Basics
Description
- Inborn errors of metabolism are inherited defects in biosynthesis, catabolism, or transport of lipids, amino acids, or carbohydrates. The first presentation of an inborn error of metabolism can be at any age, with most cases manifesting during states of metabolic catabolism and/or increased dietary intake of an offending metabolite.
- Clinical findings can range from acute life-threatening crises to milder, nonspecific clinical episodes of malaise, emesis, lethargy, anorexia, or even acute neuropsychiatric abnormalities.
- Some inborn errors of metabolism present with elevated levels of ammonia (>100 ΌM/L). Ammonia is highly neurotoxic, and elevated levels can lead to encephalopathy and death. Maintaining a high degree of clinical suspicion in sick neonates is essential.
Epidemiology
- Incidence and prevalence vary among different types of inborn errors of metabolism. Collectively, approximately 1 in 500 newborns are affected by one of the various inborn errors of metabolism.
- Estimated incidence of urea cycle defects is 1:18,000. Incidence of organic acidemias is 1:1,000 and of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency ranges from 1:4,900 to 1:17,000.
Risk Factors
Genetics
Inheritance of most inborn errors of metabolism is autosomal recessive. Ornithine transcarbamylase deficiency (the most common urea cycle defect) is X-linked.
Pathophysiology
- Nitrogen is an essential building block of amino acids and a major source of ammonia from protein degradation. Ammonia is highly toxic, especially to the central nervous system (CNS). A major mechanism for ammonia detoxification is the urea cycle, which converts ammonia in the liver to water-soluble urea. Urea is then excreted by the kidneys.
- Inborn errors of metabolism causing hyperammonemia interfere with urea cycle function, either directly through primary enzymatic defects of the urea cycle or indirectly, caused by liver failure, decreased production, increased use, or defective transport of a urea cycle intermediate as seen in aminoacidopathies, organic acidemias, fatty acid oxidation defects, and defective carbohydrate metabolism.
Etiology
Any biochemical defect that alters the amount of ammonia or that interferes with the detoxification of ammonia
Diagnosis
History
- Evidence of systemic disease: A variety of systemic newborn illnesses, including sepsis, can be complicated by secondary hyperammonemia.
- Family history of poorly explained pediatric death, developmental disability, or neuropsychiatric disorders should raise suspicion for a genetic disorder, such as an inborn error of metabolism. Diagnoses to ask about:
- Sepsis or recurrent infections (opportunistic organism or no 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.
Physical Exam
- ABCs and vital signs: Cushing triad (apnea, bradycardia, hypertension) should prompt immediate evaluation for elevated intracranial pressure, a complication of hyperammonemia.
- Head, eyes, ears, nose, and throat: macrocephaly, bulging fontanelle (elevated intracranial pressure)
- CVS: dilated or hypertrophic cardiomyopathy in some organic acidemias and fatty acid oxidation defects
- Respiratory: hyperpnea (rapid deep breathing that will lead respiratory alkalosis which is different from the rapid shallow breathing of transient tachypnea of the newborn)
- GI: Hepatomegaly occurs in some of these disorders (argininosuccinate lyase deficiency, fatty acid oxidation, galactosemia).
- Skin: Jaundice is not typical in urea cycle defects but occurs in other inborn errors of metabolism associated with hepatotoxicity.
- Neurologic: extrapyramidal signs, encephalopathy, myoclonic jerks, hyper-/hypotonia, obtundation, and coma
Diagnostic Tests & Interpretation
Lab
- Initial labs for a presumptive diagnosis in a patient with hyperammonemia:
- Dextrose stick
- Electrolytes, BUN, creatinine
- CBC, blood culture, serum ketones
- Blood gas with lactate
- Liver function tests and PT/PTT
- Urinalysis for ketones, reducing substances
- Frequent ammonia levels (q4 " 12h), obtain as free-flowing samples, placed on wet ice and immediately transport to the lab for processing
- Review state newborn screen.
