| #609200 | ||||||||||
| MYOPATHY, MYOFIBRILLAR, 3; MFM3 | ||||||||||
| Alternative titles; symbols | ||||||||||
| MYOTILINOPATHY MYOPATHY, MYOFIBRILLAR, MYOTILIN-RELATED | ||||||||||
| Phenotype Gene Relationships | ||||||||||
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| Clinical Synopsis | ||||||||||
| TEXT | ||||||||||
| A number sign (#) is used with this entry because myotilinopathy is caused by mutation in the gene encoding myotilin, also known as titin immunoglobulin domain protein (TTID; 604103). Limb-girdle muscular dystrophy type 1A (LGMD1A; 159000) is an allelic disorder with some overlapping features. For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy (MFM), see desmin-related MFM (601419). | ||||||||||
| Description | ||||||||||
| Myotilinopathy is a form of myofibrillar myopathy. 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. | ||||||||||
| Clinical Features | ||||||||||
| Selcen and Engel (2004) reported 6 unrelated patients with myofibrillar myopathy caused by mutation in the myotilin gene. Age at symptom onset ranged from 50 to 77 years (mean, 59.8 years). One patient had a brother with distal leg weakness and another patient had an affected brother and an affected son, suggesting autosomal dominant inheritance. The main features included progressive distal muscle weakness and peripheral neuropathy with hyporeflexia. One patient had generalized muscle weakness and 1 reported more severe proximal muscle weakness. Three of 6 patients had elevated creatine kinase and 3 had cardiomyopathy. EMG studies showed myopathic and neurogenic changes. Muscle biopsies from all patients showed abnormal muscle fibers with amorphous, granular, or hyaline deposits that were dark blue or blue red in color. Some hyaline structures were intensely congophilic, indicating beta-pleated amyloid (104760) sheets. Abnormal fibers stained strongly for myotilin, alpha-B crystallin (123590), dystrophin (300377), and desmin (125660), among other proteins. Electron microscopy of 2 patients showed streaks of dense material emanating from Z discs. Hyaline structures consisted of compacted fragmented filaments of variable electron density. Some muscle fibers contained membrane-bound vacuoles with degraded material. Selcen and Engel (2004) concluded that in all forms of myofibrillar myopathy, the Z disc is the earliest site of pathologic change, followed by disorganization of the fiber architecture, accumulation of degraded filamentous material in larger aggregates, and accumulation and degradation of dislocated membranous material in autophagic vacuoles. | ||||||||||
| Molecular Genetics | ||||||||||
| In 6 of 57 unrelated patients with myofibrillar myopathy, Selcen and Engel (2004) identified 4 heterozygous mutations in the myotilin gene (604103.0002-604103.0005). They termed the disorder 'myotilinopathy' to distinguish it from other forms of myofibrillar myopathy. Selcen and Engel (2004) noted that patients with LGMD1A who have mutations in the myotilin gene developed distal muscle weakness and hyporeflexia later in the disease. | ||||||||||
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