Neurology_Adams

Neurology_Adams. Muscles of the pelvic girdle, lumbosacral spine, and shoulders become weak and wasted, accounting for certain clinical peculiarities. Weakness of abdominal and paravertebral muscles accounts for a lordotic posture and protuberant abdomen when standing and the rounded back when sitting. Weakness of the extensors of the knees and hips interferes with equilibrium and with activities such as climbing stairs or rising from a chair or from a stooped posture. In standing and walking, the patient places his feet wide apart so as to increase his base of support. To rise from a sitting position, he first flexes his trunk at the hips, puts his hands on his knees, and pushes the trunk upward by working the hands up the thighs. In rising from the ground, the child first assumes a four-point position by extending the arms and legs to the fullest possible extent and then works each hand alternately up the corresponding thigh (the sign traditionally attached to Gowers’ name). In getting up from a


Neurology_Adams

Neurology_Adams. by extending the arms and legs to the fullest possible extent and then works each hand alternately up the corresponding thigh (the sign traditionally attached to Gowers’ name). In getting up from a recumbent position, the patient turns his head and trunk and pushes himself sideways to a sitting position. S.A.K. Wilson used an alliterative phrase to describe the characteristic abnormalities of stance and gait: The patient “straddles as he stands and waddles as he walks.” The waddle is the result of bilateral weakness of the gluteus medius. Many affected boys have a tendency to walk on their toes as a consequence of contractures in the gastrocnemii muscles. Calf pain is frequent. Weakening of the muscles that fix the scapulae to the thorax (serratus anterior, lower trapezius, rhomboids) causes winging of the scapulae, and the scapular angles can sometimes be seen above the shoulders when one is facing the patient.


Neurology_Adams

Neurology_Adams. Later, weakness and atrophy spread to the muscles of the legs and forearms. The muscles that are preferentially affected among these are the neck flexors, wrist extensors, brachioradialis, costal part of the pectoralis major, latissimus dorsi, biceps, triceps, and anterior tibial and peroneal muscles. The ocular, facial, bulbar, and hand muscles are usually spared, although weakness of the facial and sternocleidomastoid muscles and of the diaphragm occurs in the late stages of the disease. As the trunk muscles atrophy, the bones stand out like those of a skeleton. The space between the lower ribs and iliac crests diminishes with atrophy and weakness of the abdominal muscles.


Neurology_Adams

Neurology_Adams. The limbs are usually loose and slack, but as the disability progresses, fibrous contractures appear as a result of the limbs remaining in one position and the imbalance between agonists and antagonists. Early in the ambulatory phase of the disease, the feet assume an equinovarus position as a result of shortening of the posterior calf muscles, which act without the normal opposition of the pretibial and peroneal muscles. Later, the hamstring muscles become permanently shortened because of a lack of counteraction of the weaker quadriceps muscles. Similarly, contractures occur in the hip flexors because of the relatively greater weakness of hip extensors and abdominal muscles. This leads to a pelvic tilt and compensatory lordosis to maintain standing equilibrium. The consequences of these contractures account for the habitual posture of the patient with Duchenne dystrophy: lumbar lordosis, hip flexion and abduction, knee flexion, and plantar flexion. As they become severe, these


Neurology_Adams

Neurology_Adams. these contractures account for the habitual posture of the patient with Duchenne dystrophy: lumbar lordosis, hip flexion and abduction, knee flexion, and plantar flexion. As they become severe, these contractures contribute importantly to the eventual loss of ambulation. Scoliosis, as a result of unequal weakening of the paravertebral muscles, and flexion contractures of the forearms appear, usually after walking is no longer possible.


Neurology_Adams

Neurology_Adams. The tendon reflexes are diminished and then lost as muscle fibers disappear, the ankle reflexes being the last to go. The bones are thin and demineralized, and the appearance of ossification centers is delayed. Smooth muscles are spared, but the heart is affected by various types of arrhythmias. The ECG shows prominent R waves in the right precordial leads and deep Q waves in the left precordial and limb leads, the result of cardiac fiber loss and replacement fibrosis of the basal part of the left ventricular wall (Perloff et al). Death is usually the result of pulmonary infections and respiratory failure and sometimes, of cardiac decompensation. Patients with Duchenne dystrophy usually survive until late adolescence, but not more than 20 to 25 percent live beyond the twenty-fifth year. The last years of life are spent in a wheelchair; finally the patient becomes bedfast.


Neurology_Adams

Neurology_Adams. Mild degrees of developmental delay as mentioned, which is nonprogressive, are observed in many cases. The average IQ is 85 and approximately one-quarter have an IQ below 70, but the range has been 40 to 130. As mentioned earlier, female carriers of the disease (i.e., the mothers of affected boys) and described slight weakness and enlargement of the calves as well as elevated CK values and abnormalities of the electromyelogram (EMG) and muscle biopsy, all slight in degree, in more than half; as mentioned, this is far higher than in our experience and that of our colleagues. A small number of female carriers manifest a moderate myopathy that may mimic limb-girdle dystrophy (see further on). The muscle fibers of such patients (referred to as manifesting or symptomatic carriers) show a mosaic immunostaining pattern mentioned earlier, some fibers containing dystrophin and others lacking it (Hoffman et al, 1988). This diagnostic information is particularly helpful in genetic counseling.


Neurology_Adams

Neurology_Adams. The serum CK values are 25 to 200 times normal, which, with the EMG and muscle biopsy findings, help exclude spinal muscular atrophy. The EMG shows fibrillations, positive waves, low-amplitude and brief polyphasic motor unit potentials, and, sometimes, high-frequency discharges. The female carrier may occasionally display the same abnormalities, but to a much milder degree. The molecular and genetic bases of the disease are discussed further on.


Neurology_Adams

Neurology_Adams. This milder dystrophy is closely related to the Duchenne type clinically, genetically, and ultrastructurally, involving the same DMD gene as in the Duchenne type. It had long been noted that mixed with the Duchenne group were relatively benign cases. In 1955, Becker and Keiner proposed that the latter be separated as a distinct entity, now called Becker muscular dystrophy. The incidence is difficult to ascertain, but it has been estimated as 3 to 6 per 100,000 male births. Like the Duchenne form, it is an X-linked disorder, practically limited to males and transmitted by females. It causes weakness and hypertrophy in the same muscles as Duchenne dystrophy, but the onset is much later (mean age: 12 years; range: 5 to 45 years). While boys with Duchenne dystrophy are usually dependent on a wheel-chair by early in the second decade, it is not uncommon for those with Becker dystrophy to walk well into adult life. In comparison to Duchenne dystrophy, those with Becker and intermediate


Neurology_Adams

Neurology_Adams. a wheel-chair by early in the second decade, it is not uncommon for those with Becker dystrophy to walk well into adult life. In comparison to Duchenne dystrophy, those with Becker and intermediate types retain their ability to raise the head fully off the bed. We have, for example, encountered patients who served in the military with the disease undetected. If maternal uncles are affected by the disease and are still walking, the diagnosis is relatively easy. Mentation is usually normal and cardiac involvement is far less frequent than in Duchenne dystrophy, but there are cases that present with a cardiomyopathy and we have been made aware of 2 brothers who had cardiac transplantation before the disease was detected. Kuhn and associates have reported a genealogy in which early myocardial disease and cramping myalgia were prominent features. The molecular-genetic basis of this form is discussed below.


Neurology_Adams

Neurology_Adams. Pathology of Duchenne and Becker Dystrophies


Neurology_Adams

Neurology_Adams. In the early stages of Duchenne dystrophy, the most distinctive features are prominent segmental degeneration and phagocytosis of single muscle fibers or groups of fibers and evidence of regenerative activity (basophilia of sarcoplasm, hyperplasia and nucleation of sarcolemmal nuclei, and the presence of myotubes and myocytes). The necrosis excites a regenerative or restorative process, which explains the forking of fibers and clustering of small fibers with prominent nuclei. The necrotic sarcoplasm and sarcolemma are removed by mononuclear phagocytic (macrophage) cells. There may also be a few T lymphocytes in the region, suggesting inflammation. There is a hyalinization of the sarcoplasm of many degenerating and nondegenerating fibers. In longitudinal sections these are seen as “contraction bands,” expressive of the irritability of dystrophic muscle. This phenomenon may be present before there is any significant degree of degeneration and is more extensive in Duchenne than in any of


Neurology_Adams

Neurology_Adams. bands,” expressive of the irritability of dystrophic muscle. This phenomenon may be present before there is any significant degree of degeneration and is more extensive in Duchenne than in any of the other dystrophies. Eventually, there are histologic changes that are common to all types of advanced muscular dystrophies: loss of muscle fibers, residual fibers of larger and smaller size than normal, all in haphazard arrangement, and the secondary reaction of an increase in lipocytes and fibrosis.


Neurology_Adams

Neurology_Adams. Hypertrophy of muscle is apparently the result of work-induced enlargement of the remaining sound fibers in the face of adjacent fiber injury. However, examples of true hypertrophy of entire muscles prior to the first sign of weakness also occur and are difficult to explain. In these cases, large fibers may be present when at most there are only a few degenerating fibers. The more common feature of pseudohypertrophy is a result of lipocytic replacement of degenerated muscle fibers, but in its earlier stages, the presence of many enlarged fibers may contribute to the enlargement of muscle. Thus a true hypertrophy appears to give way to pseudohypertrophy. In the late stage of the dystrophic process, only a few scattered muscle fibers remain, almost lost in a sea of fat cells. It is notable that the late, or burned-out, stage of chronic polymyositis resembles muscular dystrophy in that the fiber population is depleted, the residual fibers are of variable size, and fat cells and


Neurology_Adams

Neurology_Adams. notable that the late, or burned-out, stage of chronic polymyositis resembles muscular dystrophy in that the fiber population is depleted, the residual fibers are of variable size, and fat cells and endomysial fibrous tissue are increased; lacking only are the hypertrophied fibers of dystrophy. This resemblance confirms that many of the typical changes of muscular dystrophy are nonspecific, reflecting mainly the chronicity of the myopathic process.


Neurology_Adams

Neurology_Adams. Molecular Biology of Duchenne and Becker Dystrophies The first important development in our understanding of the Duchenne and Becker muscular dystrophies was the discovery by Kunkel of the mutation on the X chromosome in what was later named DMD and of its gene product, dystrophin (Hoffman et al, 1987). The protein is expressed in skeletal, cardiac, and smooth muscle, as well as in brain. To date, the dystrophin gene is the largest one known in humans, spanning more than 2 Mb of DNA. This is in part the explanation for the observation that one-third of affected boys have a spontaneous mutation in the gene. Most mutations are deletions and combined with the less frequent duplications, account for over two-thirds of cases.


