PDF(Pubmed)
Abstract：
NOTCH1-related leukoencephalopathy is a new diagnostic entity linked to heterozygous gain-of-function variants in NOTCH1 that neuroradiologically show some overlap with the inflammatory microangiopathy Aicardi-Goutières syndrome (AGS). To report a 16-year-old boy harbouring a novel NOTCH1 mutation who presented neuroradiological features suggestive of enhanced type I interferon signalling. We describe five years of follow-up and review the current literature on NOTCH1-related leukoencephalopathy. Clinical evaluation, standardised scales (SPRS, SARA, CBCL, CDI-2:P, WISCH-IV and VABS-2) and neuroradiological studies were performed, as well as blood DNA analysis. For the literature review, a search was performed on Pubmed, Scopus and Web of Science up to December 2023 using the following text word search strategy: (NOTCH1) AND (leukoencephalopathy). Our patient presents clinical features consistent with other reported cases with NOTCH1 mutations but is among the minority of patients with an onset after infancy. During the five-year follow-up, we observed an increase in the severity of spasticity and ataxia. However, at the age of 16 years, our proband is still ambulatory. As for other reported patients, he manifests psychiatric features ranging from hyperactivity during childhood to anxiety and depression during adolescence. The neuroradiological picture remained essentially stable over five years. In addition to the typical findings of leukoencephalopathy with cysts and calcifications already described, we report the presence of T2-hyperintensity and T1-hypotensity of the transverse pontine fibres, enhancement in the periventricular white matter after gadolinium administration and decreased NAA and Cho peaks in the periventricular white matter on MRS. We identified a novel heterozygous variant in NOTCH1 (c.4788_4799dup), a frame insertion located in extracellular negative regulatory region (NRR)-domain as in previously published cases. Blood interferon signalling was not elevated compared to controls. This case provides further data on a new diagnostic entity, i.e., NOTCH1-related leukoencephalopathy. By describing a standardised five-year follow-up in one case and reviewing the other patients described to date, we outline recommendations relating to monitoring in this illness, emphasising the importance of psychiatric and gastroenterological surveillance alongside neurological and neuropsychological management. Studies are needed to better understand the factors influencing disease onset and severity, which are heterogeneous.
摘要：
NOTCH1相关的白质脑病是一种新的诊断实体，与NOTCH1中的杂合功能获得变异有关，在神经放射学上显示与炎性微血管病Aicardi-Goutières综合征（AGS）有一些重叠。报告一个16岁的男孩，他有一个新的NOTCH1突变，他的神经放射学特征提示I型干扰素信号增强。我们描述了五年的随访，并回顾了目前关于NOTCH1相关白质脑病的文献。临床评价,标准化量表(SPRS，萨拉,CBCL,CDI-2:P,进行了WISCH-IV和VABS-2）和神经放射学研究，还有血液DNA分析.对于文献综述，在Pubmed上进行了搜索，截至2023年12月，Scopus和WebofScience使用以下文本词搜索策略：（NOTCH1）和（白质脑病）。我们的患者表现出与其他报道的NOTCH1突变病例一致的临床特征，但在婴儿期后发病的患者中占少数。在为期五年的后续行动中，我们观察到痉挛和共济失调的严重程度增加。然而,16岁时,我们的先证者仍在门诊。至于其他报告的患者，他表现出从童年多动到青春期焦虑和抑郁的精神特征。神经放射学图像在五年内基本保持稳定。除了已经描述的具有囊肿和钙化的白质脑病的典型发现外，我们报告了横向脑桥纤维的T2-高强度和T1-低血压的存在，钆给药后脑室周围白质的增强和脑室周围白质中NAA和Cho峰的降低。我们在NOTCH1中鉴定了一个新的杂合变体（c.4788_4799dup），与先前发表的病例一样，位于细胞外负调节区（NRR）结构域的框架插入。与对照相比,血液干扰素信号没有升高。此案例提供了有关新诊断实体的进一步数据，即，NOTCH1相关白质脑病。通过描述一个病例的标准化五年随访，并回顾迄今为止描述的其他患者，我们概述了有关监测这种疾病的建议，强调精神和胃肠病监测与神经和神经心理管理的重要性。需要进行研究以更好地了解影响疾病发作和严重程度的因素，这是异质的。
