中国现代神经疾病杂志 ›› 2017, Vol. 17 ›› Issue (7): 534-540. doi: 10.3969/j.issn.1672-6731.2017.07.010

• 神经系统遗传性疾病 • 上一篇    下一篇

2 脂肪酸羟化酶相关性神经变性病四例临床表型及基因突变分析

黄啸君, 刘晓黎, 王田, 沈隽逸, 陈生弟, 唐维国, 曹立   

  1. 201801 上海交通大学医学院附属瑞金医院北院神经内科(黄啸君);200025 上海交通大学医学院附属瑞金医院神经科 上海交通大学医学院神经病学研究所(刘晓黎,王田,沈隽逸,陈生弟,曹立);316021 浙江省舟山医院神经内科(唐维国)
  • 出版日期:2017-07-25 发布日期:2017-08-02
  • 通讯作者: 曹立(Email:caoli2000@yeah.net)
  • 基金资助:

    国家自然科学基金资助项目(项目编号:81571086);国家自然科学基金青年科学基金资助项目(项目编号:81600978);上海交通大学医学院高峰高原计划(项目编号:20161401);上海交通大学“医工交叉研究基金”资助项目(项目编号:YG2016MS64);浙江省科学技术厅2014年度公益性技术应用研究计划项目(项目编号:2014C33132)

Clinical phenotype and genetic mutation of fatty acid hydroxylase - associated neurodegeneration: analysis of four cases

HUANG Xiao-jun1, LIU Xiao-li2, WANG Tian2, SHEN Jun-yi2, CHEN Sheng-di2, TANG Wei-guo3, CAO Li2   

  1. 1Department of Neurology, North Department of Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201801, China
    2Department of Neurology and Institute of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200025, China
    3Department of Neurology, Zhoushan Hospital, Zhoushan 316021, Zhejiang, China
  • Online:2017-07-25 Published:2017-08-02
  • Contact: CAO Li (Email: caoli2000@yeah.net)
  • Supported by:

    This study was supported by the National Natural Science Foundation of China (No. 81571086), the National Natural Science Foundation of China for Young Scientists (No. 81600978), Shanghai Jiaotong University School of Medicine Peak and Plateau Program (No. 20161401), Crossing Program between Medicine and Industry supported by Shanghai Jiaotong University (No. YG2016MS64), and Non - Profit Technical Application Plan Project of Science Technology Department of Zhejiang Province, China in the Year 2014 (No. 2014C33132).

摘要:

目的 报道4例脂肪酸羟化酶相关性神经变性病患者,并复习相关文献,总结该病临床表型和基因突变特点。 方法 收集4 例脂肪酸羟化酶相关性神经变性病患者临床资料和家系资料,标准酚氯仿法提取患者及其父母基因组DNA 并行Sanger测序。 结果 4 例患者中3 例(例2、例3 和例4)具有典型脂肪酸羟化酶相关性神经变性病表现,1 例(例1)表现为非典型。FA2H 基因检测显示,4 例患者均存在FA2H 基因突变,其中例1 为复合杂合突变c.461G > A(p.Arg154His)和c.794T > G(p.Phe265Cys);例2 仅发现1 种已报道的杂合突变c.703C > T(p.Arg235Cys),进一步对例2 及其母进行单核苷酸多态性检测,亦未发现缺失突变;例3 为杂合突变c.688G > A(p.Glu230Lys)和插入突变c.172_173insGGGCCAGGAC(p.Ile58ArgfsX47);例4 为复合杂合突变c.688G > A(p.Glu230Lys)、c.968C > A(p.Pro323Gln)和c.976G > A(p.Gly326Asp),其父为c.688G > A(p.Glu230Lys)突变携带者,其母为c.968C > A(p.Pro323Gln)和c.976G > A(p.Gly326Asp)突变携带者。根据美国医学遗传学和基因组学会标准,例1的FA2H 基因杂合突变c.461G > A(p.Arg154His)为“可能致病”、c.794T > G(p.Phe265Cys)为“可能致病”;例2 的FA2H 基因杂合突变c.703C > T(p.Arg235Cys)为“ 可能致病”;例3 的FA2H 基因杂合突变c.688G > A(p.Glu230Lys)为“致病”、插入突变c.172_173insGGGCCAGGAC(p.Ile58ArgfsX47)为“致病”;例4 的FA2H基因杂合突变c.688G > A(p.Glu230Lys)为“ 致病”、c.968C > A(p.Pro323Gln)为“ 致病”、c.976G > A(p.Gly326Asp)为“可能致病”。 结论 脂肪酸羟化酶相关性神经变性病具有高度临床和遗传异质性,痉挛性截瘫是最主要的临床表现,对于复杂型常染色体隐性遗传性遗传性痉挛性截瘫,尤其合并构音障碍、智力减退、脑白质病变和小脑萎缩等临床特征的患者,应考虑FA2H 基因突变导致的脂肪酸羟化酶相关性神经变性病。

