Alternative titles; symbols
ORPHA: 98912; DO: 0080095;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q23.2 | Myopathy, myofibrillar, 4 | 609452 | Autosomal dominant | 3 | LDB3 | 605906 |
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 10q23.
Myofibrillar myopathy-4 (MFM4) is an autosomal dominant disorder characterized by adult-onset distal muscle weakness primarily affecting the lower limbs at onset. Affected individuals usually present with gait difficulties in their forties, followed by slow progression with eventual involvement of the hands and proximal muscles of the lower limbs. Rare patients may develop cardiomyopathy. Skeletal muscle biopsy shows myopathic changes with myofibrillar changes (Selcen and Engel, 2005; Griggs et al., 2007).
For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419).
Markesbery et al. (1974) reported a large multigenerational family of Irish/French ancestry from Rochester, NY, with late-onset distal myopathy showing autosomal dominant inheritance. This family was studied again by Markesbery et al. (1977) and Griggs et al. (2007). Disease symptoms began in adulthood (late forties), although signs of distal leg weakness were detected a bit earlier in some patients. Features included tripping while walking with weakness of the feet and ankles. The disorder was slowly progressive, eventually involving the small hand muscles and proximal muscles. All patients remained ambulatory up to age 70. Some patients developed cardiomyopathy later in life. Muscle imaging showed involvement of the posterior calf muscles with later involvement of the proximal muscles of the lower limbs. Skeletal muscle biopsies showed myopathic changes with fiber size variation, central nuclei, and rimmed vacuoles with focal accumulation of myofibrillar material (Griggs and Udd, 2011). In affected members of the family reported by Markesbery et al. (1974), Griggs et al. (2007) identified a heterozygous missense mutation in the ZASP gene (A165V; 605906.0002), confirming the diagnosis of myofibrillar myopathy-4.
Selcen and Engel (2005) reported 11 unrelated patients with MFM4. 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.
The transmission pattern of MFM4 in the family reported by Markesbery et al. (1974) and Griggs et al. (2007) was consistent with autosomal dominant inheritance with age-dependent penetrance. Penetrance appeared to be 100% by age 60 years.
In 11 of 54 unrelated patients with MFM, Selcen and Engel (2005) identified 3 different heterozygous missense mutations in the ZASP gene (605906.0001-605906.0003).
In affected members of a large multigenerational family with adult-onset distal myopathy originally reported by Markesbery et al. (1974), Griggs et al. (2007) identified a heterozygous missense mutation in the ZASP gene (A165V; 605906.0002). Haplotype analysis in this family and in 5 other families of European ancestry with this mutation showed a founder effect. Western blot analysis of patient skeletal muscle showed amounts of ZASP protein isoforms similar to controls. Functional studies of the variant were not performed.
Griggs, R. C., Udd, B. A. Markesbery disease: autosomal dominant late-onset distal myopathy: from phenotype to ZASP gene identification. Neuromolec. Med. 13: 27-30, 2011. [PubMed: 20809097] [Full Text: https://doi.org/10.1007/s12017-010-8134-6]
Griggs, R., Vihola, A., Hackman, P., Talvinen, K., Haravuori, H., Faulkner, G., Eymard, B., Richard, I., Selcen, D., Engel, A., Carpen, O., Udd, B. Zaspopathy in a large classic late-onset distal myopathy family. Brain 130: 1477-1484, 2007. [PubMed: 17337483] [Full Text: https://doi.org/10.1093/brain/awm006]
Markesbery, W. R., Griggs, R. C., Herr, B. Distal myopathy--electron microscopic and histochemical studies. Neurology 27: 727-735, 1977. [PubMed: 196233] [Full Text: https://doi.org/10.1212/wnl.27.8.727]
Markesbery, W. R., Griggs, R. C., Leach, R. P., Lapham, L. W. Late onset hereditary distal myopathy. Neurology 24: 127-134, 1974. [PubMed: 4855680] [Full Text: https://doi.org/10.1212/wnl.24.2.127]
Selcen, D., Engel, A. G. Mutations in ZASP define a novel form of muscular dystrophy in humans. Ann. Neurol. 57: 269-276, 2005. [PubMed: 15668942] [Full Text: https://doi.org/10.1002/ana.20376]