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

Abstract

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.

A Review of Disparities and Unmet Newborn Screening Needs over 33 Years in a Cohort of Mexican Patients with Inborn Errors of Intermediary Metabolism

“…The evolution of our technological platform could explain this, mainly the implementation of MS/MS in 2010 and the consolidation of a specialized interdisciplinary team composed of metabolic pediatricians, dietitians, biochemists, geneticists, and other professionals, such as quality-of-life experts. This team exerts joint efforts to increase the knowledge and awareness of health personnel to promote continuous training and diffusion of knowledge about NBS throughout the country [ 20 , 21 , 22 , 23 , 26 , 27 , 28 , 55 , 56 , 57 ]. Another reason could be the increase in private laboratories, including the expanded NBS service following the U.S. RUSP panel [ 12 , 31 ].…”

“…Few works have been published on the epidemiology of IEiM in Mexico, and most cover regional or local experiences regarding specific disorders [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. Therefore, Mexican patients with IEiM are under-represented in the current literature.…”

The BMI Z-Score and Protein Energy Ratio in Early- and Late-Diagnosed PKU Patients from a Single Reference Center in Mexico

“…Subjects enrolled had the following inclusion criteria: patients from one month to 18 years old who had a diagnosis of PAH deficiency confirmed biochemically (high Phe blood levels and a Phe/Tyrosine (Tyr) ratio >3) and by molecular studies (two demonstrated pathogenic variants in PAH [ 33 ]; HPA/PKU patients whose nutritional follow-up had been carried out in our reference center, and who had had nutritional treatment with Phe restriction supplemented with Phe-free metabolic formula according to the guidelines of the Southeast Regional Genetics Network (SERN) and the Genetic Metabolic Dietitians International (GMDI) [ 29 ]. Patients were categorized into two groups as follows: (1) early-diagnosed patients detected by NBS, whose treatment began in the first month of life and (2) late-diagnosed patients, those who started treatment after the first month of life.…”

Genotypic spectrum underlying tetrahydrobiopterin metabolism defects: Experience in a single Mexican reference center

“…The patients studied herein were selected from a total of 142 unrelated Mexican individuals who were confirmed to have HPA (Phe blood levels >120 μmol/L) at our laboratory as previously described ( Vela-Amieva et al, 2021 ). In 124 of these patients, the identification of biallelic PAH genotypes confirmed the underlying genetic etiology of their HPA deficiency; four patients showed a monoallelic PAH genotype, while in the remaining 14 patients, no PAH pathogenic variants were found ( Vela-Amieva et al, 2021 ). These 14 patients were included in the present study, and their medical follow-up was available for periods ranging from 2 to 31 years.…”