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Inborn Errors of Metabolism, Emergency Medicine

Basics

Description

- Disorders may present with either a rapid decompensation or a chronic indolent course - Neonates, initial presentation: - Asymptomatic - Hypothermia (mitochondrial defects) - Hypotonia/hypertonia (peroxisomal disorders) - Apnea (urea cycle defects, organic acidosis) - Seizures (peroxisomal disorders, glucose transporter defects) - Coma (numerous) - Vomiting (numerous) - Poor feeding, growth (numerous) - Jaundice (galactosemia, Niemann-Pick C) - Hypoglycemia (galactosemia, maple syrup urine) - Dysmorphic features (lysosomal storage disorders, congenital adrenal hyperplasia, Smith-Lemli-Opitz)

- Often misdiagnosed as sepsis, dehydration, failure to thrive, toxic ingestion, or nonaccidental trauma - Infection: - Sepsis - Meningitis - Encephalitis

- Metabolic: - Reye syndrome - Hepatic encephalopathy - Hyperinsulinemia - Hormonal abnormality

- Increase urine output to help in removal of some toxins. - Initially, stop all oral intake; amino acid metabolites may be neurotoxic. - Treat severe hyperammonemia (≥500-600 mmol/L) with immediate dialysis or with ammonia-trapping drugs such as: - Arginine hydrochloride - Sodium benzoate - Sodium phenylacetate - Sodium phenylbutyrate - Doses vary with disease; consult metabolic physician before use.

  • Defect in the type, amount, and toxicity of metabolites that accumulate due to an inherited abnormal pathway in children; result in a variety of clinical findings; >400 human diseases are caused by inborn errors of metabolism
  • Epidemiology:Incidence:Variable: 1:10,000-1:200,000 births
  • Genetics:Common inherited metabolic diseases:Amino acid disordersUrea cycle defectsOrganic acidemiasDefects in fatty acid oxidationMitochondrial fatty acid defects and carnitine transport defectsMitochondrial diseaseCarbohydrate disordersMucopolysaccharidosesSphingolipidosesPeroxisomal disordersProtein glycosylation disordersLysosomal disordersRhizomelic chondrodysplasia punctata
  • Pathophysiology:Related to defect in a metabolic pathway

Etiology

Diverse group of disorders involving genetic deficiency of an enzyme of an intermediary metabolite or a membrane transport system.

Diagnosis

Signs and Symptoms

  • Disorders may present with either a rapid decompensation or a chronic indolent course
  • Neonates, initial presentation:AsymptomaticHypothermia (mitochondrial defects)Hypotonia/hypertonia (peroxisomal disorders)Apnea (urea cycle defects, organic acidosis)Seizures (peroxisomal disorders, glucose transporter defects)Coma (numerous)Vomiting (numerous)Poor feeding, growth (numerous)Jaundice (galactosemia, Niemann-Pick C)Hypoglycemia (galactosemia, maple syrup urine)Dysmorphic features (lysosomal storage disorders, congenital adrenal hyperplasia, Smith-Lemli-Opitz)
  • Older children, untreated:Failure to thrive (urea cycle defects)Dehydration (organic acidosis)Vomiting (urea cycle defects and others)Diarrhea (numerous)Food intolerance (lipid defects, amino acid defects)Lethargy (urea cycle defects)Ataxia (urea cycle defects)Seizures (numerous)Mental retardation (phenylketonuria and others)

History

Complete history of current and concomitant illness:

  • Newborn screening
  • Dietary
  • Family
  • Consanguinity
  • Other

Physical Exam

  • Abnormal odor
  • Altered mental status
  • Tachypnea
  • Abnormal facies
  • Cataract
  • Cardiomyopathy
  • Hepatomegaly
  • Splenomegaly
  • Dermatitis
  • Jaundice

Essential Workup

Key is to consider in differential diagnosis:

  • Deteriorating neurologic status
  • Unexplained failure to thrive, with dehydration, persistent vomiting, or acidosis
  • Shock unresponsive to conventional resuscitative measures

Diagnosis Tests & Interpretation

Lab

  • Bedside glucose determination
  • Electrolytes, BUN/creatinine, glucose
  • CBC with differential
  • Calcium level
  • LFTs, fractionated bilirubin, PTT
  • Arterial or venous blood gas
  • Lactate and pyruvate level
  • Uric acid
  • Urinalysis
  • Chemistries, as indicated:Ammonia levelQuantitative serum amino acidsUrine organic and amino acids
  • Cultures:

Imaging

  • CT scan of head for altered mental status
  • CXR

Diagnostic Procedures/Surgery

Lumbar puncture

Differential Diagnosis

  • Often misdiagnosed as sepsis, dehydration, failure to thrive, toxic ingestion, or nonaccidental trauma
  • Infection:SepsisMeningitisEncephalitis
  • Metabolic:Reye syndromeHepatic encephalopathyHyperinsulinemiaHormonal abnormality
  • Renal:Renal failureRenal tubular acidosis
  • Toxic ingestion
  • CNS mass lesions
  • Nonaccidental trauma

Treatment

Pre-Hospital

  • ABCs
  • Bedside glucose
  • IV glucose infusion takes precedence over fluid boluses unless patient in shock. Correction can occur concurrently.
  • Avoid lactated Ringer solution.
  • Keep child NPO.

