Metabolic Diseases in Hyperammonemic Newborns
Metabolic Diseases in Hyperammonemic Newborns: Excerpt from The 5-Minute Pediatric Consult
Ralph J. DeBerardinis, MD, PhDSulagna C. Saitta, MD, PhD
Metabolic Diseases in Hyperammonemic Newborns - BASICS
Metabolic Diseases in Hyperammonemic Newborns - description
Inborn errors of metabolism are inherited defects in biochemical pathways affecting metabolism of fats, amino acids, or carbohydrates. Some inborn errors of metabolism present with elevated ammonia in newborns (>100 ์micromolar). Because these conditions are life threatening if not treated promptly, maintaining a high degree of clinical suspicion in sick neonates is essential. In the newborn period, the immediate goals include:
- Establish a tentative diagnosis.
- Initiate presumptive management.
- Send confirmatory studies.
- Involve a team trained in treating patients with inborn errors of metabolism.
Metabolic Diseases in Hyperammonemic Newborns - risk factors
Metabolic Diseases in Hyperammonemic Newborns - genetics
Generally autosomal recessive. Ornithine transcarbamylase deficiency (the most common urea cycle defect) is X linked.
Metabolic Diseases in Hyperammonemic Newborns - pathophysiology
The urea cycle coverts ammonia (NH3) to water-soluble urea in the liver and is the major mechanism for ammonia disposal. Inborn errors of metabolism causing hyperammonemia interfere with urea cycle function, either directly or indirectly, including the following mechanisms:
- Genetic defects in a urea cycle enzyme per se
- Decreased production, increased use, or defective transport of a urea cycle intermediate. Examples:
- Hyperornithinemia, hyperammonemia, homocitrullinemia (HHH) syndrome
- Lysinuric protein intolerance
- Fatty acid oxidation defects
- Hyperammonemia/Hyperinsulinemia syndrome
- Organic acidemias
- Pyruvate carboxylase deficiency
- Hepatotoxicity (galactosemia, hereditary fructose intolerance)
Metabolic Diseases in Hyperammonemic Newborns - DIAGNOSIS
Metabolic Diseases in Hyperammonemic Newborns - signs & symptoms
Metabolic Diseases in Hyperammonemic Newborns - history
- Evidence of systemic disease: A variety of systemic newborn illnesses, including sepsis, can be complicated by a secondary hyperammonemia.
- Family history of poorly explained pediatric death or developmental disability raises suspicion for a genetic disorder, such as an inborn error of metabolism. Diagnoses to ask about:
- Sepsis (was an organism identified?)
- Sudden infant death syndrome
- Cardiomyopathy
- Uncontrollable seizures
- Coma
- Liver failure
- Current diet and feeding schedule: In urea cycle defects, hyperammonemia is exacerbated by protein intake.
- Failure to wake and feed spontaneously is a sign of CNS dysfunction in neonates.
- Perinatal hypoxia can cause temporary liver dysfunction and reduced urea cycle capacity. Relative immaturity of the urea cycle can cause hyperammonemia in premature infants.
Metabolic Diseases in Hyperammonemic Newborns - physical exam
- ABCs and vital signs: Cushing’s triad (apnea, bradycardia, hypertension) should prompt immediate evaluation for elevated intracranial pressure, a complication of hyperammonemia.
- Skin: Jaundice is not typical in urea cycle defects, but occurs in other inborn errors of metabolism associated with hepatotoxicity.
- Head, eyes, ears, nose, and throat: Bulging fontanelle suggests elevated intracranial pressure.
- Respiratory: Effects of hyperammonemia on the brainstem respiratory center may cause tachypnea.
- GI: Hepatomegaly occurs in some of these disorders (fatty acid oxidation, galactosemia).
- Neurologic: Hyperammonemia causes a variety of neurologic abnormalities, including abnormal tone, obtundation, and coma.
Metabolic Diseases in Hyperammonemic Newborns - tests
Metabolic Diseases in Hyperammonemic Newborns - lab
The goal of lab testing is to make a presumptive diagnosis as soon as possible. In many cases, definitive diagnosis requires specialized tests. 2 critical management points:
- Presumptive treatment should not await a definitive diagnosis, but should be based on clinical suspicion and initial labs. Delays in treatment can be fatal.
- Involvement of a biochemical genetics team is invaluable in directing the workup of suspected inborn errors of metabolism.
- Initial labs to evaluate neonatal hyperammonemia:
- Dextrose stick
- Electrolytes, BUN, creatinine
- CBC, blood culture
- Blood gas with lactate
- Liver function tests and PT/PTT
- Urinalysis for ketones, reducing substances
- Frequent ammonia levels
- Suspected disorders and follow-up testing:
- Urea cycle defects: Pasma amino acids and urine orotic acid
- Organic acidemias: Urine organic acids, plasma amino acids, and acylcarnitine profile
- Fatty acid oxidation defects: Creatine phosphokinase, urine organic acids, plasma acylcarnitine profile
- Galactosemia: Urine galactitol, red blood cell galactose-1-phosphate uridyltransferase (GALT) activity, and total galactose from blood
- Definitive diagnosis may require enzyme testing or mutation analysis.