- Suspected disorders and follow-up testing:
- Urea cycle defects: plasma 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
- Open ductus venosus: low urea and glutamine
- Definitive diagnosis may require enzyme testing or mutation analysis.
Imaging
Brain MRI/CT may show demyelination; circumscribed brain atrophy; cerebellar hypoplasia or aplasia, symmetric and/or fluctuation; and abnormalities of brainstem, basal ganglia, thalamus, and/or hypothalamus, especially in "cerebral " organic acidurias.
Differential Diagnosis
- Neonatal hyperammonemia not caused by inborn errors of metabolism
- Sepsis or other severe illness
- Liver failure (drugs, toxins, others)
- Transient neonatal hyperammonemia (e.g., open ductus venosus)
- Perinatal depression/hypoxia
- Iatrogenic (valproic acid, asparaginase)
- Inborn errors of metabolism
- Urea cycle defects (N-acetylglutamate [NAG] synthetase deficiency, carbamoyl phosphate synthase deficiency, ornithine transcarbamylase deficiency, argininosuccinate synthetase deficiency, argininosuccinate lyase deficiency)
- Organic acidemias (isovaleric acidemia, propionic acidemia, methylmalonic acidemia, etc.)
- Fatty acid oxidation defects (medium-chain acyl-CoA dehydrogenase deficiency, etc.)
- Hyperornithinemia, hyperammonemia, homocitrullinemia (HHH) syndrome
- Pyruvate carboxylase deficiency
- Hepatopathy (due to galactosemia, hereditary fructose intolerance)
- Hyperinsulinism-hyperammonemia syndrome (HIHA; glutamate dehydrogenase deficiency)
Treatment
Presumptive treatment should not await a definitive diagnosis but should be based on clinical suspicion and initial labs. Delays in treatment can be fatal and will cause brain damage.
General Measures
- Many patients will require admission to an intensive care unit and may require ventilator support.
- Obtain IV access.
- Promote renal ammonia excretion through increased maintenance fluids.
- Immediately discontinue exogenous protein intake, which exacerbates ammonia production.
- Enhance anabolism with calories from high-rate dextrose infusion (10 mg/kg/min) with insulin (0.1 " 1 IU/kg/h) and intralipids (0.5 " 1 g/kg/24 h) (exclude long-chain fatty acid disorder).
- Consider total parenteral nutrition or semi synthetic amino acid formulas during crises.
- Nitrogen-scavenging agents enable ammonia to bind to amino acids which yield products that can be excreted in the urine:
- Sodium benzoate (250 mg/kg/24 h)
- Sodium phenylacetate (250 mg/kg/24 h) intravenously when ill, or
- Sodium phenylbutyrate (400 " 600 mg/kg/24 h) orally when well. Note that high levels (or serum concentrations) of sodium benzoate and sodium phenylbutyrate can be toxic, >2 mmol/L and >4 mmol/L, respectively. Monitor sodium and potassium levels when using these scavengers.
- Arginine (180 " 360 mg/kg) or citrulline therapy to supplement residual urea cycle function
- L-carnitine supplementation (100 " 200 mg/kg/24 h) to support mitochondrial metabolism (unless urea cycle defect is identified as the cause)
- Administration of N-carbamyl-L-glutamic acid (Carbaglu) (100 " 200 mg/kg/24 h) has been shown to reduce ammonia levels in NAG synthetase deficiency, CPS1 deficiency, and the organic acidemias.
- Antiemetics (e.g., ondansetron)
- Metronidazole (10 " 20 mg/kg/24 h for 10 days every month) to decrease bacterial gut flora as a major source of ammonia and propionate
- Dialysis in severe hyperammonemia (>250 Όmol/L) if unresponsive to IV scavengers
- Monitor ammonia, electrolytes, and neurologic status closely during a crisis.