关键词: 神经变性疾病, 脂肪酸类, 混合功能氧化酶类, 表型, 基因, 突变

Abstract:

Objective   To report 4 cases of fatty acid hydroxylase - associated neurodegeneration (FAHN) and to summarize the clinical and genetic characteristics of FAHN by literatures review.  Methods   Four cases of FAHN patients' clinical and family data were collected in detail. The gDNA of patients and their parents were extracted from peripheral blood. FA2H gene was conducted and followed by Sanger sequencing.  Results  Among the 4 cases, 3 cases (Case 2, Case 3, Case 4) presented typical manifestations of FAHN while the other (Case 1) was atypical. Genetic sequencing showed FA2H gene mutation in all affected patients. Compound heterozygous mutation c.461G > A (p.Arg154His) and c.794T > G (p.Phe265Cys) were seen in Case 1. In Case 2, only one documented heterozygous mutation c.703C > T (p.Arg235Cys) was found, and dificit mutation was not found in single nucleotide polymorphism (SNP) chip test of the patient and her mother. Compound heterozygous mutation c.688G > A (p.Glu230Lys) and insertion mutation c.172_173insGGGCCAGGAC (p.Ile58ArgfsX47) were presented in Case 3. In Case 4, compound heterozygous mutation c.688G > A (p.Glu230Lys), c.968C > A (p.Pro323Gln) and c.976G > A (p. Gly326Asp) were seen, while his father was the carrier of c.688G > A (p.Glu230Lys) mutation and his mother was the carrier of c.968C > A (p.Pro323Gln) and c.976G > A (p.Gly326Asp) mutation. According to the standard of American College of Medical Genetics and Genomics (ACMG), c.461G > A (p.Arg154His) and c.794T > G (p.Phe265Cys) in Case 1, and c.703C > T (p.Arg235Cys) in Case 2 were considered as "likely pathogenic", while FA2H gene compound heterozygous mutation c.688G > A (p.Glu230Lys), insertion mutation c.172_173insGGGCCAGGAC (p.Ile58ArgfsX47) in Case 3 was as "pathogenic", and in Case 4, the FA2H gene mutation c.688G > A (p.Glu230Lys) and c.968C > A (p.Pro323Gln) were "pathogenic" and c.976G > A (p.Gly326Asp) was "likely pathogenic".  Conclusions  FAHN has highly clinical and genetic heterogenieity in which spastic paraplegia is the main clinical presentation. In typing diagnosis for patietns with autosomal recessive herditary spastic paraplegia (HSP), especially combined with dyslalia, dysnoesia, and clinical features of white matter lesion and cerebellar atrophy, FA2H gene mutation-induced FAHN should be considered.

Key words: Neurodegenerative diseases, Fatty acids, Mixed function oxygenases, Phenotype, Genes, Mutation