Inbornerrorsofmet
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INBORN ERRORS OF METABOLISM
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Inbornerrorsofmet
- 1. Inborn Errors Of Metabolism DR.P.S.K. RAJKUMAR SHANKAR 1st YEAR MDS DEPT.PUBLIC HEALTH DENTISTRY TNGDC&H. 17/12/2014 1
- 2. Contents • Introduction • Epidemiology • Pathophysiology • Various Disorders of Metabolism • Clinical Features of IEMs • Diagnosis • Treatment 17/12/2014 2
- 3. Introduction6 Inborn errors of metabolism are group of genetically determined biochemical disorder in which inherited defect in a single specific enzyme that results in disruption or abnormality in a specific metabolic pathway • Single gene defects • Mostly autosomal recessive(exepct hunter’s,fabry’s,lesch-nyhan) 17/12/2014 3
- 4. Epidemiology • According to a study in British Columbia, the overall incidence is approximately 40 cases per 100,000 live births . • Approximately 24 children per 100,000 births have a disease involving amino acids (e.g. PKU), organic acids, primary lactic acidosis, galactosemia, or a urea cycle disease. • Approximately 2.3 children per 100,000 births have some form of glycogen storage disease. • Approximately 8cases per 100,000 births (1 in 12,500) have a lysosomal storage disease; • Approximately 3cases per 100 000 births have a respiratory chain-based mitochondrial disease and 3 to 4 cases per 100 000 of births have a peroxisomal disorder. 17/12/2014 4
- 5. Epidemiology cont…, • Mortality/Morbidity Asymptomatic with slow degeneration over decades can be life-threatening over hours Episodic with intermittent decompensations • Race Incidence varies with different race and ethnic groups Incidence of Cystic fibrosis,1/1600people of European descent Incidence of Sickle cell anemia,1/600people of African descent Incidence of Tay-Sachs,1/3500people of Ashkenazi Jews • Sex Male-to-female ratio 1:1 for autosomal recessive transmission and X-linked recessive transmission. • Age Presenting at birth- phenylketonuria Or later life -diabetes mellitus 17/12/2014 5
- 6. Pathophysiology Gene mutations or gene deletions of ,,,, DNA Enzyme which code for a Receptor Transport vehicle Membrane pump Structural element Single gene defects result in abnormalities in the synthesis or catabolism of Proteins, carbohydrates, fats or complex molecules. Defect in an enzyme or transport protein, which results in block in a pathway. Effects are due to toxic accumulations of substances . 17/12/2014 6
- 7. Integrated View of the Metabolic Pathways 17/12/2014 7
- 8. IEMs - Categories Disorders that result in toxic accumulation • Disorders of protein metabolism • Disorders of carbohydrate intolerance • Lysosomal storage disorders Disorders of energy production, utilization • Fatty acid oxidation defects • Disorders of carbohydrate utilization • Mitochondrial disorders • Peroxisomal disorders 17/12/2014 8
- 9. Various Metabolic Disorders Disorders of : • Carbohydrate Metabolism • Amino acid Metabolism • Organic acid Metabolism • Lipid Metabolism • Nucleotide Metabolism • Porphyrin Metabolism • Mineral and Electrolyte Metabolism • Mitochondrial Function • Peroxisomal Function • Steroid Metabolism • Hereditary Anemias 17/12/2014 9
- 10. DISORDERS OF CARBOHYDRATE METABOLISM 17/12/2014 10
- 11. Glycogen Storage Diseases4 Disorder Enzyme Defect Organ(s)involved Characteristic Features Von Gierke’s disease Type I*** Glucose 6-phosphatase Liver, kidney, Intestine Glycogen accumulates in hepatocytes & renal cells, enlarged liver & kidney, fasting hypoglycemia,lactic acidemia, hyperlipidemia,ketosis,gouty arthritis Pompe’s disease Type II*** Lysosomal α-1,4-glucosidase All organs Glycogen accumulates in lysosomes in allmost all the tissues;enlarged heart &liver, nervous system also affected, death occurs at earlier age due to heart failure Cori’s Type III Amylo α-1,6-glucosidase Liver,muscle,heart, leukocytes Branched chain glycogen accumulates, liver enlarged Anderson’s disease Type IV Glucosyl 4,6-transferase Most tissues A rare disease, glycogen with only few branches accumulates,liver cirrhosis McArdle’s disease Type V*** Muscle glycogen phosphorylase Skeletal muscle Very high muscle glycogen stores, muscle cramps, muscle damage Her’s disease Type VI Liver glycogen phosphorylase liver Enlarged liver,hypoglycemia, ketoacidosis Tarui’s disese Type VII phosphofructokinase Skeletal muscle, erythrocytes Muscle cramps,hemolysis 17/12/2014 11