Initial Stabilization/Therapy

For altered mental status, administer Narcan, glucose (ideally after Accu-Chek and thiamine)

Ed Treatment/Procedures

  • Establish airway, breathing, and circulation.
  • For fluid boluses, use normal saline and avoid lactated Ringer and avoid hypotonic fluid.
  • Initiate IV glucose at rate of 8-10 mg/kg/min to prevent catabolism:Corresponds to D10 at 1.5 times maintenance.Do not delay glucose infusion to give a "bolus" of isotonic saline; may be given concurrently in a child in shock.If patient is severely hypoglycemic, give IV glucose bolus of D25.
  • Rehydrate if patient is hypoglycemic:Restore normal acid-base balance.
  • Administer bicarbonate if pH is <7.0:Initiate dialysis if severe acidosis does not improve quickly.
  • Increase urine output to help in removal of some toxins.
  • Initially, stop all oral intake; amino acid metabolites may be neurotoxic.
  • Treat severe hyperammonemia (≥500-600 mmol/L) with immediate dialysis or with ammonia-trapping drugs such as:Arginine hydrochlorideSodium benzoateSodium phenylacetateSodium phenylbutyrateDoses vary with disease; consult metabolic physician before use.
  • Identify and treat intercurrent or precipitating infection/illness.
  • Consult metabolic physician when any child presents with suspected inherited metabolic disease.

Medication

  • D25: 2-4 mL/kg IV
  • Sodium bicarbonate: 1-2 mEq/kg IV
  • Other disease-specific drugs, including pyridoxine and levocarnitine as indicated

First Line

Glucose:

Second Line

Bicarbonate therapy for pH <7.0:

Follow-Up

Disposition

Admission Criteria

  • Infants and children presenting with new onset of suspected inherited metabolic disease
  • Significant urinary ketones or not tolerating oral intake
  • ICU:Significant altered mental statusSevere or persistent acidosisUnresponsive hypoglycemiaHyperammonemia
  • Transfer to specialized pediatric center may be indicated.

Discharge Criteria

  • Normal mental status
  • Normal hydration with unremarkable labs
  • No evidence of significant intercurrent illness
  • Close follow-up arranged with primary care physician

Issues for Referral

Neurodevelopment:

Follow-Up Recommendations

  • Primary care physician
  • Metabolic disease specialist

Pearls and Pitfalls

Watch for dehydration:

  • Treat dehydration with normal saline fluid bolus:Follow glucose level carefully; avoid hypoglycemia.Use bicarbonate cautiously and only consider if pH <7.0.Hemodialysis may be necessary for hyperammonemia.

Additional Reading

  • Alfadhel M, Al-Thihli K, Moubayed H, et al. Drug treatment of inborn errors of metabolism: A systematic review. Arch Dis Child. 2013;98(6):454-461. Published Online First: 2013 Mar 26 [Epub ahead of print].
  • Barness LA. An approach to the diagnosis of metabolic diseases. Fetal Pediatr Pathol. 2004;23:3-10.
  • Fernhoff PM. Newborn screening for genetic disorders. Pediatr Clin North Am. 2009;56:505-513.
  • Leonard JV, Morris AA. Inborn errors of metabolism around time of birth. Lancet. 2000;356:583-587.
  • Levy PA. Inborn errors of metabolism: Part 1: Overview. Pediatr Rev. 2009;30(4):131-137.
  • Levy PA. Inborn errors of metabolism: Part 2: Specific disorders. Pediatr Rev. 2009;30(4):e22-e28.
  • Weiner DL. Metabolic emergencies. In: Fleisher GR, Ludwig S, Henretig FM, eds. Textbook of Pediatric Emergency Medicine. 6th ed. Philadelphia, PA: Lippincott; 2010.
  • Wolf AD, Lavine JE. Hepatomegaly in neonates and children. Pediatr Rev. 2000;21:303-310.

Codes

ICD9

  • 270.6 Disorders of urea cycle metabolism
  • 270.9 Unspecified disorder of amino-acid metabolism
  • 277.9 Unspecified disorder of metabolism
  • 276.2 Acidosis
  • 271.9 Unspecified disorder of carbohydrate transport and metabolism
  • 277.5 Mucopolysaccharidosis
  • 277.87 Disorders of mitochondrial metabolism

ICD10

  • E72.9 Disorder of amino-acid metabolism, unspecified
  • E72.20 Disorder of urea cycle metabolism, unspecified
  • E88.9 Metabolic disorder, unspecified
  • E87.2 Acidosis
  • E74.9 Disorder of carbohydrate metabolism, unspecified
  • E76.3 Mucopolysaccharidosis, unspecified
  • E88.40 Mitochondrial metabolism disorder, unspecified

SNOMED

  • 86095007 Inborn error of metabolism (disorder)
  • 42930003 Inborn error of amino acid metabolism (disorder)
  • 36444000 Disorder of the urea cycle metabolism (disorder)
  • 70731005 Acidemia (disorder)
  • 11380006 mucopolysaccharidosis (disorder)
  • 20957000 Disorder of carbohydrate metabolism (disorder)
  • 240096000 mitochondrial cytopathy (disorder)