NOTCH2NLC 在帕金森病中的作用：一项临床、神经影像学和病理学研究。
The role of NOTCH2NLC in Parkinson's disease: A clinical, neuroimaging, and pathological study.
机构信息
Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, The Second Affiliated Hospital, Cancer Institute, Zhejiang University School of Medicine, Hangzhou, China.
出版信息
Eur J Neurol. 2022 Jun;29(6):1610-1618. doi: 10.1111/ene.15283. Epub 2022 Mar 3.
BACKGROUND AND PURPOSE
Recently, the pathogenic and intermediate GGC repeat expansion in NOTCH2NLC was detected in Parkinson's disease (PD). However, detailed clinical, neuroimaging, and pathological information of clinically diagnosed PD patients with pathogenic GGC repeat expansion in NOTCH2NLC remains scarce. Thus, we aimed to elucidate the clinical, neuroimaging, and pathological characteristics of PD patients carrying the pathogenic GGC repeat expansion in NOTCH2NLC.
METHODS
The NOTCH2NLC GGC repeat expansion was screened in 941 sporadic PD patients and 244 unrelated probands. Comprehensive assessments were performed in three PD patients with pathogenic GGC repeat expansion in NOTCH2NLC. The repeat expansion length was estimated using CRISPR/Cas9-based targeted long-read sequencing.
RESULTS
The three patients (two PD patients from Family 1 and one sporadic PD) carrying the pathogenic NOTCH2NLC expansion were reconfirmed with a diagnosis of clinically established PD. Although they lacked the typical neuronal intranuclear inclusion disease (NIID) magnetic resonance imaging (MRI) feature, the typical PD pattern of striatal dopamine transporter loss was detected. Notably, all three patients presented with systemic areflexia, and other secondary causes of polyneuropathy were excluded. Skin biopsy showed intranuclear inclusions and an absence of phosphorylated alpha-synuclein deposition in the skin nerve fibers of all three patients.
CONCLUSIONS
Although these clinically diagnosed PD patients with pathogenic GGC repeat expansion in NOTCH2NLC were hardly distinguishable from idiopathic PD based on clinical course and neuroimaging features, the pathological findings indicated that their phenotype was a PD phenocopy of NIID. Systemic areflexia may be an important and unique clinical clue suggesting further genetic testing and skin biopsy examination to confirm the diagnosis of NIID in patients presenting with a PD phenocopy.
背景与目的
最近，在帕金森病（PD）中检测到 NOTCH2NLC 致病和中间 GGC 重复扩展。然而，具有 NOTCH2NLC 致病性 GGC 重复扩展的临床诊断 PD 患者的详细临床、神经影像学和病理学信息仍然很少。因此，我们旨在阐明携带 NOTCH2NLC 致病性 GGC 重复扩展的 PD 患者的临床、神经影像学和病理学特征。
方法
在 941 名散发性 PD 患者和 244 名无关个体中筛选 NOTCH2NLC GGC 重复扩展。对 3 名具有 NOTCH2NLC 致病性 GGC 重复扩展的 PD 患者进行了综合评估。使用基于 CRISPR/Cas9 的靶向长读测序估计重复扩展长度。
结果
携带致病性 NOTCH2NLC 扩展的三名患者（来自家族 1 的两名 PD 患者和一名散发性 PD 患者）被重新确认为临床确诊的 PD。尽管他们缺乏典型的神经元核内包涵体病（NIID）磁共振成像（MRI）特征，但检测到典型的纹状体多巴胺转运体丧失的 PD 模式。值得注意的是，所有三名患者均表现为全身反射消失，且排除了其他多发性神经病的继发性原因。皮肤活检显示，所有三名患者的皮肤神经纤维中均存在核内包涵体和磷酸化 α-突触核蛋白沉积缺失。
结论
尽管这些具有 NOTCH2NLC 致病性 GGC 重复扩展的临床诊断 PD 患者在临床病程和神经影像学特征上与特发性 PD 几乎无法区分，但病理发现表明其表型为 NIID 的 PD 表型。全身反射消失可能是一个重要且独特的临床线索，提示对表现为 PD 表型的患者进行进一步的遗传检测和皮肤活检检查，以确认 NIID 的诊断。
Zotero 插件