Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
Center for Bioinformatics and Computational Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
J Med Genet. 2022 Apr;59(4):351-357. doi: 10.1136/jmedgenet-2020-107383. Epub 2021 Apr 2.
Progressive cavitating leukoencephalopathy (PCL) is thought to result from mutations in nuclear genes affecting mitochondrial function and energy metabolism. To date, mutations in two subunits of complex I, and , have been reported to be related to PCL.
Patients underwent clinical examinations, brain MRI, skin biopsy and muscle biopsy. Whole-genome or whole-exome sequencing was performed on the index patients from two unrelated families with PCL. The effects of the mutations were examined through complementation of the mutation by cDNA expression.
The common clinical features of the patients in this study were recurring episodes of acute or subacute developmental regression that appeared in the first years of life, followed by gradual remissions and prolonged periods of stability. MRI showed leukoencephalopathy with multiple cavities. Three novel missense mutations were identified in these families. Complex I deficiency was confirmed in affected individuals' fibroblasts and a muscle biopsy. Functional and structural analyses revealed that these mutations affect the structural stability and function of the NDUFV2 protein, indicating that defective function is responsible for the phenotypes in these individuals.
Here, we report the clinical presentations, neuroimaging and molecular and functional analyses of novel mutations in in two sibling pairs of two Chinese families presenting with PCL. We hereby expand the knowledge on the clinical phenotypes associated with mutations in and the genotypes causative for PCL.
进行性囊性脑白质病（PCL）被认为是由于核基因突变影响线粒体功能和能量代谢所致。迄今为止，已报道复合物 I 的两个亚基 和 的突变与 PCL 相关。
患者接受了临床检查、脑部 MRI、皮肤活检和肌肉活检。对来自两个无关联的 PCL 家系的先证者进行了全基因组或全外显子组测序。通过 cDNA 表达来检验突变的影响。
本研究中患者的共同临床特征是反复发作的急性或亚急性发育性倒退，出现在生命的前几年，随后逐渐缓解并长时间稳定。MRI 显示伴有多个腔的脑白质病。在这些家系中发现了三个新的 错义突变。受影响个体的成纤维细胞和肌肉活检证实存在复合物 I 缺陷。功能和结构分析表明，这些突变影响 NDUFV2 蛋白的结构稳定性和功能，表明缺陷的 功能是这些个体表型的原因。
本研究报道了两个中国家系的 2 对同胞兄妹中 的新突变的临床表现、神经影像学以及分子和功能分析。我们在此扩展了与 突变相关的临床表型以及导致 PCL 的基因型的知识。
