ORNITHINE TRANSCARBAMYLASE DEFICIENCY - PATHOGENESIS OF THE CEREBRAL DISORDER AND NEW PROSPECTS FOR THERAPY

Ornithine Transcarbamylase (OTC) is a key urea cycle enzyme. Congenita l OTC deficiencies in humans result in hyperammonemia and a spectrum o f neurological symptoms including hypotonia, seizures and mental retar dation. Neuropathologic evaluation reveals cerebral atrophy, ventricul ar enlargement and Alzheimer type II astrocytosis. Using an animal mod el of congenital OTC deficiency, the sparse fur (spf) mouse, recent st udies have revealed significant alterations of cholinergic, serotonine rgic and glutamatergic neurotransmitter systems. Possible pathophysiol ogic mechanisms responsible for neuronal cell loss in OTC deficiency i nclude a deficit in cerebral energy metabolism, and glutamate excitoto xicity. Therapy continues to rely on alternative substrate administrat ion including sodium benzoate and sodium phenylacetate. Experimental e vidence suggests that acetyl-l-carnitine and glutamate (NMDA) receptor antagonists could be potentially useful therapeutic agents. Liver tra nsplantation is effective in many patients and recent experimental stu dies using adenoviral vectors suggest that gene therapy may ultimately be useful in the treatment of congenital OTC deficiency.