WORKUP	Section 5 of 11
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Lab Studies:

• Laboratory abnormalities can be transient. Therefore, values within the reference range do not rule out an IEM.

• Studies may need to be repeated during other episodes of illness or during provocative testing under carefully controlled circumstances in a clinical research center.

• Most IEMs with acute life-threatening presentation can be categorized based on findings of initial laboratory evaluations with presence of at least 1 of the following (see Image 1):

• Metabolic acidosis

• Hypoglycemia: A prospective study revealed that in the ED, hypoglycemia (plasma glucose <50 mg/dL) is rare in children (0.44% of those tested), even during periods of poor enteral intake. In a study of 40 children with hypoglycemia, 32 had a metabolic workup performed on initial samples, and 28% of those had a previously undiagnosed fatty acid oxidation defect or endocrine disorder.

• Hyperammonemia: Early manifestations include anorexia, abdominal pain, headache, irritability, fatigue, late-tachypnea, vomiting, lethargy, seizures, coma, and death.

• Major exceptions include congenital adrenal hyperplasia (hyponatremia and hyperkalemia in a child with apparent sepsis), nonketotic hyperglycinemia (lethargy, coma, seizures, hypotonia, spasticity, hiccups, apnea), and pyridoxine deficiency (encephalopathy, intractable seizures).

• Initial laboratory evaluation (see Image 2)

• Complete blood count (CBC) to screen for neutropenia, anemia, and thrombocytopenia

• Serum electrolytes, bicarbonate, and blood gases levels to detect electrolyte imbalances and evaluate anion gap (usually elevated) and acid/base status

• Blood urea nitrogen and creatinine levels to evaluate renal function

• Bilirubin level, transaminases levels, prothrombin time, and activated partial thromboplastin time to evaluate hepatic function

• Ammonia: Obtain if altered level of consciousness, persistent or recurrent vomiting, primary metabolic acidosis with increased anion gap, or primary respiratory alkalosis in the absence of toxic ingestion. Preferably, use an arterial sample, because skeletal muscle releases ammonia. If a venous sample is obtained, the sample must be flow free (no tourniquet). Ice the sample immediately and assay promptly. Normal values are less than 100 mcg/dL in the neonate and less than 80 mcg/dL in those older than 1 month.

• Blood glucose and urine pH, ketones, and reducing substances

• False-positive results for reducing substances are caused by penicillin and glucuronides.

• Neonates - Inappropriate ketones (ie, ketonuria)

• Child - Ketonuria with normal glucose, low or absent ketones with hypoglycemia

• Obtain lactate dehydrogenase, aldolase, creatinine kinase, and urine myoglobin levels in patients with evidence of neuromyopathy.

Other Tests:

• Enzyme assay or DNA analysis in leukocytes, erythrocytes, skin fibroblasts, liver, or other tissues

• Histologic evaluation of affected tissues such as skin, liver, brain, heart, kidney, and skeletal muscle

• Secondary studies

• If initial test results are outside the reference range, consider consultation with an IEM specialist to determine which tests are appropriate, how specimens are to be collected and stored, and where they should be sent.

• Plasma or serum lactate, pyruvate, albumin, triglycerides, uric acid, quantitative amino acids, organic acids, acylcarnitines, (1-2 mL in ethylenediaminetetraacetic acid [EDTA] or heparin tube, on ice)

• Urine amino acids, acylglycine, organic acids, and/or orotic acid (5-10 mL, freeze immediately)

• Cerebrospinal fluid (CSF) lactate, pyruvate, organic acids, neurotransmitters, and/or disease-specific metabolites collected at the same time as plasma (1-2 mL)

• If a child has died, attempting to diagnose a metabolic disease is still important because of the possibility that presently asymptomatic siblings are affected or that future children will be affected.

• Plasma, serum, urine, and possibly CSF, skin, and selected organ specimens should be collected and frozen.

• A metabolic specialist may be helpful in directing the evaluation of patients with suspected metabolic disease.

	TREATMENT	Section 6 of 11
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Prehospital Care: Establish adequate airway, breathing, and circulation.

Emergency Department Care: Initial ED treatment does not require knowledge of the specific metabolic disease or even disease category (see Image 3). In any critically ill child, airway, breathing, and circulation must be established first. Consider antibiotics in any child who may be septic.

Initial treatment of IEMs is aimed at correcting metabolic abnormalities. Even the apparently stable patient with mild symptoms may deteriorate rapidly with progression to death within hours. With appropriate therapy, patients may completely recover without sequelae. Start empirical treatment for a potential IEM as soon as the diagnosis is considered.

• Eliminate potentially harmful protein or sugars. All oral intake should be stopped.

• Treat hypoglycemia and prevent catabolism.

