Metabolic Disorders Inborn Errors Of Metabolism

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Metabolic Disorders Inborn Errors Of Metabolism. DR. ABDULLAH ALOMAIR MB ChB , MRCP ( Edin ), FRCP ( Edin .), DCH ( Glas .) Associate Professor of Pediatrics Consultant Pediatrician Department of Pediatrics PRESIDENT SAUDI PEDIATRIC ASSOCIATION. - PowerPoint PPT Presentation

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<ul><li><p> Metabolic Disorders Inborn Errors Of Metabolism*DR. ABDULLAH ALOMAIR </p><p> MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.) </p><p>Associate Professor of PediatricsConsultant PediatricianDepartment of Pediatrics</p><p>PRESIDENT SAUDI PEDIATRIC ASSOCIATION</p></li><li><p>*</p><p> Inborn Errors Of Metabolism (IEM) - A large group of hereditary biochemical diseases - Specific gene mutation cause abnormal or missing proteins that lead to altered function.Metabolic Disorders Inborn Errors Of Metabolism</p></li><li><p>Pathophysiology </p><p>SINGLE GENE DEFECTS in synthesis or catabolism of proteins, carbohydrates, or fats. </p><p>Defect in an ENZYME or TRANSPORT PROTEIN , which results in a block in a metabolic pathway. </p></li><li><p>Pathophysiology </p><p> EFFECTS : - toxic ACCUMULATION of substrates before the block, - intermediates from ALTERNATIVE pathways - defects in ENERGY production and utilization caused by a deficiency of products beyond the BLOCK. Every metabolic disease has several forms that vary in AGE OF ONSET , clinical severity and, often, MODE OF INHERITANCE. </p></li><li><p> Metabolic Disorders</p><p>From history:</p><p>Parental history :</p><p>Consanguineous parents</p><p>Previous unexplained neonatal deaths</p><p>Particular ethnic group (in certain diseases) *Features suggestive of metabolic disorder :</p></li><li><p>Features suggestive of metabolic disorder : Metabolic DisordersExamination findings:</p><p>Organomegaly (e.g. hepatomegaly)</p><p>Cardiac disease</p><p>Ocular involvement (e.g. cherry red spot)</p><p>Skin manifestations</p><p>Unusual odour</p><p>Non-specific neurological findings</p></li><li><p>Neonatal and Post Neonatal Presentation</p><p> Neonatal presentationNormal-appearing child at birth (some conditions are associated with dysmorphic features)poor feedinglethargyvomitingseizurescomaunusual odourhypoglycaemia, acidosis (in some defects) *</p></li><li><p> Neonatal and Post Neonatal PresentationPost neonatal presentationEncephalopathyDevelopmental regressionReye syndromeMotor deficitsSeizuresIntermittent episodes of vomiting, acidosis, hypoglycaemia and/or coma triggered by stress e.g. infections, surgery.</p></li><li><p>Newborn ScreeningPKU - in NICU even if not advanced to full feedsGalactosemiaHypothyroidismHemoglobinopathiesBiotinidase defic, CAH (21-OHase def), Maple syrup urine disease ( MSUD )</p><p> - GUTHRIE TEST</p></li><li><p>Specific Tests:</p><p>Direct biochemical assays of metabolites or their metabolic by-products, or of an enzymes function.</p><p>DNA studies</p><p>Neuro-radiology * PROCEDURES FOR DIAGNOSIC CONFIRMATIONNon Specific Tests:</p><p>Blood glucose, ammonia, bicarbonate and PHPeripheral Blood smear WBC or bone marrow vacuolization , foam cells or granules.</p><p> C.S.F. glycine , other amino acids , lactate.</p></li><li><p>* INBORN ERRORS OF AMINO ACID METABOLISM ASSOSIATED WITH ABNORMAL ODOR</p></li><li><p>Genetic:</p><p>Establish diagnosis.