Developmental and Cognitive Outcomes in 342 Patients With Different Types of Hyperphenylalaninemia

Area of Science:

• Pediatric Metabolism and Nutrition
• Neurodevelopmental Disorders
• Genetics and Rare Diseases

Background:

• Hyperphenylalaninemia (HPA) encompasses a spectrum of conditions including phenylketonuria (PKU), characterized by elevated plasma phenylalanine (Phe) levels.
• Neurodevelopmental and cognitive outcomes in HPA patients are influenced by various factors, necessitating a deeper understanding for optimal management.

Purpose of the Study:

• To evaluate neurodevelopmental and cognitive outcomes in patients with different types of HPA.
• To identify factors influencing these outcomes, including age at diagnosis, treatment, and plasma Phe levels.
• To inform the debate on plasma Phe thresholds for initiating dietary treatment.

Main Methods:

• Retrospective assessment of 342 HPA patients (mild, moderate, classic PKU, and untreated HPA) with developmental/cognitive evaluations (1984-2018).
• Utilized Denver Developmental Screening Test (DDST), Stanford-Binet, and Wechsler Intelligence Scale for Children (WISC-R) for assessments.
• Analyzed relationships between intellectual disability/developmental delay (ID/DD), age at diagnosis, diagnostic methods, plasma Phe levels, and brain MRI findings.

Main Results:

• Significant associations found between ID/DD and age at diagnosis/diagnostic method in treated patients (p < 0.001, p < 0.01).
• Higher median plasma Phe levels observed in patients with ID/DD during follow-up (p < 0.024).
• White matter abnormalities on MRI correlated with PKU severity, ID/DD, and late-stage plasma Phe levels (p = 0.01, p < 0.001).
• Notably, 10% of untreated HPA patients exhibited ID/DD without other known risk factors.

Conclusions:

• Lifelong adherence and regular follow-up are crucial for normal neurodevelopmental and cognitive outcomes in PKU.
• Heterogeneity in clinical management across centers requires attention.
• The 10% developmental delay in untreated HPA patients necessitates urgent re-evaluation of plasma Phe treatment initiation thresholds.