Congenital Myopathies

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The initial definition of the so-called congenital myopathies implied the onset at birth of a nonprogressive primary myopathy, that could not be explained on the basis of a dystrophic or metabolic abnormality. However, in some morphologically and genetically identical cases, no symptoms are not present at birth and instead occur later. Furthermore, some cases of congenital myopathies such as nemaline myopathy and centronuclear myopathy are characterized by progressive weakness with a fatal outcome. The assumption that all of these congenital myopathies had no metabolic basis reflected ignorance about their etiology. The various congenital myopathies continue to be diagnosed in most instances on the basis of their morphological characteristics as seen on muscle biopsy. For some of these diseases, there is a large body of literature defining a clear phenotype, but others have been described in only one or two case reports, and the specificity of the morphological changes described and their validity as a disease entity must remain doubtful. The recent descriptions of the gene lesion for most of the disorders are rapidly changing the classification of these conditions. All of the congenital myopathies are rare, with an incidence of less than 1 per 100,000.

Since many of the congenital myopathies have a similar clinical picture, their differential diagnosis, evaluation, and management are also similar. The specific distinguishing clinical features of the individual congenital myopathies are described. Although the diagnostic label of congenital myopathy has historically implied that muscle weakness is present at birth, there are several exceptions. Presentation may occur in utero with reduced fetal movements, and there may be a delayed second stage of labor. Additionally, a higher incidence of assisted delivery with its consequent complications resulting from fetal hypotonia is reported. The commonest presentation in these disorders is a floppy baby who has delayed motor milestones. In school, these individuals usually have difficulty in keeping up with their peers, either in sports or simply in walking. Some patients may present in later childhood or even as adults. Early weakness usually becomes manifest as difficulty in rising from a chair or the floor and in climbing stairs. In some patients with congenital myopathies, facial weakness or ophthalmoplegia is seen. In those in whom the disease has an early onset, the muscle weakness can lead to skeletal defects, causing dysmorphic features, kyphoscoliosis, and pes cavus. Diaphragmatic or chest wall involvement can give rise to respiratory weakness with carbon dioxide retention, particularly at night, causing morning headaches or daytime somnolence. Such respiratory weakness is usually a late feature of the congenital myopathies, but in nemaline myopathy it occurs early. As a rule, the congenital myopathies are stable or only slowly progressive, and many patients are remarkably active despite their weakness.

NEMALINE MYOPATHY

This particular congenital myopathy is defined by the presence of rods in the muscle biopsy. These structures stain red using Gomori trichrome stain, and it is their threadlike appearance that gives this condition its name, nema being Greek for thread. Electron microscopy shows that the rods represent an abnormal deposition of Z-band material. The cause of this and its relevance to the subsequent development of nemaline myopathy are unknown. Rods are not exclusive to nemaline myopathy and can be seen in other muscle disorders, including polymyositis, human immunodeficiency virus (HIV)-related myopathy, and muscle injured by tenotomy. Nemaline myopathy occurs sporadically quite often, but autosomal dominant inheritance linked to chromosome 1q (alpha tropomyosin), y and autosomal recessive cases linked to chromosome 2qy have been demonstrated.

The usual clinical picture of nemaline myopathy is one of mild and progressive myopathy present from birth; however, some individuals are more severely affected, and early death is associated. In addition, some patients with adult-onset disease appear to have profuse rods on muscle biopsy but lack the usual clinical phenotype. Typical clinical signs include generalized reduction of muscle bulk, generalized limb weakness, and mild facial weakness but no ocular signs. Cardiac involvement is unusual. The facial appearance is characteristic and is marked by a high arched palate and a long thin face. Respiratory failure, due to involvement of the diaphragm, is an early feature that can have a major impact on the prognosis.

MYOTUBULAR-CENTRONUCLEAR MYOPATHY

The key morphological abnormality in this disorder is the presence of central nuclei, which occupy between 25

and 80 percent of the muscle fibers, more often the type 1 fibers. A halo around the central nuclei is often present, which shows increased oxidative enzyme activity, and glycogen staining, but reduced amounts of ATPase staining. The original term, myotubular myopathy, was based on the resemblance of these morphological abnormalities to that of myotubes. The later and preferred term of centronuclear myopathy is more descriptive and avoids assumptions about the cause of the abnormality. Because of the resemblance to myotubes, the findings in this disorder were thought to represent a maturational arrest with failure of the normal peripheral migration of nuclei during differentiation. However, the morphological similarities of this disorder to myotubes are only superficial, and central nuclei can appear after infancy. Many of these cases are hereditary, and autosomal recessive, autosomal dominant, and X-linked varieties have been described. The X-linked variety has been linked to chromosome Xq28 (myotubularin). U

Prominent ptosis and ophthalmoplegia distinguish this disease from the other congenital myopathies. Cardiac involvement is not common. A variety of skeletal malformations occur, resulting in a Marfanoid habitus with a long narrow face and a high arched palate. A more severe X-linked variety that has an in utero and neonatal presentation is recognized. These patients have severe generalized weakness with bulbar and respiratory involvement but less ptosis and ophthalmoparesis.y With intensive initial support, some improvement may occur, but these patients remain severely disabled and are prone to sudden death from aspiration. A late childhood or adult-onset variant is also seen; these patients present with mild limb weakness without ptosis, ophthalmoparesis, or dysmorphic features.

