Chen Zhiyong, Tan Yi Jayne, Lian Michelle M, Tandiono Moses, Foo Jia Nee, Lim Weng Khong, Kandiah Nagaendran, Tan Eng-King, Ng Adeline S L
Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore, Singapore.
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
Front Neurol. 2021 Feb 1;12:631407. doi: 10.3389/fneur.2021.631407. eCollection 2021.
Leukodystrophies are a diverse group of genetic disorders that selectively involve the white matter of the brain and are a frequent cause of young-onset cognitive impairment. Genetic diagnosis is challenging. Data on the utility of incorporating brain magnetic resonance imaging (MRI) diagnostic algorithms with next-generation sequencing (NGS) for diagnosis in a real-life clinical setting is limited. We performed sequencing using a custom-designed panel of 200 neurodegeneration-associated genes on 45 patients with young-onset cognitive impairment with leukodystrophy, and classified them based on van der Knaap et al.'s MRI diagnostic algorithm. We found that 20/45 (44.4%) patients carried pathogenic variants or novel variants predicted to be pathogenic (one in , two in and 17 in ). All patients with an established genetic diagnosis had an MRI brain pattern consistent with a specific genetic condition/s. More than half (19/37, 51.4%) of patients with MRI changes consistent with vascular cognitive impairment secondary to small vessel disease (VCI-SVD) had pathogenic variants, including all patients with pathogenic (17/19, 89.5%) and variants (2/19, 11.5%). Amongst patients harboring pathogenic variants, 13/17 (76.5%) carried the p.R544C variant seen predominantly in East Asians. Anterior temporal white matter involvement was seen only in patients with pathogenic variants (6/17, 35.3%). Overall, we demonstrated a high diagnostic utility incorporating a targeted neurodegeneration gene panel and MRI-based diagnostic algorithms in young-onset cognitive impairment patients with leukodystrophy.
脑白质营养不良是一组多样的遗传性疾病，选择性累及脑白质，是青年期认知障碍的常见原因。基因诊断具有挑战性。关于在实际临床环境中将脑磁共振成像（MRI）诊断算法与下一代测序（NGS）结合用于诊断的效用的数据有限。我们对45例患有脑白质营养不良的青年期认知障碍患者，使用定制设计的包含200个神经退行性疾病相关基因的基因panel进行测序，并根据范德克纳普等人的MRI诊断算法对他们进行分类。我们发现，20/45（44.4%）的患者携带致病变异或预测为致病的新变异（其中1个在[具体基因1]，2个在[具体基因2]，17个在[具体基因3]）。所有已确诊基因诊断的患者，其脑部MRI模式均与特定的基因状况一致。超过一半（19/37，51.4%）的MRI改变与小血管病继发的血管性认知障碍（VCI-SVD）一致的患者携带致病变异，包括所有携带致病[具体基因4]变异（17/19，89.5%）和[具体基因5]变异（2/19，11.5%）的患者。在携带致病[具体基因4]变异的患者中，13/17（76.5%）携带主要在东亚人中出现的p.R544C变异。仅在携带致病[具体基因4]变异的患者中观察到颞前白质受累（6/17，35.3%）。总体而言，我们证明了在患有脑白质营养不良的青年期认知障碍患者中，结合靶向神经退行性疾病基因panel和基于MRI的诊断算法具有很高的诊断效用。
