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Ornithine transcarbamylase deficiency: Pathogenesis of the cerebral disorder and new prospects for therapy

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Abstract

Ornithine Transcarbamylase (OTC) is a key urea cycle enzyme. Congenital OTC deficiencies in humans result in hypermmonemia and a spectrum of neurological symptoms including hypotonia, seizures and mental retardation. Neuropathologic evaluation reveals cerebral atrophy, ventricular enlargement and Alzheimer type II astrocytosis. Using an animal model of congenital OTC deficiency, the sparse fur (spf) mouse, recent studies have revealed significant alterations of cholinergic, serotoninergic and glutamatergic neurotransmitter systems. Possible pathophysiologic mechanisms responsible for neuronal cell loss in OTC deficiency include a deficit in cerebral energy metabolism, and glutamate excitotoxicity. Therapy continues to rely on alternative substrate administration including sodium benzoate and sodium phenylacetate. Experimental evidence suggest that acetyl-L-carnitine and glutamate (NMDA) receptor antagonists could be potentially useful therapeutic agents. Liver transplantation is effective in many patients and recent experimental studies using adenoviral vectors suggest that gene therapy may ultimately be useful in the treatment of congenital OTC deficiency.

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  1. Neuroscience Research Unit, Hôpital Saint-Luc (University of Montreal), Montreal, Quebec, Canada

    Adrianna Michalak & Roger F. Butterworth

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  1. Adrianna Michalak
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  2. Roger F. Butterworth
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This review article is dedicated to Professor Jean-Pierre Colombo, a pioneer investigator in urea cycle deficiencies, on the occasion of his retirement.

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Michalak, A., Butterworth, R.F. Ornithine transcarbamylase deficiency: Pathogenesis of the cerebral disorder and new prospects for therapy. Metab Brain Dis 12, 171–182 (1997). https://doi.org/10.1007/BF02674610

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