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.

What is known: • It is known that phenylalanine levels between 120 and 360 μmol/L typically do not require intervention in non-PKU mild HPA patients, but outcomes for levels near this threshold remain unclear.

What is new: • Children with PA levels exceeding 240 µmol/L are at a higher risk of fine motor skill impairment, requiring a reassessment of safe PA levels to prevent developmental delays. • In addition, the Denver Developmental Screening Test II reveals developmental delays in multiple areas in children with non-PKU mild HPA, particularly in males, highlighting the need for gender-specific monitoring and intervention strategies.