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An Updated PAH Mutational Spectrum of Phenylketonuria in Mexican Patients Attending a Single Center: Biochemical, Clinical-Genotyping Correlations

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Laboratorio de Errores Innatos del Metabolismo y Tamiz, Subdirección de Medicina Experimental, Instituto Nacional de Pediatría, Secretaría de Salud, Ciudad de Mexico 04530, Mexico
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Laboratorio de Biología Molecular, Subdirección de Investigación Médica, Instituto Nacional de Pediatría, Secretaría de Salud, Ciudad de Mexico 04530, Mexico
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Unidad de Genética de la Nutrición, Instituto de Investigaciones Biomédicas, UNAM/Instituto Nacional de Pediatría, Ciudad de Mexico 04530, Mexico
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Academic Editor: David N. Cooper
Genes 2021, 12(11), 1676; https://doi.org/10.3390/genes12111676
Received: 27 September 2021 / Revised: 18 October 2021 / Accepted: 19 October 2021 / Published: 23 October 2021
(This article belongs to the Section Human Genomics and Genetic Diseases)
Establishing the genotypes of patients with hyperphenylalaninemia (HPA)/phenylketonuria (PKU, MIM#261600) has been considered a cornerstone for rational medical management. However, knowledge of the phenylalanine hydroxylase gene (PAH) mutational spectrum in Latin American populations is still limited. Herein, we aim to update the mutational PAH spectrum in the largest cohort of HPA/PKU Mexican patients (N = 124) reported to date. The biallelic PAH genotype was investigated by Sanger automated sequencing, and genotypes were correlated with documented biochemical phenotypes and theoretical tetrahydrobiopterin (BH4) responsiveness. Patients were biochemically classified as having classic PKU (50%, 62/124), mild PKU (20.2%, 25/124) and mild HPA (29.8%, 37/124). Furthermore, 78.2% of the included patients (97/124) were identified by newborn screening. A total of 60 different pathogenic variants were identified, including three novel ones (c. 23del, c. 625_626insC and c. 1315 + 5_1315 + 6insGTGTAACAG), the main categories being missense changes (58%, 35/60) and those affecting the catalytic domain (56.6%, 34/60), and c. 60 + 5G > T was the most frequent variant (14.5%, 36/248) mainly restricted (69.2%) to patients from the central and western parts of Mexico. These 60 types of variants constituted 100 different biallelic PAH genotypes, with the predominance of compound-heterozygous ones (96/124, 77%). The expected BH4 responsiveness based on the PAH genotype was estimated in 52% of patients (65/124), mainly due to the p. (Val388Met) (rs62516101) allele. Instead, our study identified 27 null variants with an allelic phenotype value of zero, with a predominance of c. 60 + 5G > T, which predicts the absence of BH4 responsiveness. An identical genotype reported in BIOPKUdb was found in 92/124 (74%) of our patients, leading to a genotype–phenotype concordance in 80/92 (86.9%) of them. The high number of variants found confirms the heterogeneous and complex mutational landscape of HPA/PKU in Mexico. View Full-Text
Keywords: phenylketonuria; rare diseases; tetrahydrobiopterin; phenylalanine; newborn screening; Latin America; PAH molecular spectrum phenylketonuria; rare diseases; tetrahydrobiopterin; phenylalanine; newborn screening; Latin America; PAH molecular spectrum
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MDPI and ACS Style

Vela-Amieva, M.; Alcántara-Ortigoza, M.A.; Ibarra-González, I.; González-del Angel, A.; Fernández-Hernández, L.; Guillén-López, S.; López-Mejía, L.; Carrillo-Nieto, R.I.; Belmont-Martínez, L.; Fernández-Lainez, C. An Updated PAH Mutational Spectrum of Phenylketonuria in Mexican Patients Attending a Single Center: Biochemical, Clinical-Genotyping Correlations. Genes 2021, 12, 1676. https://doi.org/10.3390/genes12111676

AMA Style

Vela-Amieva M, Alcántara-Ortigoza MA, Ibarra-González I, González-del Angel A, Fernández-Hernández L, Guillén-López S, López-Mejía L, Carrillo-Nieto RI, Belmont-Martínez L, Fernández-Lainez C. An Updated PAH Mutational Spectrum of Phenylketonuria in Mexican Patients Attending a Single Center: Biochemical, Clinical-Genotyping Correlations. Genes. 2021; 12(11):1676. https://doi.org/10.3390/genes12111676

Chicago/Turabian Style

Vela-Amieva, Marcela, Miguel A. Alcántara-Ortigoza, Isabel Ibarra-González, Ariadna González-del Angel, Liliana Fernández-Hernández, Sara Guillén-López, Lizbeth López-Mejía, Rosa I. Carrillo-Nieto, Leticia Belmont-Martínez, and Cynthia Fernández-Lainez. 2021. "An Updated PAH Mutational Spectrum of Phenylketonuria in Mexican Patients Attending a Single Center: Biochemical, Clinical-Genotyping Correlations" Genes 12, no. 11: 1676. https://doi.org/10.3390/genes12111676

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