Güttler F, Guldberg P
Danish Center for Human Genome Research, John F Kennedy Institute, Glostrup.
Acta Paediatr Suppl. 1994 Dec;407:49-56. doi: 10.1111/j.1651-2227.1994.tb13451.x.
Phenylalanine hydroxylase (PAH) deficiency is a heterogeneous disease at the phenotype level. The spectrum of clinical and metabolic phenotypes spans from the potential pathogenic disease classical phenylketonuria (PKU) to the benign condition non-PKU hyperphenylalaninemia (non-PKU HPA). This review provides an introduction to the clinical variants of PAH deficiency, and summarizes our attempts to define the disease at the molecular level and to relate mutation genotype to clinical outcome. Complete genotype determination in a large number of patients with PAH-deficient hyperphenylalaninemia demonstrates that clinical heterogeneity can be explained by a multiplicity of mutations in the PAH gene. Some combinations of mutations are associated with phenylalanine levels fluctuating around the border between PKU and non-PKU HPA. However, certain mutations seem always to cause non-PKU HPA irrespective of the mutation on the second allele and can, therefore, unambiguously be designated as being associated with the non-PKU HPA phenotype. Our results suggest that mutation analysis in newborns presenting with hyperphenylalaninemia can be used for rapid and highly efficient differential diagnosis of PAH deficiency, and for predicting the severity of the disease. These possibilities may facilitate and optimize the management of hyperphenylalaninemia and thereby improve prognosis.
苯丙氨酸羟化酶（PAH）缺乏症在表型水平上是一种异质性疾病。临床和代谢表型的范围从潜在的致病性疾病经典苯丙酮尿症（PKU）到良性的非PKU高苯丙氨酸血症（非PKU HPA）。本文综述了PAH缺乏症的临床变异型，并总结了我们在分子水平上对该疾病进行定义以及将突变基因型与临床结果相关联的尝试。对大量PAH缺乏性高苯丙氨酸血症患者进行完整的基因型测定表明，临床异质性可以由PAH基因中的多种突变来解释。某些突变组合与苯丙氨酸水平在PKU和非PKU HPA之间的边界附近波动有关。然而，某些突变似乎总是导致非PKU HPA，而与第二个等位基因上的突变无关，因此，可以明确地将其指定为与非PKU HPA表型相关。我们的结果表明，对出现高苯丙氨酸血症的新生儿进行突变分析可用于PAH缺乏症的快速高效鉴别诊断，并预测疾病的严重程度。这些可能性可能有助于并优化高苯丙氨酸血症的管理，从而改善预后。
