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 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.
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).
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 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.