共济失调伴选择性维生素E缺乏症患者临床及基因突变特点

Clinical and genetic study of ataxia with isolated vitamin E deficiency

目的 探讨共济失调伴选择性维生素E缺乏症（ataxia with isolated vitamin E deficiency,AVED）患者的临床特征及其致病基因TTPA的突变特点.方法 应用聚合酶链反应（PCR）结合DNA直接测序法,对160例已排除Friedreich共济失调致病基因Frataxin内含子区（GAA）n三核苷酸纯合突变的常染色体隐性遗传家系先证者进行TTPA基因突变筛查;基于高效液相色谱法检测外周血维生素E水平;详细分析阳性病例的临床表型.结果 通过上述检测,发现2例患者（12.5‰）携带TTPA基因突变,分别是位于第3号外显子的纯合无义突变c.400C〉T（p.R134X）和位于第1号外显子的纯合插入突变c.83_84insGCGGCGCC.这2例患者外周血维生素E浓度分别为1.95、0.19mg/L[正常值（10.8±3.3）mg/L].除具有典型的共济失调表现外,2例患者还伴有脊柱侧弯.结论 我们在中国常染色体隐性遗传共济失调家系患者中发现2例患者携带TTPA基因纯合突变,插入突变c.83_84insGCGGCGCC为新突变.2例患者均伴有明显的血浆维生素E降低,且均表现为明显的脊柱侧弯,后者提示AVED存在一定的临床变异.

Objective To investigate the clinical features and genetic mutations of ataxia with isolated vitamin E deficiency （AVED）. Methods The TTPA gene was analyzed by polymerase chain reaction combined with sanger sequencing in the probands of 160 autosomal recessive cerebellar ataxia families, which had been excluded from GAA triplet repeat expansions of Frataxin gene. Furthermore, serum vitamin E was detected by high performance liquid chromatography. The clinical features of the positive cases were precisely analyzed. Results Sequencing of the TTPA gene revealed 2 patients （12. 5%o） carried mutations, one with homozygous nonsense mutation （ c. 400C 〉 T, p. R134X） in exon 3, and the other with homozygous insertional mutations （ c. 83_84insGCGGCGCC） in exon 1. Serum vitamin E were 1.95 mg/L and 0. 19 mg/L separately （normal （10. 8 ± 3.3） rag/L）. In addition to the typical characteristics of AVED, the cases presented with scoliosis. Conclusions We reported two cases with homozygous mutations of ＇Iq＇PA gene in Chinese autosomal recessive ataxia families, and c. 83_84insGCGGCGCC in exon 1 is a novel mutation. Severe decrease of serum vitamin E was detected. The two cases presented with scoliosis, indicating the clinical variability of the disease.