</p><p>Carrier testing.</p><p>Pedigree analysis, risk counseling.</p><p>Consideration of Prenatal diagnosis for pregnancies at risk.*MANAGEMENT OF IEM</p></li><li><p>Family counseling and support.</p><p>Education to promote increased compliance with special form of therapy such as Protein restricted diet.</p><p>Assessment of community resources and support groups. *PSYCHOSOCIAL , EDUCATIONAL , FAMILIAL MANAGEMENT OF IEM</p></li><li><p> TREATMENT OF GENETIC DISEASESModify environment, e.g., diet, drugsAvoid known environmental triggersBMTSurgical, correct or repair defect or organ transplantation</p><p>Modify or replace defective gene product, megadose vitamin therapy or enzyme replacement </p><p>Replace defective gene</p><p>Correct altered DNA in defective gene</p></li><li><p>Galactosemia*</p></li><li><p> : Carbohydrates </p><p>GalactosemiaEnzyme deficiency: Galactose-1-phosphate uridyl transferase deficiency.</p><p>Rare . Autosomal recessive</p><p>Follows feeding with lactose containing (breastmilk / formula) Patient feeds poorly , have vomiting, jaundice, hepatomegaly and hepatic failureChronic liver diseaseCataractsDevelopmental delay develop if condition is untreated. *</p></li><li><p>CYSTIC FIBROSIS</p><p>Cause : Loss of 3 DNA bases in a gene for the protein that transports Cl ions so salt balance is upset. Causes a build up of thick mucus in lungs and digestive organs. </p></li><li><p> AMINO ACID DISORDERS</p><p> Phenyl Ketonuria (PKU)</p><p>*PhenylalanineTyrosine</p><p>Hydroxylase</p><p>PhenylalaninePhenyl ethylamine Phenyl pyruvic acid</p></li><li><p> Phenylketonuria PKU*</p></li><li><p>Hyperactivity, athetosis, vomiting.</p><p>Blond.</p><p>Seborric dermatitis or eczema skin.</p><p>Hypertonia.</p><p>Seizures.</p><p>Severe mental retardation.</p><p>Unpleasant odor of phenyl acetic acid.</p><p>*PKU </p><p>DIAGNOSISScreening : Guthrie Test.</p><p>High Phenylalanine &gt; 20 mg/dl.</p><p>High Phenyl pyruvic acid.</p><p>TREATMENT DIET.</p><p> BH4 (Tetrahydrobiopterin).</p><p> L dopa and 5- hydroxytryptophan.CLINICAL FEATURES </p></li><li><p>*PKU</p></li><li><p> Albinism*</p></li><li><p>HomocystinuriaElevated homocystine levels affect collagen , result in a Marfanoid habitus, ectopia lentis, mental retardation and strokes*</p></li><li><p> METHIONINE CYSTATHIONINE*HomocystinuriaCysathionine</p><p>Synthatase</p><p>DIAGNOSIS:</p><p> High methionine and homocystine.</p><p> TREATMENT:</p><p>High dose of B6 and Folic Acid.Low methionine and high cystine diet,Betain (trimethylglycine)</p></li><li><p> Homocystinuria*</p></li><li><p>Amino acid disorders :Urea cycle defects and hyperammonemia All present with lethargy, seizures, ketoacidosis, neutropenia, and hyperammonemia</p><p>Ornithine carbamyl transferase (OTC) deficiencyCarbamyl phosphate synthetase deficiencyCitrullinemiaArginosuccinic AciduriaArgininemiaTransient tyrosinemia of prematurity</p></li><li><p>First Steps in Metabolic Therapy for IEMReduce precursor substrate load</p><p>Provide caloric support</p><p>Provide fluid support</p><p>Remove metabolites via dialysis</p><p>Divert metabolites</p><p>Supplement with cofactor(s)</p></li><li><p>An essential nutrient found in highest concentration in red meat. Primary function : Transport long-chain fatty acids into mitochondria for oxidation.Carnitine supplementation in fatty acid oxidation disorders and organic acidosis may augment excretion of accumulated metabolites , but may not prevent metabolic crises in such patients .