In all the neonatal hyperammonemic diseases, the liver is often enlarged and liver cells appear to be inadequate in their metabolic functions, but how the enzymatic deficiencies or other disorders of amino acid metabolism affect the brain remains uncertain. It must be assumed that in some the saturation of the brain by ammonia impairs the oxidative metabolism of cerebral neurons, and when blood levels of ammonium increase (from protein ingestion, constipation, etc.), episodic coma or a more chronic impairment of cerebral functions occurs—as it does in adults with cirrhosis of the liver and portal-systemic encephalopathy. In the acutely fatal cases, the brain is swollen and edematous, and the astrocytes are diffusely increased in number and enlarged. The neurons are normal. Astrocytic swelling has been attributed to the accumulation of glutamate secondary to a suppression of glutamate synthetase. These changes have been reproduced in animals by the injection of ammonium chloride. When the hyperammonemia is abrupt in onset and severe, the resulting combination of encephalopathy, brain swelling, and respiratory alkalosis simulates the Reye syndrome (see “Reye-Johnson Syndrome” in Chap. 39).
As in all forms of liver disease, valproic acid and other hepatic toxins may cause hepatic coma by further impairing the urea cycle enzymes. Notable are a few cases of inherited hyperammonemia that come to light in childhood or adulthood only after the administration of one of these drugs. Most cases of OTC present in the neonatal period with hyperammonemia but milder forms may appear later in life with episodic symptoms such as stupor, ataxia, and seizures. The other features have been mentioned above.
Treatment of the hyperammonemic syndromes The treatment of acute hyperammonemic syndromes is directed at lowering ammonia levels, initially by hemodialysis, exchange transfusions, and administration of phenylacetate and sodium benzoate, which may divert nitrogen from the ureagenesis cycle or act as ammonia scavengers. A report of treatment for 299 patients treated with phenylacetate (or phenylbutyrate) and benzoate showed an overall survival of 84 percent including a large proportion of children who were comatose on admission (see Enns et al).
With subsidence of the acute symptoms, a systematic form of management should be undertaken, as outlined by Brusilow and colleagues and by Msall and colleagues Arginine (50 to 150 mg/kg) should be added to the diet, as a deficiency of this substance may be responsible for the mental retardation and skin rashes associated with the native disorder. In more chronic cases, treatment consists of decreasing the ammonium load by the use of dietary protein restriction and by administration of oral antibiotics and lactulose. In infants with inborn errors of ureagenesis, there is a constant danger of recurrent episodes of hyperammonemia and coma, particularly in response to infections. In a few instances, careful management of the metabolic error has resulted in normal psychomotor development. Liver transplantation is curative.
These conditions are caused by a deficiency of a-keto acid dehydrogenase, resulting in the accumulation of the branched-chain amino acids leucine, isoleucine, and valine and the corresponding branched-chain a-keto acids, which may be detected in plasma and urine. Detection is part of most newborn screening panels. Maple syrup urine disease may be taken as the prototype. The pattern of inheritance of maple syrup urine disease is autosomal recessive and at least three types have been detected, each with a different genetic locus. The incidence is highest in Amish, Mennonite, and Jewish populations.