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Inborn errors of metabolism

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An inherited enzyme deficiency leading to the disruption of normal bodily metabolism.
Accumulation of a toxic substrate.
Impaired formation of a product normally produced by the deficient enzyme.

Veröffentlicht in: Gesundheit & Medizin
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Inborn errors of metabolism

  1. 1. Tapeshwar Yadav (Lecturer) BMLT, DNHE, M.Sc. Medical Biochemistry INBORN ERRORS OF METABOLISM
  2. 2. Garrod coined the term `INBORN ERRORS OF METABOLISM`
  3. 3. An inherited enzyme deficiency leading to the disruption of normal bodily metabolism. Accumulation of a toxic substrate. Impaired formation of a product normally produced by the deficient enzyme. Garrod`s hypothesis :- A B C D substrate excess product deficiency toxic metabolite
  4. 4. Small molecule disease Carbohydrate Protein Lipid Nucleic Acids  Organelle disease Lysosomes Mitochondria Peroxisomes Cytoplasm
  5. 5. Prenatal Diagnosis Newborn Screening Later life diagnosis
  6. 6. Prenatal Diagnosis
  7. 7. Index of suspicion Family History Have a child already affected by an inherited disorder. One of the parents affected by autosomal or X- linked disorder.  H/O Neonatal deaths, fetal losses Maternal family history males - X-linked disorders all - mitochondrial DNA is maternally inherited A positive family history may be helpful!
  8. 8. Enzymatic assay of cultured amniocytes Chorionic villi sampling to determine the chromosomal,enzymatic or molecular genetic status of the fetus. Cytogenetics Enzyme assay.
  9. 9. Newborn Screening
  10. 10. Reliable screen test and low false negative results. Test is simple and inexpensive Available results soon to start effective therapy Definite follow up test Outcome without treatment is very bad Effective therapy is available
  11. 11.  Index of suspicion “with any full-term infant who has no antecedent maternal fever or PROM (premature rupture of the membranes) and who is sick enough to warrant a blood culture or LP, one should proceed with a family history & few simple lab tests.
  12. 12. Family History Most IEM’s are recessive - a negative family history is not reassuring! Consanguinity, ethnicity, inbreeding neonatal deaths, fetal losses maternal family history males - X-linked disorders all - mitochondrial DNA is maternally inherited A positive family history may be helpful!
  13. 13. Simple laboratory tests Glucose, Electrolytes, Gases, Ketones, BUN Creatinine Lactate, Ammonia, Bilirubin, LFT Amino acids, Organic acids, Reducing subst.
  14. 14. Specialized biochemical testing Amino acid analysis Maple syrup urine disease with increase leucine, valine and isoleucine Hyperglycinemia: increase glycine Organic acid : propionic acidemia Carnitine level Chromatography of glycolipid Increased level of long chain fatty acid with perioxisomal disorder
  15. 15. Carbohydrate metabolism
  16. 16. GalactosemiaGalactosemia Enzyme deficiency:- Galactose-1-p uridyl transferase Galactokinase Uridine diphosphate galactose 4 epimerase Screening :- Failure to thrive Hypoglycemia Urine demonstrates the presence of reducing substance that does not react to glucose oxidase. Galactose can be identified by chromatography. Galactose & galactose-1-p in blood Confirmed :- Assaying red blood cell transferase activity.
  17. 17. Fructosuriaa Enzyme deficiency:- • Essential Fructosuria - Fructokinase • Inherited Fructose Intolerance - Fructose-1-P aldolase • Hereditary fructose-1,6-diphosphatase deficiency Screening :- • Fructosuria after eating fructose containing food • Hypoglycemia Confirmed :- • Enzyme defect in liver biopsy.
  18. 18. Hemolytic diseases Enzyme deficiency:- Pyruvate kinase Glucose-6-phosphate dehydrogenase Screening :- Lactic acidosis on glucose load Hemolytic anemia Confirmed :- Specific enzyme activity.
  19. 19. Glycogen Storage DisordersGlycogen Storage Disorders Type 1-Von Gierke’s Enzyme deficiency:- Glucose-6-phosphatase Screening :- Life threatening Hypoglycemia Lactic acidosis Hyper-uricemia Hyper lipidemia Adverse response to Glucagon with worsening Lactic acidosis. Confirmed :- Glucose-6-phosphatase enzyme activity assay in liver biopsy.
  20. 20. Enzyme deficiency:- Type 2- Pompe’s disease- Acid α-glucosidase Type 3- Deficency of Glycogen debranching enzyme Type 4- Deficiency of Branching enzyme Type 5- McArdle`s Syndrome- Muscle phosphorylase Type 6- Liver phosphorylase or phosphorylase kinase Screening :- Almost same as type I Confirmed :- Respective enzyme activity assay in liver & muscle biopsy.
