Della Vecchia Stefania, Tessa Alessandra, Pasquariello Rosa, Seabra Luis, Crow Yanick J, Battini Roberta
Department of Molecular Medicine and Neurogenetics, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy.
Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy.
Int J Mol Sci. 2024 Mar 1;25(5):2864. doi: 10.3390/ijms25052864.
-related leukoencephalopathy is a new diagnostic entity linked to heterozygous gain-of-function variants in that neuroradiologically show some overlap with the inflammatory microangiopathy Aicardi-Goutières syndrome (AGS). To report a 16-year-old boy harbouring a novel 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 -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: () 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 (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.
NOTCH1相关白质脑病是一种新的诊断实体，与NOTCH1基因杂合功能获得性变异有关，其神经放射学表现与炎症性微血管病Aicardi-Goutières综合征（AGS）有一些重叠。报告一名携带新的NOTCH1突变的16岁男孩，其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情况，并回顾了关于NOTCH1相关白质脑病的当前文献。进行了临床评估、标准化量表（SPRS、SARA、CBCL、CDI-2:P、WISC-IV和VABS-2）和神经放射学研究，以及血液DNA分析。对于文献综述，截至2023年12月，使用以下文本词搜索策略在Pubmed、Scopus和Web of Science上进行了搜索：（NOTCH1）AND（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，但属于婴儿期后发病的少数患者。在五年的随访中，我们观察到痉挛和共济失调的严重程度增加。然而，在16岁时，我们的先证者仍可行走。与其他报道的患者一样，他表现出从儿童期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。除了已经描述的白质脑病伴有囊肿和钙化的典型表现外，我们报告了桥横纤维的T2高信号和T1低信号、钆剂注射后脑室周围白质强化以及磁共振波谱显示脑室周围白质中NAA和Cho峰降低。我们在NOTCH1基因中鉴定出一个新的杂合变异（c.4788_4799dup），这是一个位于细胞外负调控区域（NRR）结构域的框内插入，与先前发表的病例相同。与对照组相比，血液中的干扰素信号没有升高。该病例为一种新的诊断实体，即NOTCH1相关白质脑病提供了进一步的数据。通过描述一个病例的标准化五年随访并回顾迄今描述的其他患者，我们概述了有关该疾病监测的建议，强调了在神经和神经心理管理的同时进行精神和胃肠病学监测的重要性。需要开展研究以更好地了解影响疾病发病和严重程度的因素，这些因素是异质性的。
