Degenerative Muscular Disorders

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The muscular dystrophies are hereditary, degenerative dystrophinopathies and disorders of dystrophin-associated proteins. In 1987, with the identification of a defect in the dystrophin gene as the cause of Duchenne muscular dystrophy (DMD), Monaco and Kunkel opened the door

TABLE 36-4 -- FAMILIAL SPASTIC PARAPLEGIA (SPG), GE

NE LOCUS, AN

D PROTEIN PRODUCT

Type

Genetic Nomenclature

Inheritance

Gene Locus

Population

Product

Complicated

SPG1

X-llnked

Xq28

L1CAM

"Pure" (uncomplicated)

SPG2

X-llnked

Xq28

Proteolipoprotein

SPG3

AD

14ql2-q21

European, North American

?

SPG4

AD

2p24-21

European, North American

SPG5A

AR

8p11-q13

Tunisian

?

SPG5B

AR

?

Tunisian, European

?

SPG6

AD

15q11-1

North American

?

SPG7

X-llnked

?

Single family

?

Spastic paraplegia with amyotrophy

ALS4

AD

9q34

Single family

?

AR, Autosomal recessive; AD, autosomal dominant, LICAM, L1 cell adhesion molecule. for research into its role in muscle function and maintenance.

Dystrophin is controlled by a very large gene, at least 2300 kb and 79 exons, that encodes a 3685 amino acid protein product with four distinct domains. It has an

I-beam shape with globular domains at each end and a rodlike segment in the middle ( Fig 36-3 ). At the aminoterminal end, it binds to cytoplasmic actin filaments, whereas at the other end, it binds to a complex of proteins and glycoproteins called dystrophin-associated proteins and dystrophin-associated glycoproteins. Transcripts, each with its own promotor, suggest that dystrophin influences a number of distinct functions. Muscle dystrophin is found on the plasma membrane surface in skeletal muscle fibers, on the surfaces of plasma membrane and transverse tubules of cardiac muscle fibers, and on smooth muscle membranes. Cortical dystrophin is found in the hippocampus, amygdala, thalamus, hypothalamus and neocortex, and a

Figure 36-3 Localization of dystrophin and utrophin in the muscle cell. Dystrophin is found throughout the sarcolemma, whereas utrophin is confined to the neuromuscular junction. Both proteins are associated with a glycoprotein complex that binds to the extracellular martrix(Reprinted with permission from Campbell KP, Crosbie RH: The structure of dystophin. Nature 1996;384:308. Copyright 1996 MacMillan Magazines Limited.)

Purkinje cell isoform is found in the cerebellum.y y y A second protein product of the DMD gene, which is structurally different from dystrophin, has not been found in muscle, but its level in other tissues is comparable to that of dystrophin in muscle. y

It is now known that there are at least three subcomplexes that form the glycoprotein complex involved with dystrophin in muscle support. Several components of these subcomplexes have now been identified and some of their relationships determined. The dystroglycan subcomplex consisting of

-dystroglycan and beta-dystroglycan functions as a connecting axis, called the dystrophin-axis, between the extracellular matrix and the subsarcolemma cytoskeleton. These dystroglycans are ubiquitously expressed in various tissues. The basal lamina is a network of several components, including laminin, that surrounds each muscle fiber in fixed contact with the sarcolemma and provides protection from mechanical damage. beta-Dystroglycan is an extracellular protein that binds to the laminin subunit merosin in the basement membrane, as well as to beta-dystroglycan, a transmembrane protein, which, in turn, binds to the cysteine-rich and carboxyl-terminus domains of dystrophin within the cell. Then the n-terminus domain of dystrophin binds to actin filaments, which forms the cytoskeleton of the subsarcolemma.y Utrophin, a dystrophin homolog, binds to actin and most likely the dystroglycan complex. y It is possible that utrophin and these proteins form a utrophin axis similar to the dystrophin-axis.

Four other transmembrane glycoproteins, called the sarcoglycans, have been identified:

-sarcoglycan (in some sources called 50DAG, A2, and adhalin), beta-sarcoglycan (43DAG, A3b), gamma-sarcoglycan (35DAG, A4), and delta-sarcoglycan. It has been proposed that the sarcoglycan complex is fixed to the dystrophin-axis by lateral association, although the binding site is not yet known. The sarcoglycan complex is expressed specifically in skeletal and cardiac muscle. y

Finally, the components of the syntrophin complex (alpha-syntrophin, which is specific for muscle; beta 1 -syntrophin, which is ubiquitous, and beta2 -syntrophin, which is localized to the neuromuscular junction) bind to the distal part of the carboxy-terminal domain of dystrophin. y

In the last few years, disruptions in these proteins and glycoproteins have been implicated in several types of muscular dystrophy( iiJable 36:5 ). Dystrophinopathies

Different mutations in the dystrophin gene produce different allelic disorders, most commonly either the lethal DMD or Becker muscular dystrophy (BMD), a milder myopathy. Very rarely, patients with cardiomyopathy with mild weakness, dilated cardiomyopathy without weakness, exercise intolerance associated with myalgias, muscle cramps, or myoglobinuria, and asymptomatic elevation of serum CK have also been identified. '25!

