Expanding diversity within phenylketonuria in ecuadorian patients: genetic analysis and literature review of newborn screenings

Abstract
Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by a deficiency in the phenylalanine
hydroxylase (PAH) enzyme, leading to the accumulation of phenylalanine and its metabolites, which are toxic to the
central nervous system. Without treatment, PKU can result in severe intellectual disability and neurological issues.
This study aims to present the first cohort of clinically described Ecuadorian PKU patients, analyzing genotypephenotype correlations and comparing these variants with global databases to improve diagnosis and treatment
in Ecuador. Detailed clinical histories were collected, and an analysis of genotype versus phenotype (affected
protein domain) of the variant was performed. Among the PAH genotypes identified, we found 15 distinct variants,
with c.[754 C>T](p.Arg252Trp); [754 C>T](p.Arg252Trp) being the most frequent genotype (23.68%), followed by
c.[1045T>C](p.Ser349Pro); [1045T>C](p.Ser349Pro) (15.79%) and c.[441+5G>T]; [754 C>T](p.Arg252Trp) (13.16%).
Additionally, several unique genotypes were identified, such as c.[140G>A](p.Ala47Val); [140G>A](p.Ala47Val)
and c.[331 C>T](p.Arg111Ter); [1243G>A](p.Asp415Asn), which are not commonly reported in other populations.
Most genotypes were heterozygous (63.2%). The majority of variants were missense variants (66.6%) affecting the
catalytic domain (53.3%). The highest phenylalanine levels were found in patients with c.[754 C>T](p.Arg252Trp);
[754 C>T] (p.Arg252Trp) (2700 umol/L). Phenotypic data were available for 11 patients, showing 45.45% with
classic PKU, 45.45% with mild hyperphenylalaninemia, and 9% with mild PKU. There was a 63.6% concordance with
the BIOPKU database. Five low-frequency genotypes not reported in BIOPKU were identified, suggesting unique
regional variants. Our study highlights the genetic complexity of PKU in Ecuador, with a high prevalence of unique
variants not commonly found in other regions. This underscores the necessity for region-specific genetic analysis
to improve PKU diagnosis and treatment. The findings emphasize the importance of tailored therapeutic strategies
and continued research to enhance outcomes for PKU patients in Latin America.