Hyperammonemia in Inherited Metabolic Diseases

Abstract

Ammonia is a neurotoxic compound which is detoxified through liver enzymes from urea cycle. Several inherited or acquired conditions can elevate ammonia concentrations in blood, causing severe damage to the central nervous system due to the toxic effects exerted by ammonia on the astrocytes. Therefore, hyperammonemic patients present potentially life-threatening neuropsychiatric symptoms, whose severity is related with the hyperammonemia magnitude and duration, as well as the brain maturation stage. Inherited metabolic diseases caused by enzymatic defects that compromise directly or indirectly the urea cycle activity are the main cause of hyperammonemia in the neonatal period. These diseases are mainly represented by the congenital defects of urea cycle, classical organic acidurias, and the defects of mitochondrial fatty acids oxidation, with hyperammonemia being more severe and frequent in the first two groups mentioned. An effective and rapid treatment of hyperammonemia is crucial to prevent irreversible neurological damage and it depends on the understanding of the pathophysiology of the diseases, as well as of the available therapeutic approaches. In this review, the mechanisms underlying the hyperammonemia and neurological dysfunction in urea cycle disorders, organic acidurias, and fatty acids oxidation defects, as well as the therapeutic strategies for the ammonia control will be discussed.

Keywords: Ammonia; Defects of fatty acids oxidation; Hyperammonemia; Organic acidurias; Urea cycle disorders.

Fig. 1

Urea cycle reactions. The urea cycle initiates in the mitochondria of hepatocytes from the reaction between ammonia and bicarbonate to form carbamylphosphate, which requires N-acetylglutamate (NAG) as an allosteric activator. Carbamylphosphate reacts with ornithine to produce citrulline that leaves the mitochondria and originates arginine in the cytosol. Arginine is cleaved by arginase 1 (ARG), restoring the ornithine and forming urea which is eliminated by kidneys. CPS1 carbamylphosphate synthase; OTC ornithine transcarbamylase; ASS argininosuccinate synthase; ASL argininosuccinate lyase

Fig. 2

Mechanisms of hyperammonemia in MMA and PA. Methylmalonyl-CoA and propionyl-CoA, the main metabolites of MMA and PA, respectively, exert inhibitory effects on N-acetyl glutamate synthase (NAGS). Besides, the enzymatic deficiencies involved in these disorders harm the synthesis of succinyl-CoA, therefore favoring the degradation of glutamine to produce 2-oxoglutarate. The consequence of these metabolic events is a high formation of ammonia which accumulates in blood of patients

Fig. 3

Suggested mechanisms of hyperammonemia in fatty acid oxidation disorders (FAOD) based on Fig. 1. In FAOD and carnitine cycle defects, the reduced acetyl-CoA availability (reduced availability of N-acetylglutamate (NAG) precursors) and the enzymatic inhibition of carbamylphosphate synthase 1 (CPS1; first enzyme of the urea cycle, which transforms ammonia to carbamylphosphate) impair the urea cycle detoxification capacity. The result of these restrictions processes can contribute to hyperammonemia in FAOD