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

• Published in: American journal of medical genetics. Part A 2006-02, Vol.140A (4), p.322-330
• Main Authors: Mehta, Sarju G., Watts, Giles D.J., McGillivray, Barbara, Mumm, Steven, Hamilton, Sara Jane, Ramdeen, Sheena, Novack, Deborah, Briggs, Christine, Whyte, Michael P., Kimonis, Virginia E.
• Format: Article
• Language: English
• Subjects: Adult; adult-onset myopathy; Age of Onset; Aged; Alkaline Phosphatase - metabolism; Biological and medical sciences; bone fragility; Chromosomes, Human, Pair 9 - genetics; coagulopathy; Creatine Kinase - metabolism; Diseases of striated muscles. Neuromuscular diseases; Diseases of the osteoarticular system; Female; fibrous dysplasia; fractures; Fractures, Bone - diagnosis; Fractures, Bone - genetics; Genes, Dominant; Genetic Linkage; Genetic Markers; Genetic Predisposition to Disease; hereditary inclusion body myopathy (HIBM); Humans; Injuries of the limb. Injuries of the spine; limb girdle myopathy; Male; Medical sciences; Microsatellite Repeats; Middle Aged; Muscular Dystrophies, Limb-Girdle - diagnosis; Muscular Dystrophies, Limb-Girdle - genetics; Mutation - genetics; myopathy; Neurology; Osteoporosis. Osteomalacia. Paget disease; osteosarcoma; Paget disease of bone (PDB); Pedigree; premature graying; Traumas. Diseases due to physical agents
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.31008

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. © 2006 Wiley‐Liss, Inc.