Neurology_Adams

Neurology_Adams. The biochemical assay of dystrophin and its histochemical demonstration near the sarcolemma have made possible the accurate diagnosis of the Duchenne and Becker phenotypes from biopsy material and have clarified the relationship between these two disorders. Whereas dystrophin is absent in patients with the Duchenne phenotype, it is present but structurally abnormal in the Becker type. Moreover, phenotypes that fall between the classic Duchenne and Becker forms exist and are characterized by a lower-than-normal amount of dystrophin. The Duchenne and Becker dystrophies and their intermediate forms are spoken of as dystrophinopathies.


Neurology_Adams

Neurology_Adams. Duchenne and Becker dystrophies and their intermediate forms are spoken of as dystrophinopathies. A slightly different form of dystrophin, originating in a different part of the gene, is found in neurons of the cerebrum and brainstem and in astrocytes, Purkinje cells, and Schwann cells at nodes of Ranvier (Harris and Cullen). A deficiency of cerebral dystrophin may in some yet unexplained way account for the mild cognitive developmental delay. It will be interesting to learn how such a deficiency might impair brain development and whether there is any connection to some cases of mental deficiency without muscular dystrophy.


Neurology_Adams

Neurology_Adams. Figure 45-2 schematically represents the structural basis of the dystrophinopathies and certain of the limb-girdle and congenital dystrophies described further on. In normal skeletal and cardiac muscle, dystrophin is localized to the cytoplasmic surface of the sarcolemma, where it interacts with F-actin of the cytoskeleton (the filamentous reinforcing structure of the muscle cell). Dystrophin is also tightly bound to a complex of sarcolemmal proteins known as dystrophin-associated proteins (DAPs) and to dystrophin-associated glycoproteins (DAGs). Of special biologic importance in this complex are these proteins and a 156-kDa glycoprotein called dystroglycan. The latter actually lies just outside the muscle cell and links the sarcolemmal membrane to the extracellular matrix (the inner portion of the basement membrane) by binding with merosin, a subunit of laminin. The dystrophin–glycoprotein complex functions in this scheme as a transsarcolemmal structural link between the


Neurology_Adams

Neurology_Adams. inner portion of the basement membrane) by binding with merosin, a subunit of laminin. The dystrophin–glycoprotein complex functions in this scheme as a transsarcolemmal structural link between the subsarcolemmal cytoskeleton and the extracellular matrix. Moreover, each of these membrane-binding proteins (adhalin, merosin, and laminin) is implicated in specific muscular dystrophies, as discussed later in this chapter.


Neurology_Adams

Neurology_Adams. The loss of dystrophin leads to a parallel loss of DAPs and to disruption of the dystroglycan–protein complex. This change renders the sarcolemma susceptible to breaks and tears during muscle contraction, a hypothesis proposed first by Mokri and Engel and entirely consistent with the ultrastructural abnormalities that characterize Duchenne dystrophy. These authors demonstrated defects of the plasma membrane (sarcolemma) in a large proportion of nonnecrotic hyalinized muscle fibers, allowing ingress of extracellular fluid and calcium. The entrance of calcium is speculated to activate proteases and to increase protein degradation. The membrane defects and the associated alterations in the underlying region of the fiber represent the earliest and most basic pathologic change in Duchenne dystrophy and account for the leakage into the serum of CK and other enzymes of muscle. Diagnosis of Duchenne and Becker dystrophies


Neurology_Adams

Neurology_Adams. Diagnosis of Duchenne and Becker dystrophies Analysis of the dystrophin gene in DNA obtained from white blood cells or from 50 mg of skeletal muscle can demonstrate the gene mutations in Duchenne and Becker patients and discriminate between these diseases. Also, immunostaining of muscle for dystrophin makes possible the differentiation of Duchenne, Becker, the carrier state, and other muscle disorders. An alternative method, developed by Byers and colleagues, uses an ELISA to measure the dystrophin levels in muscle biopsy samples. This testing is a rapid and relatively inexpensive tool for establishing the diagnosis of Duchenne and Becker muscular dystrophies and distinguishing them from unrelated disorders.


Neurology_Adams

Neurology_Adams. Testing for the dystrophin protein has also brought to light several much rarer types of dystrophin abnormalities. One, described by Gospe and coworkers, takes the form of a familial X-linked myalgic-cramp-myoglobinuric syndrome, resulting from the deletion of the first third of the dystrophin gene. The muscle changes are mild and relatively nonprogressive. Another dystrophinopathy takes the form of an X-linked cardiomyopathy characterized by progressive heart failure in young persons without clinical evidence of skeletal muscle weakness; biopsy of skeletal muscle reveals reduced immunoreactivity to dystrophin (Jones and de la Monte). In yet another type, a glycerol-kinase deficiency is associated with varying degrees of adrenal hypoplasia, mental retardation, and myopathy.


Neurology_Adams

Neurology_Adams. This is a group of disorders that encompasses at least six different genetic types, the most common probably being an X-linked muscular dystrophy characterized by the special feature of muscle contractures. That process is relatively benign in comparison with the Duchenne dystrophy, at least in so far as most affected individuals live into adulthood. It was described originally by Emery and Dreifuss and subsequently by Hopkins and by Merlini and their colleagues. The primary gene defect is a deficiency of the protein emerin, a constituent of the nuclear membrane, encoded by EMD on the X chromosome (Fig. 45-3). However, also described are autosomal dominant forms with mutations in the gene for laminin A/C (called LGMD 1B, obviously affecting both girls and boys), an additional X-linked form due to mutations in FHL-1 as well as sporadic and dominant mutations of other genes encoding for entirely disparate proteins. Making a complete understanding of this syndrome even more complex is


Neurology_Adams

Neurology_Adams. due to mutations in FHL-1 as well as sporadic and dominant mutations of other genes encoding for entirely disparate proteins. Making a complete understanding of this syndrome even more complex is the recent appreciation that many of cases have none of these mutations.


Neurology_Adams

Neurology_Adams. The age of onset varies from childhood to late adolescence or adulthood. Weakness affects first the upper arm and pectoral girdle musculature and later the pelvic girdle and the distal muscles in the lower extremities. The distinguishing feature of the most typical form of the disease is the early appearance of contractures in the flexors of the elbow, extensors of the neck, and posterior calf muscles. Facial muscles are affected occasionally. There is no hypertrophy or pseudohypertrophy, and cognition is unaffected. However, severe cardiomyopathy with variable sinoatrial and atrioventricular conduction defects is a common accompaniment. The course of the myopathy is generally benign, more like that of Becker dystrophy, but weakness and contractures are severe in some cases and sudden cardiac death is a not infrequent occurrence. For this reason, close monitoring by a cardiologist and the prophylactic insertion of a pacemaker at the appropriate time may be lifesaving.


Neurology_Adams

Neurology_Adams. The less common types of Emery-Dreifuss dystrophy, as mentioned, may have a scapuloperoneal (FHL-1 gene) or humeroperoneal (laminin mutation). Facioscapulohumeral Muscular Dystrophy (FSH, Landouzy-Dejerine Muscular Dystrophy, DUX4 Mutation) This is a slowly progressive dystrophy involving primarily the musculature of the face and shoulders, often with long periods of nearly complete arrest. The pattern of inheritance is usually autosomal dominant. Almost all are of the facioscapulohumeral muscular dystrophy 1 (FSHD1) type; 5 to 10 percent are designated FSHD2, for which the mutation has recently been identified. The clinical presentations are very similar.


Neurology_Adams

Neurology_Adams. Although less common than the Duchenne and myotonic dystrophies, FSH is not rare (an estimated yearly incidence rate of 5:100,000) and we have seen 1 or more cases yearly. The age of onset is usually between 6 and 20 years, but cases beginning in early adult life are occasionally encountered. Weakness and atrophy of the involved muscles are the major physical findings; pseudohypertrophy occurs only rarely and is slight. As a rule, the first manifestations are difficulty in raising the arms above the head and winging of the scapulae, although bifacial weakness may have initially attracted attention, even in early childhood. There is involvement especially of the orbicularis oculi, the zygomaticus, and the orbicularis oris, whereas the masseters, as well as the temporalis, extraocular, pharyngeal, and respiratory muscles are spared. There is an inability to close the eyes firmly, to purse the lips, and to whistle; the lips have a peculiar looseness and tendency to protrude. The lower


Neurology_Adams

Neurology_Adams. and respiratory muscles are spared. There is an inability to close the eyes firmly, to purse the lips, and to whistle; the lips have a peculiar looseness and tendency to protrude. The lower parts of the trapezius muscles and the sternal parts of the pectorals are almost invariably affected. By contrast, the deltoids may seem to be unusually large and strong, an appearance that may be mistaken for pseudohypertrophy. The advancing atrophic process involves the sternocleidomastoid, serratus magnus, rhomboid, erector spinae, latissimus dorsi, and eventually the deltoid muscles as well. The bones of the shoulders become prominent; the scapulae are winged and elevated (“angel-wing” appearance), and the clavicles stand out. The anterior axillary folds slope down and out as a result of wasting of the pectoral muscles. Usually the biceps waste less than the triceps, and the brachioradialis muscles even less, so that the upper arm may be thinner than the forearm (“Popeye” effect). Pelvic


Neurology_Adams

Neurology_Adams. of the pectoral muscles. Usually the biceps waste less than the triceps, and the brachioradialis muscles even less, so that the upper arm may be thinner than the forearm (“Popeye” effect). Pelvic muscles are involved later and to a milder degree, giving rise to a slight lordosis and pelvic instability. The pretibial muscles weaken, and foot-drop is added to the waddling gait. The Beevor sign, an upward movement of the umbilicus on flexing the neck as a result of weakness of the lower abdominal muscles, is reportedly common (Awerbuch et al), but we have not seen it in early cases. Life expectancy is said to not be shortened.


Neurology_Adams

Neurology_Adams. Initially, and even throughout the course, the muscular weakness may be asymmetrical (winging of only one scapula). Many of the patients with milder degrees of this form of dystrophy are unaware that they have the disease. This was true of nearly half of the large series of patients described by Tyler and Stephens in the Utah Mormon population. At any point, the disease may become virtually arrested. Nevertheless, 15 to 20 percent of patients eventually require a wheelchair (Tawil et al).


Neurology_Adams

Neurology_Adams. An interesting feature of this group of diseases is the occasional congenital absence of a muscle (amyoplasia of one pectoral, brachioradialis, or biceps femoris) or part of a muscle in patients who later develop the typical features of the disease. The external ocular muscles are known to occasionally become affected late in the illness. Although cardiac involvement is rare, in a few cases tachycardia, cardiomegaly, and arrhythmias have occurred. Mental function is normal. Serum CK values are normal or slightly elevated.


