Myopathy, Myofibrillar, 3

A number sign (#) is used with this entry because myofibrillar myopathy-3 (MFM3) is caused by heterozygous mutation in the TTID gene (MYOT; 604103) on chromosome 5q31.

Spheroid body myopathy (182920) is an allelic disorder with overlapping features.

Description

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).

Nomenclature

Some cases of myofibrillar myopathy-3 were previously classified as a form of limb-girdle muscular dystrophy (type 1A; LGMD1A). Straub et al. (2018), on behalf of the LGMD workshop study group, reclassified LGMD1A as a form of myofibrillar myopathy.

Clinical Features

Gilchrist et al. (1988) reported a large family from southeastern West Virginia diagnosed with autosomal dominant limb-girdle muscular dystrophy. Sixteen members had onset in their early to mid-twenties of proximal leg weakness which progressed to inhibit ambulation and to involve their proximal upper extremities. The patients had elevated CK levels and myopathic EMG and biopsy findings. No conclusive linkage was demonstrated. Gilchrist et al. (1988) reported that the same pedigree had been enlarged to include 51 affected members over 7 generations. Other manifestations included absent ankle jerks, heel-cord contractures, and dysarthria. Penetrance was incomplete and age-dependent, as there were several obligate carriers who were clinically unaffected. Gilchrist et al. (1988) also reported a second family with 4 affected members in 2 generations.

In the large family with LGMD1A first reported by Gilchrist et al. (1988), Speer et al. (1998) studied 25 parent-offspring pairs in which the parents were 3 (3R), 4 (4R), or 5 (5R) generations removed from a common founding ancestor. A life table showed significant decreases in age at first reported symptoms in the offspring of the 3R and 4R parents, suggesting anticipation. Pairwise analysis confirmed this decrease, with a median decrease of 13 years in transmission to offspring from 3R parents and 18 years in transmission to offspring from 4R parents. Speer et al. (1998) concluded that LGMD1A may result from the expansion of an unstable trinucleotide repeat.

Hauser et al. (2002) noted that some individuals with LGMD1A exhibit a distinctive nasal, dysarthric pattern of speech.

Reilich et al. (2011) reported a Turkish woman with a rapidly progressive disease course of LGMD1A. She developed progressive proximal weakness of the lower limbs at age 40 years followed by proximal upper limb weakness, and subsequently developed mild distal muscle weakness. She was wheelchair-dependent at age 50. Within the next 3 years, she developed respiratory insufficiency and dysphagia, resulting in death from pneumonia at age 55. Muscle imaging showed fatty degeneration of most proximal muscles in both the upper and lower limbs, as well as in the thoracic and abdominal cavities. Muscle biopsy at age 40 showed a mild myopathic pattern with increased fiber size variability, some central nuclei, some autophagocytic vacuoles, and mild fibrosis; there were no signs of a myofibrillar myopathy. The patient's mother and 1 sister were reportedly less severely affected.

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.

Mapping

In the family containing 51 affected individuals first reported by Gilchrist et al. (1988), Speer et al. (1992) found linkage to CA(n) microsatellite repeat markers on chromosome 5 and localized the LGMD1 gene to 5q22.3-q31.3. They excluded linkage to 15q.

From information on the same large family studied by Speer et al. (1992), Yamaoka et al. (1994) developed a microsatellite genetic map in 5q31-q33 and used this to refine the localization further. Using multipoint analysis, they localized LGMD1A to a 7-cM region between markers IL9 and D5S178. Again using the same large family, Bartoloni et al. (1998) further narrowed the location of the LGMD1A gene to an interval bounded by D5S479 and D5S594, estimated to be 2 Mb in size. They used a high-resolution physical map of the region to identify and provisionally localize 25 polymorphic markers. Using a CEPH meiotic breakpoint panel, they then ordered a subset of these markers genetically and constructed an integrated physical-genetic map of the region.

Diagnosis

Falk et al. (1998) proposed the methods of artificial neural-network analysis to determine disease status in conditions such as LGMD1A where there is confusion because of variability in diagnostic criteria, age at onset, and differential presentation of disease. The method entails 'training' an artificial neural network with input facts (based on diagnostic criteria) and related results (based on disease diagnosis). The network contains weight factors connecting input 'neurons' to output 'neurons,' and these connections are adjusted until the network can reliably produce the appropriate outputs for the given input facts. The trained network can be 'tested' with a second set of facts. Falk et al. (1998) applied the method to members of the large pedigree with LGMD1A originally reported by Gilchrist et al. (1988). They used diagnostic criteria and disease status to train a neural network to classify individuals as 'affected' or 'not affected.' The trained network reproduced the disease diagnosis of all individuals of known phenotype with 98% reliability.

Molecular Genetics

In the large family that was first diagnosed with LGMD1A by Gilchrist et al. (1988), Hauser et al. (2000) identified a mutation in the myotilin gene (T57I; 604103.0001) that segregated with the disease.

Of 42 families diagnosed with autosomal dominant LGMD, Hauser et al. (2002) identified an Argentinian family with a mutation in the myotilin gene (S55F; 604103.0002) that segregated with the disease.

In a Turkish woman diagnosed with LGMD1A, Reilich et al. (2011) identified a heterozygous mutation in the MYOT gene (R6H; 604103.0007).

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 diagnosed with LGMD1A who have mutations in the myotilin gene develop distal muscle weakness and hyporeflexia later in the disease.