A distinctive autosomal dominant vacuolar neuromyopathy linked to 19p13

Objective: To characterize a kindred with a distinctive autosomal dominant neuromuscular disorder. Background: The authors studied a large Italian fam ily affected by a progressive neuromyopathy. Ten individuals over three gen erations were affected. The disease was characterized by onset from the lat e teens-to early 50s with distal leg weakness and atrophy, development of g eneralized muscle weakness with distal-to-proximal progression sparing faci al and ocular muscles, dysphonia and dysphagia, pes cavus and areflexia, va riable clinical expression ranging from subclinical myopathy to severely di sabling weakness, and mixed neurogenic and myopathic abnormalities on elect romyography. Methods: Morphologic, immunocytochemical, and ultrastructural studies were performed in muscle biopsies from three affected patients. A g enomewide linkage analysis through the genotyping of 292 microsatellite mar kers spanning the 22 autosomes was undertaken to map the disorder segregati ng in this family. Results: All muscle biopsies showed variation of fiber s ize, panesterase-positive angular fibers, mild to severe fibrosis, and nume rous "rimmed vacuoles." Electron microscopy failed to demonstrate the nucle ar or cytoplasmic filamentous inclusions specific of inclusion-body myopath ies and, accordingly, immunohistochemistry did not show any positivity with SMI-31 antibodies detecting hyperphosphorylated tau. Preliminary analysis of 292 microsatellite markers provided evidence for Linkage to chromosome 1 9p13. Conclusions: This distinctive autosomal dominant disorder is characte rized by a vacuolar neuromyopathy. Localization to chromosome 19p13 will al low the genetic relationship between this disease and inherited myopathies with rimmed vacuoles, in particular autosomal dominant inclusion-body myopa thies, to be defined.