Medical Genetics, Clinical Developmental Sciences, St George's University of London, London, UK.
Hum Mutat. 2010 Apr;31(4):E1251-60. doi: 10.1002/humu.21205.
Hereditary spastic paraplegia (HSP) describes a heterogeneous group of inherited neurodegenerative disorders in which the cardinal pathological feature is upper motor neurone degeneration leading to progressive spasticity and weakness of the lower limbs. Using samples from a large Omani family we recently mapped a gene for a novel autosomal recessive form of HSP (SPG35) in which the spastic paraplegia was associated with intellectual disability and seizures. Magnetic resonance imaging of the brain of SPG35 patients showed white matter abnormalities suggestive of a leukodystrophy. Here we report homozygous mutations in the fatty acid 2-hydroxylase gene (FA2H) in the original family used to define the SPG35 locus (p.Arg235Cys) as well as in a previously unreported Pakistani family with a similar phenotype (p.Arg53_Ile58del). Measurement of enzyme activity in vitro revealed significantly reduced enzymatic function of FA2H associated with these mutations. These results demonstrate that mutations in FA2H are associated with SPG35, and that abnormal hydroxylation of myelin galactocerebroside lipid components can lead to a severe progressive phenotype, with a clinical presentation of complicated HSP and radiological features of leukodystrophy. (c) 2010 Wiley-Liss, Inc.
遗传性痉挛性截瘫（HSP）描述了一组异质性遗传性神经退行性疾病，其主要病理学特征是上运动神经元变性，导致下肢进行性痉挛和无力。我们最近使用来自一个大型阿曼家族的样本，将一种新型常染色体隐性遗传性 HSP （SPG35）基因定位于一个与智力残疾和癫痫相关的位置。SPG35 患者的大脑磁共振成像显示出白质异常，提示白质营养不良。在这里，我们报告了原始家族中 FA2H 基因（p.Arg235Cys）的纯合突变，该家族用于定义 SPG35 基因座，以及一个以前未报道的具有类似表型的巴基斯坦家族（p.Arg53_Ile58del）。体外酶活性测定显示，与这些突变相关的 FA2H 酶活性显著降低。这些结果表明，FA2H 基因突变与 SPG35 相关，髓鞘半乳糖脑苷脂脂质成分的异常羟化可导致严重的进行性表型，表现为复杂的 HSP 和白质营养不良的影像学特征。（c）2010 年 Wiley-Liss, Inc.
