Inherited Hyperammonemic Syndromes

Abstract

The term congenital hyperammonemia is generic, and the condition can be caused by inborn deficiencies of urea cycle enzymes, by some disorders of ornithine and lysine metabolism, and by some inborn errors of branched-chain amino acid catabolism. Ammonia toxicity produces similar clinical manifestations in all disorders causing hyperammonemia. The toxicity is primarily neurological, other metabolic consequences of hyperammonemia being less serious. Electroencephalographic changes, metabolic disturbances, disruption of neuronal microtubules, and histopathological appearance of Alzheimer type II astrocyte nuclei all occur with experimental as well as clinical hyperammonemia. When blood ammonia levels are excessive, particularly with alkalosis, fever, hypoxia, or hypoglycemia, there is irrationality, irritability, gastrointestinal upset, alternating hypotonia and hypertonia, convulsions, coma, and death. The early effects of hyperammonemia are reversible, but recurrent or persistent hyperammonemia can result in irreversible brain damage in those who survive. Characteristic aggravation or precipitation of symptoms by increased dietary protein or constipation, or a history of protein aversion, should raise the suspicion of hyperammonemia. After the confirmation of hyperammonemia, the precise biochemical diagnosis will require testing for abnormalities of blood and urine amino acids, and may require assays for specific enzymes in blood cells, cultured cells, or even liver biopsies. Treatment is by restriction of protein intake and prevention of constipation. Moderately severe hyperammonemia can be successfully treated with a low protein diet, perhaps supplemented by lactulose or other cathartic therapy. Severe hyperammonia is lethal in the newborn period, and attempts at treatment have often been unsuccessful. Prevention of recurrence is possible by genetic counseling and by antenatal diagnosis of some of these disorders.