Inborn Errors of Metabolism

Inborn Errors of Metabolism
By:Robert D. Steiner, MD
Associate Professor, Pediatrics and Molecular and Medical Genetics
Head: Division of Metabolism, OHSU

Inborn Errors of Metabolism
* IEM as a group are not rare: occur 1 in 5000 births collectively
* Often treatable if diagnosed
* Most difficult task for clinician is to know when to consider IEM and which tests to order for evaluation
* Don’t be fooled--other diagnoses like sepsis, ICH, pulm. hem. may accompany IEM
* Clues to presence of IEM may often be found in FH

Metabolic Diseases Which Can Present in Crisis
“Stumbling Blocks” in Diagnosing Inborn Errors of Metabolism
* Signs and symptoms are often nonspecific
o Routine childhood illnesses excluded 1st
o Inborn errors considered only secondarily
* Unfamiliarity with biochemical interrelationships/ diagnostic tests
o Inappropriate sample collection
o Inappropriate sample storage
* Every child with unexplained . . .
o Neurological deterioration
o Metabolic acidosis
o Hypoglycemia
o Inappropriate ketosis
o Hypotonia
o Cardiomyopathy
o Hepatocellular dysfunction
o Failure to thrive

. . . should be suspected of having a metabolic disorder

When to suspect an IEM
EFFECT ON OTHER METABOLIC ACTIVITY
e.g., activation, inhibition, competition
Theoretical consequences of an enzyme deficiency.
First Steps in Metabolic Therapy for Inborn Errors of Metabolism
* Reduce precursor substrate load
* Provide caloric support
* Provide fluid support
* Remove metabolites via dialysis
* Divert metabolites
* Supplement with cofactor(s)

Therapeutic Measures for IEM
* D/C oral intake temporarily
* Usually IVF’s with glucose to give 12-15 mg/kg/min glu and at least 60 kcal/kg to prevent catabolism (may worsen PDH)
* Bicarb/citrate Carnitine/glycine
* Na benzoate/arginine/citrulline
* Dialysis--not exchange transfusion
* Vitamins--often given in cocktails after labs drawn before dx is known

Treatment of the Acutely Sick Child
General Therapy
* Maintain vital functions
o Oxygenation
o Hydration
o Acid/Base balance

Specific Therapy
* Treat infection
* High dose I.V. glucose
* Carnitine supplementation

STRIVE TO IDENTIFY PRIMARY METABOLIC DISORDER
TREATMENT OF GENETIC DISEASES
* MODIFY ENVIRONMENT, e.g., diet, drugs
* SURGICAL, correct or repair defect or organ transplantation
* MODIFY OR REPLACE DEFECTIVE GENE PRODUCT, megadose vitamin therapy or enzyme replacement
* REPLACE DEFECTIVE GENE
* CORRECT ALTERED DNA IN DEFECTIVE GENE

Newborn Screening
* PKU - must do on all infants in NICU even if not advanced to full feeds
o Positive--transient HPA, tyr, liver disease, benign HPA, classical PKU
* Galactosemia-
* Hypothyroidism
* Hemoglobinopathies
* Biotinidase def, CAH (21-OH’ase def),
* MSUD

Metabolic Disorders Presenting as Severe Neonatal Disease
What to do for the Dying Infant Suspected of Having an IEM

Inborn Errors of Metabolism.ppt