Metabolic Diseases in Hyperammonemic Newborns - differencial diagnosis
- Neonatal hyperammonemia not caused by inborn errors of metabolism:
- Sepsis or other severe illness
- Liver failure (any cause)
- Transient neonatal hyperammonemia
- Perinatal depression/hypoxia
- Iatrogenic (valproic acid, asparaginase)
- Inborn errors of metabolism:
- Urea cycle defects (N-acetylglutamate synthetase deficiency, carbamoyl phosphate synthase deficiency, ornithine transcarbamylase deficiency, argininosuccinate synthetase deficiency (citrullinemia), argininosuccinate lyase deficiency)
- Organic acidemias (isovaleric acidemia, propionic acidemia, methylmalonic acidemia, multiple carboxylase deficiencies, others)
- Fatty acid oxidation defects (medium chain acyl-CoA dehydrogenase deficiency, multiple acyl-CoA dehydrogenase deficiency, others)
- Hyperornithinemia, hyperammonemia, homocitrullinemia syndrome
- Pyruvate carboxylase deficiency
- Hyperammonemia/Hyperinsulinemia syndrome
- Galactosemia
- Hereditary fructose intolerance
Metabolic Diseases in Hyperammonemic Newborns - TREATMENT
Metabolic Diseases in Hyperammonemic Newborns - general measures
- Discontinue protein intake, which exacerbates ammonia production. Protein/Amino acid–free formula or parenteral nutrition should be used.
- Obtain IV access.
- Many patients will require intensive care transfer. Hyperammonemia interferes with normal CNS and respiratory function, so hyperammonemic neonates often require intubation.
- Nitrogen scavenging agents (e.g., sodium benzoate, sodium phenylacetate, sodium phenylbutyrate) are used in some settings. They improve hyperammonemia by combining with amino acids to yield products that can be excreted into the urine.
- In severe hyperammonemia, dialysis may be indicated.
- In many disorders, catabolism and associated breakdown of endogenous protein exacerbates the nitrogen load. This can be treated with calories from high-rate dextrose infusion.
Metabolic Diseases in Hyperammonemic Newborns - special therapy
Specific therapies are best carried out with the help of a specialist experienced in treating inborn errors of metabolism, and a clinical nutritionist. Examples include:
- Urea cycle defects:
- Protein-restricted diet, with protein elimination during illness/stress
- Chronic therapy with nitrogen scavenging agents
- Amino acid supplements when indicated (e.g., citrulline in ornithine transcarbamylase deficiency; arginine in citrullinemia, argininosuccinate lyase deficiency)
- Fatty acid oxidation disorders:
- Low-fat, high-carbohydrate diets with frequent feeds
- Organic acidemias:
- Protein restriction, protein elimination during times of stress, and avoidance of fasting
Metabolic Diseases in Hyperammonemic Newborns - FOLLOW UP
Metabolic Diseases in Hyperammonemic Newborns - complications
- Recurrent episodes of hyperammonemia
- Elevated intracranial pressure
- Developmental disability
- Coma
- Death
Metabolic Diseases in Hyperammonemic Newborns - bibliography
Bachman C. Inherited Hyperammonemias. In: Blau N, Duran M, Blaskovics ME, et al., eds. Physician’s Guide to the Laboratory Diagnosis of Metabolic Diseases. 2nd ed. New York: Springer; 2003.Batshaw ML, MacArthur RB, Tuchman M. Alternative pathway therapy for urea cycle disorders: Twenty years later. J Pediatr. 2001;38:S46–S55.Brusilow SW, Horwich AL. Urea Cycle Enzymes. In: Scriver CR, Baudet AL, Sly WS, et al., eds. The Molecular and Metabolic Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001.Burton BK. Inborn errors of metabolism in infancy: A guide to diagnosis. Pediatrics. 1998;102:E69–E77.Summar M. Current strategies for the management of neonatal urea cycle disorders. J Pediatr. 2001;138(1 suppl):S30–S39.Summar M, Tuchman M. Proceedings of a consensus conference for the management of patients with urea cycle disorders. J Pediatr. 2001;138(1 suppl):S6–S10.
Metabolic Diseases in Hyperammonemic Newborns - CODES
Metabolic Diseases in Hyperammonemic Newborns - icd9
270.6 Disorders of urea cycle metabolism
271.1 Galactosemia
277.85 Disorders of fatty acid oxidation
Metabolic Diseases in Hyperammonemic Newborns - FAQ
- Q: Can females have ornithine transcarbamylase deficiency?
- A: Because ornithine transcarbamylase is an X-linked gene, females are generally asymptomatic carriers. However, “skewed” X inactivation in which the normal ornithine transcarbamylase gene is inactive in a large majority of hepatocytes has caused symptomatic disease in a number of females. They are treated similarly to affected males.
- Q: Can any of these disorders present outside of the newborn period?
- A: Disease severity depends in large part on a patient’s enzyme activity. In some patients, there is enough activity that hyperammonemia does not occur until later in life during a period of illness, stress, or high protein intake.
- Q: What determines developmental outcome in children with inborn errors of metabolism?
- A: In most inborn errors of metabolism, severe mutations cause very low enzyme activity and a greater disease severity. However, prompt initiation of appropriate therapy in the newborn period as well as compliance with chronic management contribute to developmental outcome.
Book Source Details
- Book Title: The 5-Minute Pediatric Consult
- Author(s): M. William Schwartz MD; et al.
- Year of Publication: 2008
- Copyright Details: The 5-Minute Pediatric Consult, Copyright © 2008 Lippincott Williams & Wilkins.
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Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.
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More About This Book:
Title: The 5-Minute Pediatric Consult
Authors: M. William Schwartz MD; et al.
Publisher: Lippincott Williams & Wilkins
Copyright: 2008
ISBN: 0-7817-7577-9
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