Not So Rare: Errors of Metabolism During the Neonatal Period

Sandra A. Banta-Wright, MN, RNC, NNP; Robert D. Steiner, MD


NAINR. 2003;3(4) 

In This Article


In the newborn period, a normal ammonia level is less than 50 µmol/L.[39] A blood ammonia level between 70 and 100 µmol/L should be viewed in conjunction with clinical findings. An elevated ammonia level ≥ 100 µmol/L indicates an abnormality in nitrogen balance. A typical clinical presentation of neonatal hyperammonemia is a full-term newborn who is initially well the first day of life. After 24 hours, the newborn becomes a poor feeder, lethargic with hypotonia, vomits frequently, and is hyper-pneic.[40] Hyperammonemia is a life-threatening condition, as elevated ammonia is a toxin especially on the central nervous system. If not identified and treated rapidly, the newborn will have irreversible neurological sequelae.

There are several disorders that can cause hyperammonemia in the neonatal period ( Table 5 ). When hyperammonemia is present in the newborn/infancy period, an attempt to identify a diagnosis is essential. A systematic approach for the differential diagnosis of hyperammonemia is presented in Fig 3. It is very important to remember that the first step in evaluating suspected hyperammonemia is to obtain an accurate blood ammonia level.[41] The venous ammonia sample must be collected, stored, and transported on ice to the laboratory. Once in the laboratory, this specimen must be rapidly analyzed and not run as a routine and must be reported with an adjustment for the newborn age.

Simplified flowchart for evaluation of hyperammonemia in the newborn. CSPD, carbamyl phosphate synthetase deficiency; HHH, hyperornithinemia–hyperammonemia–homocitrullinuria syndrome; IVA, isovalemic acidemia; LCHADD, long chain 3-chydroxy-acyl-CoA dehydrogenase deficiency; MCADD, medium chain acyl-CoA dehydrogenase deficiency; MMA, methylmalonic acidemia; NAGS, N-acetylglutamate synthetase deficiency; OTC, ornithine transcarbamylase deficiency; PCD, pyruvate carboxylase deficiency; PA, propionic acidemia; THAN, transient hyperammonemia of the newborn; VLCADD, very long chain acyl-CoA dehydrogenase deficiency. Adapted with permission from Hudak ML, Jones MD, Brusilow SW. Differentiation of transient hyperammonemia of the newborn and urea cycle enzyme defects by clinical presentation. J Pediatr 107:712-719, 1985.

Newborns that present with hyperammonemia during the first day of life usually are either premature or fullterm newborns with a secondary hyperammonemia, such as a pyruvate carboxylase deficiency (PCD).[42,43] The severely elevated ammonia level associated with prematurity is known as transient hyperammonemia of the newborn (THAN).[42] THAN typically presents in a preterm infant of approximately 36 weeks' gestation, who has respiratory distress and significant hyperammonemia. Survivors of THAN do not experience recurrent episodes of hyperammonemia. The neurological outcome of THAN is dependent on the extent of the neonatal insult. As a result, this disorder should not be ignored, rather rapid and vigorous medical intervention is required. The authors have had experience with premature infants with ammonia levels greater than 2,000 µmol/L and normal outcome in THAN.

Hyperammonemia after the first 24 hours following birth is more characteristic of a primary hyperammonemia, which includes mainly urea cycle defects.[44] Other categories of EM that also present after 24 hours of age with hyperammonemia include organic acidemias and fatty acid oxidation disorders.[45] The key to differentiation is the presence or absence of acidosis, ketosis, or hypoglycemia.[46] The urea cycle defects usually present with respiratory alkalosis due to the hyperpnea, induced by the hyperammonemia. In contrast, the initial presentation of many organic acidemias is severe metabolic acidosis with an increased ion gap. Also, fatty acid oxidation disorders tend to present with mild metabolic acidosis. The second distinguishing feature of the urea cycle defects is the absence of ketosis, which is easily determined by a urine dipstick to check for the presence of ketones.[44] The last variable is the absence or presence of hypoglycemia. The classical presentation of fatty acid oxidation disorders is nonketotic hypoglycemia or hypoketotic hypoglycemia.[47] Lastly, ketotic hypoglycemia with acidosis is characteristic of PCD in addition to organic acidemias.[48]

