approach to inborn errors of metabolism .. dr.padmesh

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APPROACH TO INBORN ERRORS OF METABOLISM

Dr.padmesh.v Dept of pediatrics, dr.smcsi mch, karakonam.

Dr.Padmesh.V METABOLISMMetabolism Catabolism (Breaking down)

Anabolism (Building up)

Enzymes play an important role in facilitating the process by serving as catalysts in the conversion of one chemical (metabolite) to another.

Dr.Padmesh.VCatabolism :Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy.

Dr.Padmesh.VCatabolism :Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy.

ENERGY

Dr.Padmesh.VAnabolism :Anabolism is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy.

Dr.Padmesh.VAnabolism :Anabolism is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy.

ENERGY

Dr.Padmesh.VAnabolism :Anabolism is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy.

ENERGY

Dr.Padmesh.VInborn errors of metabolism (IEM) - Inborn errors of metabolism (IEM) are disorders in which there is a block at some point in the normal metabolic pathway - IEMs occur due to mutations in DNA. DNA Enzyme which code for a Receptor Specific protein Transport vehicle Membrane pump Structural element

Dr.Padmesh.VExample of mechanisms in IEM:

Precursor Substrate End-Product A B CEnzyme ABEnzyme BC

Dr.Padmesh.V

Example of mechanisms in IEM:

Precursor Substrate End-Product A B C

Abnormal metabolic pathway Toxic Metabolite D Enzyme ABEnzyme BC

Dr.Padmesh.VThe number of diseases due to inherited point defects in metabolism now exceeds 500.

While the diseases individually are rare, they collectively account for a significant proportion of neonatal and childhood morbidity and mortality.

Diagnosis is important not only for treatment but also for genetic counselling and antenatal diagnosis in subsequent pregnancies.

Dr.Padmesh.VCLASSIFICATION OF IEM:

Amino acid metabolismCarbohydrate metabolismLipid metabolismProtein metabolismPigment metabolismUnknown biochemical defects

Dr.Padmesh.VCLASSIFICATION OF IEM:

1. Amino acid metabolism -Phenylketonuria -Tyrosinosis -Albinism -Alkaptonuria -Cystinosis -Cystinuria -Homocysteinuria -Hartnup disease -Maple syrup disease

Dr.Padmesh.VCLASSIFICATION OF IEM:

2. Carbohydrate synthesis: -Congenital lactose intolerance -Galatosemia -Glycogen storage disease -Diabetes mellitus -Scurvy

Dr.Padmesh.VCLASSIFICATION OF IEM:

3. Lipid metabolism: -Abetalipoproteinemia -Progressive lipodystrophy -Lipid storage disorders * Gaucher * Neimann-Pick * Tay-sachs * Hyperlipoproteinemia

Dr.Padmesh.VCLASSIFICATION OF IEM:

4. Protein Metabolism: -Immunoglobulin deficiencies -Absent clotting factors (Hemophilia, Christmas dis, Hypoprothrombinemia) -Metal binding protein deficiency (Wilson hepatolenticular degeneration) -Alpha-1 anti trypsin deficiency

Dr.Padmesh.VCLASSIFICATION OF IEM:

5. Pigment metabolism: -Porphyrias -Methemoglobinemias -Albinism -Crigler-Najjar dis -Dubin-Johnson dis -Gilbert dis -Rotor synd -Primary hemochromatosis

Dr.Padmesh.VCLASSIFICATION OF IEM:

6. Unknown biochemical defect: -Osteogenesis imperfecta -Marfan synd -Achondroplasia -Ehler danlos synd

Dr.Padmesh.V

APPROACH TO IEM

Dr.Padmesh.V

1. Suspecting Inborn Errors:

Dr.Padmesh.VSuspecting Inborn Errors:Inborn errors should be suspected when HISTORY:Symptoms accompany starting/changes in diet,Children with seizures, Developmental delay, Recurrent vomiting, Unusual odour of urine,Parental consanguinity,Problems suggestive of inborn error such as retardation or unexplained deaths in first- and second-degree relatives.