- 12. Von Gierkes Disease Type I2 Clinical Manifestations Constant hunger Easy bruising & nose bleeds Fatigue Puffy cheeks Thin chest Glycogen deposits in Hepatocytes 17/12/2014 12
- 15. Other Carbohydrate IEMs5 Disorder Enzyme Defect Characteristic Feature G6PD deficiency Glucose-6-phosphate dehydrogenase hemolysis Wenicke-korsakoff syndrome Alteration in the transketolase activity Mental disorder Partial paralysis Loss of memory Essential pentosuria Deficiency of xylitol dehydrogenase Asymptomatic Galactosemias*** Deficiency of enzyme galactose 1- phosphate uridyltransferase Hepatosplenomegaly Cataract , mental retardation Hyperglycemia Uncontrolled diabetes Absent or low activity of sorbital dehydrogenase Cataract,nephropathy, peripheral neuropathy 17/12/2014 15
- 17. Mucopolysaccharidosis1 Accumulation of mucopolysaccharides in tissues like liver, spleen, cornea, heart, blood vessels and these patients have coarse facial features Disorders Enzyme Defect Accumulated Product Hurler’s Syndrome*** α- idouronidase Heparan, dermatan sulfate Hunter Syndrome*** Idouronate sulfatase Heparan, dermatan sulfate MaroTeauxlamy N-acetyl galactosamine sulfatase Dermatan sulfate Mucolipidosis VIII β-glucouronidase Heparan, dermatan sulfate Sanflippo Type A Sanflippo Type B Sanflippo Type C Sanflippo Type D Heparan sulfamidase N-acetyl glucosamine Α-glucosaminide acetyl tranferase N-acetyl glucosamine 6-sulfatase Heparan sulfate Heparan sulfate Heparan sulfate Heparan sulfate Morquio Type A*** Morquio Type B Galactose 6-sulfatase Β-galactosidase Keratin/chondroitin sulfate keratin sulfate 17/12/2014 17
- 20. Morquio Syndrome6 Clinical Manifestations Coarse Features Cloudy Corneas Spinal Curvature Knock Knees Severe Skeletal Abnormalities Severe Short Strature 17/12/2014 20
- 21. DISORDERS OF AMINO ACID METABOLISM 17/12/2014 21
- 22. I. Metabolic Defects in Urea Cycle5 Disorders Enzyme defect Hyperammonemia type 1 Carbamoyl phosphate synthase I Hyperammonemia type II Ornithine transcarbamoylase Citrullinemia Arginosuccinate synthase Arginosuccinic aciduria Arginosuccinase Hyperargininemia Arginase 17/12/2014 22
- 23. II. Phenylalanine & Tyrosine5 Disorders Enzyme defect Phenylketonuria *** (mousey odour urine) Phenylalanine hydroxylase Tyrosinemia typer II Tyrosine transaminase Neonatal tyrosinemia P-Hydroxy phenylpyruvate dioxygenase Alkaptonuria (coke colour urine) Homogentisate oxidase Tyrosinosis type I (cabbage like odour) Maleyl acetoacetate isomerase Albinism *** Tyrosinase 17/12/2014 23
- 24. Phenylketonuria6 17/12/2014 24 Clinical Manifestations Mental retardation Defective myelin formation Hypopigmentation
- 25. Albinism6 Clinical Manifestations Absence of color in the hair, skin, or iris of the eye Lighter than normal skin and hair Patchy missing skin color Crossed eyes Light sensitivity Rapid eye movements Vision problems 17/12/2014 25
- 26. III. Sulfur Amino acids5 (methionine, cysteine, cystine) Disorders Enzyme defect Cystinuria Defect in renal reabsorption Cystinosis Impairment in cystine utilization Homocystinuria type I*** Cystathionine synthetase Homocystinuria type II N 5, N10-Methylene THF reductase Homocystinuria type III N 5-Methyl THF- homoscysteine methyltransferase Cystathionuria Cystathioninase 17/12/2014 26
- 27. Homocystinuria6 Clinical Manifestations Mental retardation strong glasses required to correct myopia Aphakia 17/12/2014 27
- 28. IV. Glycine5 Disorders Enzyme defect Glycinuria Defect in renal reabsorption Primary hyperoxaluria Glycine transaminase V. Tryptophan5 Disorders Enzyme defect Hartnup’s disease*** Defective intestinal absorption 17/12/2014 28
- 29. Hartnup’s Disease6 Clinical Manifestations Ataxia Rash Mental and psychological abnormalities 17/12/2014 29