Pathogenesis and Pathophysiology. Large mutations in the dystrophin gene are identified in about 75 percent of patients with DMD and 87 percent of patients with BMD. Most large mutations are deletions, and they tend to occur in regions where the introns are longer. The deletion breakpoints seem to be at sites where recombination events occur in healthy individuals. Large deletions are also common in BMD, whereas large duplications are rare. Small mutations account for about 30 percent of DMD cases and 15 percent of BMD cases. Mutations that shift the mRNA transitional reading frame usually produce a truncated dystrophin molecule, missing the carboxy terminus, which in turn does not bind adequately to dystrophin-associated proteins at the cell membrane, resulting in severe dystrophin deficiency in the Duchenne phenotype. Either no dystrophin is made or the aborted molecule is degraded rapidly. Nonframeshifting mutations produce a dystrophin molecule with a preserved carboxy terminus in which more dystrophin remains and the phenotype is the milder form of BMD. y In-frame deletions alter the clinical presentation depending on where they occur. Deletions that involve the cysteine-rich and carboxy-terminus domains required for attachment to the dystrophin-associated proteins confer the Duchenne phenotype, whereas deletions in the proximal portion of the rod domain produce a very mild phenotype. '271 Deletions in the distal region present the BMD phenotype and produce 40 to 70 percent of the normal amount of dystrophin. '28 There are rare cases to which these generalizations do not apply: There are out-of-frame deletions that can result in DMD, BMD, or an intermediate phenotype, and there are even situations in which there is no correlation between the degree of dystrophin deficiency and the severity of phenotype. y , y

Epidemiology and Risk Factors. DMD is the most common neuromuscular disease of childhood, with an estimated overall prevalence of 63 cases per million, whereas BMD has an overall prevalence of 24 cases per million. '29' Because dystrophin is at Xp21.1, nearly all patients are male. As many as 20 percent of new DMD cases and an unknown number of BMD cases are caused by gonadal mosaicism.y

Clinical Features and Associated Disorders. The hallmarks of DMD are progressive proximal muscle weakness with pseudohypertrophy of the calves. The myocardium is involved, whereas bulbar muscles are spared. There may be mild mental retardation. DMD is universally fatal, usually either from respiratory or cardiac complications.

As early as 1868, Duchenne had established criteria for the diagnosis of what would later be called DMD that still serves as an accurate description of its clinical picture: (1) weakness, appearing first in the lower extremities; (2) wide-based gait and stance, with lordosis; (3) subsequent hypertrophy of weakened muscles; (4) loss of muscle contractility with electrical stimulation; and (5) intact sensation and bowel and bladder function, with a (6) progressive, deteriorating course.

Usually, the child is asymptomatic in the neonatal period, with the earliest problems perceived by caregivers being developmental delays, particularly in walking and climbing, and the appearance of enlarged calf muscles. Between the ages of 3 and 6, the gait becomes waddling and lordotic. Gowers' sign appears, in which the child stands from a prone position by a process of climbing up the legs, using the hands first on the knees and then on the thighs to support her- or himself ( .Fig 36-4

). Usually by the age of 6 years, there is enlargement of calf, gluteal, lateral vastus, deltoid, and infraspinatus muscles, and weakness is readily

Figure 36-4 Gower's sign. (From Siegel IM: Muscle and Its Diseases: An Outline Primer of Basic Science and Clinical Method. Chicago, Yearbook Medical Publishers, 1986.)

apparent, with the proximal extremities more severely affected than the distal extremities, and lower extremities and torso more severely affected than the upper extremities ( .Fig...3§z5 ). Weakness of the arms may be present but is not obvious without careful examination. The strength of limb and torso muscles continues to decline steadily from ages 6 though 11 years. Proximal muscles continue to be more severely affected than distal muscles, with neck flexors becoming more involved than extensors, wrist extensors more than flexors, biceps and triceps more than deltoid, quadriceps more than hamstrings, and the tibialis anterior and peroni more than the gastrocnemius, soleus, and tibialis anterior. Tendon reflexes decrease and disappear as muscle weakness progresses. By the age of 10 years, 50 percent of patients have lost biceps, triceps, and knee reflexes, in contrast with the ankle reflex, which remains in one third of patients even in end-stage disease. Significant contractures of the iliotibial bands, hip flexors, and heel cords are present in 70 percent of the children by the age of 10 years. The children tend to have relatively mild functional impairment until they are about 8 years old, when they then decline more rapidly over the next 2 to 3 years. The second decade brings progressive kyphoscoliosis from weakened paraspinal muscles, and decreased vital and total lung capacities and maximal inspiratory and expiratory pressures from weakened respiratory muscles. These problems first appear between the ages of 8 and 9 years, and progress as functional status deteriorates.

