Inherited Hyperammonemias

Abstract

Hyperammonemia (systemic venous or arterial plasma ammonia >80 in newborns or >50 µmol/L after 28 days postnatally) is due either to an increased production exceeding the capacity to detoxify (as in colonization with urease containing microorganisms in an intestinal loop, a neurogenic bladder or with a ureterosigmoidostomy), or to a decreased detoxification capacity. Among the latter causes are primary or secondary defects of enzymes involved in ammonia detoxification or a deficiency of intermediates needed as substrates for a functional urea cycle, such as a nutritional, enzyme, or transport defect, or to interference with portal circulation so that portal blood does not reach the hepatocytes (a portacaval bypass or a patent ductus), which can cause “transient hyperammonemia of the premature”. Ammonia detoxification is reduced in deficiencies of urea cycle enzymes, transport proteins (estimated incidence 1:30 000 newborns, [1]) in conditions where glutamate or acetyl CoA is decreased (valproate therapy and organic acidurias), with carnitine and CoA (sequestered by pathological acyl moieties) and defects of mitochondrial beta-oxidation or carnitine metabolism. These lead to a deficient formation of N-acetylglutamate (NAG), an obligate activator of the first step of ammonia detoxification, and thus to a functional NAGS deficiency. An acetyl CoA deficiency further reduces pyruvate carboxylase, which blocks gluconeogenesis.