Dr.Padmesh.V Suspecting Inborn Errors: CLINICALLY: IEM must be also considered in the differential diagnosis of Critically ill newborns, Neurodegeneration, Mental retardation ,Coarse facies / dysmorphic features,Parenchymal liver disease, Cardiomyopathy, OrganomegalyUnexplained acidosis, Corneal opacity, cataract or dislocation of lens, Hyperammonemia, and Hypoglycemia

Dr.Padmesh.VClinical pointers towards specific IEMs:

Dr.Padmesh.VZellweger- peroxisomal import disorder.Menkes disease (kinky hair disease) is a progressive neurodegenerative condition inherited as a sex-linked recessive trait. The Menkes gene codes for a copper transporting P-type ATPase, and mutations in the protein are associated with low serum copper and ceruloplasmin levels as well as a defect in copper absorption and transport across the intestines.

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Inborn Errors of Amino Acid Metabolism Associated with Peculiar Odour:

Dr.Padmesh.VPatterns of Presentation:1. Encephalopathy with or without metabolic acidosis.2. Acute liver disease: - Jaundice alone - Hepatic failure - Neonatal cholestasis - Hypoglycemia3. Dysmorphic features.4. Cardiac disease.5. Diarrhea6. Hepatomegaly +/- Splenomegaly7. Predominant Neurological symptoms

Dr.Padmesh.V1) Encephalopathy with or without metabolic acidosis: Encephalopathy, seizures,and tone abnormalities are predominant presenting features of -organic acidemias, -urea cycle defects,and -congenital lactic acidosis.

Intractable seizures are prominent in -pyridoxine dependency, -non-ketotic hyperglycinemia, -molybdenum co-factor defect,and -folinic-acid responsive seizures.

Dr.Padmesh.V2) Acute liver disease: could manifest as-Jaundice alone: -Gilbert syndrome, -Criggler-Najjar syndromeHepatic failure (jaundice, ascites, hypoglycemia, coagulopathy): -Tyrosinemia, -galactosemia, -neonatal hemochromatosis, -glycogen storage disease type IV.Neonatal cholestasis: -alpha-1 antitrypsin deficiency, -Niemann-Pick disease type C.Persistent and severe hypoglycemia: -Galactosemia, -fatty acid oxidation defects, -organic acidemias, -glycogen storage disorders and -disorders of gluconeogenesis.

Dr.Padmesh.V3) Dysmorphic features: seen in -Peroxisomal disorders, -Pyruvate dehydrogenase deficiency, -Congenital disorders of glycosylation ,and -Lysosomal storage diseases. Some IEMs may present with non-immune hydrops fetalis -lysosomal storage disorders,and -Congenital disorders of glycosylation.

Dr.Padmesh.V4) Cardiac disease: Cardiomyopathy is a prominent feature in some IEM like in: -Fatty acid oxidation defects, -Glycogen storage disease type II , and -Mitochondrial electron transport chain defects.

Dr.Padmesh.V6. Diarrhea : a. Severe watery diarrhea: - Congenital chloride diarrhea - Galactosemia - Primary lactase,sucrase,isomaltase deficiency. b. Chronic diarrhea: -Bile acid disorders -Infantile Refsum disease -Respiratory chain disorders asso with steatorrhea -Vitamin deficiency osteopenia -Hypocholesterolemia c. Diarrhea,Failure to thrive,hypotonia,hepatomegaly: -Glycogen storage dis 1 - Wolmans disease

Dr.Padmesh.VWolman- lipd storage disorder30

7. Hepatomegaly : -Tyrosinemia -Galactosemia -Fructosemia -Alpha 1 antitrypsin deficiency.8. Hepatomegaly + Splenomegaly: -Mucolipidosis -Gauchers dis -Niemann-Pick type A

Dr.Padmesh.V

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9. Predominant Neurological Symptoms: a. Psy

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