Two disorders involving the citric acid cycle produce neonatal coma: fumarase deficiency and dihydrolipoyl dehydrogenase deficiency (Figure 79.1 B). Comatose neonates with disorders of the citric acid cycle have elevated lactate and pyruvate, and a lactate-to-pyruvate ratio above 35. Fumarase deficiency is associated with a characteristic urine organic acid pattern that consists of elevated fumaric and succinic acids. Treatment consists of a high carbohydrate diet and aspartic acid supplementation. Dihydrolipoyl dehydrogenase deficiency was previously described. More about... 73

Figure 79.1.— Metabolic pathways involved in branched chain amino acid disorders. A: maple syrup urine disease; B: dihydrolipoyl dehydrogenase deficiency; C: isovaleric acidemia; D: glutaric acidemia type II; E: multiple carboxylase deficiency; F: HMG-CoA lyase deficiency.

The urea cycle takes 2 moles of ammonia and, in the presence of N-acetylglutamate (an allosteric activator of carbomoylphosphate synthetase) and normal urea cycle enzymes activity and after a turn in the 5-step cycle, produces 1 mole of urea (Figure 79.2).

Figure 79.2.— Urea cycle and associated pathways: (1) carbamoyl phosphate synthetase I activating system and (2) orotate forming system. The blue line separates two compartments: (1) mitochondrial and (2) cytoplasmatic. Enzymes found inside the mitochondria: NAGS: N- Acetylglutamate synthetase (carbamoyl phosphate synthetase I activating system); CPS Ii: carbamoyl phosphate synthetase I inactivated; CPS Ia: carbamoyl phosphate synthetase I activated; OTC: ornithine transcarbamylase. Enzymes found in the cytoplasm: CPS II: carbamoyl phosphate synthetase II (orotate forming system); AS: arginosuccinate synthetase; AL: arginosuccinate lyase.

The urea cycle defects that present in the neonatal period are carbamyl phosphate synthetase deficiency, ornithine transcarbamylase deficiency, citrullinemia, and argininosuccinic aciduria. All urea cycle defects are autosomal recessive disorders except ornithine transcarbamylase deficiency. Ornithine transcarbamylase deficiency is an X-linked dominant disorder.
The hallmark of a urea cycle defect is hyperammonemia. A normal serum ammonia level excludes all urea cycle defects that occur in neonates. MRI of the brain in patients with urea cycle defect may show diffuse white matter edema (Figure 79.4).

Figure 79.4.— MRI and MRI spectroscopy (protron) of a newborn with urea cycle defect. Pink arrow head: choline peak; green arrow head: creatinine peak; yellow arrow head: N-acetylaspartic acid peak; blue arrow head: lactic acid peak.

The metabolic profile of each urea cycle defect occurs as the result of an elevation of the amino acids prior to the enzymatic block within the cycle and their alternate pathways. The alternate pathways lead to the production of glycine, glutamate, and orotic acid. Neonatal hyperammonemia also occurs with severe liver failure, severe perinatal asphyxia, total parenteral nutrition, isovaleric acidemia, propionic acidemia, methylmalonic acidemia, multiple carboxylase deficiency, pyruvate dehydrogenase deficiency, carboxylase complex deficiency, N-acetylglutamic acid synthetase deficiency, Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, and glutaric acidemia type II. These causes of neonatal hyperammonemia are distinguished from urea cycle defects by the presence of metabolic acidosis, abnormal liver function tests, and specific amino acid profile.