Neuropsychological attributes of urea cycle disorders: A systematic review of the literature

J Inherit Metab Dis. 2019 Nov;42(6):1176-1191. doi: 10.1002/jimd.12146. Epub 2019 Aug 1.


Urea cycle disorders (UCDs) are rare inherited metabolic conditions that impair the effectiveness of the urea cycle responsible for removing excess ammonia from the body. The estimated incidence of UCDs is 1:35 000 births, or approximately 113 new patients with UCD per year. This review summarizes neuropsychological outcomes among patients with the eight UCDs in reports published since 1980. Rates of intellectual disabilities published before (and including) 2000 and after 2000 were pooled and compared for each UCD. Since diagnoses for UCDs tended to occur earlier and better treatments became more readily available after the turn of the century, this assessment will characterize the extent that current management strategies have improved neuropsychological outcomes. The pooled sample included data on cognitive abilities of 1649 individuals reported in 58 citations. A total of 556 patients (34%) functioned in the range of intellectual disabilities. The decline in the proportion of intellectual disabilities in six disorders, ranged from 7% to 41%. Results from various studies differed and the cohorts varied with respect to age at symptom onset, age at diagnosis and treatment initiation, current age, severity of the metabolic deficiency, management strategies, and ethnic origins. The proportion of cases with intellectual disabilities ranged from 9% to 65% after 2000 in the seven UCDs associated with cognitive deficits. Positive outcomes from some studies suggest that it is possible to prevent or reverse the adverse impact of UCDs on neuropsychological functioning. It is time to "raise the bar" in terms of expectations for treatment effectiveness.

Keywords: intellectual disabilities; neuropsychological outcomes; urea cycle disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Child
  • Child, Preschool
  • Cognition / physiology*
  • Europe / epidemiology
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Intellectual Disability / diagnosis
  • Intellectual Disability / epidemiology*
  • Intellectual Disability / etiology*
  • Intellectual Disability / therapy
  • Male
  • Middle Aged
  • Neuropsychological Tests
  • Treatment Outcome
  • United States / epidemiology
  • Urea Cycle Disorders, Inborn / complications*
  • Urea Cycle Disorders, Inborn / epidemiology*
  • Urea Cycle Disorders, Inborn / psychology
  • Urea Cycle Disorders, Inborn / therapy
  • Young Adult