Servidei et al. (1999) studied a large Italian family in which 10 individuals over 3 generations were affected by a progressive neuromyopathy. The disease was characterized by onset from the late teens to early fifties with distal leg ... Servidei et al. (1999) studied a large Italian family in which 10 individuals over 3 generations were affected by a progressive neuromyopathy. The disease was characterized by onset from the late teens to early fifties with distal leg weakness and atrophy, development of generalized muscle weakness with distal-to-proximal progression sparing facial and ocular muscles, dysphonia and dysphagia, pes cavus and areflexia, variable clinical expression ranging from subclinical myopathy to severely disabling weakness, and mixed neurogenic and myopathic abnormalities on electromyography. Morphologic, immunocytochemical, and ultrastructural studies were performed in muscle biopsies from 3 affected patients. All muscle biopsies showed variation of fiber size, panesterase-positive angular fibers, mild to severe fibrosis, and numerous rimmed vacuoles. Electron microscopy failed to demonstrate the nuclear or cytoplasmic filamentous inclusions specific to inclusion body myopathies--see, e.g., inclusion body myositis (IBM; 147421) and Nonaka myopathy (NM; 605820)--and, accordingly, immunohistochemistry did not show any positivity with SMI-31 antibodies detecting hyperphosphorylated tau. Di Blasi et al. (2004) reported a second large Italian family with adult-onset autosomal dominant distal myopathy characterized by rimmed vacuoles on muscle biopsy. There were 19 affected members spanning 4 generations. Six of 10 examined patients were severely affected, with marked bilateral weakness of foot dorsiflexors and neck flexors and mild involvement of wrist and finger extensor muscles without fasciculations. Shoulder muscles were also mildly involved. Serum creatine kinase was twice normal and EMG studies showed myopathic changes. Two mildly affected patients had mild distal lower limb and scapular girdle muscle weakness with normal creatine kinase levels, and 2 patients were clinically asymptomatic, although 1 had scapular weakness and both had abnormal myopathic findings on EMG. Di Blasi et al. (2004) noted that dysphagia and dysphonia were not present. Muscle biopsies from 6 patients showed myopathic changes and rimmed vacuoles in all biopsies. The vacuoles were variable in size, contained basophilic granular material, and clustered at the fiber surface and abutted the extracellular space. Filamentous inclusions were never observed. Immunohistochemical findings suggested dysregulation of lysosomal pathways and activation of the ubiquitin-proteasomal pathway. The authors noted that the vacuole characteristics were similar to those seen in Danon disease (300257), a disorder of lysosomal processing.