Inborn errors of metabolism
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Inborn errors of metabolism
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Inborn errors of metabolism
- 1. INBORN ERRORS OF METABOLISM Soumya Ranjan Parida Basic B.Sc. Nursing 4th year Sum Nursing College
- 2. INBORN ERRORS OF METABOLISM Introduction – Inborn errors of metabolism are a group of metabolic disorders caused by deficiency of an enzyme required for the formation of a protein or for catalyzing a biochemical reaction in body. IEM are divided into six subgroups – 1 Aminoacidurias a) Disorders of aminoacid metabolism b) Urea cycle defects c) Disorders of fatty acid oxidation d) Disorders of organic acids 2 Disorders of carbohydrate metabolism 3 Lysosomal storage defects 4 Peroxisomal disorders 5 Endocrine disorders 6 Miscellaneous diseases
- 3. Diagnostic approach to neurometabolic disorders When to suspect IEM History of unexplained deaths in the neonatal period Parental consanguinity In the neonatal period – Lethargy, poor feeding, persistent vomiting, intractable seizures, tachypnea, floppyness, unusual body/ urine odor, failure to thrive Always r/o sepsis and HIE On examination – Skin and hair changes, Hepatomegaly, Jaundice, Hypotonia, Unexplained neurological signs and coma, Ambiguous genitalia
- 4. Diagnostic approach to neurometabolic disorders Older children – - Recurrent episodes of sensorial derangement, - Vomiting, hypotonia, - Hypoglycemia and acidosis - Unexplained development delay with or without seizures, - Mental retadation, - Organomegaly, - Coarse facies, - Cataract, - Dislocated lenses, - Chronic skin lesions, - Abnormal hair and urine color, - FTT
- 5. Signs Disorders Skin abnormality- Perioral / perianal erruption Multiple carboxylase deficiency Increased pigmentation Adrenoleukodystrophy Angiokeratomas Fabry’s disease Xanthomas Hyperlipidemias Ichthyosis Refsum, Sjogren-Larsen syndrome Blond skin Phenylketonuria Hair abnormality Multiple carboxylase deficiency Menkes kinky hair disease Dimorphic features Zellweger syndrome Gluteric aciduria type 2 Hepatomegaly / HSM Niemann pick disease, Gaucher, GSD Neurological Symptoms Seen in many disorders Ocular abnormalities - Cataract Zellweger syndrome, Galactosemia Heterochromia iris Zellweger syndrome Dislocated lenses Homocystinuria Retinitis pigmentosa Zellweger syndrome Clinical pointers to neurometabolic disorders
- 6. Suspected Metabolic Disorder Plasma NH3 High Normal Blood ph & co2 Blood ph & co2 normal normalAcidosis No ketosis No ketosis Ketosis +/- lactic acidosis Urea cycle defect Fatty acid oxidation defect Organic acidemia Mitochondrial disorders
- 7. Metabolic disorders with abnormal urine odor Inborn errors of metabolism Urine odor Glutaric acidemia 2 Hawkinsinuria Isovaleric acidemia MSUD Hypermethioninemia Multiple coboxylase deficiency Oasthouse urine disease PKU Trimethylaminuria Tyrosinemia Sweaty feet, acrid Swimming pool Sweaty feet, acrid Maple syrup Boiled cabbage Tomca urinet Hops-like Mousy or musty Rotting fish Boiled cabbage, rancid butter
- 8. Laboratory investigations Blood investigations – TLC, DLC, blood sugar, serum electrolytes, serum ammonia, lactate and pyruvate, liver enzymes and ABG. Urine metabolic screen – Ph, ketones, odor, reducing substances, special urine tests such as Fecl3, DNPH, nitropruside and toluidine blue spot test, chromatography
