Current concepts in the pathogenesis of urea cycle disorders

Abstract

The common feature of urea cycle diseases (UCD) is a defect in ammonium elimination in liver, leading to hyperammonemia. This excess of circulating ammonium eventually reaches the central nervous system, where the main toxic effects of ammonium occur. These are reversible or irreversible, depending on the age of onset as well as the duration and the level of ammonium exposure. The brain is much more susceptible to the deleterious effects of ammonium during development than in adulthood, and surviving UCD patients may develop cortical and basal ganglia hypodensities, cortical atrophy, white matter atrophy or hypomyelination and ventricular dilatation. While for a long time, the mechanisms leading to these irreversible effects of ammonium exposure on the brain remained poorly understood, these last few years have brought new data showing in particular that ammonium exposure alters several amino acid pathways and neurotransmitter systems, cerebral energy, nitric oxide synthesis, axonal and dendritic growth, signal transduction pathways, as well as K⁺ and water channels. All these effects of ammonium on CNS may eventually lead to energy deficit, oxidative stress and cell death. Recent work also proposed neuroprotective strategies, such as the use of NMDA receptor antagonists, nitric oxide inhibitors, creatine and acetyl-l-carnitine, to counteract the toxic effects of ammonium. Better understanding the pathophysiology of ammonium toxicity to the brain under UCD will allow the development of new strategies for neuroprotection.

Introduction

Ammonia is produced by intestinal urease-positive bacteria and amino acid metabolism, and is mostly present as ammonium $({\text{NH}}_4^{+})$ at physiological pH. ${\text{NH}}_4^{+}$ is maintained at low concentrations (50–150 μM in preterm neonates, 50–75 μM in term neonates, and <50 μM in adults) through conversion of ${\text{NH}}_4^{+}$ to urea by the urea cycle, for which complete expression occurs in liver exclusively (see [1, and references cited therein]).

Excess of ${\text{NH}}_4^{+}$ is toxic to the central nervous system (CNS). In adults, liver failure results in hyperammonemia responsible for a potentially severe neuropsychiatric disorder named hepatic encephalopathy, which progressively leads to altered mental status and coma. The symptoms of hepatic encephalopathy in adults can be reversed when ${\text{NH}}_4^{+}$ concentration returns to normal levels, provided that terminal cerebral edema is not reached. In pediatric patients, hyperammonemia can be caused by various inherited or acquired disorders [2], the most frequent being urea cycle disorders (UCD) with an overall prevalence estimated at 1:8200 in the United States [3], [4]. The developing brain is much more susceptible to the deleterious effects of ${\text{NH}}_4^{+}$ than the adult brain. Hyperammonemia can provoke irreversible damage to developing CNS, with presentation symptoms such as cognitive impairment, seizures and cerebral palsy [5], [6]. Hyperammonemic neonates and infants develop cortical atrophy, ventricular enlargement, demyelination or gray and white matter hypodensities [4], [6], [7]. The extent of the irreversible damage depends on the maturation of the brain and on the magnitude and duration of ${\text{NH}}_4^{+}$ exposure. Irreversibility mainly occurs in case of prolonged hyperammonemic crises and/or when blood ${\text{NH}}_4^{+}$ reaches levels between 200 and 500 μM, during the two first years of life [8], [9], [10], [11], [12]. This review will focus on the most recent advances in understanding the pathogenesis of UCD and ammonium toxicity on the developing CNS.