Myofibrillar myopathies

Abstract

Purpose of review: The aim of this communication is to provide an up-to-date overview of myofibrillar myopathies.

Recent findings: The most important recent advance in the myofibrillar myopathies has been the discovery that mutations in Z band alternatively spliced PDZ-containing protein and filamin C, as well as in desmin, alphaB-crystallin and myotilin, result in similar pathologic alterations in skeletal muscle that are typical of myofibrillar myopathy. Despite the increasing genetic heterogeneity, the clinical and morphologic phenotypes are remarkably homogeneous. The typical clinical manifestation is slowly progressive proximal, distal or both proximal and distal limb muscle weakness. Cardiomyopathy can be associated and is sometimes the presenting finding. Peripheral neuropathy also occurs in some patients. In every myofibrillar myopathy, there is abnormal accumulation of an array of proteins at ectopic sites as well as accumulation of degraded myofibrillar proteins forming large aggregates. The key issue now is to analyze the molecular mechanisms underlying the cascade of events that destroy the myofibrillar architecture and trigger the aberrant expression of multiple proteins.

Summary: Several disease genes have recently been recognized in myofibrillar myopathies. So far, the disease proteins identified are components of or chaperone for the Z-disk. In each case, the molecular defect leads to a stereotyped cascade of structural events in the muscle fiber.

Figure 1

Sections from nonconsecutive sections from a patient with Bag3opathy. Sections (A), (B) and (C) are from the same series. Many abnormal fibers in trichrome section (A) show abnormal accumulation of Bag3 (B), αB-crystallin (C) and heat shock protein 27 (D).