• Correct hypoglycemia, if present, by IV dextrose bolus, 25%, 0.25-0.5 g/kg/dose (1-2 mL/kg); not to exceed 25 g/dose, and followed by continuous IV administration of dextrose.

• For all patients in whom an IEM cannot be ruled out, give dextrose 10-15% IV at a rate high enough to prevent catabolism (8-10 mg/kg/min).

• Dextrose will improve most conditions.

• Add insulin, 0.2-0.3 IU/kg, as needed to maintain normoglycemia.

• Add electrolytes at maintenance concentrations with appropriate adjustments to correct electrolyte disturbances if present.

• Treat acute acidosis and electrolyte abnormalities. The pH and dose at which bicarbonate should be administered are controversial; pH <7.0-7.2, dose 0.35-0.5 mEq/kg/h up to 1-2 mEq/kg/h. When patients are symptomatic or severely hypokalemic, potassium acetate is a useful replacement fluid (1 mEq/kg/h). Rapid correction or overcorrection may have paradoxical effects on the CNS. For intractable acidosis, consider hemodialysis.

• Definitive treatment of IEM requires removal of abnormal metabolites by restricting intake of the offending substrate, by promoting renal excretion of toxic metabolites, or, in severe cases, by dialysis (preferably hemodialysis).

• Significant hyperammonemia is life threatening and must be treated immediately upon diagnosis.

• To reduce ammonia, sodium phenylacetate and sodium benzoate (Ammonul; Food and Drug Administration [FDA] approved for hyperammonemia due to urea cycle defects) can be administered to augment nitrogen excretion.

• Arginine is an essential amino acid in patients with some urea cycle defects.

• For ammonia greater than 500-600 mcg/dL, hemodialysis should be initiated.

• If hemodialysis is not readily available, peritoneal dialysis (<10% as effective as hemodialysis) or double volume exchange transfusion (even less effective) can be performed while arrangements are made to transport to a center where hemodialysis is possible, as long as this does not delay transfer.

• Two to 3 days of therapy is usually necessary.

• L-carnitine may be administered empirically in life-threatening situations associated with primary metabolic acidosis or hyperammonemia.

• Administration of carnitine to patients with fatty acid oxidation defects is controversial.

• Pyridoxine should be given to neonates with seizures unresponsive to conventional anticonvulsants.

Consultations: Consider consultation with an IEM specialist.

	MEDICATION	Section 7 of 11
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Emergency medications for inborn errors of metabolism (IEMs) in infants and children include drugs to eliminate toxic metabolites and/or amino acids and enzyme cofactors to compensate for metabolic deficiencies. These and other drugs may be required to maintain and treat the underlying IEM. Some IEMs are treated with replacement enzymes that are FDA approved, designated as orphan drugs, or investigational.

Helpful Web sites for finding information on orphan drug designation include the following:

• National Organization for Rare Disorders (NORD) (lists more than 1000 rare diseases)

• United States FDA's Other Sources of Rare Disease/Orphan Product Information (list of Web sites that provide information on rare diseases and orphan drugs)

• United States FDA's List of Orphan Drug Designations and Approvals

Drug Category: Ammonium detoxicants -- Treatment of hyperammonemia; enhances elimination of nitrogen. This drug is FDA approved for treatment of hyperammonemia due to urea cycle defects and is available only from a specialty wholesaler, Ucyclyd Pharma (888-829-2593). For more information, see
Ammonul prescribing information.

Drug Name	Sodium phenylacetate and sodium benzoate (Ammonul) -- Indicated for ammonia levels up to 500-600 mcg/dL. For higher ammonia levels, hemodialysis is the preferred treatment; however, sodium phenylacetate and sodium benzoate can be considered until dialysis can be initiated if necessary. Benzoate combines with glycine to form hippurate, which is excreted in urine. One mol of benzoate removes 1 mol of nitrogen. Phenylacetate conjugates (via acetylation) glutamine in the liver and kidneys to form phenylacetylglutamine, which is excreted by the kidneys. The nitrogen content of phenylacetylglutamine per mole is identical to that of urea (2 mol of nitrogen). Ammonul must be administered with arginine for carbamyl phophate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), or argininosuccinate lyase (ASL) deficiencies. Approved as adjunctive treatment of acute hyperammonemia associated with encephalopathy caused by urea cycle enzyme deficiencies. Serves as an alternative to urea to reduce waste nitrogen levels. Preparation contains 100 mg/mL each of sodium phenylacetate and sodium benzoate and comes in 50-mL vials. Must dilute IV dose in at least 25 mL/kg of dextrose 10% up to 600 mL. Do not mix directly with other medications, but it may be piggybacked. Give in addition to daily fluid requirement.
Adult Dose	Loading: 55 mL (5.5 g)/m2 IV over 90-120 min via central line Maintenance: 55 mL (5.5 g)/m2/d IV over 24 h via central line
Pediatric Dose	<20 kg: Loading: 2.5 mL (250 mg)/kg IV over 90-120 min via central line Maintenance: 2.5 mL (250 mg)/kg/d IV over 24 h via central line >20 kg: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Penicillin may decrease effects; probenecid may inhibit renal excretion of products of sodium benzoate and sodium phenylacetate; valproate may antagonize efficacy of sodium benzoate and sodium phenylacetate
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Closely monitor with hepatic or renal impairment; caution when administering to patients with neonatal hyperbilirubinemia (competes for bilirubin-binding sites on albumin); because of sodium content, caution when giving to patients with congestive heart failure, severe renal dysfunction, and sodium retention with edema; common adverse effects include nausea, vomiting, tinnitus, and visual disturbance; may also cause hyperglycemia or hypokalemia; if needed, may be given with furosemide for edema, insulin to maintain euglycemia, or ondansetron 0.15 mg/kg during initial 15 min of priming infusion to offset GI effects; overdose may result in death

