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