CONGENITAL MYOPATHIES

The term congenital myopathy is used to describe a group of heterogeneous disorders usually presenting with infantile hypotonia due to genetic defects causing primary myopathies with the absence of any structural abnormality of the CNS or peripheral nerves and a specific diagnosis of each entity is made on the basis of specific histologic and electron microscopic changes found on muscle biopsy. While patients may be hypotonic during early infancy, they later develop muscle weakness that is generally nonprogressive and static. The weakness is predominantly proximal, symmetric, and in a limb girdle distribution.

The serum CK values are frequently normal and the EMG may be normal or may show mild, nonspecific changes, usually of a myopathic character (small amplitude polyphasic potentials). The only congenital myopathy consistently associated with spontaneous activity is myotubular (centronuclear) myopathy. In this disorder, the EMG reveals myopathic motor unit action potentials with frequent complex repetitive discharges and diffuse fibrillation potentials. These myopathies may be considered primarily structural in nature and thus patients do not actively lose muscle fibers, as is the case in dystrophic myopathies.

Central Core Myopathy

This is an autosomal-dominant disorder with gene locus at 19ql3.1, the same gene locus as the malignant hyperthermia gene (ryanodine receptor gene, RYR1). Indeed, these patients have a high incidence of malignant hyperthermia with inhalational anesthetic agents. Histologically, the muscle fibers have amorphous-looking central areas within the muscle that may be devoid of enzyme activity. There are densely packed disorganized myofibrils ("cores") at the center of the majority of type 1 fibers. Electron microscopy shows the virtual absence of mitochondria and sarcoplasmic reticulum in the core region, reduced muscle enzymes (cytochrome oxidase, NADH), a marked reduction in the interfibrillary space and an irregular zigzag pattern (streaming) of the Z-lines. This gives rise to the characteristic central pallor. There is a predominance of high oxidative, low glycolytic type I fibers and a relative paucity of type II fibers resulting in a relative deficiency of glycolytic enzymes.

Clinically, patients generally demonstrate mild and relatively nonprogressive muscle weakness, either proximal or generalized, and areflexia which presents in either early infancy or later. There may be mild facial weakness, but normal extraocular movements. Patients often achieve gross motor milestones, such as walking, rather late and they continue having difficulty going upstairs. Proximal limb weakness is typical and patients may show a Gower's sign. The disorder remains fairly static over the years. There may be a frequent occurrence of congenital dislocation of the hip, kyphoscoliosis, and pes cavus. The condition is largely nonprogressive with affected children remaining ambulatory into adult life. One-third show anesthesia-related malignant hyperthermia. Central core myopathy and familial malignant hyperthermia appear to be allelic as the ryanodine receptor chain implicated in malignant hyperthermia has the same locus. Individuals within the same family can exhibit one or both phenotypes.

Nemaline Myopathy

Nemaline myopathy, also referred to as rod body myopathy, represents a varied group of disorders with different modes of inheritance, but the most typical form is autosomal recessive. While the rods may be easily overlooked on routine H&E staining, they can be rarely demonstrated with the Gomori trichrome stain. The rods are readily demonstrated on electron microscopy. They are thought to be an abnormal depositions of Z-band material of a protein nature and possibly alpha-actinin. The disease has been linked to at least seven distinct genes. The severe congenital form has been linked to a-Actin, Nebulin, and Troponin Tl mutations. A milder childhood form has been linked to a-Actin, Nebulin, a-tropomyosin 3 (TPM3), and P-tropomyosin (TPM2) mutations.

A severe form of the disease may present in the neonatal period with very severe weakness, respiratory insufficiency, and often a fatal outcome. Most cases present with a mild, nonprogressive myopathy with hypotonia and proximal weakness. In more severe cases, swallowing difficulty may be present in the neonatal period. Skeletal abnormalities, such as kyphoscoliosis, pigeon chest, pes cavus feet, high-arched palate, tent-shaped mouth, and an unusually long face has been noted. Cardiomyopathy has been described in both severe neonatal and milder forms of the disease. Autosomal-dominant inheritance has been described in a few instances.

 
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