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INBORN ERRORS OF METABOLISM
Dr P. O. Onifade FMCPsych NPH Aro, Abeokuta
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OUTLINE Definition Clasification Pathology common to all IEM disorders
Genetic basis of pathology Common Characteristics Examples Basic Principles of Management Relevance to neuropsychiatry peadiatric should Prognosis
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EPIDEMIOLOGY Rarely a cause of disease in neonates
Hyperphenylalaninemia 1:10,000 Galactosemia :50,000 Homocystinurea :200,000 Estimated overall incidence 1:2000 Many of metabolic diseases are under diagnosed
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DEFINITION Inborn Errors of Metabolism (IEM) comprise a group of disorders in which a single gene defect causes a clinically significant block in a metabolic pathway resulting either in accumulation of substrate behind the block or deficiency of the product.
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CLASSIFICATION Defective Proteins and Disease
Oxygen Carrying Proteins Connective Tissue Proteins Clotting Factors Defects in Carbohydrate Metabolism Glycogen Storage Diseases Fructose, Galactose and Glycerol Defects in Cholesterol and Lipoprotein Metabolism Hyperlipoproteinemias Hypolipoproteinemias
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CLASSIFICATION cont. Mucopolysaccharide and Glycolipid Diseases
Mucopolysaccharidoses Sphingolipodoses Oligosaccharidoses Mucolipidoses Errors in Amino Acid and Organic Acid Metabolism Specific Amino Acids Urea Cycle Defects Defects in Amino Acid Transport Defects in Non-Amino Acid Nitrogen Metabolism The Porphyrias Disorders in Bilirubin Metabolism
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CLASSIFICATION cont. Errors in Mitochondrial Fatty Acid Oxidation
Disorders in b-Oxidation Disorders in Carnitine-Mediated Transport and Carnitine Uptake Defects in Nucleotide Metabolism Defects in Purine Nucleotide Metabolism Defects in Pyrimidine Nucleotide Metabolism Disorders in Metal Metabolism and Transport Disorders of Copper Transport Hemochromatosis Disorders of Peroxisomes Disorders in Peroxisome Biogenesis Adrenoleukodystrophies
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PATHOLOGY COMMON TO ALL IEM
Toxic metabolite D product C EB C substrate B EAB Precursur A EAB is an enzyme converting A into B. EBC, the enzyme converting B to C is absent and is the cuase of the IEM. This leads to accumulation of substrate B to abnormal levels which then gets diverted to an abnormal pathway to yield toxic metabolite D. B or D or both could be toxic B and D can be detected and EAB can be estimated biochemically (Kunta NB Inborn arror of metabolisim (IEM) - an Idian perspective Indian journal of Pediatrics 2005:72;325-31) Mechanism of in born error of metabolism
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GENETIC BASIS Mutation in Gene defective codon defective mRNA
defective protein (enzyme) in the specific metabolic pathway
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COMMON CHARACTERISTICS2 (kumta):
Age of onset neonatal period (mostly) after neonatal period (eg neurometabolic/neurodegenerative IEM disorder) All IEM disorders are genetically transmitted typically in an autosomal recessive or X-linked recessive fashion. Often, there are characteristic triggers diet (cane suger in fructose intolerance, milk in galactosemia, protein in urea cycle disorders etc) infection, fasting and fever (certain amino acid disorders) Anaesthesia (Homocystinuria) Porphyria and G6PD deficiency) Age of Neurological manifestation and death
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EXAMPLES (kaplan) Niemann-Pick disease Group A, infantile
IEM disorder Mode Enzyme defect Prenatal diagnosis Mental retardation Clinical signs LIPID METABOLISM Niemann-Pick disease Group A, infantile Group B, adult Group C, intermediate AR Unknown Sphingomyelinase unkonwn + - + or – Hepatomegally Hepatosplenomegally Pulmonary infiltration Infantile Gaucher’s dx A.R Beta-glucosidase + or - Hepatosplenomegally, Psuedobulbar palsy Tay-Sachs disease Hexosaminidase A Macular changes, seizures, spasticity Generalized gangliosidosis Beta- galactosidase Bone changes Krabbe’s dx Galactocerebroside Stiffness, seizures
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EXAMPLES cont. Metachromatic leukodystrophy AR Cerebroside sulphate +
IEM disorder Mode Enzyme defect Prenatal diagnosis Mental retardation Clinical signs LIPID METABOLISM Metachromatic leukodystrophy AR Cerebroside sulphate + Stiffness, developmental failure Wolman’s disease A.R Acid lipase - Hepatosplenomegally, Adrenal calcification, vomiting diarrhoea Farber’s lipogranulomatosis Acid ceramidase Hoarsenes, arthopathy, subcutaneou nodules Faber’s disease XR Alpha-galactosidase Angiokeratomas, renal failure
