A novel autosomal dominant distal myopathy with early respiratory failure:Clinico-pathologic characteristics and exclusion of linkage to candidate genetic loci

We describe a novel autosomal dominant myopathy presenting in mid-adult lif e with tibialis anterior weakness. We carried out a detailed clinical asses sment of 24 individuals spanning three generations, documenting pathologic features of the muscles in 7 of the 11 affected individuals, including an a utopsy study on one case. The second generation of affected individuals pre sented at an earlier age, and the disease progressed more rapidly than in t he first generation. Lung function tests revealed progressive global respir atory muscle weakness detectable from the time of presentation, with prefer ential diaphragmatic involvement in some cases. Hip girdle and shoulder gir dle weakness appeared later in the disease course. We observed a striking c orrelation between the clinical and pathological features. Clinically unaff ected muscles had minimal pathologic change. Fiber splitting, eosinophilic inclusions, and vacuoles with basophilic rims were seen in moderately affec ted muscles, and fat and fibrous connective tissue replaced muscle fibers i n the severely involved muscles. The inclusions were Congophilic and reacte d with antibodies to desmin, P-amyloid, and phosphorylated tau protein. The disease was not linked to any of the known loci associated with distal myo pathies, confirming that the disorder in this family is both genetically an d phenotypically distinct.