Psychiatric phenotypes associated with hyperprolinemia: A systematic review

Yasmin Namavar, Denise Joanne Duineveld, Geertje Ingena Angelique Both, Ania Maria Fiksinski, Jacob Abraham Schrey Vorstman, Nanda Margriet Verhoeven-Duif, Janneke Rozemarijn Zinkstok

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7 Citations (Scopus)


Hyperprolinemia Type I and II are genetic metabolic disorders caused by disrupted proline degradation. It has been suggested that hyperprolinemia is associated with increased risk of developmental and mental disorders but detailed information on the psychiatric phenotype in hyperprolinemic patients is limited. Following PRISMA guidelines, we carried out a systematic review to clarify psychiatric phenotypes in patients with hyperprolinemia. We screened 1753 studies and included 35 for analysis, including 20 case reports and 15 case–control and cohort studies. From these studies, a common psychiatric phenotype is observed with a high prevalence of developmental delay, intellectual disability, autism spectrum disorders, and psychosis spectrum disorders. In most cases, a genetic cause of hyperprolinemia was known, these included mutations in the PRODH and ALDH4A1 genes and deletions of chromosome 22q11.2. No evidence for a biochemical phenotype-clinical phenotype correlation was found; that is, no association between higher proline levels and specific psychiatric phenotypes was observed. This suggests that genomic and environmental factors are likely to contribute to clinical outcomes. More studies are needed to clarify whether hyperprolinemia is a primary causal factor underlying the increased risk of developing psychiatric disorders seen in patients with hyperprolinemia, or whether hyperprolinemia and psychiatric disorders are both consequences of a shared underlying mechanism.
Original languageEnglish
Pages (from-to)289-317
Number of pages29
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Issue number5
Early online date2021
Publication statusPublished - Jul 2021


  • 22q11 deletion syndrome
  • ALDH4A1
  • hyperprolinemia
  • mental disorders

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