1 - Newborn Screening, Metabolic and Genetics Unit, Department of Human Genetics, National Institute of Health Dr Ricardo Jorge, Porto, Portugal
2 - i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
3 - IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
4 - FCUP - Faculty of Sciences, University of Porto, Porto, Portugal
5 - Inherited Metabolic Disease Reference Center, Pediatric Department, Centro Hospitalar Universitário do Porto, Porto, Portugal
6 - Metabolic Diseases Unit, Pediatric Department, University Center São João Hospital - HSJ, Porto, Portugal
7 - Inherited Metabolic Disease Reference Center, Pediatric Hospital, Hospital and University Center of Coimbra, Coimbra, Portugal
8 - Metabolic Unit, Hospital Dona Estefânia, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal
9 - Pediatric Department, Hospital Central of Funchal, Funchal, Portugal
10 - Pediatrics Department, Hospital of Divino Espírito Santo of Ponta Delgada, EPE, Ponta Delgada, Azores, Portugal
11 - Inherited Metabolic Disease Reference Center, Lisbon North University Hospital Center (CHULN), EPE, Lisboa, Portugal
12 - Research and Development Unit, Department of Human Genetics, National Institute of Health Dr Ricardo Jorge, Porto, Portugal
- Mol Genet Genomic Med. 2021 Mar;9(3):e1559. doi: 10.1002/mgg3.1559. Epub 2021 Jan 19. PMID: 33465300; PMCID: PMC8104178.
Resumo:
Background: 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.
Methods: In this report, the biochemical and genetic findings performed in 223 patients diagnosed through the Portuguese Neonatal Screening Program (PNSP) are presented.
Results: 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).
Conclusion: 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.