Neurology_Adams

Neurology_Adams. At a molecular level, FSHD1 has been found to have a consistent association with deletions of variable size on DUX4, located at the tip of chromosome 4q. This disorder is a consequence of alterations of a noncoding portion of DNA. Deletions in a repeated segment interfere with the structure of chromatin and allow the expression of normally inactive genes such as DUX4. Only patients with an allele that contains a repeat segment FSHD2 (called D4Z4 repeats) are susceptible to the disease. An entirely different mutation in a gene that maintains the structural integrity of chromatin accounts for the less common FSHD2; this change results in hypomethylation of the D4Z4 segments (an epigenetic mechanism) and is therefore also dependent on the permissive repeat allele.


Neurology_Adams

Neurology_Adams. A variant in which only the shoulder and arm muscles are affected, sparing the face, and a form with bilateral foot-drop are known (Krasnianski et al). In some cases, usually with severe deletions at the FSH locus on chromosome 4, there is an early-onset, relatively rapid progression and an association with facial diplegia, sensorineural deafness, and, sometimes, exudative retinal detachment (Coats disease). Using fluorescein angiography, Fitzsimmons and others have found a variety of other retinal abnormalities: telangiectasia, occlusion, leakage, and microaneurysms; in the majority of cases, suggesting that these retinal abnormalities are an integral part of the disease. Less common manifestations of FSHD include isolated scapular winging or other focal weakness such as foot drop, sparing of facial muscles, a variant with limb-girdle weakness, and rare instances of progressive external ophthalmoplegia (PEO).


Neurology_Adams

Neurology_Adams. This is a hetergenous group of myopathies that share the denominative topographic distribution of weakness and atropy, usually beginning in childgood but with wide variability. Beginning with Brossard in 1886, there were numerous reports of a distinctive pattern of progressive muscular weakness and wasting that involved the muscles of the neck, shoulders, and upper arms, and of the anterior tibial and peroneal groups, causing severe foot-drop. The nature of this disorder has been a matter of controversy, some writers claiming it to be a progressive muscular dystrophy and others, a muscular atrophy of spinal or neuropathic type. Probably both are correct in that either process can produce more or less the same pattern of weakness. Davidenkow, who wrote extensively on this subject, described a form of familial scapuloperoneal weakness and atrophy associated with areflexia and distal sensory loss (a spinal-neuronopathic form) that was later found to have a mutation in the desmin gene,


Neurology_Adams

Neurology_Adams. a form of familial scapuloperoneal weakness and atrophy associated with areflexia and distal sensory loss (a spinal-neuronopathic form) that was later found to have a mutation in the desmin gene, and others have confirmed these findings (see discussions of Munsat and Serratrice). Nevertheless, the existence of a purely myopathic form has been established. The mutation in the most common form of the disease has been found in TRPV4 but others have been connected to FHL-1 on the X-chromosome (see Table 45-1). A mutation in TRIM32 has also causes this phenotype. The onset of symptoms in their 6 patients was in early or middle adult life, with difficulty in walking because of bilateral foot-drop; symptoms referable to scapulohumeral involvement came later. Progression was slow, and none of the patients became severely incapacitated.


Neurology_Adams

Neurology_Adams. Limb-Girdle Muscular Dystrophies (LGMD, Scapulohumeral and Pelvifemoral Muscular Dystrophies, Erb Dystrophy) (See Table 45-1)


Neurology_Adams

Neurology_Adams. There is a large group of patients with muscular dystrophy who do not fit into the Duchenne/Becker, facioscapulohumeral, or scapuloperoneal categories. Children of both sexes in this group lack the hypertrophy of calves and other muscles; adults with late-onset forms have either pelvic or shoulder girdle involvement or both, and their facial muscles are spared. Because Wilhelm Erb first called attention to these types of dystrophy, they were classified by Walton and Nattrass as the “limb-girdle dystrophies of Erb.” This clinically based grouping has been problematic from the time it was proposed because, like the scapuloperoneal group, it is heterogeneous, the only unifying feature being the presence of limb-girdle weakness with sparing of the facial muscles. The inheritance is variable, but the autosomal recessive forms are the most common. Either the shoulder girdle or pelvic girdle muscles may be first affected (traditionally these forms had been referred to as the Erb juvenile


Neurology_Adams

Neurology_Adams. but the autosomal recessive forms are the most common. Either the shoulder girdle or pelvic girdle muscles may be first affected (traditionally these forms had been referred to as the Erb juvenile atrophic and Leyden-Möbius types, respectively). Weakness and atrophy may become evident during either late childhood or early adult life and spread from shoulders to hips or vice versa.


Neurology_Adams

Neurology_Adams. The status of this group of limb-girdle muscular dystrophies (LGMDs) as a clinical–genetic entity is being steadily revised. The delineation of the progressive spinal muscular atrophies and the congenital and metabolic myopathies has considerably narrowed the category of limb-girdle dystrophies as originally described. During the past decade, with the application of molecular genetic techniques, progress in this direction has accelerated greatly. The now well-populated class of limb-girdle dystrophies is classified as LGMD1 for the autosomal dominant types, and LGMD2 for the recessive types, and further subclassified based on the specific genotype. At the time of this writing, at least 19 forms of autosomal recessive (LGMD type 2A-2S) and 6 forms of autosomal dominant (LGMD type 1A-1E) limb-girdle dystrophies have been defined, most with an identifiable mutation and a protein that in most cases is a constituent of the sarcolemmal, sarcomeric, or nuclear membrane structural protein


Neurology_Adams

Neurology_Adams. limb-girdle dystrophies have been defined, most with an identifiable mutation and a protein that in most cases is a constituent of the sarcolemmal, sarcomeric, or nuclear membrane structural protein (Bushby). The later the onset of these disorders, the more likely that the course will be benign. In these lesser-affected patients the EMG is myopathic and the CK values are only moderately elevated and may be normal. More severe cases can have greatly elevated CK levels. Cardiac involvement occurs but is infrequent (mainly in the group classified as myofibrillar dystrophies), and mental function is normal, but there are exceptions including in cases of laminin A/C mutations (type 1B), FKRP (fukutin-related protein mutation) mutations (type 2I), and in the sarcoglycanopathies.


Neurology_Adams

Neurology_Adams. This information is summarized in Table 45-2 and discussion of the better-characterized types follows. Limb-Girdle Muscular Dystrophy 2I (FKRP, Fukutin Mutation)


Neurology_Adams

Neurology_Adams. The discovery of the “fukutin-related protein” initially came about because mutant forms caused a severe congenital muscular dystrophy (CMD). It later became apparent that certain mutations also cause a common type of later onset limb-girdle dystrophy. As the designation “2” indicates, it is transmitted in an autosomal recessive manner. This is the most common form of limb-girdle dystrophy in patients of Northern European descent. In a series of 16 patients from 14 families, Poppe and colleagues characterized the main features as having an onset of proximal girdle weakness in the second to fourth decades of life (but as early as age 2 years). The majority of patients eventually had respiratory failure and several displayed varying degrees of congestive heart failure, features that also accompany some of the other limb-girdle dystrophies. In most other ways, this disease reflects the heterogeneity of clinical presentation of the other subtypes of limb-girdle disease. A period of


Neurology_Adams

Neurology_Adams. accompany some of the other limb-girdle dystrophies. In most other ways, this disease reflects the heterogeneity of clinical presentation of the other subtypes of limb-girdle disease. A period of stabilization lasting several to 35 years is common, followed by a decade or more of progression that eventually involves the shoulder muscles. Most patients, particularly those with later onset, remained able to walk into their forties. Other features are variable, for example, dysphagia and ptosis; however, distal weakness is not seen and intelligence is normal.


Neurology_Adams

Neurology_Adams. The defective FKRP gene is related in function to 4 other muscle genes in addition to fukutin (hence its name). All 5 of these genes are glycosyl transferases that attach sugar groups to proteins such as alpha-dystroglycan. The severity of the clinical phenotype is inversely related to the levels of glycosylation of alpha-dystroglycan. Defects in any of the 5 genes can cause developmental lesions in the brain in addition to muscle disease, although those associated with FKRP mutations are less common and less severe. Severe Childhood Autosomal Recessive Muscular Dystrophy (Sarcoglycanopathies; LGMD 2C, D, E, and F)


Neurology_Adams

Neurology_Adams. Severe Childhood Autosomal Recessive Muscular Dystrophy (Sarcoglycanopathies; LGMD 2C, D, E, and F) These entities comprise the best-defined group of limb- girdle dystrophy. Clinically they resemble severe Duchenne dystrophy in practically all respects, including the presence of calf hypertrophy, cardiomyopathy, and marked elevation of CK in the early stages of the illness. The obvious distinction from Duchenne dystrophy is the autosomal recessive pattern of inheritance (affection of both girls and boys in the same sibship). The largest and best-studied group of this severe, recessive pelvic-pectoral dystrophy (99 children in 28 families) has come from Tunisia (Ben Hamida et al). It also occurs commonly in other Arab countries and has been observed repeatedly in Brazil, but less so in Europe and North America.


Neurology_Adams

Neurology_Adams. The basic defect is in 1 of 4 dystrophin-associated glycoproteins (DAGs)—a-, b-, g-, and d-sarcoglycan (see Fig. 45-2); a-sarcoglycan (designated 50 DAG) is also called adhalin, from the Arabic word adhal, meaning muscle. A primary deficiency of adhalin has been traced adhalin on chromosome 17q21 (Roberds et al). A primary defect in b-sarcoglycan (43 DAG) has been mapped to chromosome 4q12, of g-sarcoglycan (35 DAG) to the pericentromeric region of chromosome 13q, and of b-sarcoglycan (43 DAG) to chromosome 5q. Primary defects in 25 DAG may also lead to a deficiency of adhalin, but the latter is incomplete and represents a secondary effect, possibly explained by the proximity of the defective genes to the adhalin gene.


Neurology_Adams

Neurology_Adams. Because of clinical similarities, there may be difficulty in distinguishing limb-girdle dystrophies (formerly termed severe childhood autosomal recessive muscular dystrophy [SCARMD]) from a dystrophinopathy (except that the former occur in females). In addition to the difference in inheritance, they can be readily diagnosed by showing a loss of sarcolemmal immunostaining for any of the dystrophin-associated glycoproteins but with preservation of staining for dystrophin itself. However, it is not possible on clinical grounds to distinguish one sarcoglycanopathy from another; this can be accomplished only by specific immunostaining.


Neurology_Adams

Neurology_Adams. These forms of limb-girdle dystrophies have been described in large kindreds, in Indiana (among the Amish people), on the island of Réunion in the Indian Ocean, in Brazil, Great Britain, Italy and Spain, and elsewhere, affecting males and females equally. Both the shoulder and pelvic girdles are involved. The degree of weakness has varied considerably. In one form of the disease, called LGMD 2A, the abnormal gene codes for a calcium-activated neutral protease, or calpain (see Fig. 45-3). This “calpainopathy” is currently believed to account for approximately 40 percent of patients with LGMD. Frequently, and early in the course of disease, there are Achilles tendon contractures and very high serum CK levels (at least 10 times normal), features that may permit distinction from the sarcoglycanopathies.


