【摘要】 目的　对临床诊断为糖原累积症Ⅰa型的患儿及其父母进行葡萄糖 6 磷酸酶 (G6Pase)的基因突变筛查 ,并对基因突变完全相同的患儿进行临床特点的比较分析。方法　提取患儿及其父母外周血DNA ,分别进行G6Pase基因五个外显子的PCR扩增 ,纯化后进行DNA直接测序 ;对基因突变相同的 6家系 7例患儿进行临床表现、生化改变及对治疗反应的比较分析。结果　所有 7例患儿均为G6Pase基因外显子 5核苷酸位点第 72 7处纯合子型G→T的单个碱基突变 (G72 7T) ,而其父母均为此杂合突变的携带者。基因突变完全相同的 7例患儿临床表现的严重性、对治疗的反应不全相同 ,除经典的低血糖、生长发育落后、肝脏肿大、肾脏肿大、代谢性酸中毒和乳酸血症外 ,尚有脾大 (1例 ) ,轻度肝功能受损 (6例 ) ,多发肝腺瘤 (1例 )等。结论　G72 7T突变很可能是中国人种糖原累积症Ⅰa型的较常见突变 ;具有相同突变的患儿不仅临床表现轻重不同 ,而且 ,对生玉米淀粉治疗的反应也各有差异 ;通过典型的临床及生化表现辅以外周血基因分析 ,完全可以取代传统的有创伤性肝穿刺酶学分析的确诊方法更多还原

【Abstract】 Glycogen storage disease (GSD) type Ⅰa is an autosomal recessive disorder caused by a deficiency of glucose 6 phosphatase (G6Pase). The gene that encodes G6Pase was mapped to 17q21. The molecular genetic basis of GSD type Ia in the mainland Chinese population has not been explored. Objective To analyze the G6Pase gene mutations, and to compare the phenotypic features and the response to the corn starch treatment among patients who share the same mutation. Methods With the consent of the parents and their children, the authors studied 18 families with clinically diagnosed GSD type Ⅰa from our long time follow up groups. Direct DNA sequencing of all 5 exons and the exon intron boundaries of G6Pase gene were done on the blood specimens. Seven of the 18 patients, male 2 and female 5, aged 1.5 to 16 years, were homozygous for same mutation. The clinical symptoms, signs and the serum biochemical values before and after treatment were compared in these 7 patients. Results The 7 patients were homozygous of G→T transversion at the nucleotide 727 in exon 5 (G727T), which has previously been reported to cause abnormal splicing. The parents were heterozygous of the G727T mutation. All the patients exhibited typical features of GSD type Ⅰa with variable severity, including hypoglycemia, hepatomegaly, kidney enlargement, growth retardation, bleeding diathesis, lactic acidemia, hyperlipidemia, and hyperuricemia. Two of the patients had repeated hypoglycemic seizures before the age of 2 years. One had moderate splenomegaly when he came to our clinic at the age of 16, the spleen size was reduced to 2 cm below the left costal margin after 5 year treatment. His sister, homozygous of G727T, did not show splenomegaly. One had multiple hepatic adenoma since the age of 5 years. Four had 5 year delayed bone age when they started treatment at the age of 9 to 16 years, the bone age reached normal after 2 3 years treatment. No matter when they started corn starch treatment, the height increase in the first year was most obvious with an average of 10 cm. All the patients had abnormal liver function before treatment, 5 had constant slightly elevated liver enzymes with the treatment. All had normal urinalysis test, but the urine β 2 microglobulin was elevated. Conclusions G727T mutation may be the major cause of GSD type Ⅰa in China. Patients with the same mutation could have variable phenotypic characteristics, and the response to the corn starch treatment was different. The diagnosis of GSD type Ⅰa can be based on clinical and biochemical abnormalities combined with mutation analysis instead of enzyme assays on liver biopsy.更多还原