研究报告: TMEM163变异致髓鞘形成低下患者随访两例及iPSC构建

目的 探讨TMEM163变异导致髓鞘形成低下性脑白质营养不良（HLD）患者的临床特征及遗传学特点,归纳自然病程,以提高对该疾病认识,并构建患者来源诱导多能干细胞,为致病机制研究建立基础。方法 随访2009~2022年北京大学第一医院儿科就诊的2例TMEM163变异致病患儿,对临床表现、遗传学数据、蛋白质结构数据进行分析,总结临床遗传学特点,并采集患儿外周血构建诱导多能干细胞。结果 临床特点：2例患儿均具有早期运动语言发育迟缓、头颅磁共振成像显示脑白质髓鞘化不良,且症状随生长发育逐渐减轻的特点;均于婴儿期起病,以眼球震颤为首发症状,学龄期症状好转。遗传学特点：2例患儿均为TMEM163同一位点新发错义变异c.227T>G p.（L76R）、c.227T>C p.（L76P）,均为国际上首例报道。病例2来源外周血单个核细胞成功重编程为诱导多能干细胞。结论 本研究为国际首次随访TMEM163变异致病髓鞘形成低下性脑白质营养不良患儿,完善了其自然病程,扩展了对髓鞘形成低下性脑白质营养不良临床表型认识,并首次构建了TMEM163 c.227T>C p.（L76P）变异患者来源诱导多能干细胞,为进一步致病机制研究打下基础。

Research Papers: Clinical Follow-up of Patients With Hypomyelinating Leukodystrophy Caused by TMEM163 Variants and Generation of The Human Induced Pluripotent Stem Cell Line From a Patient

Objective To explore the clinical and genetic characteristics of patients with hypomyelinating leukodystrophy caused by TMEM163 mutation, track the natural history of the disease, and to construct patient-derived induced pluripotent stem cells, thus laying the foundation for mechanism research.Methods Clinical and genetic data of two patients (Pt1, Pt2) with TMEM163 mutation were collected from 2009 to 2022 in Department of Pediatrics, Peking University First Hospital. The clinical manifestations, genetic data, and protein structure data were analyzed. Peripheral blood of Pt2 was collected to construct induced pluripotent stem cell (iPSC).Results Clinical features: both patients showed early motor and language development retardation and hypomyelination abnormalities from brain magnetic resonance imaging (MRI), however, the symptoms gradually alleviated; nystagmus was the first symptom, abnormal gait, low muscle tone and mild to moderate developmental retardation were observed in both of them; Pt1 has the same growth and development level as children of the same age at 7 years old. Genetic features: both cases were newly detected missense variants at the same locus of TMEM163 c.227T>G p.(L76R), c.227T>C p.(L76P). The differentiation of iPSC induced by peripheral blood monocytes from Pt2 was consistent with the characteristics of iPSC.Conclusion The follow-up study of 2 children with HLD contributes to the understanding of the natural history of HLD caused TMEM163 mutation, expands the understanding of the clinical phenotype of HLD, and constructs TMEM163 c.227T>C p.(L76P) iPSC, which lays a foundation for the mechanism study.