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

2. 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

3. Incidence of Inborn Errors
Class No. of Disorders Known Incidence
Critical, life threatening
disorders of infancy ~1:5,000
Serious disorders >300 ~1:1,000
compromising health in
infants/adults
Common disorders of any age >300 ~1:50

4. Metabolic Diseases Which Can Present in Crisis
Defects of glucose homeostasis (20)
Defects of amino acids (10)
Defects of fatty or organic acids (20)
Defects of Lactate/Pyruvate (20)
Defects of Peroxisomes
Others

5. “Stumbling Blocks” in Diagnosing Inborn Errors of Metabolism
Signs and symptoms are often nonspecific
Routine childhood illnesses excluded 1st
Inborn errors considered only secondarily
Unfamiliarity with biochemical interrelationships/ diagnostic tests
Inappropriate sample collection
Inappropriate sample storage

6. Every child with unexplained . . .
Neurological deterioration
Metabolic acidosis
Hypoglycemia
Inappropriate ketosis
Hypotonia
Cardiomyopathy
Hepatocellular dysfunction
Failure to thrive
. . . should be suspected of having a metabolic disorder

7. When to suspect an IEM
Infants have only a limited repertoire of symptoms--sxs non-specific
Vomiting, lethargy, FTT, sz’s, resp (tachypnea, hyperpnea, apnea), coma, cardiomyopathy
Odor, abnormal hair, dysmorphology
Labs: metabolic acidosis, hypoglycemia, hyperammonemia, reducing substances in urine, ketonuria, pancytopenia
Not all infants with life threatening IEM have either acidosis or hyperammonemia (i.e. non-ketotic hyperglycinemia, mild lactate elev).

9. “Waiting until sepsis and other more common causes of illness are ruled out before initiating a specific diagnostic evaluation is inadvisable, as is indiscriminate study of all ill newborns for metabolic disorders.”

14. Theoretical consequences of an enzyme deficiency.
defective enzyme
Substrate
(increased)
Product
(decreased)
action
Co-factor B
Co-factor A
other
enzymes
Metabolites
(decreased)
Metabolites
(increased)
EFFECT ON OTHER METABOLIC ACTIVITY
e.g., activation, inhibition, competition
Theoretical consequences of an enzyme deficiency.

15. An integrated view of the metabolic pathways
GLYCOGEN
FAT
PROTEIN
FRUCTOSE
GALACTOSE
AMINO ACIDS
GLUCOSE
FREE FATTY ACIDS
ORGANIC ACIDS
AMMONIA
PYRUVATE
LACTATE
ACETYL CoA
UREA CYCLE
KETONES
UREA
KREBS CYCLE
NADH
ATP
An integrated view of the metabolic pathways

16. 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)

17. Therapeutic Measures for IEM
D/C oral intake temporarily
Usually IVF’s with glucose to give 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
Biotin, B6, B12, riboflavin, thiamine, folate

18. Treatment of the Acutely Sick Child
General Therapy
Maintain vital functions
Oxygenation
Hydration
Acid/Base balance
Specific Therapy
Treat infection
High dose I.V. glucose
Carnitine supplementation
STRIVE TO IDENTIFY PRIMARY METABOLIC DISORDER

19. 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

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

21. Metabolic Disorders Presenting as Severe Neonatal Disease
Disorders of Carbohydrate Metabolism
Galactosemia - presents with severe liver disease, gram negative sepsis, and/or cataracts
Enz deficiency: Gal-1-phos uridyl transferase, UDP-gal-4-epimerase
Glycogen storage disease type 1a & 1b - presents as hypoglycemia
Enz deficiency: Glucose-6 phosphatase
Lactic Acidosis - presents as lactic acidosis +/- hypoglycemia
Enz deficiency: Pyruvate carboxylase, Pyr dehydrogenase, etc.
Fructose intolerance - Needs fructose exposure, hypoglycemia and acidosis

22. Metabolic Disorders Presenting as Severe Neonatal Disease
Amino Acid Disorders
Maple syrup urine disease - presents with odor to urine and CNS problems
Enz deficiency: Branched chain ketoacid decarboxylase
Nonketotic hyperglycinemia - presents with CNS problems
Enz deficiency: Glycine cleavage system
Tyrosinemia - Severe liver disease, renal tubular dysfunction
Enz deficiency: Fumaryl acetate
Transient tyrosinemia of prematurity - progressive coma following respiratory distress

23. Metabolic Disorders Presenting as Severe Neonatal Disease
Urea Cycle Defects and Hyperammonemia
All present with lethargy, seizures, ketoacidosis, neutroenia, and hyperammonemia
Ornithine carbamyl transferase (OTC) deficiency
Carbamyl phosphate synthetase deficiency
Citrullinemia
Arginosuccinic Aciduria
Argininemia
Transient tyrosinemia of prematurity

24. Metabolic Disorders Presenting as Severe Neonatal Disease
All present with lethargy, seizures, ketoacidosis, neutropenia, hyperammonemia, and/or hyperglycinemia
Organic Acid Defects
Methylmalonic acidemia
Proprionic acidemia
Isovaleric acidemia - odor of “sweaty feet”
Glutaric aciduria type II
Dicarboxylic aciduria
Miscellaneous
Peroxisomal disorders
Lysosomal storage disease
Pyridoxine dependent seizures

25. What to do for the Dying Infant Suspected of Having an IEM
Autopsy--pref. performed within 4 hours of death
Tissue and body fluid samples
Blood, URINE, CSF (ventricular tap), aqueous humour, skin biopsy, muscle and liver--frozen in liquid nitrogen
Filter paper discs from newborn screen--call lab and ask them not to discard