Citation: Waisbren SE, Gropman AL, Members of the Urea Cycle Disorders Consortium (UCDC), Batshaw ML. Improving long term outcomes in urea cycle disorders—report from the Urea Cycle Disorders Consortium [published online May 23, 2016]. J Inherit Metab Dis. doi:10.1007/s10545-016-9942-0.
Purpose: To summarize outcome-related findings of a Urea Cycle Disorders Consortium (UCDC) longitudinal study started in 2006 and enrolling 678 patients, focusing primarily on neuropsychological and neurocognitive function across multiple subtypes, and neuroimaging findings in a cohort of patients with ornithine transcarbamylase (OTC) deficiency.
- Age group–specific neuropsychological evaluations of 528 patients indicate that each UCD subtype may associate with its own phenotype of cognitive and behavioral characteristics that can vary over time.
- Among children with OTC deficiency, half of those at school age (6-16 years) demonstrated “internalizing problems”, and 40% of preschool (aged 3-5 years) boys were rated as “withdrawn”.
- While the preschool cohort of children with argininosuccinate synthetase (ASS) deficiency exhibited strengths in reasoning abilities, they also showed weaknesses in visual-spatial understanding and fine motor skills, and were often rated as hyperactive and/or having attention issues.
- School-aged children with argininosuccinate lyase (ASL) deficiency did not show behavioral issues, yet did demonstrate deficits in memory, verbal fluency, attention, visual motor skills, motor strength, and dexterity.
- Behaviors common to children with autism spectrum disorder were noted in preschool children with carbamyl phosphate synthetase 1 (CPS1) deficiency.
- Intelligence test scores tended to remain stable in those patients with OTC, CPS1, or ASS deficiency who were examined by longitudinal and/or cross-sectional analysis.
- Identification by newborn screening showed a significant positive effect in cognitive testing scores in children with ASL deficiency when compared with initial diagnoses resulting from clinical episodes of hyperammonemia.
- Multiple neuroimaging findings published during the course of the study demonstrated the neuropathological effects of ammonia elevations in a cohort of patients with OTC deficiency that included “asymptomatic” females.
- Magnetic resonance spectroscopy suggested that low myoinositol and/or a high ratio of glutamine to myoinositoI in specific regions of the brain can be used as a biomarker of a previous episode of hyperammonemia.1
- Diffusion tensor imaging detected changes in white matter microstructure in fiber tracts that underlie executive function and working memory pathways.2,3
- Functional magnetic resonance imaging provided evidence of impaired frontal lobe processing and reduced connectivity in the brain, which could be related to inferior neuropsychological performance.4,5