CENTRAL CORE DISEASE

The key morphological abnormality in this disorder is the presence of central or eccentric cores that do not stain for glycogen or oxidative enzymes but sometimes do stain with ATPase. The cores have a predilection for type 1 muscle fibers, which are the predominant fiber type on biopsy. The cause is unknown. The resemblance of the cores to the target fibers, seen in denervating muscle, suggests that central core disease may be a disorder of innervation, but unlike the targets, cores run the whole length of the fiber. The disease is inherited in an autosomal dominant fashion or is occasionally sporadic. This disease may be allelic because malignant hyperthermia also has point mutations of the ryanodine receptor on chromosome 19q13.1. y , y

Distinguishing features are the lack of cranial involvement apart from an occasional mild facial weakness, the frequency of congenital dislocation of the hip, and the occasional coexistence of malignant hyperthermia. As in patients with malignant hyperthermia, anesthetic precautions are required.

OTHER CONGENITAL MYOPATHIES

A variety of other morphological abnormalities have been described in cases marked by a presentation typical of congenital myopathy, and they have names to match--minicore, multicore, finger print body, zebra body, sarcotubular, and hyaline body myopathies. There are too few case reports of these myopathies to be sure that they are necessarily distinct myopathies or to discern a distinct phenotype.

CONGENITAL FIBER-TYPE DISPROPORTION

There is considerable doubt about whether this entity represents a distinct type of congenital myopathy. The description of congenital fiber-type disproportion arose from a survey of congenital myopathies by Brooke, who found several patients in whom the type 1 fibers were at least 12 percent smaller than type 2 fibers. y This was an isolated finding in some cases, while in others it coexisted with other more striking pathological abnormalities. Later work suggested that the pathological criteria should be refined to include the requirement that type 2 fibers be of normal or increased size to distinguish this disorder from mild spinal muscular atrophy. y

Initially, it was suggested that these pathological appearances had some prognostic value in that all the patients in Brooke's original series showed no progression of muscle weakness after 2 years of age, and some even improved. This has not been borne out by subsequent studies. No specific pathophysiological explanation has been advanced for the pathological picture, and there is no genetic marker for it.

Differential Diagnosis. The differential diagnosis of all congenital myopathies involves the evaluation of a floppy infant. There are a wide range of causes of this condition, most of which are central or neurogenic rather than myopathic. The neurogenic causes are usually central, although hereditary neuropathies causing dysmyelination or hypomyelination as well as anterior horn disease (i.e., spinal muscular atrophy) may also present with the appearance of a floppy baby. Central nervous system disorders may be marked by upper motor neuron features, seizures, or intellectual impairment, but recognition of some of these features may be difficult. Among the myopathic causes, a distinction should be made between the congenital muscular dystrophies, congenital myotonic dystrophy, congenital myasthenia (see later discussion), and the metabolic myopathies.

Evaluation. Creatine kinase levels are normal or only mildly elevated in patients with the congenital myopathies. Neurophysiological studies are useful in excluding the neuropathies and myasthenias. In the congenital myopathies, nerve conduction studies are normal, and the EMG may show only mild, nonspecific myopathic features. Definitive diagnosis of a congenital myopathy rests on the morphological characteristics seen on muscle biopsy. These morphological abnormalities must be present in substantially increased numbers to make the diagnosis. Any of the pathological findings may be nonspecific findings in other neuromuscular disorders. In some cases of congenital myopathy, the muscle biopsy may show only minor nonspecific myopathic features. This may reflect a selectivity of muscle involvement, and when other causes have been excluded, a label of "nonspecific congenital myopathy" may be applied.

Management. There is no specific treatment for any of the congenital myopathies. The association of central core disease with malignant hyperthermia makes it prudent to avoid precipitating factors such as the volatile gases used in general anesthesia. Otherwise, management of patients with the congenital myopathies is supportive, and particular regard should be paid to the prevention of secondary complications such as contractures and progressive kyphoscoliosis. Bracing may be an effective means of maintaining ambulation but is usually unsatisfactory. Respiratory and cardiac function should be regularly assessed and appropriate support given.

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