苯丙酮尿症患者智能障碍程度与基因型相关性分析

COMPARISON OF GENOTYPE AND INTELLECTUAL PHENOTYPE IN UNTREATED PHENYLKETONURIC CHILDREN

目的了解苯丙酮尿症（ｐｈｅｎｙｌｋｅｔｏｎｕｒｉａ，ＰＫＵ）患者智能障碍程度与突变基因性质的关系。方法应用ＰＣＲ－ＡＳＯ及ＰＣＲ－ＳＳＣＰ方法对４５例经典型ＰＫＵ患儿作突变基因检测。对查明基因型的２７例患儿就其智能障碍程度及基因突变性质作一比较。结果苯丙氨酸羟化酶基因型与患儿智能障碍程度缺乏一致性。２７例中仅８例表型与基因型相符，１９例不符。结论苯丙氨酸羟化酶基因突变性质与其表达的酶活性、与治疗前血苯丙氨酸浓度高低相关，但与就诊晚。

Objective The main feature of phenylketonuria(PKU) is mental retardation. Although classical PKU is defined as that the hepatic phenylalanine hydroxylase(PAH) activity ranges 0￣1% of normal enzyme, the untreated PKU patients show a wide range of intellectual phenotype. This study sought to find the molecular basis of such variation of intellectual phenotype among PKU.Methods 45 classical PKU patients included in the research were screened for detecting six mutant alleles which were rather common among Chinese PKU patients, i.e.R243Q,R413P,Y204C,Y356X,W326X and R111X。 PCR ASO and PCR SSCP techniques were used. The expression of those mutant PAH genes was analysed by methods of site directed mutagencies. 27 PKU patients whose two mutant allelles were both defined were involved in this study. The IQ of these patients were tested by DDST system.Results Among 27 patients, 4/27(15%) were mild retardation, 10/27(37%) were moderate, the severe mental retardation accounted for 12/27(44%). The relationship between genotype and intellectual phenotype in this group was examined. It was found that the intellectual phenotype of 8 patients were compatible with genotype but not well matched in 19 cases. The enzyme activity of Y204C expressed in vitro was 100%, but all 3 patients with Y204C/Y204C were severely mental retarded. Enzyme activities of R413P and Y356X were < 3% and 0 respectively in expression analysis, but the patients in this group had mild or moderate mental retardation.Conclusion Intellectual phenotype was not well matched with the genotype in classical PKU patients, so that genotype can not be used to predicte the intellectual phenotype in PKU patients.