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Inborn error of metabolism

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Inborn error of metabolism

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Inborn error of metabolism

  1. 1. Inborn Error of Metabolism  Single gene mutations  Alteration of primary protein structure  Alteration of the amount of protein synthesized  Mild to lethal
  2. 2. Inheritance: • Most IEM…… autosomal recessive genetic traits • Urea cycle disorder ornithine transcarbamylase deficiency…….. X linked • Some are mitochondrial inheritance
  3. 3. Metabolic disorders can be classified using a variety of schemes based on:  the clinical presentation  the age of onset  the tissues or organ systems involved  the defective metabolic pathways
  4. 4. Classifications of IEM Amino acids • Phenylketonuria- Homocystinuria - tyrosinemia Lipidoses • Tay sach’s disease – Gaucher’s disease – metachromatic leukodystrophy carbohydrates • Galactosemia – fructose intolerance – Glycogen storage disorders Organic acidemia • Methylmalonic aciduria- propionic aciduria- maple syrup urine disease Transport disorders • Cystinuria cystinosis – hypercholesterlemia (AD) Peroxisomal disorders • Adrenoleukodystrophy – zellweger syndrome – chondrodysplasia punctata Lysosomal storage disorders • mucopolysaccaridosis Urea cycle disorders • Ornithine transcarbamylase deficiency- arginosucciniase deficiency- carbamyl phosphate synthetase deficiency Metal metabolic disorders • Wilson’s disease – Menkes disease
  5. 5. Group 1 Anabolism/ catabolism Lysosomal, Peroxisomal, glycosylation, and cholesterol synthesis defects some Lysosomal disorders can be efficiently treated by enzyme replacement or substrate reduction therapies Group 2 intermediary metabolism Aminoacidopathies, organic acidurias, urea cycle disorders, sugar intolerances, metal disorders and porphyrias Acute or chronic intoxications Neonatal to adulthood Most …. treatable emergency removal of the toxin by special diets, extracorporeal procedures, cleansing drugs or vitamins Group 3 energy production/ utilization Cytoplasmic defects encompass those affecting glycolysis, glycogenosis, gluconeogenesis, hyperinsulinisms, and creatine and pentose phosphate pathways; the latter are untreatable. Mitochondrial defects include respiratory chain disorders, and Krebs cycle and pyruvate oxidation defects, mostly untreatable, and disorders of fatty acid oxidation and ketone bodies that are treatable
  6. 6. Clinical presentations: • Pregnancy: acute fatty liver of pregnancy- HELLP syndrome………… long chain 3 hydroxy coenzyme A dehydrogenase deficiency (LCHADD)
  7. 7. Clinical presentations: • Sepsis like presentation • Mental retardation • Neurological impairment, Seizures, Encephalopathy, tone abnormalities • Sudden infant death • Metabolic acidosis • Hypoglycemia • Liver dysfunctions • Dysmorphic features • Cardiac disease • Hydrops fetalis • Abnormal urine odor
  8. 8. Inborn Errors of Metabolism with hydrops fetalis • Lysosomal disorders: - Mucopolysaccaridosis types I, IVA, VII - Gaucher disease - Nieman pick disease type c - Farber disease • Hematologic disorders: - G-6-PD deficiency - Pyruvate kinase defieciency • Others: - Neonatal hemochromatosis - Respiratory chain disorders
  9. 9. Evaluation • History, Family history: parental consanguinity, unexplained neonatal deaths • Physical examination: facial dysmorphism, cataracts, retinopathy, structural brain anomalies, hypertrophic or dilated cardiomyopathy, hepatomegaly, multicystic dysplastic kidneys and myopathy.
