| #159000 | ||||||||||||||||||||||||||||||||||||||||||||||||
| MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1A; LGMD1A | ||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||
| LGMD1 MUSCULAR DYSTROPHY, PROXIMAL, TYPE 1A | ||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because autosomal dominant limb-girdle muscular dystrophy (LGMD) type 1A is caused by heterozygous mutation in the gene encoding myotilin (TTID; 604103) on chromosome 5q31. See also myotiliopathy (609200), an allelic disorder with overlapping clinical features. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||||||||||||||
| LGMD1 is an autosomal dominant disorder characterized by adult onset of proximal muscle weakness, beginning in the hip girdle region and later progressing to the shoulder girdle region. Distal muscle weakness may occur later. Daniele et al. (2007) provided a review of therapeutic strategies in various forms of LGMD, including ongoing studies in gene therapy. Genetic Heterogeneity of Autosomal Dominant Limb-Girdle Muscular Dystrophy Other forms of autosomal dominant LGMD include LGMD1B (159001), LGMD1C (607801), LGMD1D (see 602067), LGMD1E (603511), LGMD1F (608423), LGMD1G (609115), and LGMD1H (613530). | ||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||||||||
| Bacon and Smith (1971) reported a late-onset familial muscular dystrophy with features of a limb-girdle type. DeCoster et al. (1974) described a family with late-onset limb-girdle muscular dystrophy in 9 males of 6 sibships in 3 generations. Changes in type II muscle fibers were described. They thought it to be different from other reported dystrophies. Henson et al. (1967) and Heyck and Laudahn (1969) described a dominant limb-girdle muscular dystrophy limited to females. Espir and Matthews (1973) described 2 brothers with what they referred to as 'quadriceps myopathy.' All 3 daughters of one of them had mild involvement. Patients presented in adulthood with severe aching in the thigh muscles followed by proximal lower limb weakness. Clinically the thighs showed islands of hypertrophy in wasted quadriceps muscles and knee reflexes were absent. In late stages, prominent areas of hypertrophy projecting from patches of atrophy gave the quadriceps a strikingly unusual appearance. The disorder showed a relatively benign course with late involvement of pelvic girdle and hand muscles. The authors found no reports of precisely similar cases. Gilchrist et al. (1988) reported a large family from southeastern West Virginia 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 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. | ||||||||||||||||||||||||||||||||||||||||||||||||
| 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, where a recessive form of limb-girdle muscular dystrophy (LGMD2A; 253600) maps. 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 with LGMD1A first reported by Gilchrist et al. (1988), Hauser et al. (2000) identified a mutation in the myotilin gene (604103.0001) that segregated with the disease. Of 42 families with autosomal dominant LGMD, Hauser et al. (2002) identified an Argentinian family with a mutation in the myotilin gene (604103.0002) that segregated with the disease. In a Turkish woman with LGMD1A, Reilich et al. (2011) identified a heterozygous mutation in the TTID gene (R6H; 604103.0007). | ||||||||||||||||||||||||||||||||||||||||||||||||
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