Confirmatory testing for OTC includes a plasma amino acid profile, which may show reduced citrulline and arginine concentrations with increased glutamate and alanine. A urine organic acid profile shows increased excretion of orotic acid after protein loading or with concurrent administration of allopurinol. Mutation testing, deletion testing, and sequencing of the entire coding region of the related genes are available as clinical tests.
Argininosuccinate lyase (ASL) deficiency is autosomal recessive, and most children in the United States are detected as a result of an elevated citrulline on newborn screening. The diagnosis is confirmed by the detection of elevated argininosuccinic acid in the urine.
Treatment of Hyperammonemia
During episodes of symptomatic hyperammonemia, proteinintake is reduced, and intravenous glucose is given in sufficient quantity to suppress catabolism of endogenous protein. Ammonia can be eliminated by use of the alternate pathway agents, sodium benzoate and sodium phenylacetate, which are excreted in the urine as conjugates of glycine andglutamine. Arginine, which is usually deficient, is supplied.When ammonia levels are very high (>1000 µM) or refractory to therapy, direct removal of ammonia using hemodialysis or hemofiltration, but not peritoneal dialysis, is required.The neurologic status must be followed closely and cerebraledema treated promptly. Despite successful management ofhyperammonemic crises, the long-term outcome for males with severe neonatal OTC deficiency and all children with severe ASL deficiency is guarded. Early liver transplantationhas increased survival, especially in males with severe OTC deficiency.
Restriction of dietary protein intake to daily needs is the mainstay of ongoing treatment for urea cycle defects. Crystalline essential amino acids can be supplied in amounts just sufficient to support protein synthesis. Arginine is an essential amino acid when arginine synthesis via the urea cycle is grossly impaired; thus arginine must be supplied except in the case of arginase deficiency. Citrulline needs to be supplied for some urea cycle disorders. For OTC deficiency and carbamoyl phosphate synthase deficiency, treatment with phenylbutyrate (which is metabolized to phenylacetate) prevents accumulation of ammonia.
Cystinuria is a disorder of renal tubular transport of cystine, lysine, arginine, and ornithine. Although intestinal transport is affected in some genetic forms, the symptoms are largely due to the renal transport abnormality. The concentration of cystine exceeds its solubility product and results in significant renal stones. Evaluation and diagnosis are based on the pattern of amino acid excretion in the urine. Mutation testing can be done. Treatment is based on increasing the solubility of cystine by complexing it with compounds such as penicillamine.
Intestinal transport of tryptophan is impaired in Hartnup syndrome; pellagra-like symptoms result from this deficiency. Diagnosis is based on the amino acid pattern in urine. Treatment with tryptophan is successful.
Organic acid disorders result from a block in the pathways of amino acid catabolism. Occurring after the amino moiety has been removed, they result in the accumulation of specific organic acids in the blood and urine. Treatment is directed at the specific abnormality, with restriction in precursor substrates and administration of enzyme cofactors, when available. Outcome is generally poor for children with neonatal-onset propionic or methylmalonic acidemia but is influenced by frequency and severity of crises and is optimal when diagnosis is made before the onset of the first episode. Liver transplantation has been used in some patients with early indicators of success. Confirmatory testing begins with a urine organic acid profile and plasma amino acid profile. More specific testing often requires enzyme measurements in appropriate tissues. When abnormal results suggest a specific disorder, DNA testing may identify the mutations involved.