AUTHOR=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. , Fiesco-Roa M. O. , Fernández-Lainez C. 

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

JOURNAL=Frontiers in Genetics

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.993612

DOI=10.3389/fgene.2022.993612

ISSN=1664-8021

ABSTRACT=<p><bold>Background:</bold> Pterin profiles or molecular analyses of hyperphenylalaninemia (HPA) caused by phenylalanine hydroxylase (PAH) deficiency or tetrahydrobiopterin deficiency (BH4D) are not always available in low- or middle-income countries, including Mexico, limiting information regarding the phenotypic and genotypic characteristics of patients exhibiting BH4D.</p><p><bold>Objective:</bold> To report the genotypes underlying BH4D and the clinical presentation in unrelated Mexican HPA pediatric patients with normal <italic>PAH</italic> genotypes who attended a single metabolic reference center in Mexico.</p><p><bold>Methods:</bold> Automated Sanger sequencing of the <italic>PTS</italic>, <italic>QDPR</italic>, and <italic>PCBD1</italic> genes of 14 HPA patients was performed. Predicted effects on protein structure caused by missense variants were assessed by <italic>in silico</italic> protein modeling.</p><p><bold>Results and discussion:</bold> A high prevalence of BH4D was noted in our HPA cohort (9.8%, N = 14/142). Clinically relevant biallelic genotypes were identified in the <italic>PTS</italic> (N = 7/14 patients), <italic>QDPR</italic> (N = 6/14 patients), and <italic>PCBD1</italic> (N = 1/14 patients) genes. Four novel <italic>QDPR</italic> variants [c.714dup or p.(Leu239Thrfs*44), c.106-1G&gt;T or p.(?), c.214G&gt;T or p.(Gly72*), and c.187_189dup or p.(Gln63dup)] were identified. <italic>In silico</italic> protein modeling of six missense variants of <italic>PTS</italic> [p.(Thr67Met), p.(Glu81Ala), and p.(Tyr113Cys)], <italic>QDPR</italic> [p.(Cys161Phe) and p.(Pro172Leu)], and <italic>PCBD1</italic> [p.(Glu97Lys)] supports their pathogenicity. Progressive neurological symptoms (mainly intellectual and motor impairment and even death in three patients) were noted in all patients with biallelic <italic>QDPR</italic> genotypes and in 5/7 patients bearing biallelic <italic>PTS</italic> genotypes. The single homozygous <italic>PCBD1</italic> p.(Glu97Lys) patient remains asymptomatic.</p><p><bold>Conclusion:</bold> A higher proportion of BH4D (9.8 vs. 1%–2% worldwide), attributable to a heterogeneous mutational spectrum and wide clinical presentation, was noted in our Mexican HPA cohort, with the <italic>PTS</italic>-related HPA disorder being the most frequent. Sequencing-based assays could be a reliable approach for diagnosing BH4D in our population.</p>