Argininemia

Urea cycle disorder that leads to hyperammonemia and neurologic symptoms, which are less severe than in other forms of urea cycle abnormalities.

Arginase Deficiency; Hyperargininemia; ARG1 Deficiency.

Unknown. No sexual predilection.

Autosomal recessive. Numerous mutations have been mapped to 6q23.

The hepatic urea cycle is the major pathway for metabolism and elimination of proteins and amino acids. Arginase is the mediator of the terminal step in the urea cycle, explaining the relatively mild clinical expression of the disease. Multiple allelic variants exist. The two isoenzymes of arginase—arginase-I (found in the liver) and arginase-II (located in the kidneys)—are specified by separate gene loci, called ARG1 (located on 6q23) and ARG2 (on 14q24.1-q24.3). The arginase-I isoenzyme contributes 98% of the arginase activity in the liver, and its absence is the cause of argininemia. Isoenzyme type II is inducible, and its activity may increase up to fourfold in patients suffering from argininemia. Arginase-II is used to metabolize arginine (released from hepatocytes) to produce urea and ornithine. While this urea is excreted, the newly synthesized ornithine returns to the liver and is incorporated in the urea cycle. Hyperammonemia in arginase deficiency can be severe but most often is mild to moderate because arginase-II can take over a certain degree of arginase-I function and because arginine (containing two nitrogen molecules) still can be released by the liver and then cleared by the kidneys. The first reason is that formed arginine, which contains two waste nitrogen molecules, can be released from the hepatocyte and excreted in urine.

Generally based on clinical findings of delayed development, protein intolerance, and spasticity. However, these symptoms are unspecific, and the diagnosis may be difficult and missed for a significant period of time. Diagnosis is confirmed by a red cell arginase assay. Prenatal diagnosis is possible using DNA analysis.

Onset typically is during the neonatal period. Main features include failure to thrive, signs of hyperammonemia (anorexia, irritability, tachypnea, lethargy, vomiting), and additional neurologic signs (progressive spastic quadriplegia, seizures, mental retardation, hyperactivity). Coma and cerebral edema may occur. Usually mild hepatomegaly can occur. Laboratory findings include hyperammonemia, hyperarginemia, di-amino-aciduria (arginuria, lysinuria, cystinuria, ornithinuria), oroticaciduria, pyrimidinuria, and elevated amino acid levels in the cerebrospinal fluid (arginine, ornithine, aspartate, threonine, glycine, methionine). Stress and infection can trigger an attack.

Assess neurologic function and review the electroencephalogram. Check liver function (clinically and with laboratory investigations such as transaminases, γ-glutamyltransferase, bilirubin levels, coagulation tests, proteins). Check for signs of hypovolemia in case of recurrent vomiting; check electrolytes.

Perioperative nutrition should aim for high carbohydrate intake and low protein intake to prevent arginine load. To prevent a catabolic state, avoid longer fasting periods and/or cover them with dextrose-containing intravenous solutions. Prevent oral, pharyngeal, and gastrointestinal bleeding (because of risk of hyperammonemia from absorption of blood) and consider a nasogastric tube for aspiration and irrigation.

Consider interactions among antiepileptic medications, liver function, and anesthetic drugs. Patients often are taking benzoate or phenylacetate (phenylbutyrate), which provide alternative routes for elimination of waste nitrogen. Transamination of benzoate leads to hippurate, which is easily excreted by the kidneys. Conversion of phenylacetate to phenylacetyl-CoA allows for conjugation with glutamine to form phenylacetyl glutamine. Both pathways result in elimination of ammonia. Phenylbutyrate offers the advantage of better taste for oral administration than phenylacetate.

Citrullinemia: Syndrome arising from argininosuccinate synthetase deficiency leading to hyperammonemia and neurologic consequences.

HHH Syndrome: Genetically transmitted inborn error of metabolism resulting from a defect in the transport of ornithine into the mitochondrial matrix, clinically characterized by early growth retardation, learning disabilities, periodic confusion, and ataxia.

Methylmalonic Acidemia (MMA): Heterogeneous inborn error of metabolism leading to metabolic acidosis and accumulation of methylmalonic acid and its by-products.

N-Acetylglutamate Synthetase Deficiency: Congenital mitochondrial disorder that affects the metabolism of ammonium and results in hyperammonemia.

Ornithine Carbamoyltransferase Deficiency (OTCD): Rare genetic disorder characterized by complete or partial lack of the enzyme ornithine transcarbamylase. Lack of this enzyme results in excessive hyperammonemia, which is a known neurotoxin. Clinically, patients present with vomiting, refusal to eat, progressive lethargy, and coma.

Propionic Acidemia: Inborn error of metabolism affecting the mitochondrial catabolism of valine and isoleucine. Untreated, the disorder results in ketoacidosis, lethargy, coma, and finally death.