两例同胞患常染色体隐性NOTCH3相关脑白质营养不良并文献复习

Autosomal Recessive NOTCH3-Related Leukodystrophy in Two Siblings and Review of the Literature.

作者信息

Al-Amrani Fatema, Al-Maawali Almundher, Al-Thihli Khalid, Al-Ajmi Eiman, Ganesh Anuradha, Al Futaisi Amna

机构信息

Pediatric Neurology Unit, Department of Child Health, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat, Sultanate of Oman.

Department of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat, Sultanate of Oman.

出版信息

Pediatr Neurol. 2023 Nov;148:73-80. doi: 10.1016/j.pediatrneurol.2023.07.007. Epub 2023 Jul 16.

DOI:10.1016/j.pediatrneurol.2023.07.007

PMID:37688971

Abstract

BACKGROUND

NOTCH3, a large type I transmembrane receptor expressed on arterial smooth muscle cells and capillary pericytes, features a diverse extracellular domain with 34 epidermal growth factor-like repeats. It exhibits distinct phenotypes due to variant zygosity and type; missense mutations cause CADASIL with cerebral vasculopathy, while null mutations lead to severe congenital manifestations.

METHODS

This report describes two cases with homozygous loss- of- function variants in NOTCH3 along with their clinical manifestations.

RESULTS

These patients presented with a severe congenital phenotype, including eye misalignment, visual impairment, epilepsy, global developmental delay, and subsequent development of pyramidal signs. Biallelic nonsense variants were discovered in both the cases (NM_000435.3:c.2203 C > T (p. [Arg735Ter]). Livedo reticularis was not reported in our cases, although it was present in previously reported patients. Autosomal recessive NOTCH3-related leukodystrophy is usually caused by biallelic null mutations in NOTCH3.

CONCLUSIONS

The phenotype of biallelic null variants is associated with a more severe phenotype than the dominantly inherited form of the disease.

摘要

背景

NOTCH3是一种在动脉平滑肌细胞和毛细血管周细胞上表达的大型I型跨膜受体，其特征是具有34个表皮生长因子样重复序列的多样细胞外结构域。由于变异的纯合性和类型，它表现出不同的表型；错义突变导致伴有脑血管病变的大脑常染色体显性动脉病伴皮质下梗死和白质脑病（CADASIL），而无效突变则导致严重的先天性表现。

方法

本报告描述了两例NOTCH3功能丧失性纯合变异病例及其临床表现。

结果

这些患者表现出严重的先天性表型，包括眼球斜视、视力障碍、癫痫、全面发育迟缓以及随后出现的锥体束征。两例均发现双等位基因无义变异（NM_000435.3:c.2203 C>T（p.[Arg735Ter]）。尽管先前报道的患者有网状青斑，但我们的病例中未报告。常染色体隐性NOTCH3相关脑白质营养不良通常由NOTCH3的双等位基因无效突变引起。