The mean age of death in a survey of 176 patients who died between 1970 and 1984 was 18.3 +/- 3 years. It was slightly increased to 20 +/- 3.9 years in the subset of 48 patients who died between 1980 and 1984. About 40 percent died of respiratory failure, and 10 to 40 percent died of cardiac complications. Although cardiac rate, rhythm, and conduction defects occur in up to 90 percent of DMD patients, they tend to be stable or slowly progressive problems. y

In BMD, disease is later in onset and slower in progression. As early as the mid-1950s, Becker proposed that these cases represented a variation of DMD. Now that it is known that DMD and BMD are allelic disorders, it is apparent that BMD phenotypes range from myalgias and muscle cramps to symptoms clinically indistinguishable from DMD.

Age of onset ranges from 1 to 70 years of age, with a mean of 12 years. Ninety percent of patients are affected by age 20. Lower extremity weakness appears on average by age 11, with upper extremity weakness by age 20. Loss of ambulation generally occurs around 40 but can occur as early as age 12. Age at death ranges from 23 to 89 years of age, with the average being 42.

Cardiac problems similar to that associated with DMD are present in about half of the patients with BMD. The extent of cardiac involvement does not correlate with degree of myopathy. Myocardial pathology includes degeneration of cardiac muscle and fibrous replacement of myocardiocytes, particularly in the posterobasal region and the adjacent lateral wall of the left ventricle.

When compared with unaffected brothers, fertility ranges from 10 to 79 percent, correlating positively with severity of phenotype. Fatty infiltration of smooth muscle may result in delayed gastric emptying with emesis, abdominal pain, and distention. Adverse reactions to succinylcholine and halothane have been reported, which ranged from

Figure 36-5 Enlarged calf muscles in a patient with Duchenne muscular dystrophyFrom Fenichel GM: Clinical Pediatric Neurology. Philadelphia, W.B. Saunders, 1997.)

marked elevation of CK in the postoperative period to cardiac arrest. y

Differential Diagnosis and Evaluation. The diagnosis of DMD and BMD has become considerably more reliable with the advent of molecular genetics. When the clinical presentation, elevation of CK, muscle biopsy, EMG findings, and inheritance pattern are consistent with a dystrophinopathy, the patient's white blood cells or muscle should be examined for deletions or duplications in the dystrophin gene. Multiplex polymerase chain reaction (PCR) amplification of commonly deleted exons detects 98 percent of the deletions that cause more than 65 percent of the dystrophinopathies. Quantitative Southern blot analysis may be needed to detect partial gene duplication because it is more sensitive. '301 , y

Immunoblot analysis of muscle homogenates with dystrophin antibodies confirms abnormalities in at least 95 percent of DMD patients and differentiates DMD from BMD. Analysis of restriction length polymorphisms and a nonradioactive direct test based on PCR amplification provides rapid, precise carrier diagnosis in women whose relatives have a known deletion. Sisters and daughters of mothers who have given birth to boys with isolated cases of DMD or BMD should also be tested and counseled. Such mothers should also consider prenatal diagnosis because the risk for recurrence in additional sons is estimated at 7 percent. Prenatal diagnosis can be performed as early as 8 weeks' gestation. y

The EMG changes seen are those common to all myopathic disorders. Motor units fire at a relatively high rate for the degree of effort, with a higher number activated than would be in a muscle of comparable strength in a neurogenic problem. As the disease progresses, fewer and fewer motor units can be activated. An increased number of motor unit potentials are polyphasic with one or more late components, as well as components reduced in duration. Fibrillation potentials are often observed. Nerve conduction velocities are normal.

Similar pathological changes are present in BMD and DMD, particularly necrotic and regenerating fibers, branching fibers, abnormal fiber size, and endomysial fibrosis. Generally there are more necrotic, hypercontracted, and regenerating fibers with a more severe phenotype. Additionally, inflammatory cells are evident at perivascular, endomysial, and perimysial sites in DMD. Plasma membrane defects that lead to segmental fiber necrosis and eventual regeneration are observed with electron microscopy. Extensive discussion of morphological and electron microscopy studies is available in Engel (see reference y ).

