Intranuclear and cytoplasmic filamentous inclusions in distal myopathy (Welander)

Abstract

Ultrastructural examination of anterior tibial muscle from four patients with late-onset autosomal dominant distal myopathy of Welander-type revealed intrasarcoplasmic filamentous inclusions in association with rimmed vacuoles. In one of the patients, identical intranuclear filamentous inclusions were also found. These filamentous inclusions are similar to those described in inclusion body myositis (IBM). They have also been observed in hereditary neuromuscular disorders including autosomal recessive distal myopathy. Thus, the filamentous inclusions occur in different neuromuscular conditions with different etiologies. These findings further raise the question of the specificity of the filamentous inclusions in IBM.

Clinical and genetic aspects of distal myopathies

“…Serum creatine kinase (CK) levels are normal or only slightly elevated (two to three times normal). 22,63 Nerve conduction studies are normal, but needle electromyography (EMG) usually shows brief, low-amplitude "myopathic" motor unit potentials. However, mixed myopathicneuropathic EMG findings have been reported.…”

“…125 Vacuoles are a common finding in several of the distal myopathies, but they have been inconsistently detected in Welander myopathy. 13,20,22,27,32,125 When present, vacuoles are usually seen in only a minority of muscle fibers. Some recent articles reporting rimmed vacuoles also describe 15-19-nm cytoplasmic and nuclear filaments, seen on electron microscopy.…”

“…Some recent articles reporting rimmed vacuoles also describe 15-19-nm cytoplasmic and nuclear filaments, seen on electron microscopy. 22,63 Such filaments can be found in a number of other myopathies, such as inclusion-body myositis (IBM), and are not specific for any particular disorder ( 30,70,107,113,116 This group shares a distinct clinical phenotype, comprising weakness beginning in the anterior compartment of the legs, and is often referred to as tibial muscular dystrophy. Symptoms begin after age 40 years.…”

Genetic linkage of Welander distal myopathy to chromosome 2p13

“…On ultrastructural examination, the rimmed vacuoles correspond to autophagic vacuoles that contain membranous bodies. 6 In the group of hereditary distal myopathies, linkage has been demonstrated for the autosomal recessive early-adult-onset Miyoshi myopathy (MM) (2p) 7 and the distal myopathy with rimmed vacuoles (IBM2) (9p1-q1), 8,9 as well as for the autosomal dominant late-onset Finnish tibial muscular dystrophy (2q) 10 and early-adult-onset distal myopathy described by Laing and associates 11 (MPD1) (14q). Previous studies have considered whether WDM represents an allelic form with any of the distal myopathies, having rimmed vacuoles as a common histopathological feature, but this has been demonstrated not to be the case.…”

Distal Myopathies

“…Serum creatine kinase (CK) level has been shown to be normal or slightly elevated (18, 19). Motor and sensory nerve conduction studies (NCS) are typically normal, and needle electromyography (EMG) shows occasional spontaneous activity comprised of fibrillation potentials, and myopathic motor units potentials (MUP), and although some authors have reported a mixed myopathic and neuropathic recruitment pattern (18–21).…”