- 9. Management Empirical management – • Stop oral feeds • Start IV fluids • Co-factor therapy • Correct dehydration,acidosis, dyselectrolytemia • Provide cardiorespiratory support • Start specific therapy • Peritoneal dialysis • Hemodialysis • Exchange blood transfusion
- 10. Phenylalanine Tyrosine 4-OH-phenylpyruvate Epoxide + cysteine Homogentisic acid Maleylacetoacetate FumarylacetoacetateSuccinylacetoacetate Succinylacetone Fumarate Acetoacetate Co2+H2o PE PP PL PA PAG 4-oH PA Glutamine DOPA Dopamine NE E DOPA DOPAquinone Melanin ohlase ohlase Tyrosinase Aminotransferase Dioxygenase Dioxygenase HA oxidase Isomerase ohlase Hawkinsine 1 PKU 2 Tyrosinemia 1, 2 3 Alcaptonuria 4 Hawkinsinuria 5 Albinism
- 11. Methionine Homocysteine Serine Cystathionine Homoserine Cysteine Sulfate α-ketobutyric acid Propionic acid Succinic Co2+H2o S-adenosylmethionine S-adenosylhomocysteine Betain FH4 MA Transferase AH ohlase CB synthase Cystathionase Sulphite oxidase 1 Methionemia 2 Homocystinuria
- 12. Ornithine Citrulline Argininosuccinic acid Arginine Carbamyll phosphate NH3+co2+ATP Glutamate Glutamine + Phenylacetic acid Glycine + Benzoyl CoA Hippurate Glutamic acid Acetyl CoA N-Acetyl-glutamic acid (NAG) CPS OTC ASA synthase ASA lyase Arginase O aminotranferase + NAG synthase Urea cycle
- 13. Blood ph, HCO3 Acidosis No acidosis Obtain organic acids Obtain plasma Amino acidosis Specific amino acid elevation No specific amino acic elevation Obtain urine orotic acid High Normal or low Obtain plasma citruline Low Normal or elevated Organic acidemia Citrullinemia Argininemia Arginosuccinic acidemia HHH syndrome OTC deficiency CPS or NAG synthase deficiency Than Clinical apprach to Hyperammonia
- 14. Treatment of hyperammonemia • Provide adequate calories, fluid and electrolytes • Give priming dose of following – • To be added to 20 ml/kg of 10% glucose and infuse with in 1-2 hours Sodium benzoate 250mg/kg Sodium phenylacetate250mg/kg Arginine hydrochloride 200-600mg/kg • These compounds are prepared as 1-2% solution for IV use • Higher doses are needed for Citrullinemia and argininsuccinic aciduria • Continue infusion of above following the priming doses • Initiate peritonial or hemodialysis if above treatment fails
- 15. Valine Isoleucine Leucine 2-Ketoisovaleric acid 2- Keto-3-methylvaleric acid 2-Ketoisocaproic acid Methacrylyl-CoA Tiglyl-CoA Methylcrotonyl-CoA Methylmalonyl-CoA Methylactoacytal-CoA Methylglutaconyl-CoA D-Methylmalonyl-CoA Propionyl-CoA 3-OH-3-CH3gluterul-CoA L-Methylmalonyl-CoA Succinyl-CoA CO2+H2O Acetoacetic acid+Acetyl CoA Acetone OHCbl TCװ OHCbl TCװ OHCbl TCװ OHCbl+3 Cbl+2 MethylCblCbl+2 Cbl+1Adensyl Cbl MSUD MSUD MSUD β Ketothiolase deficiency Propionic acidemia Methylmalonic acidemia 3-HMG aceduria MMU+HCU MMU+HCU
- 16. Refusal to feed,vomiting, acidosis dehydration, neutropenia, hypoglycemia Ketosis No Ketosis or mild ketosis No skin menifestations Skin menifestations No odor Characteristic odor 1 Methylmalonic acidemia 2 Propionic acidemia 3 Ketothiolase deficiency 1 MSUD 2 Isovaleric acidemia Multiple carboxylase deficiency 1 3OH-3-methylglutaric aciduria 2 Acyl CoA dehydrogenase deficiency 3 HMG CoA synthase deficiency Clinical approach to organic acidemia
