Phenylketonuria in Saudi Arabia: An Overview of Diagnosis, Genetics, and Therapeutic Strategies

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene, resulting in toxic phenylalanine accumulation that, if untreated, causes profound intellectual disability and neurodevelopmental impairment. PKU is especially significant in the Kingdom of Saudi Arabia (KSA), where high consanguinity rates substantially elevate disease prevalence relative to Western populations, and the country’s expanding newborn screening programs have highlighted PKU as a persistent public health concern. This review provides a translational synthesis of the Saudi PKU literature, covering epidemiology, molecular pathophysiology, genetics, clinical presentation, diagnosis, treatment, prognosis, and future directions. We summarize global and regional incidence data and show that Saudi Arabia, driven by consanguinity, is among the countries with the highest reported PKU burden worldwide. We review the metabolic basis of phenylalanine neurotoxicity and the allelic heterogeneity of the PAH gene, with attention to variants enriched in Saudi and Arab cohorts, including the founder allele p.R252W. Diagnostic pathways anchored in newborn screening and tandem mass spectrometry are discussed alongside neurodevelopmental outcomes and gaps in Saudi PKU surveillance. We outline established and emerging therapies, including dietary management, sapropterin (BH4), pegvaliase, large neutral amino acids, and investigational gene and mRNA therapies. Throughout, we identify where genuine Saudi-specific evidence exists and where general PKU knowledge is extrapolated to the Saudi context because of limited local data, most notably the absence of a national PKU registry. This review is intended to serve as a translational reference for clinicians, metabolic dietitians, geneticists, and policymakers engaged in PKU care in Saudi Arabia and the wider Arab region.