Inborn errors of Metabolism

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Background

Inborn errors of metabolism (IEM) are a heterogeneous group of diseases that may or may not be detected by newborn screening.  Early recognition of these disorders is important to institute therapy and to prevent neurologic damage.  IEM may present with an acute crisis—often with encephalopathy the neonatal period—or with a more indolent, chronic course.  In addition to the common presenting symptoms of IEM (listed below), a family history of mental retardation, neonatal death in siblings, or parental consanguinity may increase the suspicion of IEM.

 

Findings suggestive of an acute IEM crisis
(often confused with sepsis)

  • poor feeding
  • persistent vomiting
  • lethargy
  • convulsions resistant to IV glucose or calcium
  • hypotonia or spasticity
  • tachypnea/Kussmaul breathing/apnea
  • failure to thrive
  • coma
  • lack of improvement to any of the above with standard therapy

 

Findings suggestive of a chronic IEM course

  • developmental delay (especially regression)
  • seizures resistant to anticonvulsant therapy
  • movement disorder
  • peripheral muscle weakness
  • cardiomyopathy
  • hepatosplenomegaly
  • hypoglycemia
  • renal failure
  • cataracts
  • retinal abnormalities
  • macrocephaly
  • dysmorphic features
  • unusual body odors

 

Workup for suspected IEM

  1. CBC, differential, and platelets 
  2. serum electrolytes 
  3. arterial blood gas 
  4. serum glucose 
  5. plasma ammonia level 
  6. urine for reducing substances
  7. urine for organic acids
  8. urine and blood for amino acids 
  9. urine for ketones if the neonate is hypoglycemic or acidotic
  10.  liver function tests if the child has encephalopathy

 

Laboratory findings that help guide IEM diagnosis

Metabolic acidosis

  • Often characterized by persistent vomiting, tachypnea, seizures, or hypotonia
  • If anion gap is present, organ acidemias are suspected
  • If no anion gap is present, consider renal tubular acidosis or diarrheal disease

Hyperammonemia

  • Often characterized by altered consciousness, persistent vomiting, or lethargy
  • Ammonia levels drawn from venous samples must be handled properly after drawing
  • Ammonia levels > 1000 umol/L with no anion gap suggest urea cycle defects
  • Associated anion gap suggests organic acidemias
  • Associated hypoglycemia and elevated liver transaminases suggest fatty acid oxidation defects

Hypoglycemia

  • Associated acidosis suggests organic acidemias
  • Associated hepatomegaly or liver failure suggest glycogen storage disorders, galactosemia, or tyrosinemia
  • Normal anion gaps and lactic acid levels suggest hyperinsulinemia or fatty acid oxidation defects
  • Associated hyponatremia and hypotension suggest adrenal insufficiency

Emergency treatment

  1. Remove accumulating metabolites with hemodialysis 
  2. Stop all protein ingestion 
  3. Glucose if patient is hypoglycemic
  4. Arginine infusion if you suspect a urea cycle defect 
  5. B12 and biotin administration if you suspect an organic acidemia 
  6. Send appropriate labs 
  7. Consultation with geneticist or metabolic specialist
  8. If the patient is dying, it is important to obtain appropriate materials for diagnosis.  Urine and separated plasma should be frozen, a tissue sample must be obtained and placed in special medium, and a needle biopsy of the liver should be obtained. 

 

IEM categories with examples

Defects in amino acid metabolism

  • Phenylketonuria
  • Homocystinuria
  • Alcaptonuria
  • Hereditary tyrosinemia

Defects in carbohydrate metabolism

  • Galactosemia
  • Glycogen storage diseases (von Gierke, Pompe)

Defects in fatty acid oxidation

  • Short/medium/long-chain acyl-CoA dehydrogenase deficiency

Urea cycle defects

  • Ornithine transcarbamylase deficiency
  • Carbamyl phosphate synthetase deficiency

Lysosomal Storage Diseases

  • Gangliosidoses (Tay-Sachs, Gaucher, Nieman-Pick)
  • Mucopolysacharidoses (Hurler, Hunter)

Defects in heme pigment biosynthesis

  • Acute intermittent porphyria

Disorders of metal metabolism

  • Wilson’s disease
  • Hemochromatosis

Mitochondrial disorders

  • MERRF

 

Interesting associations between body/urine odor and IEM

Musty/mousy                 = phenylketonuria

Boiled cabbage                = tyrosinemia, hypermethioninemia

Maple syrup                   = maple syrup urine disease

Rotting fish                    = trimethylaminuria

Sweaty feet                     = isovaleric academia, glutaric academia (type II)

 

References

  1. Burton B.  Inborn Errors of Metabolism in Infancy: A guide to Diagnosis.  Pediatrics 1998; 102(6) 
  2. Ward, Jewell. Inborn Errors of Metabolism of Acute Onset In Infancy.  Pediatrics in Review 1990; 11(7)
  3. Debray F. et al. Long-term Outcome and Clinical Spectrum of 73 Pediatric Patients With Mitochondrial Diseases. Pediatrics 2007; 119(4)
  4. Feilett F. e3t al. Challenges and Pitfalls in the Management of Phenylketonuria Pediatrics 2010; 126(2)
  5. Levy P.  Inborn Errors of Metabolism.  Part 1: Overview. Pediatrics in Review 2009; 30(4)
  6. Levy P. Inborn Errors of Metabolism: Part 2: Specific Disorders.  Pediatrics in Review 2009; 30(4):e22
  7. Illinois Department of Health: Newborn Screening Disorder List (as of March 2011)
  8. Roth K. Inborn Errors of Metabolism: The Essentials of Clinical Diagnosis. Clinical Pediatrics 1991; 3(30)

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