Newborn screening predicts phenotype conversion and developmental outcome in hyperphenylalaninemia
Biochemical/Metabolic and Therapeutics
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Primary Categories:
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Secondary Categories:
Introduction:
Hyperphenylalaninemia (HPA), a mild form of phenylketonuria (PKU), is defined by phenylalanine (Phe) levels between 2-6 mg/dl (121-363 umol/l). Phe levels above 6 mg/dl require medical and/or dietary intervention to prevent neurodevelopmental complications. A subset of patients with HPA will eventually demonstrate elevated Phe levels above 6 mg/dl, effectively converting to a mild PKU phenotype and requiring therapy. However, the long-term outcome of HPA has been understudied and the risk factors and timeline for this conversion have not been defined. To address these questions, we performed a retrospective chart review in a cohort of individuals with HPA followed in a large metabolic center.
Methods:
Retrospective review of electronic medical records was used to evaluate 102 individuals referred to the Texas Children’s Hospital Metabolic Clinic between 2006 and 2024 for abnormal newborn screen (NBS) with elevated Phe levels. 35 individuals (20 males, 15 females) met inclusion criteria of benign HPA (Phe ≤ 6 mg/dl on NBS #1, NBS #2, and confirmatory plasma amino acids). Age at most recent visit ranged from 1 month to 14 years (average 4 years 1.9 months). Approximately 37% of this cohort (n=13) ultimately demonstrated elevated Phe level above 6 mg/dl, thus defined as “Risers”, as opposed to the “Non-Risers” group that remained within benign HPA Phe range.
Results:
NBS metabolite values, including phenylalanine, tyrosine (Tyr), and phenylalanine to tyrosine ratio (Phe/Tyr), were compared between the Risers and Non-Risers groups. Mean Phe levels at first NBS were significantly elevated in the Risers compared to Non-Risers group (4.10 mg/dl vs 3.08 mg/dl). NBS#2 Phe, Tyr levels, and Phe/Tyr ratio were not significantly different between groups. Interestingly, 69% of Risers (n=9) had reported developmental or behavioral issues, including speech delay, global developmental delay, and autism, whereas all Non-Risers had typical development. Additionally, 55% of Risers with developmental or behavioral issues showed symptoms before first documented occurrence of Phe >6 mg/dl. Genotype data was collected for each cohort; however, no genotype-phenotype correlation was found.
Conclusion:
In conclusion, we present here the long-term outcome of a cohort of individuals with HPA. Our data suggest that elevated Phe levels may be associated with increased risk for developmental delay or behavioral differences among individuals that converted to mild PKU phenotype. Importantly, NBS Phe levels may serve to predict the likelihood of conversion and indicate a need for more frequent monitoring of Phe levels so treatment can begin early in Risers. This study demonstrates that, despite the apparent benign clinical phenotype, HPA patients should be followed long term by a biochemical geneticist to track Phe levels and development.
Hyperphenylalaninemia (HPA), a mild form of phenylketonuria (PKU), is defined by phenylalanine (Phe) levels between 2-6 mg/dl (121-363 umol/l). Phe levels above 6 mg/dl require medical and/or dietary intervention to prevent neurodevelopmental complications. A subset of patients with HPA will eventually demonstrate elevated Phe levels above 6 mg/dl, effectively converting to a mild PKU phenotype and requiring therapy. However, the long-term outcome of HPA has been understudied and the risk factors and timeline for this conversion have not been defined. To address these questions, we performed a retrospective chart review in a cohort of individuals with HPA followed in a large metabolic center.
Methods:
Retrospective review of electronic medical records was used to evaluate 102 individuals referred to the Texas Children’s Hospital Metabolic Clinic between 2006 and 2024 for abnormal newborn screen (NBS) with elevated Phe levels. 35 individuals (20 males, 15 females) met inclusion criteria of benign HPA (Phe ≤ 6 mg/dl on NBS #1, NBS #2, and confirmatory plasma amino acids). Age at most recent visit ranged from 1 month to 14 years (average 4 years 1.9 months). Approximately 37% of this cohort (n=13) ultimately demonstrated elevated Phe level above 6 mg/dl, thus defined as “Risers”, as opposed to the “Non-Risers” group that remained within benign HPA Phe range.
Results:
NBS metabolite values, including phenylalanine, tyrosine (Tyr), and phenylalanine to tyrosine ratio (Phe/Tyr), were compared between the Risers and Non-Risers groups. Mean Phe levels at first NBS were significantly elevated in the Risers compared to Non-Risers group (4.10 mg/dl vs 3.08 mg/dl). NBS#2 Phe, Tyr levels, and Phe/Tyr ratio were not significantly different between groups. Interestingly, 69% of Risers (n=9) had reported developmental or behavioral issues, including speech delay, global developmental delay, and autism, whereas all Non-Risers had typical development. Additionally, 55% of Risers with developmental or behavioral issues showed symptoms before first documented occurrence of Phe >6 mg/dl. Genotype data was collected for each cohort; however, no genotype-phenotype correlation was found.
Conclusion:
In conclusion, we present here the long-term outcome of a cohort of individuals with HPA. Our data suggest that elevated Phe levels may be associated with increased risk for developmental delay or behavioral differences among individuals that converted to mild PKU phenotype. Importantly, NBS Phe levels may serve to predict the likelihood of conversion and indicate a need for more frequent monitoring of Phe levels so treatment can begin early in Risers. This study demonstrates that, despite the apparent benign clinical phenotype, HPA patients should be followed long term by a biochemical geneticist to track Phe levels and development.