- 30. VI. Branched Chain Amino Acids5 (valine,leucine,isoleucine) Disorders Enzyme defect Maple syrup urine disease*** (bunrt sugar urine) Branched chain α-keto acid dehydrogenase Intermittent branched chain ketonuria Variant of the above enzyme Hypervalinemia Valine transaminase Isovaleric acidemia Isovaleryl CoA dehydrogenase 17/12/2014 30
- 31. Maple Syrup Urine Disease6 Clinical Manifestations Neurological detoriation, Mental and physical retardation Muscular tension Coma Vomitting Seizures Fatigue Urine smells like Maple Syrup 17/12/2014 31
- 32. VII. Hystidine5 Disorders Enzyme defect Histidinemia Histidase VIII. Proline5 Disorders Enzyme defect Hyperprolinemiatype I Proline oxidase 17/12/2014 32
- 33. DISORDERS OF ORGANIC ACID METABOLISM 17/12/2014 33
- 34. Inborn Errors of Organic Acid Metabolism6 Disorders Methylmalonic acidemia Proprionic acidemia Isovaleric acidemia Glutaric aciduria type II Dicarboxylic aciduria 17/12/2014 34
- 35. DISORDERS OF LIPID METABOLISM 17/12/2014 35
- 36. Lysosomal Storage Diseases1,2 Disorders Enzyme defect Characteristic feature Niemann-Pick disease*** Sphingomyelinase Enlargement of liver,spleen,mental retardation Farber’s disease Ceramidase Painful and deformed joints Gaucher’s disease*** β-glucocerebrosidase Enlargement of liver and spleen, osteoporosis, mental retardation Krabbe’s disease*** β-galactosidase Absence of myelin formation, liver and spleen enlargement, mental retardation Tay-Sachs disease*** Hexosaminidase A Blindness, mental retardation, death within 2-3 years Fabry’s disease*** Α-galactosidase Renal failure, skin rash, pain in lower extremities Refsum’s disease Deficiency of phytanic acid oxidase Chronic polyneuropathy tachycardia, night blindness, and deafness 17/12/2014 36
- 37. Niemann-Pick Disease1,6 Clinical Manifestations Neurological Detoriation Cherry-red spot on the retina the eye Enlarged liver and spleen Lipid-laden cells in bone marrow Pulmonary disease Liver dysfunction Foam Cells 17/12/2014 37
- 39. Krabbe’s disease Globoid cellsClinical Manifestations Severe mental retardation Total absence of myelin in CNS 17/12/2014 39
- 40. Tay-Sachs Disease1,6,2 Clinical Manifestations Neurological detoriation Seizures Cherry red spot on the retina Startle reaction to sound 17/12/2014 40
- 42. DISORDERS OF NUCLEOTIDE METABOLISM 17/12/2014 42
- 43. Inborn Errors of Purine Metabolism6 Disorders Enzyme defect Anabolism Lesch-Nyhan syndrome*** Catabolism Gout Adenylosuccinate lyase deficiency Adenosine monophosphate deaminase deficiency,typeI Adenine phosphoribosyl transferase deficiency Adenosine deaminase deficiency Purine nucleotide phosphorylase deficiency Inborn Errors of Pyrimidine Metabolism6 Disorders Enzyme defect Anabolism Orotic aciduria/ Miller’s Syndrome Orotate phosphoribosyl transferase Catabolism Dihydeopyrimidine dehydeogenase deficiency 17/12/2014 43
- 44. Lesch-Nyhan syndrome6 Clinical Manifestations Neurological Impairmarnt Mental retardation Gout Kidney stones Kidney failure Self –mutilation 17/12/2014 44
- 45. Inborn Errors of Porphyrin Metabolism6 Disorders Enzyme defect Characteristic feature Acute intermittent porphyria ** Porphobilinogen deaminase deficiency Abdominal pain, constipation, muscle weakness paresthesias,dysuria,dark urine,urinary retention,incontinence, neuropsychiatric symptoms,electrolytes abnormalities SIADH leads to seizures 17/12/2014 45
- 47. Inborn Errors of Mineral and Electrolyte Metabolism6 Transition Metal Electrolyte Fe High Primary iron overload disorder Hemochromatosis aceruloplasminemia Atransferrinemia Hemosiderosis Deficiency Iron deficiency Na+ & K+ Cl- membrane transport deficiency Cystic fibrosis Ca2+ High Hypercalcemia Milk alkali syndrome(Burnett’s) Calcinosis cutis Dystrophic calcification Deficiency Hypocalcemia Osteomalacia Albright’s hereditary osteodystrophy Pseudohypoparathyroidism Cu High Copper toxicity Wilson’s disease*** Copper binding ATPase Deficiency Menkes disease Po4 3- High -Hyperphosphatemia Deficiency Hypophosphatemia Hypophosphatasia Zn High Zinc toxicity Acrodermatitis enteropathica Mg2+ High -Hypermagnesemia Deficiency Hypomagnesemia17/12/2014 47
