Abstract
Urea cycle disorders (UCD) represent a group of rare inborn errors of metabolism that carry a high risk of mortality and neurological morbidity resulting from the effects of accumulation of ammonia and other biochemical intermediates. These disorders result from single gene defects involved in the detoxification pathway of ammonia to urea. UCD include deficiencies in any of the six enzymes and two membrane transporters involved in urea biosynthesis. It has previously been reported that approximately half of infants who present with hyperammonemic coma in the newborn period die of cerebral edema; and those who survive 3days or more of coma invariably have intellectual disability [1]. In children with partial defects there is an association between the number and severity of recurrent hyperammonemic (HA) episodes (i.e. with or without coma) and subsequent cognitive and neurologic deficits [2]. However, the effects of milder or subclinical HA episodes on the brain are largely unknown. This review discusses the results of neuroimaging studies performed as part of the NIH funded Rare Diseases Clinical Research Center in Urea Cycle Disorders and focuses on biomarkers of brain injury in ornithine transcarbamylase deficiency (OTCD). We used anatomic imaging, functional magnetic resonance imaging (fMRI), diffusion-tensor imaging (DTI), and (1)H/(13)C magnetic resonance spectroscopy (MRS) to study clinically stable adults with partial OTCD. This allowed us to determine alterations in brain biochemistry associated with changes in cell volume and osmolarity and permitted us to identify brain biomarkers of HA. We found that white matter tracts underlying specific pathways involved in working memory and executive function are altered in subjects with OTCD (as measured by DTI), including those heterozygous women who were previously considered asymptomatic. An understanding of the pathogenesis of brain injury in UCD is likely to advance our knowledge of more common disorders of liver dysfunction.