting-membrane resistance. These characteristics have been demonstrated in both man and myotonic goats.99,100
There is a lack of support for the hypothesis that the defect in myotonic dystrophy is neurogenic.101 No abnormalities of peripheral nerve morphology have been demonstrated in myotonic dystrophy.102
Genetics. Myotonic dystrophy is inherited as an autosomal dominant trait. In recent years there have been interesting studies associating the alleles of myotonic dystrophy with other autosomal loci markers. This has made it possible to determine whether an embryo will result in an affected child.103,104
Treatment. Based on the foregoing observations that myotonia is the result of an unstable muscle membrane, several drugs that are "membrane stabilizers" have been tried. These include quinidine, quinine, procainamide, and phenytoin.
Phenytoin seems to be the most useful and may be the drug of choice for treatment of myotonia. It has been shown to "normalize" membrane fluidity.105 The mechanism of action may be through stabilization oí sodium conductance or stimulation of the Na+-K+ ATPase system.
Comprehensive medical care includes vigilance for the appearance of cataracts, diabetes mellitus, and cardiac arrhythmias. Contractures may necessitate surgical correction. Speech therapy is of questionable value. Hypogonadism and impotency may pose psychologic problems, requiring appropriate intervention.
The syndrome of ocular ptosis and dysphagia was first described in 1915 by Taylor.106 Oculopharyngeal dystrophy may be familial or sporadic, but its specific mode of inheritance is unknown.107 The symptoms are slowly progressive and do not have their onset until the fourth or fifth decade. The EMG findings are consistent with a myopathy. The histology of the striated muscle of the pharynx and upper third of the esophagus is typical of DMD.108 Motility studies of the esophagi of affected patients indicate diffuse weakness.109
In the ocular form, there is ophthalmoplegia and ptosis without dysphagia. Onset is frequently in the third decade. There may be weakness of the facial muscles. Intellectual impairment is not associated with either of these dystrophies. Study of muscle biopsy of the temporal muscle or gastrocnemius muscles is consistent with a chronic muscular dystrophy.
Distal muscular dystrophy also has its onset in the fifth or sixth decade, usually beginning with progressive weakness of the hands. There is wasting of the muscles of the extremities, but sensory involvement, fasciculations, or sphincter disturbances are notably lacking. Muscle biopsy and EMG are consistent with a dystrophic process.110 This entity has also been reported in conjunction with ocular dystrophy.111
These diseases have no direct relevanee for pediatricians; however, they highlight an interesting biologic phenomenon - a genetic abnormality producing progressive degeneration of a limited group of muscles decades after birth.
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COMMON MUSCULAR DYSTROPHIES
COMMONLY USED TERMS EMPLOYED TO DESCRIBE THE MUSCULAR DYSTROPHIES
REPORT OF MUSCLE BIOPSY EXAMINATION
SUMMARY OF BiOCHEMICAL ABNORMALITIES IN DUCHENNE'S MUSCULAR DYSTROPHY
NONNEUROLOGIC PROBLEMS OF MYOTONIC DYSTROPHY