Neurology_Adams

Neurology_Adams. Yet another fairly common recessive limb-girdle dystrophy of slow progression is caused by a mutation in the gene for the protein dysferlin, which localizes to the muscle fiber membrane. Noteworthy is the fact that this same protein is involved in the distal form of Miyoshi muscular dystrophy described further on. Early involvement of the gastrocnemius muscle (inability to walk on tiptoe) and extraordinarily high levels of CK, as in calpainopathy, are clues to the latter disease.


Neurology_Adams

Neurology_Adams. Several dystrophies with the LGMD phenotype are inherited as autosomal dominant traits. For example, LGMDA 1A is an autosomal dominant limb-girdle dystrophy of late onset that was described in a large North Carolina family (49 affected members in a pedigree of 218 persons). The mean age at onset was 27 years. Proximal leg weakness, with or without proximal arm weakness, and elevated CK values were the main clinical characteristics. Speer and colleagues have documented that the primary defect is in a gene encoding the protein myotilin (see Fig. 45-3). LGMDA 1A is allelic to a form of myofibrillar myopathy.


Neurology_Adams

Neurology_Adams. LGMD 1B is a dominantly inherited disorder arising from mutations in the gene encoding the nuclear membrane protein lamin A/C (Fig. 45-3). Mercuri and colleagues note that the phenotypes of these mutations vary widely. The muscle disorders range from severe cases that mimic CMD to milder ones with features of limb girdle dystrophy or Emery-Dreifuss muscular dystrophy. The diverse, nonmuscular manifestations of lamin A/C mutations include a cardiomyopathy, a form of lipodystrophy, a syndrome of accelerated aging (Hutchinson-Gilford progeria), and a recessively inherited axonal neuropathy. Progressive External Ophthalmoplegia (Kearns-Sayre Syndrome) (See Also “Progressive External Ophthalmoplegia [PEO] and Kearns-Sayre Syndrome” Under Mitochondrial Myopathies in Chap. 36)


Neurology_Adams

Neurology_Adams. Progressive External Ophthalmoplegia (Kearns-Sayre Syndrome) (See Also “Progressive External Ophthalmoplegia [PEO] and Kearns-Sayre Syndrome” Under Mitochondrial Myopathies in Chap. 36) This has proved to be a confusing group of processes characterized by slowly progressive myopathy primarily involving and often limited to the extraocular muscles. Usually, the levators of the eyelids are the first to be affected, causing ptosis, followed by progressive balanced ophthalmoparesis. This disorder usually begins in childhood, sometimes in adolescence, and rarely in adult life (as late as 50 years).


Neurology_Adams

Neurology_Adams. Several types have been described. The most common one arises from either deletions or point mutations in mitochondrial DNA and are discussed in Chap. 37 with other metabolic disorders. However, when the foregoing progressive external ophthalmoplegia (PEO) categories are eliminated, there remains a distinctly different category of dominantly inherited PEO. Males and females are equally affected; the pattern of inheritance is autosomal dominant in some and recessive or uncertain in others. Once started, the disease progresses relentlessly until the eyes are motionless. Simultaneous involvement of all extraocular muscles permits the eyes to remain in a central position, so that strabismus and diplopia are uncommon (in rare instances, one eye is affected before the other). The pupillary responses and accommodation are normal. As the patient attempts to raise his eyelids and to see under them, the head is thrown back and the frontalis muscle is contracted, wrinkling the forehead


Neurology_Adams

Neurology_Adams. responses and accommodation are normal. As the patient attempts to raise his eyelids and to see under them, the head is thrown back and the frontalis muscle is contracted, wrinkling the forehead (hutchinsonian facies). The eyelids are abnormally thin due to atrophy of the levator muscles. The orbicularis oculi muscles are frequently involved in addition to the extraocular muscles. Thus, in PEO, as in myasthenia gravis and myotonic dystrophy, there can be a characteristic combination of weakness of eye closure and eye opening, a combination that is nearly always myopathic. Other facial muscles, masseters, sternocleidomastoids, deltoids, or peronei are variably weak and wasted in approximately 25 percent of cases. The characteristic feature of PEO is that ptosis and ocular paralysis precede involvement of other muscles by many years.


Neurology_Adams

Neurology_Adams. Given that there is considerable clinical overlap between the mitochondrial syndrome and dominantly inherited PEO, it is not surprising that some of the dominantly inherited gene defects causing PEO result in disturbances in mitochondrial DNA. Mutations in three nuclear genes have been implicated. (These are twinkle, a mitochondrial DNA binding protein; ANT1, an adenine nucleotide transporter in the intermembrane space in the mitochondrion; and POLG, a subunit of the mitochondrial DNA polymerase.) There are also recessively inherited instances of familial PEO, one of which involves a nuclear gene. Oculopharyngeal Dystrophy (PABPN1 Mutation, See Table 45-2) Oculopharyngeal dystrophy is inherited as an autosomal dominant trait and is unique in its late onset (usually after the forty-fifth year) and the restricted muscular weakness, manifest mainly as a bilateral ptosis and dysphagia.


Neurology_Adams

Neurology_Adams. E.W. Taylor first described the disease in 1915 and assumed that it was caused by a nuclear atrophy (oculomotor-vagal complex). However, Victor and colleagues, in 1962, showed that the descendants of Taylor’s cases had a late-life dystrophy (myopathic EMG and biopsy). One of the families described by Victor, Hayes, and Adams was subsequently traced by Barbeau through 10 generations to an early French-Canadian immigrant, who was the progenitor of 249 descendants with the disease. Other families showing a dominant (rarely recessive) pattern of inheritance and a number of sporadic cases have been observed in many parts of the world.


Neurology_Adams

Neurology_Adams. Difficulty in swallowing and change in voice are associated with slowly progressive ptosis. Swallowing becomes so difficult that food intake is limited, resulting in cachexia, which can be ameliorated by cutting the cricopharyngeus muscles, or, if that fails, by a gastrostomy or nasogastric tube. Later in the disease, in some families the external ocular muscles and shoulder and pelvic muscles become weakened and atrophic to a varying extent. In the few autopsied cases, a loss of fibers of modest proportions was widespread in these and many other muscles. Rimmed vacuoles in the sarcoplasm and, by electron microscopy, intranuclear tubular filaments are characteristic but not specific histologic findings (these features are seen in other myopathies, particularly in inclusion body myositis). The brainstem nuclei and cranial nerves are normal. As in the other mild and restricted muscular dystrophies, the serum CK and aldolase levels are normal and the EMG is altered only in the affected


Neurology_Adams

Neurology_Adams. The brainstem nuclei and cranial nerves are normal. As in the other mild and restricted muscular dystrophies, the serum CK and aldolase levels are normal and the EMG is altered only in the affected muscles.


Neurology_Adams

Neurology_Adams. The gene product of the mutatued gene, PABN1, is a protein that binds to RNA (poly-A binding protein). The defect is an expansion of a string of alanines. Normally, there are 6 repeats; in dominantly inherited oculopharyngeal dystrophy, there are 8 to 13 repeats; in the recessively inherited form there are 7 repeats on each allele. Thus this represents one of the most subtle nucleotide expansion diseases yet discovered. There are 2 types of myotonic dystrophies (DM1 and DM2/PROMM). Type 1 (DM1) is the most common adult muscular dystrophy. It was described in 1909 by Steinert, who considered it to be a variant of congenital myotonia (Thomsen disease; see Chap. 46) and in the same year by Batten and Gibb, who recognized it as a unique clinical entity.


Neurology_Adams

Neurology_Adams. DM1 is distinguished by an autosomal dominant pattern of inheritance with a high level of penetrance, special topography of the muscle atrophy, associated obvious myotonia, and occurrence of dystrophic changes in nonmuscular tissues (lens of eye, testicle and other endocrine glands, skin, esophagus, heart, and, in some cases, the cerebrum). Certain muscles, the levator palpebrae, facial, masseter, sternocleidomastoid, and forearm, hand, and pretibial muscles, are consistently involved in the dystrophic process. It is possible that Gowers’ famous case of an 18-year-old youth with weakened and wasted anterior tibial and forearm muscles and sternocleidomastoids, in conjunction with paresis of the orbicularis and frontalis muscles, was an example of this disease.


Neurology_Adams

Neurology_Adams. Despite some clinical variability of myotonic dystrophy, the defective gene in the first type has been the same in every population that has been studied. At this locus on chromosome 19q there is a specific molecular defect, an unstable trinucleotide sequence (CTG) in the DMPK gene that is longer in affected individuals than it is in healthy siblings or unaffected subjects. Whereas healthy individuals will have 5 to 30 CTG repeats, patients with myotonic dystrophy have 50 to 2,000. Longer sequences are associated with more severe disease, and they increase in size through successive generations lead to earlier occurrence (genetic anticipation), particularly in DM1. The CTG repeats reside within the myotonin protein kinase gene. It is of considerable interest that these CTG repeating segments do not code for a protein (i.e., they are intronic), quite unlike conditions such as Huntington disease in which the triplet expansion codes for amino acid sequences within a protein.


Neurology_Adams

Neurology_Adams. The milder type 2 myotonic dystrophy (DM2) is caused by an expanded triplet repeat in the CNBP gene on chromosome 3, as discussed further on under “Proximal Myotonic Myopathy (PROMM, DM2).” A critical element in the pathogenesis of this disease in both types is the intranuclear accumulation of the expanded RNA sequences; these disrupt the regulation of alternative splicing of mRNA and perturb the expression of many genes, thus the multiple systems affected clinically. Clinical Features of Myotonic Dystrophy 1 (DM1, DMPK Mutation)


Neurology_Adams

Neurology_Adams. Clinical Features of Myotonic Dystrophy 1 (DM1, DMPK Mutation) In most instances of myotonic dystrophy, the weakness and muscular wasting do not become evident until early adult life, but they may present in childhood, usually with facial weakness and ptosis. Myotonia is perhaps more obvious and earlier in this disorder than in most others that display the sign as one component. Myotonic dystrophy is, for example, far more common than myotonia congenita. Myotonia combined with distal weakness in DM1 stands out from other myopathies. Cardiac arrhythmias, sometimes evident on in conduction defects in EKG, are common as noted below. A severe neonatal (congenital) form of the disease is well known and is described separately further on.


