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

Neurol Sci. 2022 Sep;43(9):5593-5603. doi: 10.1007/s10072-022-06194-6. Epub 2022 Jun 21.


Background: This systematic review study aims to evaluate the cognitive function of patients with mild hyperphenylalaninemia (mHPA) without treatment.

Methods: A systematic literature search was done from the 1st of May to the 30th of July in 2021 on published studies. The search strategy was ((hyperphenylalaninemia) OR (phenylketonuria) AND (cognition)). We use PubMed, Scopus, and the Web of Science databases. Studies which reported their findings regarding the cognitive function of patients with mHPA (screening serum phenylalanine > 120 and < 600 μmol/L) were included and reviewed.

Results: From initially retrieved 2805 studies, finally, 15 studies (10 on untreated patients with Phe levels below 360 μmol/L, 7 on untreated patients with Phe levels between 360 and 600 μmol/L, four 120-600 μmol/L) were selected. Most of the studies used the Wechsler Intelligence Scale for IQ evaluation, two (2/15) of them used the Stanford-Binet test and two used both tests. Four studies have reported a worse cognitive outcome compared to the control group, and in one study, relative defects in attention and working memory were reported. Other studies have reported normal IQ levels and no significant cognitive defects.

Conclusion: It is suggested that Phe levels between 120 and 360 μmol/L are generally safe. Some studies showed that untreated patients with higher levels might show some degrees of cognitive impairment. In conclusion, current knowledge is insufficient to state that treatment is not required for HPA patients to preserve their cognitive status, especially in patients with Phe levels of 360-600 μmol/L. Further studies with a larger sample size and standardized cognitive function evaluation tools are needed.

Keywords: Cognitive function; Executive function; Hyperphenylalaninemia; Phenylketonuria.

Publication types

  • Systematic Review

MeSH terms

  • Attention / physiology
  • Cognition
  • Humans
  • Memory, Short-Term
  • Phenylalanine
  • Phenylketonurias* / complications


  • Phenylalanine