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).
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 consider this to be a muscular dystrophy because mutations have been found in genes for several muscle constituent proteins.
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.
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).
Problems in Diagnosis of the Muscular Dystrophies