Inborn Errors of Metabolism Treatment & Management

Updated: Sep 20, 2017
  • Author: Debra L Weiner, MD, PhD; Chief Editor: Robert P Hoffman, MD  more...
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Treatment

Approach Considerations

Goals of treatment for patients with an inborn error of metabolism (IEM) are prevention of further accumulation of harmful substances, correction of metabolic abnormalities, and elimination of toxic metabolites. 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 inborn error of metabolism as soon as the diagnosis is considered. Treatment of patients with a known inborn error of metabolism should be disease and patient specific. Families may have treatment protocols with them developed by an IEM specialist. They may also have instructions for what resuscitation measures should be given if resuscitation is necessary. Protocols for acute illness are available on the New England Consortium of Metabolic Programs. [2]

Strict adherence to dietary and pharmacologic regimen is recommended for patients diagnosed with an inborn error of metabolism. Early treatment symptoms and recognition that physiologic stressors, including intercurrent illness, trauma, surgery, and changes in diet, may precipitate symptoms is important in avoiding metabolic decompensation.

Medical therapy specific for the inborn error of metabolism diagnosed will need to be continued, usually for life. [13, 14]  Long-term, routine follow-up screening should be provided for potential disease complications.

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Medical Care

Emergent treatment

Initial ED treatment does not require knowledge of the specific metabolic disease or even disease category. [15] In any critically ill child, airway, breathing, and circulation must be established first. Hypoglycemia, acidosis, and hyperammonemia must be corrected. Consider antibiotics in any child who may be septic.

Initiate treatment as quickly as possible. Delay in recognition and treatment may result in long-term neurologic impairment or death. See the following steps: [15]

  • Access and establish airway, breathing, circulation: D10 normal saline should be used as bolus fluid unless the patient is hypoglycemic--in which case, dextrose should instead be given as a bolus as detailed below. Avoid lactated Ringer solution. Avoid hypotonic fluid load because of the risk of cerebral edema, particularly if hyperammonemia is present.

  • Discontinue oral intake in patients with decreased level of consciousness and patients who are vomiting.

  • Eliminate intake or administration of potentially harmful protein or sugars, especially galactose and fructose. Disease-specific offending agents should be eliminated for those with known IEM and those with positive newborn screen results.

  • Correct hypoglycemia, prevent catabolism, and promote urinary excretion of toxic metabolites. Correct hypoglycemia, if present, with IV dextrose bolus, as D10 for neonates and D10 or D25 beyond the neonatal period, 0.25-1 g/kg/dose, not to exceed 25 g/dose, and followed by continuous IV administration of dextrose. For all patients in whom IEM cannot be ruled out, give dextrose 10% IV at 1-1.5 maintenance (7-8 mg/kg/min) to keep glucose level at 120-150 mg/dL, which should prevent catabolism. High-volume maintenance fluid will also promote urinary excretion of some toxic metabolites. Add insulin, 0.2-0.3 IU/kg, as needed to maintain glucose level in the desired range.

  • Correct metabolic acidosis and electrolyte abnormalities. Sodium bicarbonate or, if the patient is hypokalemic, potassium acetate should be administered to correct acidosis. The pH (< 7.0-7.2) and dose of 0.25-0.5 mEq/kg/hr (up to 1-2 mEq/kg/hr) IV at which sodium bicarbonate or potassium acetate should be administered are controversial because data are lacking. Rapid correction or overcorrection may have paradoxical effects on the CNS. For intractable acidosis, consider hemodialysis. Add electrolytes at maintenance concentrations, with appropriate adjustments to correct electrolyte disturbances if present.

  • Correct hyperammonemia. Significant hyperammonemia is life-threatening and must be treated immediately upon diagnosis. To reduce ammonia, sodium phenylacetate and sodium benzoate (Ammonul; Ucyclyd Pharma, 888-829-2593, FDA approved for hyperammonemia due to urea cycle defects and neonatal hyperammonemic coma) can be administered to augment nitrogen excretion. If < 20 kg, administer a loading dose of 250 mg/kg (2.5 mL/kg) in 10% glucose via central line over 90-120 minutes, then 250 mg/kg/day (2.5 mL/kg/day) in 10% glucose via central continuous infusion; if >20 kg, administer 5.5 g/m2 (55 mL/m2) over 90-120 minutes, then 5.5 g/m2/day (55 mL/m2/day). Ammonul must be given by central line. Arginine is an essential amino acid in patients with urea cycle defects and should be administered as arginine HCL (600 mg/kg, ie, 6 mL/kg, IV in 10% glucose over 90-120 minutes, then 600 mg/kg/day IV continuous infusion) unless the patient has arginase deficiency, in which case it should not be given. Arginine dose should be decreased to 200 mg/kg for known carbamyl phosphate synthetase (CPS) or ornithine transcarbamylase (OTC) deficiency. Arginine can be mixed with Ammonul.

  • For ammonia level greater than 500-600 mg/dL before Ammonul or greater than 300 mg/dL and rising after Ammonul, hemodialysis should likely be initiated. If hemodialysis is not redily 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 three days of therapy is usually necessary.

  • Administer cofactors if indicated. L-carnitine (25-50 mg/kg IV over 2-3 minutes or as infusion, followed by 25-50 mg/kg/day, maximum 3 g/day) may be administered empirically in life-threatening situations associated with primary carnitine deficiency. Administration of L-carnitine to patients with secondary carnitine deficiency is controversial. Consultation with an IEM specialist is recommended. [15]  Carnitine cannot be given with Ammonul. Pyridoxine (B6) (100 mg IV) should be given to neonates with seizures unresponsive to conventional anticonvulsants. 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.

Inpatient Care

Further inpatient care may include the following:

  • Once toxic metabolites have been normalized, protein can be reintroduced using an essential amino acid solution, initially at 0.5-0.75 g/kg/day and gradually increased. For amino and organic acidopathies and urea cycle defects, protein intake should be restricted to 40-50% of recommended daily allowance (RDA). Lipids, 2-3 g/kg/day 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/day PO up to 500 mg/day, biotin 5-20 mg/day PO, riboflavin [B-2] 200-300 mg PO tid, cobalamin [B-12] 1-2 mg/day IM) may be given. Vitamins may be given empirically.

  • Transplantation (organ or bone marrow)

  • Enzyme replacement therapy

  • Gene therapy

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Diet

Nutritional interventions for IEM include medical foods and dietary supplements along with dietary modifications to exclude nutrients that cannot be metabolized due to the specific IEM. The use of medical foods and/or dietary supplements prevent death, intellectual disability, or other adverse health outcomes. [5]

Two types of medical foods are used in the treatment of IEMs. One type meets the majority of nutritional requirements while excluding the IEM-specific nutrient that cannot be metabolized. The second type includes products modified to be low in protein and are used in natural protein-restricted diets to provide energy and variety in the diet (eg, specially modified flour, cereals, and baked goods, meat and cheese substitutes, pasta, and rice). [5]

 

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