Neurology_Adams

Neurology_Adams. In the common early adult form of the disease, the small muscles of the hands along with the extensor muscles of the forearms are often the first to become atrophied. Difficulty grapsing (due to weakness of hand muscles) and then releasing objects (because of the myotonia) is typical. In other cases, ptosis of the eyelids and thinness and slackness of the facial muscles may be the earliest signs, preceding other muscular involvement by many years. Atrophy of the masseters leads to narrowing of the lower half of the face, and the mandible is slender and malpositioned so that the teeth do not occlude properly. This, along with the ptosis, frontal baldness, and wrinkled forehead, imparts a distinctive appearance that, once seen, can be recognized at a glance (“hatchet” face). The sternocleidomastoids are almost invariably thin and weak and are associated with an exaggerated forward curvature of the neck (“swan neck”). Atrophy of the anterior tibial muscle groups, leading to foot-drop, is


Neurology_Adams

Neurology_Adams. are almost invariably thin and weak and are associated with an exaggerated forward curvature of the neck (“swan neck”). Atrophy of the anterior tibial muscle groups, leading to foot-drop, is an early sign in some families.


Neurology_Adams

Neurology_Adams. Pharyngeal and laryngeal weakness results in a weak, monotonous, nasal voice. The uterine muscle may be weakened, interfering with normal parturition, and the esophagus is often dilated because of loss of muscle fibers in the striated as well as smooth muscle parts. Megacolon occurs in some patients. Diaphragmatic weakness and alveolar hypoventilation, resulting in chronic bronchitis and bronchiectasis, are common late features, as are cardiac abnormalities; the latter are most often a result of disease of the conducting apparatus, giving rise to bradycardia and a prolonged P-R interval. Patients with extreme bradycardia atrial tachyarrhythmia or high degrees of atrioventricular block may die suddenly; for such individuals, insertion of a pacemaker is often recommended (Moorman et al; Groh et al). Mitral valve prolapse and left ventricular dysfunction (cardiomyopathy) are less frequent abnormalities. In this disorder, as in Emery-Dreifuss dystrophy, careful assessment by a


Neurology_Adams

Neurology_Adams. et al; Groh et al). Mitral valve prolapse and left ventricular dysfunction (cardiomyopathy) are less frequent abnormalities. In this disorder, as in Emery-Dreifuss dystrophy, careful assessment by a knowledgeable cardiologist is required.


Neurology_Adams

Neurology_Adams. The disease progresses slowly, with gradual involvement of the proximal muscles of the limbs and muscles of the trunk. Tendon reflexes are lost or much reduced. Contracture is rarely seen, and the thin, flattened hands are consequently soft and pliable. Most patients are confined to a wheelchair or bed within 15 to 20 years of the first signs, and death occurs before the normal age from pulmonary infection, heart block, or heart failure.


Neurology_Adams

Neurology_Adams. The phenomenon of myotonia, which expresses itself in prolonged idiomuscular contraction following brief percussion or electrical stimulation and in delay of relaxation after strong voluntary contraction, is the third striking attribute of the disease (the other two being the facial, ptotic, and limb weakness, and the cardiac-autoimmune features). Not as widespread or severe as in myotonia congenita, it is, nonetheless, easily elicited in the hands and tongue in almost all cases, and in the proximal limb muscles in half of the cases. Gentle movements do not evoke it (eye blinks, movements of facial expression, and the like are not impeded), whereas strong closure of the lids and clenching of the fist are followed by a long delay in relaxation.


Neurology_Adams

Neurology_Adams. Myotonia may precede weakness by several years. Indeed, Maas and Paterson have claimed that many cases diagnosed originally as myotonia congenita eventually proved to be examples of myotonic dystrophy. Of interest is the fact that in congenital or infantile cases of myotonic dystrophy, the myotonic phenomenon is not elicited until later in childhood, after the second or third year of life (see later). The child often becomes accustomed to the myotonia and does not complain about it. The relation of myotonia to the dystrophy is not direct. Certain muscles that show the myotonia best (tongue, flexors, of fingers) are seldom weak and atrophic. Moreover, there may be little or no myotonia in certain families that show the other characteristic features of myotonic dystrophy. The muscle hypertrophy that is characteristic of myotonia congenita is not a feature of myotonic dystrophy.


Neurology_Adams

Neurology_Adams. The fourth major characteristic of the disease is the dystrophic change in nonmuscular tissues. The most common of these is lenticular opacities, found by slit-lamp examination in 90 percent of patients. At first dust-like, they then form small, regular opacities in the posterior and anterior cortex of the lens just beneath the capsule; under the slit lamp they appear blue, blue-green, and yellow, and are highly refractile. Microscopically, the crystalline material (probably lipids and cholesterol, which cause the iridescence) lies in vacuoles and lacunae among the lens fibers. In older patients, a stellate cataract slowly forms in the posterior cortex of the lens.


Neurology_Adams

Neurology_Adams. Mild to moderate degrees of developmental cognitive delay are common in DM1, and the brain weight in several of our patients was 200 g less than that in normal individuals of the same age. Late in adult life, some patients become suspicious, argumentative, and forgetful. In some families, a hereditary sensorimotor neuropathy may be added to the muscle disease (Cros et al). Other nonspecific abnormalities, such as hyperostosis of the frontal bones and calcification of the basal ganglia, both readily discerned by CT, seem to be more common in patients with myotonic dystrophy than they are in healthy persons.


Neurology_Adams

Neurology_Adams. Progressive frontal alopecia, beginning at an early age, is a characteristic feature in both men and women with this disease. Testicular atrophy with androgenic deficiency, reduced libido or impotence, and sterility are additional frequent manifestations. In some patients gynecomastia and elevated gonadotropin excretion are found. Testicular biopsy shows atrophy and hyalinization of tubular cells and hyperplasia of Leydig cells. (Thus all the clinical characteristics of the Klinefelter syndrome may be present but without the “sex chromatin” mass [Barr body].) Ovarian deficiency occasionally develops in the female patient, but it is seldom severe enough to interfere with menstruation or fertility. The prevalence of clinical or chemical diabetes mellitus is slightly increased in patients with myotonic dystrophy, but an increased insulin response to a glucose load has proved to be a common abnormality. Numerous surveys of other endocrine functions have yielded little of significance.


Neurology_Adams

Neurology_Adams. Finally, heart block, atrial and ventricular tachycardias, unexplained cardiomyopathy with heart failure, and sudden death are well known in the disorder and require repeated EKG evaluation. Insertion of a pacemaker has become common. We have been impressed with the variability of clinical expression. In many patients, intelligence has been unimpaired and the myotonia and muscle weakness have been so mild that the patients were unaware of any difficulty. Pryse-Philips and associates emphasized these features in their description of a large Labrador kinship in which 27 of 133 patients had only a partial syndrome and only minor muscle symptoms at the time of examination.


Neurology_Adams

Neurology_Adams. In addition to displaying most of the common findings of muscular dystrophy, there are several highly unusual myopathologic features. Peripherally placed sarcoplasmic masses and circular bundles of myofibrils (ringbinden) are found. There is hypertrophy of type 1 fibers with centrally placed nuclei (this may be a marked finding) and many atrophic fibers show nuclear clumping. In many of the muscle spindles there is an excess of intrafusal fibers (particularly in the congenital form; see later). Many of the terminal arborizations of the peripheral nerves are unusually elaborate and elongated.


Neurology_Adams

Neurology_Adams. Brief reference was made earlier to this inherited, distinctive, and potentially lethal form of myotonic dystrophy. Harper’s (1975) study of 70 personally observed patients and 56 others gathered from the medical literature suggests this disease exists in every pediatric neurology service. Profound hypotonia and facial diplegia at birth are the most prominent clinical features; myotonia is notably absent. Drooping of the eyelids, the tented upper lip (“carp” mouth), and the open jaw impart a characteristic appearance, which allows immediate recognition of the disease in the newborn infant and child. Difficulty in sucking and swallowing, bronchial aspiration (because of palatal and pharyngeal weakness), and respiratory distress (because of diaphragmatic and intercostal weakness and pulmonary immaturity) are present in varying degrees; the latter disorders are responsible for a previously unrecognized group of neonatal deaths (24 such deaths among siblings of affected patients in


Neurology_Adams

Neurology_Adams. immaturity) are present in varying degrees; the latter disorders are responsible for a previously unrecognized group of neonatal deaths (24 such deaths among siblings of affected patients in Harper’s study). In surviving infants, delayed motor and speech development, swallowing difficulty, mild to moderately severe mental retardation, and talipes or generalized arthrogryposis are common. Once adolescence is attained, the disease follows the same course as the later form. As stated earlier, clinical myotonia in the congenital form of the disease becomes evident only later in childhood, although EMG study may disclose myotonic discharges in early infancy. The diagnosis may be suspected by the simple test of eliciting myotonia in the mother. ECG changes occur in one-third of the patients.


Neurology_Adams

Neurology_Adams. In the congenital form of this disease the affected parent is always the mother with type 1 (DM1) myotonic dystrophy, in whom the disease need not be severe. Electrophysiologic testing will bring out the myotonia in the mother if it is inevident on percussion of muscle. (In cases of adult onset, transmission is maternal or paternal.) These data suggest that in addition to inheriting the myotonic dystrophy gene, the congenital cases also receive some maternally transmitted factor, possibly methylation of DNA that allows expansion of the trinucleotide repeat in oocytes. The prenatal diagnosis of myotonic dystrophy is readily accomplished by examination for CTG repeats in the amniotic fluid or in a biopsy of chorionic villi. However, it is not possible to predict whether a fetus with an expanded mutation will have congenital myotonic dystrophy or later-onset myotonic dystrophy. Proximal Myotonic Myopathy (DM2, PROMM,


Neurology_Adams

Neurology_Adams. Proximal Myotonic Myopathy (DM2, PROMM, Under this name, Ricker and colleagues (1994) described a myopathy characterized by autosomal dominant inheritance (unlike the limb-girdle dystrophies, the numeral 2 denotes the second type of DM, not recessive inheritance), proximal muscle weakness, myotonia, and cataracts. Seventeen families containing 50 affected members were studied by these authors. Onset was between 20 and 40 years of age, with intermittent myotonic symptoms of the hands and proximal leg muscles, followed by a mild, slowly progressive weakness of the proximal limb muscles without significant atrophy. In contrast to DM1, cataracts developed in one-half of their patients and cardiac arrhythmias in only two. Onset in infancy, ptosis, weakness of facial, jaw, and distal limb muscles, and mental abnormalities were notably absent, further distinguishing PROMM from the conventional (DM1) form of myotonic dystrophy.


