Myopathy, Myofibrillar, 4

A number sign (#) is used with this entry because myofibrillar myopathy-4 (MFM4) is caused by heterozygous mutation in the ZASP gene (LDB3; 605906) on chromosome 10.

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

Clinical Features

Selcen and Engel (2005) reported 11 unrelated patients with MFM. Age at onset ranged from 44 to 73 years (mean, 54 years). All patients presented with muscle weakness except 1 who presented with palpitations and mildly increased serum creatine kinase. Several patients had family histories consistent with autosomal dominant inheritance. Five patients had more prominent distal weakness than proximal weakness; 1 had only distal weakness, 2 had only proximal weakness, and 3 had both proximal and distal weakness. Three patients had cardiac involvement, and 5 patients had peripheral nerve involvement. EMG showed myopathic changes in 8 patients and both myopathic and neurogenic changes in 2 patients. Ten patients had abnormal electrical irritability. All patients showed MFM on skeletal muscle biopsy, including pleomorphic hyaline, granular, and amorphous deposits on trichrome staining. Ten patients had intensely congophilic hyaline structures, indicating amyloid material. A variable number of fibers had small vacuoles. Immunohistochemistry showed multiple protein deposits, and electron microscopy showed streaming and disintegration of the Z discs, as well as degraded and fragmented filaments in autophagic vacuoles. Selcen and Engel (2005) noted that the clinical and laboratory features of the patients were similar to those in other forms of MFM.

Molecular Genetics

In 11 of 54 unrelated patients with MFM, Selcen and Engel (2005) identified 3 different heterozygous mutations in the ZASP gene (605906.0001-605906.0003).