The relationship between serum phenylalanine levels, genotype, and developmental assessment test results in non-phenylketonuria mild hyperphenylalaninemia patients

Phenylalanine (PA) levels below 360 µmol/L do not require treatment; however, cognitive deficits have been observed in patients with elevated PA levels, necessitating a safe upper limit for treatment and therapeutic objectives. The main purpose of this study is to evaluate the correlation between developmental assessments (Denver Developmental Screening Test-II [DDST-II] and Ankara Developmental Screening Inventory [ADSI]) and electroencephalogram (EEG) findings with blood PA levels and genotypic data in non-phenylketonuria mild Hyperphenylalaninemia (HPA) patients, to re-evaluate their treatment status based on potential adverse outcomes. This study encompassed 40 patients aged 1–5 years diagnosed with HPA and not on treatment, identified through initial blood PA levels, and monitored for a minimum of 1 year on an unrestricted diet. Data on demographics, serum PA levels during presentation and follow-up, and genetic mutations were retrieved from hospital records. Patients were categorized into two groups as well-controlled (120–240 µmol/L) and at-risk (240–360 µmol/L) based on average PA levels. Sleep-activated EEGs and developmental assessments using the DDST-II and ADSI were conducted to compare outcomes with PA levels and genetic findings. Developmental delays in the DDST-II were observed across language, gross motor, fine motor, and personal-social domains, predominantly in males. No significant difference in delays was noted between the well-controlled and at-risk groups based on PA levels. The ADSI revealed delays in similar developmental areas, with fine motor skills being particularly prominently affected in the at-risk group. Only a well-controlled patient showed abnormal EEG results deemed unrelated to HPA.

Conclusion: Our findings indicate that children with untreated PA levels above 240 µmol/L are particularly susceptible to fine motor skill impairments, suggesting a need to reassess the PA level thresholds for initiating treatment. This study highlights the potential requirement for amending current guidelines to ensure early and appropriate intervention in non-PKU mild HPA patients, thereby mitigating the risk of developmental delays.