</p><p>CARNITINE METABOLISM</p></li><li><p>Important IEM Treatment supplements:Carnitine for elimination of Organic Acid through creation of carnitine esters. Sodium Benzoate, phenylacetate and phenylbutyrate for Hyperammonemia elimination. </p></li><li><p>Therapeutic Measures for IEMD/C oral intake temporarilyUsually IVFs with glucose to give 12-15 mg/kg/min glu and at least 60 kcal/kg to prevent catabolism (may worsen PDH)Bicarb/citrateCarnitine/glycineNa Benzoate/arginine/citrullineDialysis--not exchange transfusionVitamins--often given in cocktails after labs drawn before dx is knownBiotin, B6, B12, riboflavin, thiamine, folate</p></li><li><p>ORGANIC ACIDEMIADisorder</p><p>Methyl malonic Acidemia.</p><p>Propionic Acidemia.</p><p>Multiple carboxylase deficiency.</p><p>Ketothiolase deficiency .</p><p>Enzyme </p><p>Methyl malonyl COA mutase.</p><p>Propionyl COA Carboxylase.</p><p>Malfunction of all carboxylase.</p><p>2 methylacetyl COA thiolase def.</p><p>*</p></li><li><p> ORGANIC ACIDEMIA</p><p>Clinical Features</p><p>Vomiting, ketosis.</p><p>Thrombocytopenia , neutropenia.</p><p>Osteoporosis.</p><p>Mental retardation.Treatment</p><p>Hydration / alkali.</p><p>Calories to catabolic state.</p><p>Exchange transfusion.</p><p>Low protein diet.</p><p>*</p></li><li><p>ORGANIC ACIDEMIA*</p></li><li><p> LYSOSOMAL STORAGE DISORDERS</p><p>Glycogen Storage Diseases</p><p>Sphingolipidoses (Lipidoses And Mucolipidoses)</p><p>Mucopolysaccharidoses</p><p>*</p></li><li><p>*Lysosomal Storage Disease</p><p>DiseaseEnzyme Defiency Major Accumulating MetaboliteGlycogenosisType II (Pompe disease)GlucosidaseGlycogenSphingolipidosesGM1 gangliosidoses</p><p>GM2 gangliosidoses Tay-Sachs disease Gaucher disease Niemann-Pick disease-galactosidase</p><p>Hexosaminidase AGlucocerebrosidaseSphingomyelinaseGM1 gangliosides, galactose-containing oligosaccharides</p><p>GM2 gangliosideGlucocerebrosideSphingomyelinMucopolysaccharidoses MPS I H (Hurler)</p><p> MPS II (Hunter)(X-linked recessive)-L-Iduronidase</p><p>L-Iduronosulfate sulfataseHeparan sulfateDermatan sulfate</p><p>Heparan sulfateDermatan sulfate</p></li><li><p>Glycogen Storage Diseases</p></li><li><p>Name</p><p>Enzyme</p><p>Symptoms</p><p>Type O</p><p>Glycogen synthetase</p><p>Enlarged, fatty liver; hypoglycemia when fasting</p><p>von Gierke</p><p>(Type IA)</p><p>Glucose-6-phosphatase</p><p>Hepatomegaly; slowed growth; hypoglycema; hyperlipidemia</p><p>Type IB</p><p>G-6-P translocase</p><p>Same as in von Gierke's disease but may be less severe; neutropenia</p><p>Pompe</p><p>(Type II)</p><p>Acid maltase</p><p>Enlarged liver and heart, muscle weakness</p><p>Forbe (Cori) </p><p>(Type III)</p><p>Glycogen debrancher</p><p>Enlarged liver or cirrhosis; low blood sugar levels; muscle damage and heart damage in some people</p><p>Andersen</p><p>(Type IV)</p><p>Glycogen branching enzyme</p><p>Cirrhosis in juvenile type; muscle damage and CHF</p><p>McArdle's</p><p>(Type V)</p><p>Muscle glycogen phosphorylase</p><p>Muscle cramps or weakness during physical activity</p><p>Her</p><p>(Type VI)</p><p>Liver glycogen phosphorlyase</p><p>Enlarged liver; often no