Inborn Errors of Metabolism

1. Inborn Errors of Metabolism • An inherent deficiency in a key metabolic pathway resulting in • Cellular Intoxication • Energy deprivation • Mixture of the two

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 • Remember some IEMs are dysmorphic!

4. 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).

5. When to suspect an IEM p.2 • Rapid deterioration in an otherwise well infant. • Septic appearing infant or abnl sepsis such as E.coli. • Failure to thrive. • Regression in milestones. • Recurrent emesis or feeding difficulty, alterations in respirations, abnl urine/body smell, changing MS/lethargy, jaundice, sz, intractable hiccups. • Can masquerade like pyloric stenosis. • Dietary aversion- proteins, carbs.

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. Importance of history • Catabolic state induction (sepsis,fasting,dehydration) • Protein intake • Change or addition of PO proteins, carbs, etc… in formula • **Consanguinity • FHx of SIDS

8. 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

9. 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

10. 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

11. 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

12. 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)

13. 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 • Biotin, B6, B12, riboflavin, thiamine, folate

14. 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

15. 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

16. 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

20. Stable Patient, Now what?

21. Patient is stabilized. Now what: • Broad DDx for IEMs scares people. • You can group into KEY features. • Can focus on initial labs = Hyperammonia, hypoglycemia,metabolic acidosis. • Can focus on Prominent neurologic features. • Can focus on Dysmorphic features. • If these don’t exactly fit, resort back to categories of IEMs and Neurodegenerative Disorders.

22. Quick References:

23. Fatty Acid Oxidation Defects: • **Autosomal recessive inheritance** • Examples are MCAD, LCAD, VLCAD • Defect in acyl-CoA Dehydrogenase, amitochondrial duty, and important in fasting state. • KEY features: • Acute attack of life-threatening coma with Hypoglycemia • Absence ofurine ketones, and reducing substances, nl serum AAs. • +/- mild acidosis, or hyperammonemia, elevated LFTs, abnl coags. +/-Hepatomegaly-/+ • Dx with serum Acylcarnitine Profile or fibroblast enzyme assay

24. Glycogen Storage Disorders: • Type 2- Pompe’s disease: • Normal Glucose • Do to an accumulation of glycogen in lysosomes. • **Ancient city of Pompeii was destroyed by Mt. Vesuvius- 79 AD** • Manifested by massive Cardiomegaly, Hepatomegaly, Macroglossia. • Fatal If results in CHF. • Limited therapies in Neonatal Variant. • Attempts at enzyme replacement ongoing.

25. Mitochondrial Disorders: • Spectrum of diseases with life-time variation of presentation. • Infantile/Neonatal: may present with encephalopathic picture, regressed milestones, cerebral cortical atrophy. • Generally lab findings of: • Lactic Acidosis • Nl to low serum pyruvate, incomparison to Lactate • Nl organic acids. • *** Important to check CSF values of the above***

26. Leigh’s Disease • AKA- Subacute necrosing encephalopathy • Due to defects in the mitochondrial electron transport chain. • May have devastating presentation with significant developmental regression. • Unfavorable natural history. • May respond to host of supplements. • **Other Mitochondrial disorders for completion sake** • MELAS, MERRF, Leber’s HON

27. Peroxisomal Disorders • Zellweger Syndrome • aka: Cerebro-hepato-renal syndrome • Typical and easily recognized dysmorphic facies. • Progressive degeneration of Brain/Liver/Kidney, with death ~6 mo after onset. • When screening for PDs. obtain serum Very Long Chain Fatty Acids- VLCFAs

28. Random Questions for the Boards: • Amino Acids responsible for MSUD? • Valine, Leucine, Isoleucine • Name 1 of the 3 classic Metal Storage disorders? • Menke’s Kinky Hair Syndrome (X-link recessive) • Wilson’s Disease • Neonatal Hemachromatosis

29. Menke Syndrome

30. Board questions • Name some classic Mucopolysaccharidosis? • Hunter’s (X-linked, no corneal clouding) • Hurler’s (presence of Corneal clouding) • Morquio Syndrome (nl IQ, short, cloudy cornea) • -How are mucopolysaccharidoses Diagnosed? • Urine MPSs, definite with Skin Fibroblast Bx

31. Hurler syndrome • Boy and brother Liver

32. Smith-Lemli-Opitz Syndrome: due to defect in cholesterol synthesis.

33. Smith Lemli Opitz syndrome

34. For the Boards: • Most common Urea cycle defect and also only X-linked: • Ornithine Transcarbamylase Deficiency

35. Musty or Mousy: PKU Boiled Cabbage Tyrosinemia or hypermethioninemia Maple Syrup maple syrup urine disease Sweaty feet: isovaleric acidemia or glutaric acidemia type II Cat urine multiple carboxylase deficiencies (Biotin deficiency) What’s that smell?