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Approach to Diagnosis of Inborn Errors of Metabolism. Stanley Korman Department of Genetics & Metabolic Diseases korman@hadassah.org.il. Approach to Inborn Errors of Metabolism. diagnose the metabolic defect. understand the pathogenesis. design the treatment.
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Approach to Diagnosis of Inborn Errors of Metabolism Stanley Korman Department of Genetics & Metabolic Diseaseskorman@hadassah.org.il
Approach to Inborn Errors of Metabolism diagnose the metabolic defect understand the pathogenesis design the treatment
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
amino acids • organic acids • isovaleric acidemia • propionic acidemia • methylmalonic acidemia • lactic acidemias • pyruvate dehydrogenase complex • pyruvate carboxylase • glutaric acidemia type 1
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)
amino acids • organic acids • glycogen storage • types 0-XIII • gluconeogenesis • PEPCK • FDPase • galactose • galactosemia • galactokinase • epimerase • fructose • hereditary fructoseintolerance • fructosuria • hyperammonemia • carbohydrates
amino acids • organic acids • hyperammonemia • carbohydrates • fatty acid oxidation • carnitine • β-oxidation • ketogenesis • ketolysis
amino acids • organic acids • hyperammonemia • carbohydrates • fatty acid oxidation • mitochondria • peroxisomes • lysosomes • organelles
amino acids • organic acids • hyperammonemia • carbohydrates • fatty acid oxidation • organelles • purines and pyrimidines
amino acids • organic acids • hyperammonemia • carbohydrates • fatty acid oxidation • organelles • purines and pyrimidines • neurotransmitters
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
amino acids • organic acids • Cu Transport • Wilson • Menkes • Fe • hemochromatosis • Molybdenum Cofactor • hyperammonemia • carbohydrates • fatty acid oxidation • organelles • purines and pyrimidines • neurotransmitters • vitamins • metals
amino acids • steroid • organic acids • hyperammonemia • carbohydrates • Smith Lemli Opitz • Niemann-Pick • CTX • fatty acid oxidation • organelles • purines and pyrimidines • neurotransmitters • vitamins • metals
amino acids • lipids • porphyrins • hormones • ………... • organic acids • hyperammonemia • carbohydrates • fatty acid oxidation • others • organelles • purines and pyrimidines • neurotransmitters • vitamins • metals
Inborn Errors: Pathogenesis precursor substrate X X X ENZYME ENZYME end-product product
Inborn Errors: Pathogenesis precursor substrate X ENZYME ENZYME end-product product
Inborn Errors: Pathogenesis precursor substrate X ENZYME ENZYME end-product product
Inborn Errors: Pathogenesis precursor substrate precursor substrate X ENZYME ENZYME alternatemetabolites end-product product
Inborn Errors: Pathogenesis CF CF precursor substrate Co- Factor ENZYME APOENZYME end-product product
Inborn Errors: Pathogenesis precursor substrate TRANSPORTER RECEPTOR ENZYME end-product product
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
Diagnostic Clues undiagnosed patient multisystem disease consanguinity family history
Diagnosis: Metabolites substrate precursor alternate metabolites end-product product ENZYME
Diagnosis: Enzyme precursor substrate • WHICH TISSUE? • plasma • blood cells • lymphocytes • platelets • fibroblasts • muscle • liver ENZYME ENZYME end-product product
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?
Make the most of simple, available tests • smell MSUD (maple syrup urine disease)
Make the most of simple, available tests • smell isovaleric acidemia
Make the most of simple, available tests • smell multiple carboxylase deficiency
Make the most of simple, available tests • smell tyrosinemia type I
Make the most of simple, available tests • smell trimethylaminuria
Make the most of simple, available tests • smell phenylketonuria
Make the most of simple, available tests • smell • pH • glucose • ketones
KREBS free fatty acid fatty acyl-CoA β acetyl-CoA ketones
KREBS free fatty acid fasting free fatty acid fatty acyl-CoA X β acetyl-CoA ketones ketones
free fatty acid fasting free fatty acid fatty acyl-CoA β acetyl-CoA ketones
Make the most of simple, available tests • smell • pH • glucose • ketones • reducing substances (Clinitest)
Urine Reducing Sugars 5 drops urine + 10 drops H20 + 1 Clinitest® tablet
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)
Make the most of simple, available tests • smell • pH • glucose • ketones • reducing substances (Clinitest) • creatinine, uric acid • sulfite test
Sulfite Oxidase Deficiency • intractable neonatal seizures • profound encephalopathy sulfites SULFITE OXIDASE sulfates
Molybdenum Cofactor Deficiency MoCo sulfites xanthine SULFITE OXIDASE XANTHINE OXIDASE ALDEHYDE OXIDASE sulfates uric acid molybdenum cofactor