  10. 10. Evaluation Initial Evaluation CBC Blood glucose Plasma ammonia Plasma lactate, pyruvate Liver functions tests Urine reducing substances Urine ketones Electrolytes, Ca, Mg
  11. 11. 2nd line Evaluation carnitine, acylcarnitine s, vLCFA enzymes Magnetic resonance imaging (MRI) Magnetic resonance spectrosco py (MRS) Plasma aminoaci d analysisUrine organic acid analysis EEG Mutation analysis CSF aminoacid analysis
  12. 12. PhenylketonuriaDisorder 1:15000Incidence Autosomal recessiveInheritance Phenylalanine hydroxylase (> 98 percent) Biopterin metabolic defects (< 2 percent) Metabolic error Mental retardation, acquired microcephalyKey manifestation Plasma phenylalanine concentrationKey laboratory test Diet low in phenylalanineTherapy approach
  13. 13. Maple syrup urine diseaseDisorder 1:150,000Incidence Autosomal recessiveInheritance Branched-chain 3-keto acid dehydrogenase Metabolic error Acute encephalopathy, metabolic acidosis, mental retardation Key manifestation Plasma amino acids and urine organic acids Dinitrophenylhydrazine for ketones Key laboratory test Restriction of dietary branched-chain amino acids Therapy approach
  14. 14. Carbohydrate metabolism GalactosemiaDisorder 1:40000Incidence Autosomal recessiveInheritance Galactose 1-phosphate uridyltransferase (most common); galactokinase; epimerase Metabolic error Hepatocellular dysfunction, cataractsKey manifestation Enzyme assays, galactose and galactose 1-phosphate assay, molecular assay Key laboratory test Lactose-free dietTherapy approach
  15. 15. Glycogen storage disease, type Ia (von Gierke's disease) Disorder 1:100000Incidence Autosomal recessiveInheritance Glucose-6-phosphataseMetabolic error Hypoglycemia, lactic acidosis, ketosisKey manifestation Liver biopsy enzyme assayKey laboratory test Corn starch and continuous overnight feeds Therapy approach
  16. 16. Fatty acid oxidation Medium-chain acyl-CoA dehydrogenase deficiency Disorder 1:15000Incidence Autosomal recessiveInheritance Medium-chain acyl-CoA dehydrogenaseMetabolic error Nonketotic hypoglycemia, acute encephalopathy, coma, sudden infant death Key manifestation Urine organic acids, acylcarnitines, gene test Key laboratory test Avoid hypoglycemia, avoid fastingTherapy approach
  17. 17. Lactic acidemia Pyruvate dehydrogenase deficiencyDisorder 1:100000Incidence X linkedInheritance E1 subunit defect most commonMetabolic error Hypotonia, psychomotor retardation, failure to thrive, seizures, lactic acidosis Key manifestation Plasma lactate Skin fibroblast culture for enzyme assay Key laboratory test Correct acidosis; high-fat, low- carbohydrate diet Therapy approach
  18. 18. Lysosomal storage Gaucher diseaseDisorder 1:60,000; type 1–1:900 in Ashkenazi Jews Incidence Autosomal recessiveInheritance β-glucocerebrosidaseMetabolic error Coarse facial features, hepatosplenomegaly Key manifestation Leukocyte β-glucocerebrosidase assayKey laboratory test Enzyme therapy, bone marrow transplantTherapy approach
  19. 19. Fabry's diseaseDisorder 1:80,000Incidence X linkedInheritance α-galactosidase AMetabolic error Acroparesthesias, angiokeratomas hypohidrosis, corneal opacities, renal insufficiency Key manifestation Leukocyte α-galactosidase A assayKey laboratory test Enzyme replacement therapyTherapy approach
  20. 20. Hurler's syndromeDisorder 1:100000Incidence Autosomal recessiveInheritance α-l-iduronidaseMetabolic error Coarse facial features, hepatosplenomegaly Key manifestation Urine mucopolysaccharides Leukocyte α- l-iduronidase assay Key laboratory test Bone marrow transplantTherapy approach
  21. 21. Organic aciduria Methylmalonic aciduriaDisorder 1:20000Incidence Autosomal recessiveInheritance Methylmalonyl-CoA mutase, cobalamin metabolism Metabolic error Acute encephalopathy, metabolic acidosis, hyperammonemia Key manifestation Urine organic acids Skin fibroblasts for enzyme assay Key laboratory test Sodium bicarbonate, carnitine, vitamin B12, low-protein diet, liver transplant Therapy approach
  22. 22. Propionic aciduriaDisorder 1:50000Incidence Autosomal recessiveInheritance Propionyl-CoA carboxylaseMetabolic error Metabolic acidosis, hyperammonemiaKey manifestation Urine organic acidsKey laboratory test Dialysis, bicarbonate, sodium benzoate, carnitine, low-protein diet, liver transplant Therapy approach
  23. 23. Peroxisomes Zellweger syndromeDisorder 1:50000Incidence Autosomal recessiveInheritance Peroxisome membrane proteinMetabolic error Hypotonia, seizures, liver dysfunctionKey manifestation Plasma very-long-chain fatty acidsKey laboratory test No specific treatment availableTherapy approach
  24. 24. Urea cycle Ornithine transcarbamylase deficiencyDisorder 1:70000Incidence X linkedInheritance Ornithine transcarbamylaseMetabolic error Acute encephalopathyKey manifestation Plasma ammonia, plasma amino acids Urine orotic acid Liver (biopsy) enzyme concentration Key laboratory test Sodium benzoate, arginine, low-protein diet, essential amino acids; dialysis in acute stage Therapy approach
  25. 25. Treatment Prevent Catabolism: Administration of calories is used in the treatment of acute episodes to try to slow down catabolism. Limit the Intake of the Offending Substance: the basis of treatment in Galactosemia, fructose intolerance and PKU. Increase Excretion of Toxic Metabolites: by exchange transfusion, peritoneal dialysis (PD), hemodialysis, forced diuresis, using alternative pathways for the excretion of toxic metabolites. For example, carnitine is useful in the elimination of organic acids in the form of carnitine esters. Sodium benzoate and phenylacetate are useful in treating hyperammonemia.
