Newborn Screening, Metabolic and Genetics Unit, Department of Human Genetics, National Institute of Health Dr Ricardo Jorge, Porto, Portugal.
i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
Mol Genet Genomic Med. 2021 Mar;9(3):e1559. doi: 10.1002/mgg3.1559. Epub 2021 Jan 19.
The impairment of the hepatic enzyme phenylalanine hydroxylase (PAH) causes elevation of phenylalanine levels in blood and other body fluids resulting in the most common inborn error of amino acid metabolism (phenylketonuria). Persistently high levels of phenylalanine lead to irreversible damage to the nervous system. Therefore, early diagnosis of the affected individuals is important, as it can prevent clinical manifestations of the disease.
In this report, the biochemical and genetic findings performed in 223 patients diagnosed through the Portuguese Neonatal Screening Program (PNSP) are presented.
Overall, the results show that a high overlap exists between different types of variants and phenylalanine levels. Molecular analyses reveal a wide mutational spectrum in our population with a total of 56 previously reported variants, most of them found in compound heterozygosity (74% of the patients). Intragenic polymorphic markers were used to assess the haplotypic structure of mutated chromosomes for the most frequent variants found in homozygosity in our population (p.Ile65Thr, p.Arg158Gln, p.Leu249Phe, p.Arg261Gln, p.Val388Met, and c.1066-11G>A).
Our data reveal high heterogeneity at the biochemical and molecular levels and are expected to provide a better understanding of the molecular basis of this disease and to provide clues to elucidate genotype-phenotype correlations.
肝脏酶苯丙氨酸羟化酶（PAH）的缺陷会导致血液和其他体液中苯丙氨酸水平升高，从而导致最常见的氨基酸代谢遗传缺陷（苯丙酮尿症）。苯丙氨酸持续高水平会对神经系统造成不可逆转的损害。因此，早期诊断受影响个体非常重要，因为这可以预防疾病的临床表现。
本报告介绍了通过葡萄牙新生儿筛查计划（PNSP）诊断的 223 名患者进行的生化和遗传研究结果。
总体而言，结果表明不同类型的变异体与苯丙氨酸水平之间存在高度重叠。分子分析显示我们人群中的突变谱很广，共有 56 种先前报道的变异体，其中大多数为复合杂合性（患者的 74%）。使用基因内多态性标记来评估在我们人群中发现的纯合子中最常见的变异体（p.Ile65Thr、p.Arg158Gln、p.Leu249Phe、p.Arg261Gln、p.Val388Met 和 c.1066-11G>A）的突变染色体的单倍型结构。
我们的数据揭示了生化和分子水平的高度异质性，有望更好地理解该疾病的分子基础，并为阐明基因型-表型相关性提供线索。