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EXAMPLES cont. AR iduronidase + ? X.R sulphase
IEM disorder Mode Enzyme defect Prenatal diagnosis Mental retardation Clinical signs MUCOPOLYSACCHARIDE METABOLISM Hurler’s syndrome MPS I AR iduronidase + ? Hurler’s disease II X.R sulphase Sanflippo’s syndrome III Various sulphatases (types A - D) Various degrees of bone changes, hepatosplenomegally Morquio’s disease IV N-Acetylgalactosamine-6sulfate sulfatase - Maroteaux-Lamy syndrome Arylsulfatase B + of -
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EXAMPLES cont. IEM disorder Mode Enzyme defect Prenatal diagnosis Mental retardation Clinical signs OLIGOSACCHARIDE AND GLYCOPROTEIN METABOLISM I-cell disease AR Glycoprotein N-acetylglucosaminyl-phospho-transferase + Hepatomegally, bone changes, swollen gingivae mannosidosis mannosidase Hepatomegally, bone changes, facial coarseness Fucosidosis fucosidase
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EXAMPLES cont. AR Phenylalanine hydroxylase - +
IEM disorder Mode Enzyme defect Prenatal diagnosis Mental retardation Clinical signs AMINO ACID METABOLISM Phenylketonuria AR Phenylalanine hydroxylase - + Eczema, londe hair, musty odor Hemocystinuria Cystathionine beta-synthase Ectopia lentis, Marfanlike phenotype CVS anomalies Tyrosinosis Tyrosine amine transaminase Hyperkeratotic skin lesions, conjuctivitis Marple syrup disease Branched chain ketoacid decarboxylase Reurrent ketoacidosis Methylmalonic acidemia Methylmanonyl-CoA mutase Recurrent ketoacidosis hepatomegally, growth retardation Propionic acidemia Propionyl-CoA carboxylase
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EXAMPLES cont. AR Glycine cleavage enzyme + Seizures
IEM disorder Mode Enzyme defect Prenatal diagnosis Mental retardation Clinical signs AMINO ACID METABOLISM cont Non-ketotic hyperglycemia AR Glycine cleavage enzyme + Seizures Urea cycle disorders Mostly AR Urea cycle enzymes Recurrent acute encephalopathy, vomiting Hartnup’s disease Renal transport disorder - Non cosistent
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EXAMPLES cont. AR Galactose-1-phosphate uridyltransferase +
IEM disorder Mode Enzyme defect Prenatal diagnosis Mental retardation Clinical signs OTHERS Galactosemia (disaccharide) AR Galactose-1-phosphate uridyltransferase + Hepatomegally, cataract, ovarian failure Wilson’s hepatolenticular degenaration Unknown factor in copper metabolism - + or - Liver disease, Kayser-Fleiscer ring, neurological problems Menke’s kinky-hair disease XR Abnormal hair, cerebral degeneration Lesch-Nyhan syndrome Hypoxanthine quanine phosporibosyltransferase Behavioural abnormality
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Basic Principles of Management
Prevention of the accumulation of toxic levels of the precursor substances. Restrict offending substance in the diet Stimulation of elimination of a toxic substrate/precursor by an alternative pathway Supply the deficient product Enhanace the activities of the deficient enzyme by providing co-factors eg vitamine Supply essential nutrients/disease specific diet after the diagnosis is established, sometimes specific synthetic medical formulae are ideal.
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Basic Principles of Management cont
Table: vitamin responsive IEM disorders IEM disorder Vitamin used in treatment Maple syrup urine disease Thiamine Homocystinuria Pyridoxine, folic acid, vitamine B12 Propionic academia Biotin Methylmalonic acidemia Hydroxycobalamin Glutaric academia Riboflavin Biotinidase deficiency Hartnup disease Nicotin acid Pyruvate dehydrogenase deficiency/Leigh’s disease Respiratory chain disorder
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Prognosis Few metabolic diseases are treatable
At present, for most IEMs, prognosis for survival or normal neurological outcome is guarded, despite appropriate and aggressive therapy. It is likely that the outcomes will improve with (a) presymptomatic diagnosis (i.e., by prenatal detection or expanded neonatal screening), (b) identification of genes and other factors which impact on phenotype, response to treatment, and outcome, and (c) alternative novel approaches to therapy.
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Relevance to neuropsychiatry
Mental retardation (mention 4 examples) Seizures (mention 2 examples) Abnormal behaviour (mention 1 example) Acute organic brain syndrome (mention 1 examples) Chronic organic brian disorder (mention 1 examples)
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THANK YOU FOR YOUR ATTENTION
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