Abstract:

BACKGROUND: In hereditary myopathy with early respiratory failure (HMERF), cytoplasmic bodies (CBs) are often localised in subsarcolemmal regions, with necklace-like alignment (necklace CBs), in muscle fibres although their sensitivity and specificity are unknown.
OBJECTIVE: To elucidate the diagnostic value of the necklace CBs in the pathological diagnosis of HMERF among myofibrillar myopathies (MFMs).
METHODS: We sequenced the exon 343 of TTN gene (based on ENST00000589042), which encodes the fibronectin-3 (FN3) 119 domain of the A-band and is a mutational hot spot for HMERF, in genomic DNA from 187 patients from 175 unrelated families who were pathologically diagnosed as MFM. We assessed the sensitivity and specificity of the necklace CBs for HMERF by re-evaluating the muscle pathology of our patients with MFM.
RESULTS: TTN mutations were identified in 17 patients from 14 families, whose phenotypes were consistent with HMERF. Among them, 14 patients had necklace CBs. In contrast, none of other patients with MFM had necklace CBs except for one patient with reducing body myopathy. The sensitivity and specificity were 82% and 99%, respectively. Positive predictive value was 93% in the MFM cohort.
CONCLUSIONS: The necklace CB is a useful diagnostic marker for HMERF. When muscle pathology shows necklace CBs, sequencing the FN3 119 domain of A-band in TTN should be considered.

日本語要旨:

筋病理学的に筋原線維性ミオパチー(MFM)に分類された日本人患者187名(175家系)を対象に、早期呼吸障害を伴う遺伝性ミオパチー(HMERF)の原因遺伝子であるtitin遺伝子(エクソン 343)変異をスクリーニングした。HMERF患者 17名(14家系)が同定され、日本人MFMコホートにおいてtitin遺伝子変異が既知のMFM原因遺伝子の中で今のところ最も高頻度であることがわかった。またネックレス状に配列するcytoplasmic bodyがHMERFの優れた病理診断マーカーであることが示された(感度82%、特異度99%、陽性的中率93%)。なお、本稿はJNNP誌のEditorial commentaryで取り上げられた(J Neurol Neurosurg Psychiatry [Epub Oct 2014] ahead of print doi.org/10.1136/jnnp-2014-309009. PMID: 25313263)