Cognitive and behavioral impairment in mild hyperphenylalaninemia.

Area of Science:

• Neuroscience
• Pediatrics
• Metabolic Disorders

Background:

• Elevated phenylalanine (Phe) levels can negatively impact brain function.
• A threshold of 360 μmol/L is currently accepted as safe, not requiring treatment for hyperphenylalaninemia (HPA).
• The neurocognitive and behavioral effects of Phe levels between 240-600 μmol/L remain under investigation.

Purpose of the Study:

• To compare cognitive functions and attention-related problems in children with HPA and healthy controls.
• To evaluate the impact of untreated blood Phe levels within the 240-600 μmol/L range on neurodevelopment.
• To reassess the established safe upper limit for blood Phe levels.

Main Methods:

• A cohort of 41 untreated HPA patients (aged 6-16 years) with blood Phe levels between 240-600 μmol/L and 29 healthy controls were assessed.
• Patients were categorized into 'Phe 360-600 μmol/L' and 'Phe 240-360 μmol/L' subgroups based on lifetime median blood Phe.
• Comprehensive neurocognitive, attention, and behavioral assessments included WISC-IV, Conners' CPT, SDQ, and K-SADS-PL.

Main Results:

• All HPA patients exhibited significantly lower scores on most WISC-IV indexes compared to controls, with the exception of Working Memory.
• Both HPA subgroups showed reduced Full Scale IQ and Verbal Comprehension scores compared to controls.
• HPA patients demonstrated attention deficits (longer reaction times) and behavioral problems (more peer issues).

Conclusions:

• Untreated HPA patients, even with Phe levels between 240-360 μmol/L, are at risk for cognitive and attention-related problems.
• The current safe upper limit of 360 μmol/L for blood Phe may need reconsideration.
• Early intervention and treatment initiation for HPA should be considered at lower Phe thresholds to prevent neurodevelopmental impairments.