Urea cycle enzymopathies

Abstract

Inborn errors of urea cycle enzymes and transporters related to the urea cycle have been described. Ornithine transcarbamylase (OTC) deficiency, an X-linked genetic disorder is well characterised from the molecular genetic standpoint and over 100 mutations have been described. Clinical symptomatology varies according to the residual enzyme activity and may include seizures, mental retardation and cerebral palsy. Neuropathologic evaluation reveals brain atrophy, ventricular dilatation and delayed myelination. A well characterised animal model of OTC deficiency, the sparse fur (spf) mouse has been employed to study the neurochemistry of the disorder; abnormalities of the glutamatergic, cholinergic and serotoninergic neurotransmitter systems have been identified. Studies on the pathogenesis of the neuronal cell death in congenital OTC deficiency suggest that cerebral energy compromise and NMDA receptor-mediated excitotoxicity are implicated. Current therapy in congenital urea cycle disorders involves the reduction of circulating ammonia (using agents such as sodium benzoate and phenylacetate), L-carnitine administration to improve cellular energy metabolism and liver transplantation. Clinical trials using gene therapy are currently under evaluation. © 2007 Springer-Verlag US.