Drug Category: Amino acid -- Essential amino acid used for certain urea cycle defects.

Drug Name	Arginine (R-Gene) -- Enhances production of ornithine, which facilitates incorporation of waste nitrogen into the formation of citrulline and argininosuccinate. Provides 1 mol of urea plus 1 mol ornithine per mol of arginine when cleaved by arginase. Preparation is 10% arginine hydrochloride. Can be given with sodium phenylacetate and sodium benzoate. If administering separately, mix with sodium bicarbonate.
Adult Dose	25 g (dilute in D5W 500-1000 mL) IV over 1-4 h
Pediatric Dose	210 mg/kg/d IV over 90 min followed by infusion of 210 mg/kg/d over 24 h (Arginine can also be given by nasogastric tube, g-tube)
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause electrolyte disturbances; elevated potassium levels may occur (caution in patients with hepatic or renal disease or anuria); flushing, nausea, and vomiting may occur if administered too quickly; dilute to avoid extravasation

Drug Category: Enzyme cofactor -- Used to enhance the activity of cofactor-dependent enzymes.

Drug Name	Pyridoxine -- Precursor of pyridoxal, which functions in the metabolism of proteins, carbohydrates, and fats. Also aids in the release of liver- and muscle-stored glycogen and in the synthesis of GABA (within the CNS) and heme. Involved in synthesis of GABA within the CNS. Indicated for seizures of unknown etiology unresponsive to conventional anticonvulsants and for seizures in patients with known pyridoxine-dependent IEM. Give undiluted or mix with other solutions. Incompatible with alkaline or oxidizing solutions and iron salts. Not to be mixed with sodium bicarbonate.
Adult Dose	Up to 600 mg/d PO/IV/IM until seizures abate, then 50 mg/d
Pediatric Dose	Not established Suggested dosing: 100 mg/d IV/IM initial, then 2-10 mg/d IM or 10-100 mg/d PO
Contraindications	Documented hypersensitivity
Interactions	May cause 50% decrease in serum concentration of phenobarbital and phenytoin; may decrease levodopa levels; oral contraceptives may increase pyridoxine requirement
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	>200 mg/d may precipitate withdrawal effects when medication is discontinued; may cause flushing, warmth, paresthesia, and lethargy

Drug Category: Nutritional supplement -- Used for the treatment of primary and secondary carnitine deficiency.

Drug Name	Levocarnitine (Carnitor) -- An amino acid derivative, synthesized from methionine and lysine, required in energy metabolism. Can promote excretion of excess fatty acids in patients with defects in fatty acid metabolism or specific organic acidopathies that bioaccumulate acyl-CoA esters.
Adult Dose	25-50 mg/kg IV over 2-3 min; range 25-100 mg/kg/d IV, up to 300 mg/kg/d has been reported
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; controversial if fatty acid oxidation defect
Interactions	Increases INR (caution with anticoagulants)
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Monitor blood chemistries, plasma carnitine concentrations, vital signs, and overall clinical condition of the patient; nausea, vomiting, abdominal cramps, and diarrhea may occur; IV administration may cause hypertension, tachycardia, or, with end-stage renal disease, atrial fibrillation

	FOLLOW-UP	Section 8 of 11
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Further Inpatient Care:

• Once toxic metabolites have been normalized, protein can be reintroduced using an essential amino acid solution, initially at 0.5-0.75 g/kg/d and gradually increased.

• For amino and organic acidopathies and urea cycle defects, protein intake should be restricted to 40-50% of RDA.
  • Lipids, 2-3 g/kg/d as 20% intralipid, can be given to increase caloric intake, but they are contraindicated for certain fatty acid oxidation defects.

  • For patients able to tolerate enteral feeding, protein-restricted preparations (eg, Meade Johnson 80056) may be given.