Ongoing Care
Specific therapies are best carried out under the supervision of a metabolic specialist and a metabolic nutritionist. Goal of every long-term treatment is to achieve a protein-sparing anabolic effect of an optimal diet that limits the episodes of acute crises and promotes adequate growth:
Adjust diet to underlying metabolic defect by restricting metabolites prior to their respective enzymatic block and/or their precursors from the diet, for example:
- Urea cycle defects
- Restrict natural protein; protein elimination during times of stress during illness/stress; avoid fasting
- Chronic therapy with nitrogen-scavenging agents
- Amino acid supplements when indicated (e.g., citrulline in ornithine transcarbamylase deficiency; arginine in citrullinemia, argininosuccinate lyase deficiency)
- Long-term therapy may involve an orthotopic liver transplant.
- Fatty acid oxidation disorders
- Low-fat, high-carbohydrate diets with frequent feeds; avoid fasting
- Organic acidemias
- Protein restriction, semisynthetic amino acid formulas lacking the offending amino acid; protein elimination during times of stress during illness/stress; and avoidance of fasting; intermittent metronidazole in propionic acidemia to eliminate intestinal propionate production; liver and/or kidney transplant
- Provide vitamins, minerals, trace elements, cofactors, and calories in accordance to the Recommended Daily Allowance (RDA) to promote adequate growth and an anabolic state because catabolism may trigger acute crises, especially in urea cycle defects and organic acidemias, to assess adequate nutritional therapy; measure height, weight, and head circumference; and obtain CBC, plasma protein and albumin, plasma amino acids, iron and ferritin, lipid panel, renal and hepatic function test, as well as calcium and phosphorus levels frequently
- Dietary protocol for treatment of intercurrent illness at home
- Emergency letter/protocol and bracelet
- Early treatment of infection
- Routine vaccination
Complications
- Recurrent episodes of hyperammonemia
- Malnutrition ’ growth retardation, osteoporosis
- Elevated intracranial pressure
- Intellectual disability
- Vision loss due to optic neuropathy
- Nephropathy, cardiomyopathy
- Coma, metabolic strokes, early death
Additional Reading
- Champion MP. An approach to the diagnosis of inherited metabolic disease. Arch Dis Child Educ Pract Ed. 2010;95(2):40 " 46. [View Abstract]
- Ficicioglu C, Bearden D. Isolated neonatal seizures: when to suspect inborn errors of metabolism. Pediatr Neurol. 2011;45(5):283 " 291. [View Abstract]
- H €berle J. Clinical practice: the management of hyperammonemia. Eur J Pediatr. 2011;170(1):21 " 34. [View Abstract]
- Kasapkara C, Ezgu F, Okur U, et al. N-carbamylglutamate treatment for acute neonatal hyperammonemia in isovaleric academia. Eur J Pediatr. 2011;170(6):799 " 801. [View Abstract]
Codes
ICD09
- 277.89 Other specified disorders of metabolism
- 270.6 Disorders of urea cycle metabolism
- 271.1 Galactosemia
- 270.6 Disorders of urea cycle metabolism
- 277.85 Disorders of fatty acid oxidation
ICD10
- E88.89 Other specified metabolic disorders
- E72.20 Disorder of urea cycle metabolism, unspecified
- E72.4 Disorders of ornithine metabolism
- E72.22 Arginosuccinic aciduria
SNOMED
- 86095007 Inborn error of metabolism (disorder)
- 36444000 Disorder of the urea cycle metabolism (disorder)
- 237928008 Disorder of ornithine metabolism (disorder)
- 41013004 Argininosuccinate lyase deficiency (disorder)
- 124711003 Deficiency of argininosuccinate synthase (disorder)
FAQ
- Q: Can females have ornithine transcarbamylase deficiency?
- A: Ornithine transcarbamylase is an X-linked gene, and females are generally asymptomatic carriers. However, due to "skewed " X inactivation of the OTC, affected female may exhibit symptoms after increased protein intake or states of catabolism.
- 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. Therefore, hyperammonemia can occur at any age during a period of metabolic stress.
- Q: What determines developmental outcome in children with inborn errors of metabolism?
- A: Outcome depends on prompt diagnosis, residual enzyme activity, early treatment, and compliance with long-term treatment.