Inborn Errors of Metabolism, Emergency Medicine

Basics

Description

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 disorders
  - Urea cycle defects
  - Organic acidemias
  - Defects in fatty acid oxidation
  - Mitochondrial fatty acid defects and carnitine transport defects
  - Mitochondrial disease
  - Carbohydrate disorders
  - Mucopolysaccharidoses
  - Sphingolipidoses
  - Peroxisomal disorders
  - Protein glycosylation disorders
  - Lysosomal disorders
  - Rhizomelic 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:
- 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)
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 level
- Quantitative serum amino acids
- Urine organic and amino acids
Cultures:
- Blood
- CSF

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:
- Sepsis
- Meningitis
- Encephalitis
Metabolic:
- Reye syndrome
- Hepatic encephalopathy
- Hyperinsulinemia
- Hormonal abnormality
Renal:
- Renal failure
- Renal 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 hydrochloride
- Sodium benzoate
- Sodium phenylacetate
- Sodium phenylbutyrate
- Doses 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:

0.9% NS at 20 mL/kg

Second Line
Bicarbonate therapy for pH <7.0:

Hemodialysis as needed

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 status
- Severe or persistent acidosis
- Unresponsive hypoglycemia
- Hyperammonemia
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:

Diet
Medications

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)

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