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Neurology_Adams. Histologically, there are many fibers with multiple (5 to 10 or more) internalized nuclei, without ringbinden or subsarcolemmal masses. In addition, there are atrophic fibers with nuclear clumps. Analysis of leukocyte and muscle DNA discloses no expansion of the CTG component of the myotonic dystrophy gene. Rather, the gene defect for this disease has been mapped to the CNBP gene on chromosome 3q where there is an expansion of a CCTG repeats. Like the expanded CTG repeat in myotonic dystrophy, the CCTG expansion in PROMM is associated with intranuclear accumulation of the expanded RNA transcript, and like the CTG repeats of myotonic dystrophy, the CCTG segments do not code for a protein. Distal Muscular Dystrophies (Welander, Miyoshi, and Other Types) (See Table 45-3)


Neurology_Adams

Neurology_Adams. Distal Muscular Dystrophies (Welander, Miyoshi, and Other Types) (See Table 45-3) Included in this group are several slowly progressive distal myopathies with onset principally in adult life. Weakness and wasting of the muscles of the hands, forearms, and lower legs, especially the extensors, are the main clinical features. Although such cases had been reported by Gowers and others, their differentiation from myotonic dystrophy and peroneal muscular atrophy was unclear until relatively recently. Several types of distal dystrophies are inherited as autosomal dominant traits. A different dominantly inherited distal dystrophy was described by Welander in a study of 249 patients from 72 Swedish pedigrees (not to be confused with the


Neurology_Adams

Neurology_Adams. Kugelberg-Welander juvenile spinal muscular atrophy affecting proximal muscles; see Chap. 38). Weakness developed first in the small hand muscles and then spread to the distal leg muscles, causing a steppage gait. Fasciculations, cramps, pain, sensory disturbances, and myotonia were notably absent. Some patients have a low-grade sensory neuropathy, suggesting that pathology in this disorder may not be exclusively in muscle. Cataracts appeared after the age of 70 years in 3 patients and can be discounted as having special significance. No endocrine disorders were detected. Dystrophic changes were demonstrated in 3 autopsies and 22 biopsy specimens. Some muscle biopsy material has shown rimmed vacuoles and inclusions that are similar to inclusion body myopathy. Progression of the disease was very slow; after 10 years or so, some wasting of proximal muscles was seen in a few of the patients. Welander dystrophy has been linked to mutations in T1A1 on chromosome 2p13, near the locus for


Neurology_Adams

Neurology_Adams. was very slow; after 10 years or so, some wasting of proximal muscles was seen in a few of the patients. Welander dystrophy has been linked to mutations in T1A1 on chromosome 2p13, near the locus for the below described Miyoshi myopathy.


Neurology_Adams

Neurology_Adams. Markesbery and colleagues reported a late-onset distal myopathy in which weakness began in the distal leg muscles (tibialis anterior) and later spread to the hands; there was also cardiomyopathy and heart failure. A mutation in the ZASP gene has been found. Very similar distal myopathies have been described in Finnish patients by Udd and colleagues and caused by dominant mutations in the “titin” gene. A form beginning in childhood has been described and attributed to a mutation in the gene (MYHC7) that codes for myosin heavy chain 1 protein. The characteristic feature in all these cases is progressive bilateral foot-drop.


Neurology_Adams

Neurology_Adams. A type of distal dystrophy characterized by autosomal recessive pattern of inheritance is particularly prevalent in Japan (Miyoshi et al), but numerous cases exist in all parts of the world. The Miyoshi myopathy is the one we have encountered most often among the distal muscular dystrophies. Onset of the disease is in early adult life, with weakness and atrophy of the leg muscles most prominent in the peroneal or the gastrocnemius and soleus muscles. Over many years the weakness extends to the thighs, gluteal muscles, and arm muscles, including the proximal ones. Serum CK concentrations are greatly increased in the early stages of the disease. In this type of dystrophy the mutation lin DYSF leads to an absence of the muscle protein dysferlin, a membrane protein that does not interact with any of the dystrophin-binding elements. Whereas dystrophin and its binding partners are believed to confer tensile strength, dysferlin and its associated proteins (e.g., the annexins) function in


Neurology_Adams

Neurology_Adams. any of the dystrophin-binding elements. Whereas dystrophin and its binding partners are believed to confer tensile strength, dysferlin and its associated proteins (e.g., the annexins) function in calcium-mediated membrane repair (Lennon et al). As mentioned earlier, limb-girdle dystrophy 2B has been linked to the same chromosomal locus and it also lacks the dysferlin protein. It is also striking that different family members with the same dysferlin mutation can have disease onset in either a proximal (LGMD) or distal (Miyoshi) pattern, suggesting that additional factors modify the pattern of weakness produced by dysferlin deficiency. We have encountered a family in which 2 individuals with dysferlin mutations had proximal weakness at onset while another sibling with the same disease had anterior tibial weakness.


Neurology_Adams

Neurology_Adams. An apparently separate form of distal myopathy with autosomal dominant inheritance and onset before 2 years of age has been described. Whether these infantile-onset cases represent a true muscular dystrophy has not been established. Several even rarer distal myopathies with linkage to specific genetic sites are summarized in the review by Illa, but most are not well-enough characterized to require elaboration here. A discussion can be found in the text from our colleagues Amato and Russell. Congenital Muscular Dystrophy (Fukuyama, Walker-Warburg, Merosin Deficient, Rigid Spine, and Other Types) (Table 45-4)


Neurology_Adams

Neurology_Adams. Early in the twentieth century there were scattered reports of congenital myopathy, but the status of this condition was difficult to evaluate. Some cases may have represented congenital myotonic dystrophy or one of the congenital myopathies described later. In 1957, Banker and associates described 2 patients (siblings), 1 dying 1.5 h after birth and the other dying at the age of 10 months of a congenital muscular dystrophy (CMD) with arthrogryposis. The pathologic changes consisted of muscle fiber degeneration, variation in fiber size, fibrosis, and fat cell replacement. The central and peripheral nervous systems were intact. The severity of the degenerative changes was such that a developmental disorder of muscle could be excluded. Pearson and Fowler, in 1963, reported a brother and sister with similar clinical and pathologic findings, and Walton and colleagues described yet another patient, 4 years of age. By 1967, Vassella and colleagues were able to collect 27 cases from the


Neurology_Adams

Neurology_Adams. sister with similar clinical and pathologic findings, and Walton and colleagues described yet another patient, 4 years of age. By 1967, Vassella and colleagues were able to collect 27 cases from the medical literature and to add 8 cases of their own. The high incidence of sibling involvement pointed to an autosomal recessive inheritance.


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Neurology_Adams. Preceding the modern genetic findings, in 1976, Bethlem and van Wijngaarden described an autosomal dominant, early-onset limb-girdle dystrophy in 28 members of 3 unrelated Dutch families. Flexion contractures of the elbows, ankles, and hyperextensible interphalangeal joints of the fingers were present from the beginning stages of weakness, but neither the weakness nor the contractures were disabling. Also unlike Emery-Dreifuss dystrophy, contractures of the neck and spine were not present. Uniformity of clinical expression, slow progression with long periods of arrest, and normal longevity are other important features of the illness. Mohire and coworkers have proposed the designation Bethlem myopathy. A milder form that is allelic with the Bethlehem type is termed Ulrich myopathy; many of these patients survive into their fifties because of the slow progression of disease.


Neurology_Adams

Neurology_Adams. Defined as a muscle dystrophy already present at birth, often with contractures of proximal muscles and trunk, the severity of the weakness and degree of progression have varied widely. Of the 8 cases reported by Rotthauwe and colleagues, 1 had a benign course, but the others all had weakness and hypotonia at birth, and difficulty in sucking and swallowing had interfered with nutrition. Their oldest patients, 14 and 23 years of age, and several others had walked, but at a late age. In the Finnish series of Donner and associates, congenital dystrophy accounted for 9 percent of the 160 cases of neuromuscular disease seen at their hospital over a decade. The weakness and hypotonia were generalized, and 3 had ECG abnormalities. The CK values were elevated and the EMGs were myopathic.


Neurology_Adams

Neurology_Adams. This group of dystrophies began to come into focus in the 1960s with a series of articles from Japan relating the details in more than 100 patients with congenital dystrophy (Fukuyama et al). Although it is the second most common muscular dystrophy in Japan, it is rare elsewhere. The special feature of these cases was the coexistence of severe mental retardation and developmental anomalies of the cerebral cortex. Hyperlucency in the periventricular white matter (by CT) was frequently observed. In another group of cases, CMD was associated with lissencephaly as well as cerebellar and retinal malformations (Walker-Warburg syndrome; see Dobyns et al). In a series reported by Santavuori and coworkers, CMD was associated with retinal degeneration and optic atrophy, hydrocephalus, pachygyria-polymicrogyria, and hypoplastic or absent septum pellucidum and corpus callosum (“muscle-eye-brain” [MEB] disease). Lebenthal and colleagues later described a large Arab pedigree with CMD and patent


Neurology_Adams

Neurology_Adams. and hypoplastic or absent septum pellucidum and corpus callosum (“muscle-eye-brain” [MEB] disease). Lebenthal and colleagues later described a large Arab pedigree with CMD and patent ductus arteriosus. Some patients had contractures at birth; in others, contractures developed at a later age. The EMG disclosed a myopathic pattern and CK levels were moderately elevated.


Neurology_Adams

Neurology_Adams. In recent years, the classification and relationships of the congenital muscular dystrophies have been clarified to some extent by a number of genetic studies (see Table 48-4). Remarkably, the major congenital muscular dystrophies share an important biologic attribute: each involves either an abnormality of a protein that binds to the dystrophin complex (e.g., laminin a2 or merosin) or an abnormality of a protein in the Golgi apparatus that is important in processing proteins (such as the dystroglycans and sarcoglycans) that interact with the dystrophin complex (see Figs. 45-2 and 45-3).


Neurology_Adams

Neurology_Adams. The most frequent congenital dystrophy in the white population is the “Occidental” type, so called because it is characterized exclusively by muscle involvement. There are only occasionally abnormal white matter signals on MRI. Tomé and colleagues showed that in approximately 50 percent of such patients, merosin is completely absent (“merosin-negative” cases). Merosin, the predominant isoform of a-laminin in the basement membrane of the muscle fiber, is closely bound to alpha-dystroglycan, which in turn is bound to the dystrophin cytoskeleton (see Fig. 45-2). An absence of merosin interrupts this linkage and leads to muscle degeneration. The diagnosis of merosin deficiency can be made prenatally by immunostaining chorionic villi cells, and postnatally by staining skeletal muscle biopsy material. In most cases that are merosin deficient, the disorder is genetically linked to the merosin (laminin a2) gene that either alters or prevents expression of the protein. An additional member of


Neurology_Adams

Neurology_Adams. In most cases that are merosin deficient, the disorder is genetically linked to the merosin (laminin a2) gene that either alters or prevents expression of the protein. An additional member of the group of merosin-positive congenital muscular dystrophies is termed rigid spine syndrome (RSS). The term first proposed by Dubowitz and the clinical syndrome, as outlined by Flanigan and coworkers, consists of (1) infantile hypotonia with early weakness of neck muscles and poor head control; (2) stabilization with only slight decrease in muscle strength but marked loss of muscle bulk; (3) prominent contractures of spinal muscles resulting in scoliosis and rigidity in flexion and, to a lesser extent, contractures of limb joints; (4) respiratory insufficiency with onset before adolescence; and (5) normality of intellectual and cardiac function. This unusual CMD with RSS (CMD-RSS) arises from mutations in a gene encoding a so-called selenoprotein.