- 49. Inborn Errors of Mitochondrial Function6 Disorders Chronic progressive external ophthalmoplegia Kearns-Sayre Syndrome Lebers hereditary optic neuropathy Isolated myopathy Severe encephalomyopathy pearsonsyndrome 17/12/2014 49
- 50. Inborn Errors of Peroxisomal Function6 Disorders Zellweger syndrome Adrenoleukodystrophy Refsum disease 17/12/2014 50
- 51. Inborn Errors of Steroid Metabolism6 Disorders Lipoid congenital adrenal hyperplasia Congenital adrenal hyperplasia Disorders Sickle cell anemia Thallasemia Inborn Errors of Hereditary Anemia3 17/12/2014 51
- 52. When to suspect an IEM?6 Every child with unexplained …. -neurological detoriation Metabolic acidosis Hypoglycemia Inappropriate ketosis Hypotonia Cardiomyopathy Hepatocellular dysfunction Failure to thrive Abnormal hair Odour …should suspected of having a metabolic disorder 17/12/2014 52
- 53. Neonatal Clinical Manifestations of IEMs6 Neurologic Signs: Poor suck Lethargy (progressive to coma) Abnormalities of tone Loss of reflexes Seizures Gastrointestinal Signs: Poor feeding Vomitting Diarrhea Respiratory Signs Hyperpnea Respiratory failure: Organomegaly Liver Heart 17/12/2014 53
- 55. Common Screening Tests6 • Ferric chloride test • Ninhydrin paper chromatography • Quantitative measurement of amino acids in plasma and urine • Ninhydrin post column liquid ion-exchange chromatography • Urine organic acid analysis by Gas chromatography-mass spectrometry • Plasma acylcarnitines analysis by mass spectrometry • Urine purines and pyrimidines analysis by gas chromatography • Tissue biopsy or necropsy; liver, muscle, brain, bone marrow. Skin biopsy and fibroblast cultivation for specific enzyme testing • Specific DNA testing 17/12/2014 55
- 56. Diagnosis6 • IEM can be detected in fetus in utero by the examination of blood cells obtained by amniocentesis and fetoscopy • New born screening ( must do on all infants in NICU) PKU Hemoglobinopathies MSUD • Laboratory tests after birth show higher than normal levels of particular metabolites in the blood and urine The values are higher in homozygous than in heterozygous carriers Signs of various defects are usually seen only homozygous carriers 17/12/2014 56
- 58. Management6 • Dietary restriction • Removal of food in the diet containing the non-degradable metabolite prevent its accumulation . In those cases of IEM in which the non-degradable metabolite is endogenous no treatment is available. • Dietary supplementation or replacement • Vitamins • Intermediary metabolites, compounds or drugs that facilitate or retard specific metabolic pathways • Dialysis • Enzyme replacement • Gene therapy • Bone marrow or organ transplantation • Treatment of symptoms and complications • Prenatal diagnosis and avoidance of pregnancy or abortion of an affected fetus 17/12/2014 58
- 59. Treatment of Acutely-Sick Child6 General therapy: • Maintain vital functions • Oxygenation • Hydration • Acid/base balance Specific therapy: • Treat infection • High dose I.V glucose • Carnitine supplementation TO IDENTIFY PRIMARY METABOLIC DISORDER 17/12/2014 59
- 60. Therapeutic Measures of IEMs6 • D/C oral intake temporarily • IVF’s with glucose to give 12-15 mg/kg/min glucose and atleast 60 kcal/kg to prevent catabolism(may worsen PDH) • Bicarbonate/citrate carnitine/glycine • Na benzoate/arginine /citrulline • Dialysis-not exchange transfusion • Vitamins-often given in cocktails before dx is known -biotin, B6, B12, riboflavin, thiamine, folate 17/12/2014 60
- 61. Treatment of Genetic Diseases6 • Modify environment e.g., diet , drugs • Surgical ,correct or repair defect or organ transplantation • Modify or replace defective gene product, mega dose vitamin therapy or enzyme replacement • Replace defective gene • Correct altered DNA in defective gene 17/12/2014 61
- 62. References • Robbin’s Basic Pathology, Kumar, Abbas, Aster; IXth Edition, pg 218 – 234 • W.A.D. Anderson’s Pathology Vth Edition Chap 31, pg 1041 • Anderson’s Pathology VIIIth Edition chap 3, pg 101 - 104 • Fundamentals of Biochemistry, A.C. Deb • Text book of Biochemistry, U. Sathyanarayana, U.Chakrapani; Chap 13, 15 • Net resources 17/12/2014 62