Cognitive function in untreated subjects with mild hyperphenylalaninemia: a systematic review

Area of Science:

• Biochemistry
• Neuroscience
• Genetics

Background:

• Mild hyperphenylalaninemia (mHPA) is a metabolic disorder characterized by elevated phenylalanine levels.
• Cognitive function in untreated mHPA patients requires further evaluation to determine safe phenylalanine thresholds.

Purpose of the Study:

• To systematically review and evaluate the cognitive function of patients with mild hyperphenylalaninemia (mHPA) who are not undergoing treatment.
• To assess the impact of different phenylalanine (Phe) levels on cognitive outcomes in untreated mHPA.

Main Methods:

• A systematic literature search was conducted across PubMed, Scopus, and Web of Science databases from May 1 to July 30, 2021.
• Included studies focused on patients with mHPA (serum phenylalanine 120–600 μmol/L) and reported cognitive function findings.
• The search strategy targeted studies combining "hyperphenylalaninemia" or "phenylketonuria" with "cognition".

Main Results:

• Fifteen studies were selected, analyzing cognitive function in untreated patients with phenylalanine levels ranging from 120 to 600 μmol/L.
• Four studies reported worse cognitive outcomes compared to controls, with one noting attention and working memory deficits.
• Most studies utilized the Wechsler Intelligence Scale for IQ assessment; others used the Stanford-Binet test or both.

Conclusions:

• Phenylalanine levels between 120–360 μmol/L appear generally safe for cognitive function in untreated mHPA.
• Higher phenylalanine levels (360–600 μmol/L) may be associated with cognitive impairment, suggesting treatment may be necessary.
• Current evidence is insufficient to conclude that treatment is unnecessary for all HPA patients; further large-scale studies with standardized tools are recommended.