Neurology_Adams

Neurology_Adams. In the Fukuyama type of CMD, as noted previously, fukutin is one of 5 genes whose mutations alter protein glycosylation, deranging function of both muscle and brain. Thus, the genes for MEB and the Walker-Warburg syndrome are also glycosyltransferases (respectively, POMGnT1 and POMT1), as is the aforementioned fukutin-related peptide. It has been shown that another form of CMD follows mutations of another glycosylation gene (known as LARGE).


Neurology_Adams

Neurology_Adams. The field of chronic and congenital myopathies has been muddied by a plethora of reports describing curious inclusions in muscle fibers under a bewildering array of terms: myopathy with inclusion bodies, atypical myopathy with myofibrillar aggregates; cytoplasmic body myopathy; spheroid body myopathy; myopathy with characteristic sarcoplasmic bodies and skeleton (desmin) filaments; and others. Implied by these reports is the notion that each of these structural abnormalities represented a new and distinctive myopathy. More recently, in a careful light microscopic evaluation of published reports and their own cases, Nonaka and Engel and Ozawa and their colleagues have demonstrated that most of these changes are the consequence of a single pathologic process, a focal dissolution of myofibrils, followed by an accumulation of degradative products. These authors proposed the term myofibrillar myopathy to encompass the entire spectrum of these pathologic changes. Most authorities now


Neurology_Adams

Neurology_Adams. followed by an accumulation of degradative products. These authors proposed the term myofibrillar myopathy to encompass the entire spectrum of these pathologic changes. Most authorities now consider this to be a muscular dystrophy because mutations have been found in genes for several muscle constituent proteins.


Neurology_Adams

Neurology_Adams. Mutations of one of the proteins that relate to the Z-disc (the connection between adjacent sarcomeres, which are the structural units of the myofibril) of muscle are the unifying feature. Some of these abnormalities can be traced to a dominant mutation in the genes coding for the filament proteins myotilin, also implicated in one of the limb-girdle dystrophies, in desmin, and in the chaperone protein ab-crystallin, as described in the review by Selcen and colleagues. Presumably, mutations in either gene predispose to protein aggregation, the former by destabilizing desmin and the latter by altering the capacity of the ab-crystallin to facilitate normal desmin folding.


Neurology_Adams

Neurology_Adams. The diagnosis of myofibrillar myopathy is usually made in adult life by muscle biopsy. Men and women are equally affected. Slowly progressive weakness of the muscles of limbs and trunk is the main clinical feature. Both proximal and distal muscles are affected, more in the legs than in the arms. Hyporeflexia is usual. Cardiac involvement, usually abnormalities of conduction, is present in approximately 25 percent of the patients. The pattern of inheritance is most often autosomal dominant, but autosomal recessive and X-linked patterns also have been described. An astonishing 63 patients were studied by Selcen and associates; their article can be consulted for further details. Genetically there is considerable heterogeneity. At the time of writing, several chromosomal loci for myofibrillar myopathy have been documented (desmin, myotilin, ZASP, ab-crystallin, BAG3, filamin C, DNAJB6, TNP03) and more are likely to exist (Engel and Franzini-Armstrong).


Neurology_Adams

Neurology_Adams. Problems in Diagnosis of the Muscular Dystrophies The following are some of the common problems that arise in the diagnosis of muscular dystrophy: 1. The diagnosis of muscular dystrophy in a child who has just begun to walk or in whom walking is delayed. Tests of peak power on command cannot be used with reliability in small children. The most helpful points in identifying Duchenne dystrophy are (1) unusual difficulty in climbing stairs or arising from a crouch or from a recumbent position on the floor, showing greater weakness at the hips and knees than at the ankles; (2) unusually large, firm calves; (3) male sex; (4) high serum CK, aldolase, and myoglobin levels; (5) myopathic EMG; (6) biopsy findings; and (7) special methods of testing for dystrophin protein (see previous discussion).


Neurology_Adams

Neurology_Adams. 2. The adult patient with diffuse or proximal muscle weakness of several months’ duration, raising the question of polymyositis versus dystrophy. Even biopsy may be misleading in showing a few inflammatory foci in an otherwise dystrophic picture. As a rule, polymyositis evolves more rapidly than dystrophy. It may be associated with higher CK and aldolase values than most of the dystrophies except the Duchenne and distal Miyoshi types. With these points in mind, if immunostaining of a muscle biopsy fails to reveal the diagnosis of a dystrophy, there may still be uncertainty, in which instance a trial of prednisone may be indicated for a period of 6 months. Unmistakable improvement favors polymyositis; questionable improvement (physician’s and patient’s judgment not in accord) leaves the diagnosis unsettled but suggests inclusion of body myositis or a dystrophy. Pompe disease, a treatable metabolic glycogen storage myopathy discussed elsewhere in this chapter, may simulate Becker or


Neurology_Adams

Neurology_Adams. diagnosis unsettled but suggests inclusion of body myositis or a dystrophy. Pompe disease, a treatable metabolic glycogen storage myopathy discussed elsewhere in this chapter, may simulate Becker or limb-girdle dystrophy in an adult or child. Clues to the diagnosis are early respiratory involvement, myotonic or pseudomyotonic discharges in the EMG. Muscle biopsy with immunohistochemistry establishes the diagnosis, but the standard stains may be unrevealing.


Neurology_Adams

Neurology_Adams. 3. An adult with a very slowly evolving proximal weakness. In addition to facioscapular and limb-girdle dystrophies, myositis and inclusion body myopathy, several of the congenital polymyopathies may begin to cause symptoms or to worsen in adult years. These include central core and nemaline myopathy. Examples have been reported in the adult of mild forms of acid maltase or debrancher enzyme deficiency with glycogenosis, progressive late-stage hypokalemic polymyopathy, mitochondrial myopathy, the abovementioned Pompe disease, and carnitine myopathy. Muscle biopsy and histochemical staining of the muscle usually provide the correct diagnosis.


Neurology_Adams

Neurology_Adams. 4. The occurrence of subacute or chronic symmetrical proximal weakness in a child or adolescent that raises the question of spinal muscular atrophy as well as of polymyositis and muscular dystrophy. EMG and muscle biopsy settle the matter by distinguishing neuropathic from myopathic changes. Some of the same problems arise in an adult with distal dystrophy.


Neurology_Adams

Neurology_Adams. 5. Weakness of a shoulder or one leg with increasing atrophy. This is usually a result of a radiculopathy or mononeuritis, the beginning of motor system disease (progressive spinal muscular atrophy), but rarely may be the early stage of a muscular dystrophy. The first two diseases may develop silently, in mild form, and attract notice only when wasting begins (denervation atrophy takes 3 to 4 months to reach its peak). Points in favor of these acquired diseases are (1) acute or subacute onset and pain; (2) confinement of the disease to muscles originally affected and sparing of other muscles; and (3) an EMG showing denervation effects. Facioscapulohumeral dystrophy may begin with asymmetrical shoulder weakness. Biopsy is seldom performed under such circumstances, because, by temporizing, the problem eventually settles itself. Invariably muscle dystrophy becomes bilateral and symmetrical; mononeuritis stabilizes or recovers; motor neuron disease declares itself by the presence of


Neurology_Adams

Neurology_Adams. the problem eventually settles itself. Invariably muscle dystrophy becomes bilateral and symmetrical; mononeuritis stabilizes or recovers; motor neuron disease declares itself by the presence of fasciculations and relatively rapid progression of weakness.


Neurology_Adams

Neurology_Adams. 6. The distinctions, in the child or adolescent, between dystrophy and one of the congenital or metabolic myopathies are considered later in this chapter. Treatment of the Muscular Dystrophies There has, until recently, been no specific treatment for any of the muscular dystrophies. The physician is forced to stand by and witness the unrelenting progression of weakness and wasting. The various vitamins, amino acids, testosterone, and drugs, such as penicillamine, recommended in the past, have all proved to be ineffective. The administration of prednisone appears to slightly retard the tempo of progression of Duchenne dystrophy for a period of up to 3 years (Fenichel et al). The optimal dose is 0.75 mg/kg given daily, but it must often be reduced because of intolerable side effects (weight gain, behavioral and gastrointestinal disorders).


Neurology_Adams

Neurology_Adams. In recent years, there has been interest in three novel approaches to treatment of Duchenne dystrophy in particular. One is the injection of human myoblasts, stem cells, or satellite cells that contain a full complement of dystrophin and other structural elements into the muscles of patients with muscular dystrophy. The preclinical aspects of this strategy have been summarized by Blau and are being slowly implemented in patients. There is an analogous effort to use the technology of viral-mediated gene delivery to allow gene and protein replacement in the recessively inherited dystrophies. The difficulties of injecting every dystrophic muscle are obvious.


Neurology_Adams

Neurology_Adams. With another remarkable approach, it has been possible to cause the skipping of selected exons during splicing of pre-mRNA and to correct the open reading frame in mutated dystrophin. For example, van Deutekom and colleagues have been able to elicit expression of normal dystrophin in the anterior tibialis at the site of injection of an antisense oligonucleotide that promotes the exon skipping. The same oligonucleotide administered subcutaneously for 5 weeks was shown by Goermans and coworkers to produce dystrophin expression and modestly improve the ability of patients to accomplish a standardized 6-min walk test.


Neurology_Adams

Neurology_Adams. Respiratory failure occurs in virtually all patients affected with Duchenne dystrophy after they become wheelchair-bound, as well as in some of the other dystrophic diseases. It may be so insidious as to become evident only as sleep apnea, as retention of carbon dioxide that causes morning headache, or as progressive weight loss that reflects the excessive work of breathing. If there are frequent episodes of oxygen desaturation, some improvement in daytime strength and alertness can be attained by assisting ventilation at night. This may be accomplished in the early stages of disease by a negative-pressure cuirass-type of device that expands the chest wall periodically or, more conveniently, by nasal-positive pressure (NIPPV [noninvasive positive-pressure ventilation] or BiPAP [bilevel positive airway pressure]). Later, positive-pressure ventilation through a fenestrated tracheostomy is required that allows nighttime ventilation but leaves the patient free to speak and breathe during


Neurology_Adams

Neurology_Adams. airway pressure]). Later, positive-pressure ventilation through a fenestrated tracheostomy is required that allows nighttime ventilation but leaves the patient free to speak and breathe during the day. With regard to earlier or anticipatory treatment, in patients free of respiratory failure with vital capacities between 20 and 50 percent of predicted values, a randomized trial of nasal mechanical ventilation failed to demonstrate improvement or prolonged survival (Raphael et al). There has been a clinical impression that even more severely affected patients can be managed at home for prolonged periods with respiratory assistance. Needless to say, the common complications of muscular dystrophy—pulmonary infections and cardiac decompensation—must be treated symptomatically. Surgical management of cataracts is indicated when they become mature.


