Manifestations in a family with autosomal dominant bone fragility and limb‐girdle myopathy

Abstract

We report on an unusual family with an autosomal dominant limb-girdle type of myopathy and bone fragility. This family was previously reported by Henry et al. [1958] as autosomal dominant progressive limb girdle "muscular dystrophy" with propensity to fractures and defective healing of long bones. Clinical, biochemical, and radiological aspects were evaluated in eight living relatives in this family (three males and five females) and in eight deceased individuals. The average age-of-onset of the limb-girdle myopathy was 31 years occurring in 87% of affected individuals. The average age of onset of fractures was 24 years occurring in 88% of affected individuals. Biochemical analysis showed a mean alkaline phosphatase (ALP) of 64 U/L (normal 30-120) and borderline high creatine kinase (CK) of 213 U/L (normal 4-220). Radiographs revealed coarse trabeculation, patchy sclerosis, cortical thickening, and narrowing of the medullary cavity with an appearance not considered typical of Paget disease of bone (PDB) or of fibrous dysplasia. Results of nerve conduction studies were normal, and electromyograms and muscle biopsies documented non-specific myopathic changes. There is premature graying with thin hair, thin skin, hernias and the affected individuals appear older than their chronological age, and three members had a clotting disorder. Linkage analysis for markers for the chromosome 9p22.3-q12 locus indicated that the disorder in this family does not segregate with markers in the critical region of limb-girdle/inclusion body myopathy, PDB, and frontotemporal dementia (FTD) [IBMPFD, OMIM #605382]. Sequencing of Valosin-containing protein (VCP), the gene associated with IBMPFD, did not identify mutations. We have excluded linkage to the known loci for limb-girdle type of myopathy and bone disease and excluded several candidate genes. Elucidation of the novel molecular basis of this disorder may provide valuable links between bone, collagen and muscle, and targeted therapeutic options.

Rehabilitation in Muscular Dystrophies: Changing Approach

“…The initiation of the pharyngeal phase is typically normal in patients with NMD, but problems with solid food and residue after swallow are reported in patients with SMA type II (van den Engel-Hoek 2009), DMD (Aloysius 2008;Shinonaga 2008), in MD (Leonard 2001) and congenital myopathies (Mehta 2006;de Swart 2002). In all patient groups the problems occurred more in advanced stages.…”

Late-onset autosomal dominant limb girdle muscular dystrophy and Paget's disease of bone unlinked to the VCP gene locus

“…However, in addition to the families with VCP gene mutations, the combination of familial Paget's disease of bone with myopathy has been previously reported in only one family unlinked to the VCP gene locus and three other unrelated families with distinct phenotypes [12][13][14][15].…”

Mapping autosomal dominant progressive limb-girdle myopathy with bone fragility to chromosome 9p21-p22: a novel locus for a musculoskeletal syndrome

“…As part of our overall approach to identify the genetic defect underlying this syndrome, exclusion linkage studies were undertaken in this multigenerational family to the LGMD and other myopathy loci (Mehta et al 2005). The known bone disorders with overlapping pathological features, such as inclusion body myopathy, PDB and frontotemporal dementia (IBMPFD), Camurati-Engelmann disease (CED), familial expansile osteolysis, juvenile Paget's disease, and Kenny-Caffey disease were excluded by sequencing of the genes encoding VCP (valosin containing protein), TGFB1, RANK (TNFRSF11A), OPG (TNFRSF11B), and Sequestosome 1 (SQSTM1), and by the lack of distinctive radiological features of these conditions, respectively.…”

“…PCR amplification, sequencing reactions, and mutation analysis were performed as described elsewhere (Watts et al 2005).…”

“…Hereditary myopathy of limb-girdle distribution and bone fragility is a rare, complex, and debilitating autosomal dominant disorder (Mehta et al 2005). The family studied here for genetic mapping was originally reported (Henry et al 1958) as having autosomal dominant 'limbgirdle muscular dystrophy' with easy fracturability and poor healing of the long bones.…”