Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
Department of Neurology, The Sixth Medical Center of PLA General Hospital, Beijing, China.
Ann Clin Transl Neurol. 2020 Apr;7(4):517-526. doi: 10.1002/acn3.51021. Epub 2020 Apr 6.
Trinucleotide GGC repeat expansion in the 5'UTR of the NOTCH2NLC gene has been recognized as the pathogenesis of neuronal intranuclear inclusion disease (NIID). Previous studies have described that some NIID patients showed clinical and pathological similarities with multiple system atrophy (MSA). This study aimed to address the possibility that GGC repeat expansion in NOTCH2NLC might be associated with some cases diagnosed as MSA.
A total of 189 patients with probable or possible MSA were recruited to screen for GGC repeat expansion in NOTCH2NLC by repeat-primed PCR (RP-PCR). In addition, long-read sequencing (LRS) was performed for all patients with RP-PCR-positive expansion, five patients with RP-PCR-negative expansion, and five controls on the Nanopore platform. Skin biopsies were performed on two patients with GGC expansion.
Five of 189 patients (2.6%) were found to have GGC expansion in NOTCH2NLC. LRS results identified that the five patients had GGC expansion between 101 and 266, but five patients with RP-PCR-negative expansion and five controls had GGC expansion between 8 and 29. Besides the typical symptoms and signs of MSA, patients with GGC expansion might have longer disease duration, severe urinary retention, and prominent cognitive impairment. In the skin samples from the patients with GGC expansion, typical p62-postive but alpha-synuclein-negative intranuclear inclusions were found in fibroblasts, adipocyte and ductal epithelial cells of sweat glands.
Trinucleotide GGC repeat expansion in NOTCH2NLC could be observed in patients with clinically diagnosed MSA. Adult-onset NIID should be considered as a differential diagnosis of MSA.
NOTCH2NLC 基因 5'UTR 中的三核苷酸 GGC 重复扩展已被认为是神经元核内包涵体病（NIID）的发病机制。先前的研究描述了一些 NIID 患者表现出与多系统萎缩（MSA）相似的临床和病理特征。本研究旨在探讨 NOTCH2NLC 中的 GGC 重复扩展是否与一些被诊断为 MSA 的病例有关。
共招募了 189 名可能或可能患有 MSA 的患者，通过重复引物 PCR（RP-PCR）筛选 NOTCH2NLC 中的 GGC 重复扩展。此外，对所有 RP-PCR 阳性扩展的患者、5 名 RP-PCR 阴性扩展的患者和 5 名对照进行长读测序（LRS）在 Nanopore 平台上。对两名具有 GGC 扩展的患者进行皮肤活检。
在 189 名患者中，发现 5 名（2.6%）患者 NOTCH2NLC 中存在 GGC 扩展。LRS 结果表明，这 5 名患者的 GGC 扩展在 101 到 266 之间，但 5 名 RP-PCR 阴性扩展的患者和 5 名对照的 GGC 扩展在 8 到 29 之间。除了 MSA 的典型症状和体征外，具有 GGC 扩展的患者可能具有更长的疾病持续时间、严重的尿潴留和明显的认知障碍。在具有 GGC 扩展的患者的皮肤样本中，在成纤维细胞、脂肪细胞和汗腺的导管上皮细胞中发现了典型的 p62 阳性但α-突触核蛋白阴性的核内包涵体。
在临床上诊断为 MSA 的患者中可以观察到 NOTCH2NLC 中的三核苷酸 GGC 重复扩展。成人发病的 NIID 应作为 MSA 的鉴别诊断。