Neurology_Adams

Neurology_Adams. As noted earlier, a vital element in the care of patients with certain of the dystrophies is monitoring for early evidence cardiac arrhythmias. In disorders such as myotonic dystrophy, Emery-Dreifuss dystrophy, the myofibrillar myopathies, and some of the mitochondrial disorders, it is imperative that cardiac status should be evaluated on a regular basis (typically yearly) with ECG and echocardiography and periodically with 24-h rhythm monitoring if the ECG is abnormal or the patient reports episodic symptoms referable to an arrhythmia such as lightheadedness, palpitations, or dyspnea. The timely use of cardiac pacemakers or defibrillators, implemented at the earliest sign of arrhythmia or prophylactically, is often needed in this patient population to reduce the chance of sudden death.


Neurology_Adams

Neurology_Adams. Mexiletine has been shown to reduce myotonia, especially in DM2 and the nondystrophic myotonias as demonstrated in the trial reported by Statland and coworkers but, like quinine that caused rare cardiac arrhythmias, is also now out of favor by some clinicians. Further discussion of myotonia and its treatment can be found in Chap. 46. Testosterone has been found to increase muscle mass in patients with myotonic dystrophy, but was of no value in preserving strength or lessening myotonia (Griggs et al, 1989).


Neurology_Adams

Neurology_Adams. Vignos, who reviewed the studies that evaluated muscle-strengthening exercises, has offered evidence that maximal resistance exercises, if begun early, can strengthen muscles in Duchenne, limb-girdle, and facioscapulohumeral dystrophies. In the study he conducted, none of the muscles was weaker at the end of a year than at the beginning. Cardiorespiratory function after endurance exercise was not significantly improved. Contractures were reduced by passive stretching of the muscles 20 to 30 times a day and by splinting at night. If contractures have already formed, fasciotomy and tendon lengthening are indicated in patients who are still ambulating, but this is not recommended early in the course of the disease. Maintenance of ambulation and upright posture will delay scoliosis. In general, preventive measures are more successful than restorative ones.


Neurology_Adams

Neurology_Adams. From such observations it may be concluded that 2 factors are of importance in the management of patients with muscular dystrophy: avoiding prolonged bed rest and encouraging the patient to maintain as full and normal a life as possible. These help prevent the rapid worsening associated with inactivity and conserve a healthy attitude of mind. Obesity should be avoided; this requires careful attention to diet. Swimming is a useful exercise. Massage and electrical stimulation are probably worthless. The education of children with muscular dystrophy should continue, with the aim of preparing them for a sedentary occupation. Prevention by prenatal counseling is available for most dystrophies, but proper diagnosis is essential. Special centers provide the genetic and psychological services necessary to carry this out properly.


Neurology_Adams

Neurology_Adams. Two main classes of metabolic diseases of muscle are recognized—one is traceable to a primary, or hereditary, metabolic abnormality of the muscle itself; another in which the myopathy is secondary to a disorder of endocrine function, that is, to disease of the thyroid, parathyroid, pituitary, or adrenal gland. Yet a third group of myopathies is the result of a large variety of myotoxic drugs and other chemical agents; they are addressed separately. The hereditary metabolic myopathies are of special interest because they reveal certain aspects of the complex chemistry of muscle fibers. Indeed, each year brings to light some new genetically determined enzymopathy of muscle. As a consequence, a number of diseases formerly classified as dystrophic or degenerative have been added to the enlarging list of metabolic myopathies. There are now so many of them that only the most representative can be presented in a textbook of neurology. The Nature of Primary Metabolic Myopathies


Neurology_Adams

Neurology_Adams. The Nature of Primary Metabolic Myopathies The chemical energy for muscle contraction is provided by the hydrolysis of adenosine triphosphate (ATP) to adenosine diphosphate (ADP); ATP is restored by phosphocreatine and ADP acting in combination. These reactions are particularly important during brief, high-intensity exercise. During periods of prolonged muscle activity, rephosphorylation requires the availability of carbohydrates, fatty acids, and ketones, which are catabolized in mitochondria. Glycogen is the main sarcoplasmic source of carbohydrate, but blood glucose also moves freely in and out of muscle cells as needed during sustained exercise. The fatty acids in the blood, derived mainly from adipose tissue and intracellular lipid stores, constitute the other major source of energy. Carbohydrate is metabolized during aerobic and anaerobic phases of metabolism; the fatty acids are metabolized only aerobically.


Neurology_Adams

Neurology_Adams. Resting muscle derives approximately 70 percent of its energy from the oxidation of long-chain fatty acids. As stated earlier, the circumstances during exercise are somewhat different. During a short period of intense exercise, the muscle uses carbohydrate derived from glycogen stores; myophosphorylase is the enzyme that initiates the metabolism of glycogen. With longer aerobic exercise, blood flow to muscle and the availability of glucose and fatty acids are increased. At first, glucose is the main source of energy during exercise; later, with exhaustion of glycogen stores, energy is provided by oxidation of fatty acids. Thus, muscle failure at a certain phase of exercise is predictive of the type of energy failure. A rising blood concentration of β-hydroxybutyrate reflects the increasing oxidation of fatty acids, and an increase in blood lactate reflects the anaerobic metabolism of glucose. The cytochrome oxidative mechanisms are essential in both aerobic and anaerobic muscle


Neurology_Adams

Neurology_Adams. oxidation of fatty acids, and an increase in blood lactate reflects the anaerobic metabolism of glucose. The cytochrome oxidative mechanisms are essential in both aerobic and anaerobic muscle metabolism; these mechanisms are considered in Chap. 36 in relation to the mitochondrial diseases in which muscle tissue is prominently involved, and they are referred to here only briefly.


Neurology_Adams

Neurology_Adams. It follows from these observations that the efficiency and endurance of muscular contraction depend on a constant supply of glycogen, glucose, and fatty acids, and on the adequacy of the enzymes committed to their metabolism. Biochemical derangements in the storage, breakdown, or utilization of these substrates give rise to a large number of muscle disorders, the most important of which are elaborated in the following pages. An abnormal accumulation of glycogen in the liver and kidneys was described by von Gierke in 1929; shortly thereafter, Pompe (1932) reported a similar disorder involving cardiac and skeletal muscle. Major contributions to our understanding of glycogen metabolism were made by McArdle, by Cori and Cori, and by Hers, who discovered the deficiency of acid maltase in Pompe disease and enunciated the concept of inborn lysosomal diseases (see


Neurology_Adams

Neurology_Adams. Chap. 36). Since then, many nonlysosomal enzyme deficiencies of muscle and other organs have been identified and have become the basis of the classification presented in Table 48-5. These enzymatic deficiencies alter the metabolism of many cells, but most strikingly those of the liver, heart, and skeletal muscle. In about half of affected individuals, a chronically progressive or intermittent myopathic syndrome is the major manifestation of the disease. It is a curious fact, that with the exception of the rare phosphoglycerate kinase deficiency (X-linked recessive inheritance), all the glycogenoses are inherited as autosomal recessive traits. The most impressive and common of these glycogen storage diseases from the standpoint of the clinical neurologist are 1,4-glucosidase (acid maltase) and myophosphorylase deficiencies. Acid Maltase Deficiency (Glycogenosis Type II; Pompe Disease and Related Disorders, GAA Mutation)


Neurology_Adams

Neurology_Adams. A deficiency of the enzyme acid maltase (also called acid alpha-glucosidase and due to mutations in the GAA gene) takes three clinical forms, of which the first (Pompe disease) is the most serious. Pompe disease typically develops in infancy, between 2 and 6 months; dyspnea and cyanosis call attention to enlargement of the heart, and the liver may be enlarged as well. The skeletal muscles are weak and hypotonic, although their bulk may be increased. The tongue may be enlarged, giving the infant a cretinoid appearance. Hepatomegaly, while often present, is not pronounced. Exceptionally, the heart is normal in size and the CNS and muscles bear the brunt of the disorder. The clinical picture then resembles infantile spinal muscular atrophy (Werdnig-Hoffmann disease) and, to add to difficulty in differential diagnosis, there may be fasciculations. The infantile disease is rapidly progressive and ends fatally in a few months. The EMG shows myopathic changes, but there are, in addition,


Neurology_Adams

Neurology_Adams. in differential diagnosis, there may be fasciculations. The infantile disease is rapidly progressive and ends fatally in a few months. The EMG shows myopathic changes, but there are, in addition, fibrillation potentials, heightened insertional activity, and pseudomyotonia. Large amounts of glycogen accumulate in muscle, heart, liver, and neurons of the spinal cord and brain. All tissues lack acid maltase (also called alpha-glucosidase) because of a mutation in its gene.


Neurology_Adams

Neurology_Adams. In the second (childhood) form, onset is during the second year, with delay in walking and slowly progressive weakness of shoulder, pelvic girdle, and trunk muscles. The toe walking, waddling gait, enlargement of calf muscles, and lumbar lordosis resemble those of Duchenne dystrophy. Cardiomyopathy is exceptional, hepatomegaly is less frequent than in the infantile form, and developmental delay is present in a minority. Death occurs between 3 and 24 years of age, usually from ventilatory failure and recurrent pulmonary infections.


Neurology_Adams

Neurology_Adams. In the third, or adult, form there is a more benign truncal and proximal limb myopathy that is slowly progressive over many years and death is usually the result of weakness of respiratory muscles. At times, the only severe weakness is of the diaphragm, as in the case reported by Sivak and colleagues, making adult acid maltase deficiency part of a select group of neuromuscular disorders that may present in this way (along with motor neuron disease, nemaline myopathy, and myasthenia gravis). The liver and heart are not enlarged. CK values can be normal or slightly increased. The EMG discloses a number of abnormalities—brief motor unit potentials, fibrillation potentials, positive waves, bizarre high-frequency discharges, and occasional myotonic discharges (without clinical evidence of myotonia). The disease must be differentiated from other chronic adult myopathies, including polymyositis and the endocrine myopathies, and from motor neuron disease.


Neurology_Adams

Neurology_Adams. Aside from the elevation of the muscle-derived enzymes CK and of aldolase, blood studies are normal. A simply implemented dried blood spot screening test for alpha-glucosidase has been developed and, if it shows that there is no enzyme detectable, a biopsy can be omitted and the clinician can proceed to genetic testing. This screening test is particularly important in babies with suspected disease, as they are susceptible to general anesthesia that may be used to accomplish a biopsy.