Chiang Han-Lin, Jih Kang-Yang, Hsiao Cheng-Tsung, Chang Fu-Pang, Chen Justus Chunyu, Liao Yi-Chu, Wu Yih-Ru, Lee Yi-Chung
Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan.
Department of Neurology, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan.
Ann Clin Transl Neurol. 2025 Jul 24. doi: 10.1002/acn3.70147.
Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder caused by NOTCH2NLC GGC repeat expansions, with heterogeneous clinical manifestations, including parkinsonism. Recent studies have identified NOTCH2NLC repeat expansions in patients with Parkinson's disease (PD) and atypical parkinsonism (aPM), suggesting a potential genetic contribution. However, it remains unclear whether such cases represent NIID-related parkinsonism or typical PD. To address this, we screened NOTCH2NLC repeat expansions in a parkinsonian cohort and analyzed associated clinical and neuroimaging features.
We examined 1017 unrelated patients with PD, 115 with aPM, 11 with multiple system atrophy, six with progressive supranuclear palsy, three with dementia with Lewy bodies, and 321 healthy controls. NOTCH2NLC GGC repeat expansions were detected using repeat-primed PCR and amplicon length analysis. Clinical data and neuroimaging findings were comprehensively reviewed.
Pathological NOTCH2NLC repeat expansions were identified in four patients with aPM and none with PD or in controls, with significantly higher frequency in aPM than in PD. An additional affected family member was also identified. All five patients showed clinical or neuroimaging features suggestive of NIID, including white matter hyperintensities in the paravermis and/or corticomedullary junction, curvilinear hyperintensities on diffusion-weighted imaging. Skin biopsies in two patients revealed eosinophilic, p62-positive intranuclear inclusions in the sweat gland cells and fibroblasts. No patient responded well to levodopa. TRODAT scans revealed normal findings in three patients, symmetric dopaminergic deficits in one, and asymmetric deficits in another.
NOTCH2NLC repeat expansions appear to be more frequently associated with aPM with NIID-like features than with typical PD.
神经元核内包涵体病（NIID）是一种由NOTCH2NLC GGC重复序列扩增引起的神经退行性疾病，临床表现多样，包括帕金森综合征。最近的研究在帕金森病（PD）和非典型帕金森综合征（aPM）患者中发现了NOTCH2NLC重复序列扩增，提示可能存在遗传因素。然而，这些病例是代表与NIID相关的帕金森综合征还是典型的PD仍不清楚。为解决这一问题，我们在帕金森病队列中筛查了NOTCH2NLC重复序列扩增，并分析了相关的临床和神经影像学特征。
我们检查了1017例无亲缘关系的PD患者、115例aPM患者、11例多系统萎缩患者、6例进行性核上性麻痹患者、3例路易体痴呆患者以及321名健康对照。使用重复引物PCR和扩增子长度分析检测NOTCH2NLC GGC重复序列扩增。全面回顾临床数据和神经影像学结果。
在4例aPM患者中发现了病理性NOTCH2NLC重复序列扩增，而在PD患者和对照组中均未发现，aPM患者中的频率显著高于PD患者。还发现了另外一名受影响的家庭成员。所有5例患者均表现出提示NIID的临床或神经影像学特征，包括蚓部旁和/或皮质髓质交界处的白质高信号、扩散加权成像上的曲线形高信号。2例患者的皮肤活检显示汗腺细胞和成纤维细胞中有嗜酸性、p62阳性核内包涵体。没有患者对左旋多巴反应良好。TRODAT扫描显示3例患者结果正常，1例患者有对称的多巴胺能缺陷，另1例患者有不对称缺陷。
NOTCH2NLC重复序列扩增似乎与具有NIID样特征的aPM的相关性比与典型PD的相关性更高。
