Vieira Neto Eduardo, Laranjeira Francisco, Quelhas Dulce, Ribeiro Isaura, Seabra Alexandre, Mineiro Nicole, Carvalho Lilian M, Lacerda Lúcia, Ribeiro Márcia G
Agência Nacional de Saúde Suplementar, Gerência de Monitoramento Assistencial, Rio de Janeiro, Brazil.
Serviço de Genética Médica, Instituto de Puericultura e Pediatria Martagão Gesteira, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Mol Genet Genomic Med. 2019 May;7(5):e610. doi: 10.1002/mgg3.610. Epub 2019 Mar 3.
Genetic heterogeneity and compound heterozygosis give rise to a continuous spectrum of phenylalanine hydroxylase deficiency and metabolic phenotypes in phenylketonuria (PKU). The most used parameters for evaluating phenotype in PKU are pretreatment phenylalanine (Phe) levels, tolerance for dietary Phe, and Phe overloading test. Phenotype can vary from a "classic" (severe) form to mild hyperphenylalaninemia, which does not require dietary treatment. A subset of patients is responsive to treatment by the cofactor tetrahydrobiopterin (BH ). Genotypes of PKU patients from Rio de Janeiro, Brazil, were compared to predicted and observed phenotypes. Genotype-based estimations of responsiveness to BH were also conducted.
Phenotype was defined by pretreatment Phe levels. A standard prediction system based on arbitrary assigned values was employed to measure genotype-phenotype concordance. Patients were also estimated as BH -responders according to the responsiveness previously reported for their mutations and genotypes.
A 48.3% concordance rate between genotype-predicted and observed phenotypes was found. When the predicted phenotypes included those reported at the BIOPKU database, the concordance rate reached 77%. A total of 18 genotypes from 30 patients (29.4%) were estimated as of potential or probable BH responsiveness. Inconsistencies were observed in genotypic combinations including the common "moderate" mutations p.R261Q, p.V388M, and p.I65T and the mild mutations p.L48S, p.R68S, and p.L249F.
The high discordance rate between genotype-predicted and observed metabolic phenotypes in this study seems to be due partially to the high frequency of the so-called "moderate" common mutations, p.R261Q, p.V388M, and p.I65T, which are reported to be associated to erratic or more severe than expected metabolic phenotypes. Although our results of BH estimated responsiveness must be regarded as tentative, it should be emphasized that genotyping and genotype-phenotype association studies are important in selecting patients to be offered a BH overload test, especially in low-resource settings like Brazil.
基因异质性和复合杂合性导致苯丙酮尿症（PKU）患者中苯丙氨酸羟化酶缺乏和代谢表型呈现出连续的谱系。PKU中用于评估表型的最常用参数是治疗前苯丙氨酸（Phe）水平、对饮食中Phe的耐受性以及Phe负荷试验。表型可从“经典”（严重）形式到轻度高苯丙氨酸血症不等，后者不需要饮食治疗。一部分患者对辅因子四氢生物蝶呤（BH）治疗有反应。将巴西里约热内卢PKU患者的基因型与预测和观察到的表型进行了比较。还基于基因型对BH反应性进行了估计。
根据治疗前Phe水平定义表型。采用基于任意赋值的标准预测系统来衡量基因型与表型的一致性。还根据先前报道的患者突变和基因型的反应性将患者估计为BH反应者。
发现基因型预测表型与观察到的表型之间的一致性率为48.3%。当预测表型包括BIOPKU数据库中报告的表型时，一致性率达到77%。30名患者中的18种基因型（29.4%）被估计具有潜在或可能的BH反应性。在包括常见的“中度”突变p.R261Q、p.V388M和p.I65T以及轻度突变p.L48S、p.R68S和p.L249F的基因型组合中观察到不一致情况。
本研究中基因型预测的代谢表型与观察到的代谢表型之间的高不一致率似乎部分归因于所谓“中度”常见突变p.R261Q、p.V388M和p.I65T的高频率，据报道这些突变与不稳定或比预期更严重的代谢表型相关。尽管我们关于BH估计反应性的结果必须被视为初步的，但应该强调的是，基因分型和基因型-表型关联研究对于选择接受BH负荷试验的患者很重要，尤其是在像巴西这样资源匮乏的地区。