  26. 26. Enzyme Replacement Therapy: Human alpha glucosidase enzyme (pompe’s disease)- Laronidase (Aldurazyme) enzyme(MPS I)patients- Fabry-specific enzyme replacement therapy (ERT) with recombinant alpha-Gal A (Fabrazyme) is safe and effective, Imiglucerase (Gaucher disease) Increase the Residual Enzyme Activity: B12 decreases the urinary levels of methyl malonate by enhancing activity of Trans Cobalmin II Reduce Substrate Synthesis: Inhibition of substrate synthesis has been used as a strategy for treating glycolipid Lysosomal storage disease.
  27. 27. Replacement of the End Product: Hypoglycaemia can be prevented by frequent feeds during the day and continuous nasogastric feeding at night, in infancy and early childhood. Raw cornstarch (2 g/kg every six hours) has been shown to be effective in preventing hypoglycaemia in older children with glycogen storage disease type I as well as decreasing the hyperlipidaemia, hyperuricaemia, and lactic acidaemia
  28. 28. Transplantation and Gene Therapy: For the last 25 years, hematopoietic cell transplantation (HCT) has been used as effective therapy for selected inborn errors of metabolism (IEMs), mainly Lysosomal storage diseases and Peroxisomal disorders. The main rational for HCT in IEMs is based on the provision of correcting enzymes by donor cells within and outside the blood compartment
  29. 29. Prevention Genetic counselling and prenatal diagnosis: The samples required are chorionic villus tissue or amniotic fluid. Modalities available are: • Substrate or metabolite detection: useful in phenylketonuria, peroxisomal defects. • Enzyme assay: useful in lysosomal storage disorders like Niemann-Pick disease, Gaucher disease. • DNA based (molecular) diagnosis: Detection of mutation in proband/ carrier parents is a prerequisite. Neonatal screening: tandem mass spectrometry
  30. 30. Selective screening for inborn errors of metabolism by tandem mass spectrometry in Egyptian children: A 5 year report • A relatively high number of patients (203/3380 (6%)) were confirmed with 17 different types of IEMs. Averages for age at diagnosis for different disorders ranged from 2.5 months to 6.6 years with general developmental delay and irreversible neurological damage being the most common presenting features (75.9% and 65.5%, respectively). Amino acid disorders (127/203 (62.6%)), mainly phenylketonuria (100/203 (49.3%)), were the most encountered, followed by organic acidemias (69/203 (34%)), while fatty acid oxidation defects (7/203 (3.4%)) were relatively rare. 88% of patients were born t consanguineous parents.
  31. 31. References • Talkad S. Raghuveer and et.al. Inborn Errors of Metabolism in Infancy and Early Childhood: An Update. American Family Physician j.2006: 17:1981-1990 • Atlas of Metabolic Diseases, 2nd edition • Ananth N Rao, J Kavitha, Minakshi Koch and Suresh Kumar V. Inborn Errors of Metabolism: Review and data from a tertiary care center. Indian Journal of Clinical Biochemistry, 2009: 24 (3) 215-222 • Anju Gupta. To Err is Genetics: Diagnosis and Management of Inborn Errors of Metabolism (IEM)
  32. 32. • Laila A. Selim and et.al. Selective screening for inborn errors of metabolism by tandem mass spectrometry in Egyptian children: A 5 year report. Clinical Biochemistry 47 (2014) 823–828

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