Department of Geriatric Neurology, Xiangya Hospital, Central South University, Changsha, China.
Department of Neurology, West China Hospital, Sichuan University, Chengdu, China.
Eur J Neurol. 2022 Dec;29(12):3600-3610. doi: 10.1111/ene.15552. Epub 2022 Sep 25.
NOTCH2NLC GGC repeat expansions have been identified to be associated with essential tremor (ET). Our aim was to characterize ET patients with NOTCH2NLC repeat expansions versus non-expansions and describe distinctive clinical features of repeat expanded patients with long-term follow-up according to the new tremor classification.
Participants included 597 ET pedigrees, 412 sporadic cases and 1085 healthy controls. Repeat expansions of GGC in NOTCH2NLC were screened, and comprehensive clinical features were investigated. A longitudinal clinical assessment and reclassification were performed in NOTCH2NLC expanded patients.
In total, 27 ET pedigrees (27/597) and three sporadic patients (3/412) were identified with pathogenic NOTCH2NLC GGC repeat expansions (≥60 repeats). Intermediate-length GGC repeats (41-59 repeats) were found in four sporadic ET cases and one control subject, and the frequency was higher than that in control participants (4/412 vs. 1/1085, p = 0.022). About 46 ET patients (43 familial cases from 27 pedigrees and three sporadic cases) with NOTCH2NLC GGC repeat expansions had higher Essential Tremor Rating Assessment Scale I, Essential Tremor Rating Assessment Scale II and Non-Motor Symptoms Scale scores and lower Mini-Mental State Examination scores than the patients without expansions. Patients with pathogenic GGC repeats were reclassified as pure ET (25/46), ET-plus (11/46) and ET-neuronal intranuclear inclusion disease (10/46) subgroups at 2-8 years of follow-up.
Our results further supported that NOTCH2NLC GGC repeat expansions were associated with ET. Patients with pathogenic GGC repeats presented with more severe motor and non-motor symptoms. Further long-term follow-up and subtype studies will help to define the role of NOTCH2NLC in ET.
NOTCH2NLC GGC 重复扩增已被确定与原发性震颤（ET）有关。我们的目的是对具有 NOTCH2NLC 重复扩增的 ET 患者与非扩增患者进行特征描述，并根据新的震颤分类对具有长期随访的重复扩增患者的独特临床特征进行描述。
参与者包括 597 个 ET 家系、412 例散发性病例和 1085 名健康对照。筛查 NOTCH2NLC 中的 GGC 重复扩增，调查全面的临床特征。对 NOTCH2NLC 扩增患者进行纵向临床评估和重新分类。
共发现 27 个 ET 家系（27/597）和 3 例散发性患者（3/412）具有致病性 NOTCH2NLC GGC 重复扩增（≥60 个重复）。在 4 例散发性 ET 病例和 1 例对照中发现了中等长度的 GGC 重复（41-59 个重复），其频率高于对照组（4/412 比 1/1085，p=0.022）。约 46 名（27 个家系中的 43 名家族性病例和 3 名散发性病例）具有 NOTCH2NLC GGC 重复扩增的 ET 患者具有更高的原发性震颤评定量表 I、原发性震颤评定量表 II 和非运动症状量表评分以及更低的简易精神状态检查表评分，而非扩增患者。在 2-8 年的随访中，具有致病性 GGC 重复的患者被重新分类为纯 ET（25/46）、ET+（11/46）和 ET-神经元核内包涵体病（10/46）亚组。
我们的结果进一步证实 NOTCH2NLC GGC 重复扩增与 ET 有关。具有致病性 GGC 重复的患者表现出更严重的运动和非运动症状。进一步的长期随访和亚型研究将有助于确定 NOTCH2NLC 在 ET 中的作用。