The largest category of disorders with hyperammonemia is urea cycle defects.[43] In the absence of acidosis, ketosis, and hypoglycemia, a tentative diagnosis of urea cycle defect should be considered. Disorders to be included in the differential diagnosis of the urea cycle defect include: N-Acetylglutamate synthetase (NAGS), carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinic acidemia (AS), and argininosuccinic lyase deficieny (AL) deficiencies.[46] NAGS, CPS, AS, and AL are autosomal recessive. OTC is X-linked. Clinically, the presentations in the neonatal period are virtually identical due to the hyperammonemia, which is the common variable. The laboratory evaluation will include the quanitative analysis of plasma amino acid and urine organic acids/urine orotic acid analyses.[26,49,50] The laboratory results will determine the compounds within the urea cycle that are increased and decreased. This is based on the detoxification of ammonia as a five-step process (Fig 4).[51] It begins with the formation of carbamyl phosphate from ammonia by carbamyl phosphate synthetase. Carbamyl phosphate is added to ornithine to form citrulline by ornithine transcarbamylase. Citrulline is converted to argininosuccinate by argininosuccinate synthetase, which is then cleaved to produce arginine by argininosuccinate lyase. Arginine is cleaved by arginase to form urea and ornithine. The urea is excreted in the urine. The ornithine is now available to restart the cycle again.

Simplified schematic of urea cycle with enzyme defects.

The plasma citrulline and argininosuccinate provide the distinguishing features among the urea cycle defects. If citrulline is absent or decreased, urine orotic acid will differentiate between NAGS, CPS, and OTC deficiency. In NAGS and CPS, the urine orotic acid will be low; while in OTC it is elevated.[52,53] After OTC, CPS and NAGS have been excluded and, if the citrulline level is normal, the disorder to consider is hyperornithinemia–hyperammone-mia–homocitrullinuria (HHH) syndrome.[54] If the citrulline level is elevated, the agrininosuccinic acid level will aid in the diagnosis between AL, also known as argininosuccinic aciduria and AS, also known as citrullinemia. In citrullinemia, argininosuccinic acid is deficient.[55] Thus, citrulline is produced in massive quantities. In AS, there will be a moderate increase in citrulline with increased levels of argininosuccinic acid and its anhydrides.[56] A defect in the last step in the urea cycle, arginase, does not usually present in the neonatal period, but increasing knowledge of this disorder and use of tandem mass spectrometry may result in earlier diagnosis during the neonatal period.[57,58,59]

Neonates with profound and prolonged hyperammonemia with coma due to urea cycle defect will have had a neurological insult to the brain that may be significant. If so, the option of withdrawal of support rather than aggressive intervention should be discussed with the parents.[60]

During the acute phase of treatment of a newborn with a urea cycle defect, the therapy is multifocused. Initial treatment at this time is directed toward the removal of the accumulating metabolites, such as ammonia. Intravenous glucose is administered to restore hydration, as the majority of the newborns with urea cycle defect are dehydrated as a consequence of poor oral intake and vomiting. With hydration, tissue perfusion is increased, which protects renal function and blunts further catabolic production of nitrogen. The preferred choice of fluids is 10% dextrose with salts until definitive therapy is available. [60] All dietary protein may be discontinued for 24 hours to decrease the protein load.[60] Caloric intake is provided as carbohydrate and fat. During this period, hemodialysis most often is needed.[29] As with a newborn with an organic acidemia, if the hospital is unable to offer hemodialysis, transfer of the newborn to another medical center with hemodialysis capability should be strongly considered. Exchange transfusions, peritoneal dialysis, or hemofiltration are less efficient than hemodialysis in managing these disorders.[30] Drug therapy is administered to provide an alternative path for nitrogen excretion. Intravenous sodium phenylacetate combines with glutamine to produce phenylacetylglutamine, which is excreted in the urine.[61,62] Sodium benzoate combines with glycine to produce hippurate. Hippurate is rapidly cleared by the kidneys.[63,64] With the removal of the excessive nitrogen, there is a decrease in arginine synthesis. As a result, arginine becomes an essential amino acid that must be replaced.[65,66,67] The assistance of a dietician with experience with EM is essential. The diet involves protein restriction for life to an amount tolerated without causing hyperammonemia and preventing excessive protein catabolism while at the same time providing the body with the nutritional needs for growth and development.[68,69]

The overall prognosis for newborns with a urea cycle defect is guarded. Without treatment, these newborns will die. Even with aggressive medical intervention, many will die. Those newborns that do survive may have neurological insult and recurrent life-threatening metabolic crises. The long-term outcome into adulthood is largely unknown, as the oldest children are just surviving past childhood. Many of the children eventually die and have developmental delays in physical growth and cognitive skills.[70,71,72] The long-term correction of a urea cycle defect is the correction of the enzymatic defect within the hepatocytes. Liver transplantation has been successful in infants with CPS and OTC.[73,74,75] After transplantation, the serum ammonia levels fall to normal levels without the need for protein restriction or medications. With advances in liver transplantation, the indications for liver transplantation for urea cycle defects are changing.[76,77] Because of the limited number of livers available for transplantation, gene therapy could provide the ultimate correction of the urea cycle defect. This area of laboratory and clinical research has the potential to reduce the morbidity and mortality seen in urea cycle defects.[78,79,80,81,82,83]


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