Myopathy, Spheroid Body

A number sign (#) is used with this entry because spheroid body myopathy is caused by heterozygous mutation in the myotilin gene (MYOT; 604103) on chromosome 5q31.

Myofibrillar myopathy-3 (MFM3; 609200) is an allelic disorder with overlapping features.

Description

Spheroid body myopathy is a form of myofibrillar myopathy (MFM). Myofibrillar myopathy refers to a genetically heterogeneous group of muscular disorders characterized by a pathologic morphologic pattern of myofibrillar degradation and abnormal accumulation of proteins involved with the sarcomeric Z disc (summary by Foroud et al., 2005).

For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419).

Clinical Features

Goebel et al. (1978) described a family from Indiana in which 15 members spanning 4 generations had a slowly progressive myopathy inherited in an autosomal dominant pattern. The disorder began in adolescence and proceeded to some motor incapacitation, but life span was not shortened. Muscle weakness was predominantly proximal, but some patients also had distal weakness. Skeletal muscle biopsy showed an accumulation of myofilamentous material within individual muscle fibers, which the authors termed 'spheroid bodies.' Most of the spheroid bodies were present in type 1 fibers and were devoid of enzyme activity. They were more common in the periphery of muscle fibers and were present as singles, multiples, and aggregates. Other skeletal muscle biopsy features included centralized nuclei, variation in fiber size, and occasional necrosis. Electron microscopy showed that the spheroid bodies were composed of fine filaments resembling a ball of twine; streaming of the Z disc was also observed. The pathologic changes were much more pronounced in biopsies from older patients compared to those from younger patients. Based on these distinct morphologic features, the authors suggested the term 'spheroid body myopathy,' and proposed a primary disturbance of contractile myofibrillar material.

Goebel et al. (1997) provided follow-up on the family reported by Goebel et al. (1978) and described a distantly related family from Oregon. Clinically, affected individuals from the Oregon family had a milder disease compared to those from the Indiana family. The Oregon family had onset in the third or fourth decade of life and usually had only mild muscle weakness. EMG findings were consistent with a myopathic disease process. However, skeletal muscle findings of spheroid bodies in the 2 families were strikingly similar. The spheroid bodies contained increased amounts of desmin (DES; 125660), alpha-beta crystallin (CRYAB; 123590), and ubiquitin (UBB; 191339), suggestive of a desminopathy.

Molecular Genetics

In 21 affected members of a large kindred with spheroid body myopathy reported by Goebel et al. (1978, 1997), Foroud et al. (2005) identified a heterozygous mutation in the TTID gene (S39F; 604103.0006). Although patients with spheroid body myopathy showed some overlapping clinical features with LGMD1A and myotilinopathy, Foroud et al. (2005) nevertheless concluded that there were enough clinical and pathologic differences to consider it a distinct disorder.