  21. 21. Mucopolysacccharidosis Mutation in a gene encoding a lysosomal hydrolase involved in the degradation of 1 or more GAGs Defective lysosomal hydrolase Accumulation of substates in various tissues including Liver,spleen,skin,bone & CNS Hurler syndrome – α l-iduronidase Hunter syndrome - iduronate sulfatase • Urinalysis for presence of ↑ GAGs • Assay of suspected enzymes in WBC,fibroblast or serum • Tissue biopsy with subsequent analysis of GAG by electrophoresis • Use of specific gene test • Prenatal diagnosis by amniotic fluid cells or chorionic villus sampling.
  22. 22. Amino acid metabolism
  23. 23. Aromatic Amino acid metabolism Phenylketonuria Enzyme deficiency:- Phenylalanine hydroxylase Dihydrobiopterine reductase 6-Pyruvoyl-tetrahydropterin synthase GTP cyclohydrolase I Pterin-4-carbinolamine dehydratase Screening :- FeCl₃ to detect urinary phenyl pyruvate Tandem mass spectrometry. Prenatal Diagnosis :- DNA probe Confirmed :- Elevated blood phenylalanine level. Enzyme activity
  24. 24. Tyrosinemia Enzyme deficiency:- Type I- Fumarylacetoacetase Type II-Tyrosine aminotransferase Type III-4-hydroxyphenylpyruvate dioxygenase Screening :- FeCl₃ Tandem mass spectrometry. Prenatal Diagnosis :- RFLP Confirmed :- Elevated conc of tyrosine in plasma Succinyllactone in urine,by product of fumaryl acetoacetic acid in urine.
  25. 25. Maple syrup urine disease Enzyme deficiency:- Branched chain ketoacid dehydrogenase complex Screening :- Acidosis Ketotic hypoglycemia Pancreatitis Odor of maple syrup Mixing urine with DNPH Prenatal Diagnosis :- DNA analysis Confirmed :- Elevated plasma level of Branched chain amino-acids. 2hydroxy valeric acid in urine.
  26. 26. Enzyme deficiency:-  Hypermethioninemia- Methionine adenosyl transferase  Homocystenuria - Cysthionine β-synthase  Cystathionuria - Cystathionase Prenatal Diagnosis :- DNA analysis Confirmed :- Elevated levels of the regarding substrates in plasma.
  27. 27. Urea cycle disorders  N-acetylglutamate synthase – Glutamine,Alanine & Citruline  CPS - Glutamine,Alanine & Citruline ,Arginine  OTC –Orotic acid(U) Glutamine,Alanine & Citruline ,Arginine  Arginisuccinate synthase - Citrulline,Orotic acid(U)  Arginisuccinate lyase- Arginisuccinic acid (B & U)  HHH syndrome – Mytochondrial ornithin transporter. Screening :- Hyperamonimia Prenatal Diagnosis :- DNA analysis
  28. 28. Disorders of heme metabolism Mutation in various genes Abnormalities of the enzymes of the heme synthesis Accumulation of ALA & PBG ↓in heme in cell & body fluid Nuropsychiatric signs & symtoms Accumulation of porphyrinogen In skin & tissues Sponteneous oxidation of Porphyrinogen to porphyrin photosensitivity Prenatal diagnosis - Appropriate DNA probe Diagnosis by ↑ corproporphyrin,uroporphyrin,ALA,PBG,protoporphyrin
  29. 29. Metabolism of Fatty acid
  30. 30. Impaired oxidation of Fatty acid 1) Transporter deficiency:- CPT-I & CPT-II deficiency Prenatal Diagnosis :- Enzyme assay in aminocentesis DNA analysis Confirmed :- Elevated levels of free carnitine & acyl carnitine in plasma. 2) Dicarboxylic aciduria- medium chain acyl coa dehydrogenase deficiency 3) Refsum disease- Accumulation of phytanic acid 4) Zellweger`s syndrome- Absence of peroxisomes
  31. 31. Lipid storage disease Tay-Sachs disease – Hexosaminidase Fabry`s disease – α-galactosidase Metachromatic leucodystrophy- Arylsulfatase A Krabbe`s disease- β- galactosidase Goucher disease- β- glucosidase Niemann-Pick disease- Sphingomyelinase Farbe`s disease - Ceramidase Diagnosis:- Analysis of tissue sample peripheral leucocyte plasma amniotic fluid Culture fibroblast for presence of enzymatic activity or accumulated lipid Prenatal diagnosis – DNA probe
  32. 32. Disorder of nucleic acid metabolism  Purine metabolism:- Gout – Genetic defect in PRPP synthetase Lesch-nyhan syndrome- hypoxanthine-guanine phosphorybosyl transferase Hypouricemia – Xanthine oxidase deficiency ADA & purine nucleoside phosphorylase deficiency- defective T & B cell function  Pyrimidine metabolism:- Hydroxy butyric aciduria- dihydropyrimidine dehydrogenase Orotic aciduria – Orotate phosphorybosyl transferase & orotidyl decarboxylase  Diagnosis :- Assay of respective enzyme activity
  33. 33. Thank you !

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