Phenylketonuria and evolutionary medicine

Evolutionary medicine applies the principles of evolution to the interpretation of epidemiology, pathophysiology, and the diversity of therapeutic responses to diseases in human populations. Phenylketonuria is the most common inherited disorder of amino acid metabolism, with an average global carrier prevalence of 1.5-2%. This autosomal recessive disorder leads to brain damage, severe intellectual disability, and neurological manifestations due to elevated blood concentrations of phenylalanine. The evolutionary interpretation of the high prevalence of deleterious mutations in the global population is based on the heterozygote advantage hypothesis. This hypothesis suggests that heterozygous carriers of the disease allele exhibited relatively higher evolutionary fitness over long periods compared to homozygotes with the normal allele. This advantage may arise from the increased phenylalanine levels in heterozygotes, which could enhance survival under conditions of low dietary protein intake. Additionally, heterozygotes may experience increased reproductive fitness, as they tend to have higher birth weights and a lower risk of fetal loss when exposed to environmental stressors, such as ochratoxin A, one of the most abundant food-contaminating mycotoxins. Further research is needed to thoroughly document the underlying mechanisms contributing to the evolutionary advantage of heterozygotes in phenylketonuria.