Approach to Diagnosis of Inborn Errors of Metabolism

1. Approach to Diagnosis of Inborn Errors of Metabolism Stanley Korman Department of Genetics & Metabolic Diseaseskorman@hadassah.org.il

2. Approach to Inborn Errors of Metabolism diagnose the metabolic defect understand the pathogenesis design the treatment

3. Diagnosis of Inborn Errors of Metabolism

4. Diagnosis of Inborn Errors of Metabolism

5. Major Categories of Inborn Errors • amino acids • metabolism • phenylketonuria (PKU) • tyrosinemia • alkaptonuria • homocystinuria • maple syrup urine disease • non-ketotic hyperglycinemia • transport • cystinuria • lysinuric protein intolerance • Hartnup disease

6. amino acids • organic acids • isovaleric acidemia • propionic acidemia • methylmalonic acidemia • lactic acidemias • pyruvate dehydrogenase complex • pyruvate carboxylase • glutaric acidemia type 1

7. amino acids • organic acids • hyperammonemia • urea cycle disorders • NAGS • CPS • OTC • ASS (citrullinemia) • ASL • arginase • others • lysinuric protein intolerance • HHH syndrome • citrin (citrullinemia type II)

8. amino acids • organic acids • glycogen storage • types 0-XIII • gluconeogenesis • PEPCK • FDPase • galactose • galactosemia • galactokinase • epimerase • fructose • hereditary fructoseintolerance • fructosuria • hyperammonemia • carbohydrates

9. amino acids • organic acids • hyperammonemia • carbohydrates • fatty acid oxidation • carnitine • β-oxidation • ketogenesis • ketolysis

10. amino acids • organic acids • hyperammonemia • carbohydrates • fatty acid oxidation • mitochondria • peroxisomes • lysosomes • organelles

11. amino acids • organic acids • hyperammonemia • carbohydrates • fatty acid oxidation • organelles • purines and pyrimidines

12. amino acids • organic acids • hyperammonemia • carbohydrates • fatty acid oxidation • organelles • purines and pyrimidines • neurotransmitters

13. amino acids • organic acids • B1 thiamine • B2 riboflavin • B6 pyridoxine • B12 cobalamin • biotin • folate • vitamin D • hyperammonemia • carbohydrates • fatty acid oxidation • organelles • purines and pyrimidines • neurotransmitters • vitamins

14. amino acids • organic acids • Cu Transport • Wilson • Menkes • Fe • hemochromatosis • Molybdenum Cofactor • hyperammonemia • carbohydrates • fatty acid oxidation • organelles • purines and pyrimidines • neurotransmitters • vitamins • metals

15. amino acids • steroid • organic acids • hyperammonemia • carbohydrates • Smith Lemli Opitz • Niemann-Pick • CTX • fatty acid oxidation • organelles • purines and pyrimidines • neurotransmitters • vitamins • metals

16. amino acids • lipids • porphyrins • hormones • ………... • organic acids • hyperammonemia • carbohydrates • fatty acid oxidation • others • organelles • purines and pyrimidines • neurotransmitters • vitamins • metals

21. Inborn Errors: Pathogenesis precursor substrate X X X ENZYME ENZYME end-product product

22. Inborn Errors: Pathogenesis precursor substrate X ENZYME ENZYME end-product product

23. Inborn Errors: Pathogenesis precursor substrate X ENZYME ENZYME end-product product

24. Inborn Errors: Pathogenesis precursor substrate precursor substrate X ENZYME ENZYME alternatemetabolites end-product product

25. Inborn Errors: Pathogenesis CF CF precursor substrate Co- Factor ENZYME APOENZYME end-product product

26. Inborn Errors: Pathogenesis precursor substrate TRANSPORTER RECEPTOR ENZYME end-product product

27. Diagnostic Clues Could this be an inborn error of metabolism? hyperammonemia hypoglycemia metabolic acidosis multisystem disease undiagnosed patients liver disease cardiomyopathy dysmorphismorganomegaly myopathyrhabdomyolysis skin disorders unexplained encephalopathy “birth asphyxia” family history consanguinity “neonatal sepsis” ophthalmic signs

28. Diagnostic Clues undiagnosed patient multisystem disease consanguinity family history

29. Think Metabolic!

30. Diagnosis: Metabolites substrate precursor alternate metabolites end-product product ENZYME

31. Diagnosis: Enzyme precursor substrate • WHICH TISSUE? • plasma • blood cells • lymphocytes • platelets • fibroblasts • muscle • liver ENZYME ENZYME end-product product

32. Diagnosis: Genetic X • ADVANTAGES • DNA accessible and readily available • target tissue not required (except mitochondrial) • simple and cheap if mutation is known • ideal for prenatal diagnosis • DISADVANTAGES • which gene? • which mutation? • polymorphism or pathogenic mutation?

33. Make the most of simple, available tests • smell MSUD (maple syrup urine disease)

34. Make the most of simple, available tests • smell isovaleric acidemia

35. Make the most of simple, available tests • smell multiple carboxylase deficiency

36. Make the most of simple, available tests • smell tyrosinemia type I

37. Make the most of simple, available tests • smell trimethylaminuria

38. Make the most of simple, available tests • smell phenylketonuria

39. Make the most of simple, available tests • smell • pH • glucose • ketones

40. KREBS free fatty acid fatty acyl-CoA β acetyl-CoA ketones

41. KREBS free fatty acid fasting free fatty acid fatty acyl-CoA X β acetyl-CoA ketones ketones

42. free fatty acid fasting free fatty acid fatty acyl-CoA β acetyl-CoA ketones

43. Make the most of simple, available tests • smell • pH • glucose • ketones • reducing substances (Clinitest)

44. Urine Reducing Sugars 5 drops urine + 10 drops H20 + 1 Clinitest® tablet

45. Make the most of simple, available tests • glucose • galactose • fructose • xylose (pentosuria) • homogentisic acid (alkaptonuria) • 4-OH-phenylpyruvate (tyrosinemias) • oxalate (hyperoxaluria) • uric acid • hippiruate • salicylates • color and smell • pH • glucose • ketones • reducing substances (Clinitest)

46. Make the most of simple, available tests • smell • pH • glucose • ketones • reducing substances (Clinitest) • creatinine, uric acid • sulfite test

47. Urine Sulfite Test

48. Sulfite Oxidase Deficiency • intractable neonatal seizures • profound encephalopathy sulfites SULFITE OXIDASE sulfates

49. Molybdenum Cofactor Deficiency MoCo sulfites xanthine SULFITE OXIDASE XANTHINE OXIDASE ALDEHYDE OXIDASE sulfates uric acid molybdenum cofactor