MFSD8变异所致的成人起病的神经元蜡样脂褐质沉积症7型患者1例的临床特征及遗传学分析

Clinical characteristics and genetic analysis of a case with adult-onset neuronal ceroid lipofuscinosis type 7 due to variant of MFSD8 gene

目的探讨1例成人起病的神经元蜡样脂褐质沉积症7型(CLN7)患者的临床表型及基因变异特点。方法选择2021年6月于河南省人民医院被确诊为CLN7女性患者为研究对象。采用回顾性分析方法,对该例患者的临床病例资料、辅助检查及基因检测结果进行分析。结果患者年龄为39岁,其主要临床表现为进行性视力下降、癫痫、共济失调和轻度认知减退;其神经影像学检查结果显示以小脑为主的全脑萎缩;眼底照相显示视网膜色素变性(RP);皮肤组织病理学活检可见腺体外周间质细胞较多的脂褐素颗粒沉积。全外显子组测序(WES)提示患者MFSD8基因存在c.1444C>T(p.R482*)和c.104G>A(p.R35Q)复合杂合变异,其中c.1444C>T为已被文献报道的致病性无义变异,而c.104G>A为迄今尚未见报道的错义变异,Sanger测序显示患者的女儿、儿子及患者兄长分别携带c.1444C>T(p.R482*)、c.104G>A(p.R35Q)、c.104G>A(p.R35Q)变异,符合CLN7常染色体隐性遗传致病特点。结论本研究发现迄今发病年龄最晚的CLN7病例,临床特征为成年期起病的多系统受累,小脑萎缩及RP可进一步提示诊断,MFSD8基因的c.1444C>T(p.R482*)和c.104G>A(p.R35Q)复合杂合变异可能为该患者的遗传学病因。

Objective To explore the clinical characteristics and genetic variants in a patient with adult-onset ceroid lipofuscinosis neuronal type 7(CLN7).Methods A female patient diagnosed with CLN7 in Henan Provincial People′s Hospital in June 2021 was selected as the study subject.Clinical data,auxiliary examination and result of genetic testing were retrospectively analyzed.Results The patient,a 39-year-old female,has mainly presented progressive visual loss,epilepsy,cerebellar ataxia and mild cognitive decline.Neuroimaging analysis has revealed generalized brain atrophy,prominently cerebellum.Fundus photography has revealed retinitis pigmentosa.Ultrastructural skin examination has revealed granular lipofuscin deposits in the periglandular interstitial cells.Whole exome sequencing(WES)revealed that she has harbored compound heterozygous variants of the MSFD8 gene,namely c.1444C>T(p.R482*)and c.104G>A(p.R35Q).Among these,c.1444C>T(p.R482*)was a well established pathogenic variant,while c.104G>A(p.R35Q)was a missense variant unreported previously.Sanger sequencing confirmed that the daughter,son and elder brother of the proband have respectively carried heterozygous c.1444C>T(p.R482*),c.104G>A(p.R35Q),and c.104G>A(p.R35Q)variants of the same gene.The family has therefore fit with the autosomal recessive inheritance pattern of the CLN7.Conclusion Compared with previously reported cases,this patient has the latest onset of the disease with a non-lethal phenotype.Her clinical features have involved multiple systems.Cerebellar atrophy and fundus photography may be indicative of the diagnosis.The c.1444C>T(p.R482*)and c.104G>A(p.R35Q)compound heterozygous variants of the MFSD8 gene probably underlay the pathogenesis in this patient.