A.P.8: Necklace cytoplasmic bodies in hereditary myopathy with early respiratory failure (HMERF)

Abstract

Hereditary myopathy with early respiratory failure (HMERF) is an adult-onset progressive myopathy characterized by early presentation of respiratory disturbance usually during ambulant stage. The disease is caused by mutations in the exon 343 of TTN that encodes the fibronectin-3 119 domain in A-band region (ENS0589042). Pathologically, HMERF is categorized into myofibrillar myopathy (MFM). Interestingly, cytoplasmic bodies (CBs) often localize in subsarcolemmal regions, with a necklace-like alignment in muscle fibers. Then we supposed that the necklace CBs might be useful in the diagnosis of HMERF. Here we aim to elucidate the diagnostic value of the necklace CBs for HMERF. We screened exon343 of TTN in genomic DNA samples from 187 subjects from 175 different families who were pathologically categorized as MFM. Furthermore we re-evaluated muscle pathology of the subjects to assess the sensitivity and specificity of the necklace CBs in the diagnosis of HMERF. TTN mutations were identified in 17 subjects from 14 families, whose phenotypes were consistent with HMERF. Among them, 14 had the necklaces CBs. In contrast, no other MFM patient had necklace CBs except for only one patient with reducing body myopathy. Thus the sensitivity and specificity of the necklace CBs for HMERF were 82% (14/17) and 99% (169/170), respectively. Positive predictive value was calculated as 93% in the MFM cohort. The necklace CBs should be a useful pathological marker for HMERF. When muscle pathology reveals the presence of the necklace CBs, exon 343 of TTN can be considered as a primary target for genetic diagnosis.