  • With definitive diagnosis, specific dietary regimens, available for most IEMs, should be initiated.

• Pharmacologic therapy to increase activity of abnormal cofactor-dependent enzymes (eg, thiamine [B-1] 5-20 mg/d PO up to 500 mg/d, biotin 5-20 mg/d PO, riboflavin [B-2] 200-300 mg PO tid, cobalamin [B-12] 1-2 mg/d IM) may be given. Vitamins may be given empirically.

• Transplantation (organ or bone marrow)

• Enzyme replacement therapy

• Gene therapy

Further Outpatient Care:

• Medical therapy specific for the IEM diagnosed will need to be continued, usually for life.

• Provide long-term routine follow-up screening for potential disease complications.

Transfer:

• Patients may require transfer to a tertiary care facility for further evaluation and treatment.

• Treatment to stabilize the patient should be initiated prior to transfer.

• Do not delay treatment to arrange transfer.

• When selecting the mode of transport and transport team, keep in mind that patients may deteriorate rapidly.

Deterrence/Prevention:

• Strict adherence to dietary and pharmacologic regimen is recommended for patients diagnosed with IEM.

• Early treatment of intercurrent illness or trauma is recommended to avoid metabolic decompensation.

Complications:

• Significant neurologic impairment

• Death

Prognosis:

• Prognosis varies based on individual IEM and may differ for different forms of a particular IEM.

• A high index of suspicion is critical for early diagnosis and treatment of IEM.

• Rapid treatment may be life saving and often results in full recovery.

Patient Education:

• Provide counseling (dietary, genetic, psychosocial) as appropriate. Professional and peer support groups exist for many IEMs.

• Provide genetic counseling to discuss prognosis, recurrence risks, screening of other family members, prenatal diagnosis, and support groups.

	MISCELLANEOUS	Section 9 of 11
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Medical/Legal Pitfalls:

• Delay in recognition and treatment may result in long-term neurologic impairment or death. Initiate treatment as quickly as possible.

• Consider IEMs in all neonates and young infants with unexplained death.

• Make every effort to collect specimens for definitive diagnosis while the child is acutely ill (particularly samples for biochemical analysis since biochemical abnormalities may be transient).

• Also obtain specimens immediately postmortem in children with unexplained death.

	PICTURES	Section 10 of 11
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Caption: Picture 1. Clinical and laboratory findings of inborn errors of metabolism (IEMs).
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Caption: Picture 2. Initial laboratory studies for inborn errors of metabolism (IEMs).
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Caption: Picture 3. Emergent treatment for inborn errors of metabolism (IEMs).
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	BIBLIOGRAPHY	Section 11 of 11
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• Arn PH, Valle DL, Brusilow SW: Inborn errors of metabolism: not rare, not hopeless. Contemp Pediatr 1988; 5: 47-63.
• Burton BK: Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics 1998 Dec; 102(6): E69[Medline].
• Calvo M, Artuch R, Macia E, et al: Diagnostic approach to inborn errors of metabolism in an emergency unit. Pediatr Emerg Care 2000 Dec; 16(6): 405-8[Medline].
• Chace DH, Kalas TA, Naylor EW: Use of tandem mass spectrometry for multianalyte screening of dried blood specimens from newborns. Clin Chem 2003 Nov; 49(11): 1797-817[Medline].
• Chow SL, Gandhi V, Krywawych S, et al: The significance of a high plasma ammonia value. Arch Dis Child 2004 Jun; 89(6): 585-6[Medline].
• Enns GM, Packman S: Diagnosing inborn errors of metabolism in the newborn: clinical features. Neo Reviews 2001; 2000: e183-90.
• Fernandes J, Saudubray JM, Van den Berghe G: Inborn Metabolic Diseases: Diagnosis and Treatment. 3rd ed. Springer-Verlag; 2000.
• Goodman SI: Inherited metabolic disease in the newborn: approach to diagnosis and treatment. Adv Pediatr 1986; 33: 197-223[Medline].
• Hoffman GF, Nyhan WL, Zschocke J: Inherited Metabolic Diseases. Philadelphia: Lippincott Williams & Wilkins; 2002.
• McKusik VA: OMIM Online Mendelian Inheritance in Man [database online]. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), 2000. Available at: http://www.ncbi.nlm.nih.gov/omim.[Full Text].
• Ward JC: Inborn errors of metabolism of acute onset in infancy. Pediatr Rev 1990 Jan; 11(7): 205-16[Medline].
• Weinstein DA, Butte AJ, Raymond K: High incidence of unrecognized metabolic and endocrinologic disorders in acutely ill children with previously unrecognized hypoglycemia. Pediatr Res 2001; 49: 103A#578.

Pediatrics, Inborn Errors of Metabolism excerpt