- 17. Transporter OCNT2 CarnitineLong chain free fatty acid(C16-Pamitate) Long chain free fatty acid(C16-Pamitate) Carnitine+ CPT1 CPT װ TRANS Carnitine cycle LC aceyl carnitine LC fattyaceyl- CoA Carnitine VLCAD LCAD ETF ETF-DH TFP 2,3(C16-10) Enoyl CoA C14-10 Aceyl CoA Long chain β oxidation MCAD SCAD ETF ETF-DH Hydratase 3-OH-ACD SCHAD Thiolase Short & medium chain β oxidation Acetyl-CoA HMG-CoA synthase HMG-CoA lyase Acetacetate Β-Hydroxybutyrate Ketone synthesis HMG-CoA LC aceyl carnitine Enoyl CoA 3-OHaceyl-CoA 3-Ketoaceyl-CoA C8-4 Aceyl-CoA Medium chain fatty acid Leucine TCA cycle Respiratory chain e-
- 18. Gal—Nacgal—gal—glc—ceramide NANA Gal—Nacgal—gal—glc-ceramide NANA NAcgal—gal—glc-ceramide NANA Gal—glc-ceramide NANA Gal—glc-ceramide Glc-ceramide ceramide Sphingosine+fatty acid PC-ceramide SO4 Gal--ceramide Gal-ceramide Neurominidase Sialidosis GM1 gangliosidosis Gm1 gangliosidosis β-Hexosaminidase GM2 gangliosidosis Tay-sachs,Sandhoff Lactosylceramide β-galoctsidase Gm1 gangliosidosis, Krabbe disease Glucosylceramide β-galoctsidase Gaucher disease Sufatide sulfatase Metachromaticleukodytrophy Krabbe disease Lactosylceramide β-galoctsidase Ceramidase Farberdisease Sphingomyelinase Niemann-Pick disase Lipidoses
- 19. Gly Gly GlyGly BrancherDebrancher Glc-1-P Glc-6-P F-6-P F-1,6-P2 Glyceraldehyde-3-P 1,3-Biphosphonate 3-Phosphoglycerate 2-Phosphoglycerate Phosphoenolpyruvate Pyruvate Lactate Mitochondria GLUT2 GLUT2 Fructose Galactose Gal-1-P Glucose FructoseF-1-P DHA-P GLUT2 GLUT2 Trans- locase RPR Glc-6-P Glucose Glycogen Glucose α--Glucosidase UDP-Glc UDP-Gal Lactate dehydrogenate PK Enolase Phosphoglycerate mutase Phosphoglycerate kinase G-3-P dehydrogenase AldolaseAldolase Phosphofructokinase Phosphohexose isomerase Phosphoglucomutase Glucokinase Hexokinase F-1,6-dptase Fructokinase Glc-6-Pase Galactokinase G-1-PUT UDP-Gal-epimerase Galactilol Galactoconic acid GS GS Pa Pb PaP PbKa PbKb Oxaloacetate Carboxylase Carboxykinase Glycogen, Galactose, Fructose disorders Glucose
- 20. Mucopolysaccharidoses Number Eponym Enzyme Deficiency Stored MPS Clinical menifestations MPS 1H MPS 1S MPS1H/S MPS 2 MPS 3 MPS 4 MPS 6 MPS7 Hurler Scheie Hurler-Scheie Hunter Sanfilippo A,B,C,D Morquio A, B Maroteaux- Lamy Sly α-L-Iduronidase α-L-Iduronidase - Iduronate sulfatase Hepara-n- sulfatase, α-N-acetyl- glucosaminidase, α-glucosaminidase acetyltransferase, N- acetylglucosamine 6-sulfatase, Galactose-6-sulfatase, β-Galactosidase N-Acetylgalactosamine-4- sulfatase β-Glucuronidase DS,HS DS,HS - DH, HS HS KS DS DH, HS MR,CHD, corneal clouding, coarse facies, dysostosis multiplex, HSM, hydrocephalus, joint stiffness hearing loss. Intelligence, life spanand stature are normal. Others same as above - Intelligence-N. Others same Hyperactivity, mild somatic features, mental retardation, coarse hair, hirsuitism, sleep disorders Odontoid hypoplasia, short trunk, IQ-N, Spleen-N IQ-N. Others same as 1 Same as 1
- 21. Mitochondria SuccinylCoA + Glycine ALA Synthase ALA PBG HMB Uro’gen 3Uro’gen1 Copr’ogen3Copr’ogen1 Proto’gen ix Protoporphyrin Ix Heam ALA dehydratase PBG deaminase Uro’gen 3 cosynthase Uro’gen decarboxylase Copro’gen oxidase Proto’gen oxidase ferrochelatase ADP AIP CEP PCT HEP HCP VP EPP Porphyrias
- 22. THANKS