PAH genotypes and their impact on sapropterin responsiveness in Thai patients with phenylalanine hydroxylase deficiency

Phenylketonuria (PKU) and hyperphenylalaninemia (HPA) are inherited metabolic disorders caused by phenylalanine hydroxylase (PAH) deficiency, leading to phenylalanine (Phe) accumulation and subsequent neurological impairment. Sapropterin therapy effectively reduces Phe levels in responsive patients, yet its efficacy among Thai patients with PAH deficiency remains unclear. A cohort study incorporating prospective and retrospective data enrolled 13 Thai patients with PAH deficiency from three rare disease centers. Participants underwent a 48-hour sapropterin loading test (20 mg/kg/day) with serial Phe measurements. Responsiveness was defined as a > 30% reduction in Phe levels. Genotype and Allelic Phenotype Value (APV) analyses were performed. In the five responsive patients who continued long-term sapropterin therapy, natural protein intake and psychometric outcomes were assessed longitudinally over six months. Sapropterin responsiveness was observed in 61.5% of patients, higher than previously reported. No patients with classic PKU responded, compared with 80% of those with mild PKU and 100% with mild HPA. Concordance between APV-predicted and observed phenotypes was 77.8%. Thai-specific PAH variants, p.(Arg169Leu), p.(Asp229GlufsTer54), and p.(Tyr317Asn), and a novel variant, p.(Gln226Glu), were identified. The 48-hour protocol improved detection of responsiveness compared with shorter durations. Among the five responsive patients who continued sapropterin treatment, natural protein tolerance increased, whereas no clear change in short-term psychometric outcomes was observed. This study represents the first cohort evaluating sapropterin responsiveness in Thai patients with PAH deficiency. Although limited by the small sample size, our findings suggest that sapropterin responsiveness may be relatively common among patients with milder phenotypes and provide preliminary data on genotype–phenotype correlations in the Thai population.