Serum CK is the most useful of the serum enzyme tests, with CK increased up to two orders of magnitude during the first 3 years when it peaks and the declines exponentially by about 20 percent annually. Myoglobinemia is roughly correlated with elevations in CK. Ambulatory DMD patients have diurnal fluctuations in myoglobin and CK, with increases corresponding to physical activity. '331 In the cerebrospinal fluid, protein fractions are increased in most dystrophies and upsilon-globulin is decreased. Because excretion of total creatinine declines with decreasing functional muscle mass, urinary creatinine is 40 to 90 percent below normal.y Urinary creatine excretion is about twice normal between ages 6 and 11, and it increases with age.

It is essential to evaluate the heart. Ninety percent of patients with DMD have myocardial fibrosis, revealed by elevated right precordial R waves and deep Q waves in left precordial and limb leads on EKG. '351 Persistent or labile sinus tachycardia, sinus arrhythmias, and interatrial conduction defects are also common abnormalities. Echocardiography demonstrates small internal ventricles, hypokinesis of the posterobasal ventricular wall, and slowed ventricular relaxation.

Examination of dystrophin can prevent misdiagnosis in patients with disorders that mimic the clinical presentation of DMD and BMD, particularly the spinal muscular atrophies, congenital muscular dystrophy, acid maltase deficiency, and Emery-Dreifuss muscular dystrophy (ED MD). Dystrophin should also be evaluated in males with dilated cardiomyopathy, even in the absence of muscle weakness, and in girls with symptoms of DMD.

Management and Prognosis. Thus far, the only medication to improve functioning of boys with DMD when evaluated in carefully controlled trials is a regimen of alternate-day prednisone with a dosage range of 0.75 to 1.5 mg/kg/day. Improvement began about 1 month after beginning treatment and peaked by 3 months, with significant and sustained benefits still evident at 3 years. The decrease in muscle strength and increase in muscle mass was slower than expected, and the extent of disability was less. Side effects included those common to all steroids: altered behavior, Cushinoid appearance, gastrointestinal disturbance, rashes, and hirsutism. y

Effective gene therapy remains elusive. A carefully controlled study determined that injecting normal myoblasts

into affected muscle did not increase muscle force generation or the amount of dystrophin in muscle. y

Much of the management of the dystrophinopathies remains supportive, and there is controversy regarding appropriate active exercise regimens in the dystrophinopathies. The review by Spenser and Vignos provides a balanced discussion of the role of active exercise in DMD. y In one short-term controlled study, resistance exercises neither hastened physical deterioration, as has been proposed, nor maintained strength any better than free exercises. More clearly, passive exercises and joint stretching are important in delaying the onset of contractures. Maintaining ambulation as long as possible is crucial because its loss is associated with contractures and scoliosis, which, in turn, is associated with restrictive respiratory syndrome. Release of hip and ankle contractures by subcutaneous tenotomy while the patient is still ambulatory has been shown to preserve ambulation for about 2 additional years. y

Inspiratory resistive exercises have been shown to increase endurance of respiratory muscles but not vital capacity. y When indicated, intermittent ventilatory assistance ameliorates symptoms of hypoventilation but does not slow the deterioration of respiratory function. If assisted ventilation is employed when vital capacity falls below 10 percent of normal, it can prolong survival by 3 to 4 years. y

Bregman has outlined strategies families can employ to result in more effective management of the childhood neuromuscular disorders: (1) maintaining a regular schedule of activities for both the affected child and other family members, (2) providing interesting activities appropriate to the degree of disability that enhance the affected child's experiences, (3) assisting the affected child in setting realistic goals, (4) encouraging as much independence as possible in the affected child, (5) employing stress reduction strategies, (6) including all family members in decision making, and (7) maintaining active relationships with the primary physician and support groups in the community.y

Data indicate that DMD patients are living somewhat longer than they used to, probably because of more aggressive respiratory and cardiac care, but as yet, there is nothing that reverses the basically relentless course of either the Duchenne or Becker phenotype.

Future Perspectives. Recent work suggests that a disruption of basement membrane organization occurring in rare homozygotes for a null allele of dystroglycan may be the common feature of muscular dystrophies associated with the dystroglycan complex.y Effective treatment may involve either replacement of dystrophin or upregulation of a related protein, such as utrophin. Two recent papers report the development of adenoviral vectors from which protein-producing genes have been removed, allowing transport of more DNA and eliminating proteins that trigger the host response. y , y Although upregulation of utrophin theoretically could occur pharmacologically, recent work with the utrophin transgene is very exciting. High expression of the utrophin transgene in skeletal and diaphragmatic muscle of the dystrophin-deficient mdx mouse markedly reduced dystrophic pathology. y

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