The outstanding pathologic features of the disease are the smallness of muscles and their constituent fibers and central nucleation. In one group of centronuclear myopathies, there is hypotrophy of type 1 fibers (Bethlem et al; Karpati et al). Surrounding most of the centrally placed nuclei is a clear zone, in which there is a lack of organization of contractile elements. Because of central nucleation, the disease has incorrectly been referred to as myotubular myopathy, implying an arrest in development of muscle at the myotubular stage. Actually, the nature of the pathologic process is obscure. The small, centrally nucleated fibers do not really resemble typical myotubes. There is evidence from electron microscopic studies of changes in the central parts of the fibers (lack of enzymatic activity in the clear zones surrounding the nuclei), leading in all probability to fiber loss. Such changes argue against a purely developmental abnormality.
The accumulation of tubular aggregates in the subsarcolemmal or more interior regions of muscle fibers was first observed in patients with hypokalemic periodic paralysis and myotonia congenita, and later with a number of diverse conditions, such as chronic drug intoxication, hypoxia, and congenital myasthenic syndromes. However, tubular aggregates are also the defining feature of several rare and purely myopathic syndromes: (1) a slowly progressive muscular weakness, in a limb-girdle distribution, with onset in childhood or early adult life; inheritance is either autosomal dominant or recessive in type; (2) a childhood onset of proximal weakness, easy fatigability, and myasthenic features; heredity is autosomal recessive. This syndrome may respond to pyridostigmine; and (3) muscle pain, cramps, and stiffness induced by exercise; the cases to date have been sporadic.
The histologic changes are readily overlooked in paraffin sections. Frozen sections show masses of material that is basophilic with hematoxylin and eosin and bright red with Gomori trichrome and shows an intense reaction with reduced form of nicotinamide adenine dinucleotide (NADH) dehydrogenase. By electron microscopy, the bundles of tubular aggregates are sharply demarcated from myofibrils.
The foregoing congenital myopathies—central core, nemaline, centronuclear, and tubular aggregate types—are fairly well-defined clinicopathologic entities. Other less common types have been described, each named according to a distinctive morphologic alteration of organelles in muscle fibers in histochemical and electron microscopic preparations. In none of these additional types has the pattern of inheritance or the gene locus been identified. Some of these myopathies (multicore [minicore], fingerprint body, sarcotubular) have been reported in only a few cases, quite insufficient to allow their categorization as disease entities. Two other types, congenital fiber type disproportion and congenital fiber type predominance, originally designated as congenital myopathies, have proved to be nonspecific histochemical alterations observed in many infants and children with congenital developmental abnormalities, delays in motor development, and other conditions. Other putative congenital myopathies include so-called reducing body, trilaminar, and cap disease; zebra body; and familial myopathy with lysis in type 1 fibers, among others. They most likely also represent nonspecific reactions in muscle or fixation artifacts; as yet there is no evidence that any one of them represents a clinicopathologic entity.
This entity, more a group of myopathies, was formerly included among the congenital myopathies but now clearly belongs in the category of dystrophies and is discussed in an earlier section on that class of diseases.
As stated in the introductory section, there is currently no treatment for any of the congenital myopathies.
THE SPINAL MUSCULAR ATROPHIES OF INFANCY AND CHILDHOOD (SEE CHAP. 38)