symptoms</p><p>Tarui</p><p>(Type VII)</p><p>Muscle phosphofructokinase</p><p>Muscle cramps during physical activity; hemolysis</p><p>Type VIII</p><p>Unknown</p><p>Hepatomegaly; ataxia, nystagmus</p><p>Type IX</p><p>Liver phosphorylase kinase</p><p>Hepatomegaly; Often no symptoms</p><p>Type X</p><p>Cyclic 3-5 dependent kinase</p><p>Hepatomegaly, muscle pain (1 patient)</p><p>Type XI</p><p>Unknown</p><p>Hepatomegaly. Stunted growth, acidosis, Rickets</p></li><li><p>Principle Groups of Glycogen Storage Diseases*</p></li><li><p>*</p></li><li><p> LYSOSOMAL STORAGE DISORDERS Lipidoses And Mucolipidoses*</p></li><li><p>*Gauch. cell</p></li><li><p>*Sandhoff - Dense thalam</p></li><li><p>*Leucodys..</p></li><li><p>*Lipid-retina</p></li><li><p> LYSOSOMAL STORAGE DISORDERS Mucopolysaccharidoses*</p></li><li><p>Clinical And Pathological Ultra structure Of Mucopolysaccharidoses*</p><p>DiseaseClinical ManifestationUltrastructure of Stored MaterialMPS type IHurlerEarliest, most severe developmental regressioncoarse facial featuresHepatosplenomegalydystosis of bonecardiac involvementcorneal cloudingFibrillogranular mucopolysaccharides in cells of viscera and brainMPS type IIHunterX-linkedLater developmental regressioncoarse facial featureshepatosplenomegaly dystosis of bone cardiac involvementminimal corneal cloudingFibrillogranular mucopolysaccharides in cells of viscera and brain</p></li><li><p>*Hurlers</p></li><li><p>*Hurlers</p></li><li><p>*</p></li><li><p>* Mcopolysacch. Morquio</p></li><li><p>Due to dysfunction of a single or multiple peroxisomal enzymes, or to failure to form or maintain a normal number of functional peroxisomes.</p><p>Peroxisomes = Subcellular organelles involved in various essential anabolic or catabolic processes, biosynthesis of Plasmalogens and bile acids. </p><p>*PEROXISOMAL DISORDERS</p></li><li><p>Hypotonia.</p><p>Dysmorphia.</p><p>Psychomotor delay and seizures.</p><p>Hepatomegaly.</p><p>Abnormal eye findings such as retinitis pigmentosa or cataract.</p><p>Hearing impairment.* PEROXISOMAL DISORDERS Clinical Manifestations:</p></li><li><p> Peroxisomal Disorders Zellweger Syndrome (Cerebro-hepato-renal syndrome)</p><p>Typical and easily recognized dysmorphic facies. </p><p>Progressive degeneration of Brain/Liver/Kidney, with death ~6 mo after onset.</p><p>When screening for PDs. obtain serum Very Long Chain Fatty Acids- VLCFAs</p></li><li><p>*Zellweger</p></li><li><p>*Chond punct</p></li><li><p>*</p></li><li><p>*THANK YOU</p></li><li><p>*</p></li><li><p>Metabolic DisordersDue to inherited reduced activities of proteins involved in the synthesis, breakdown or transport of amino acids, organic acids, fats, carbohydrates and complex macromolecules. Most are autosomal recessive due to mutations that result in reduced enzyme activity or reduced amount of enzyme.Pathogenesis may include: accumulation of a toxic intermediate, reduced amount of a necessary end product or activation of an alternate pathway.*</p></li><li><p> Inborn Errors of Metabolism of Acute Onset: Nonacidotic, Nonhyperammonemic Features</p><p>Neurologic Features Predominant (Seizures, Hypotonia, Optic Abnormality)</p><p>Glycine encephalopathy (nonketotic hyperglycinemia)</p><p>Pyridoxine-responsive seizures</p><p>Sulfite oxidase/santhine oxidase deficiency</p><p>Peroxisomal disorders (Zellweger syndrome, neonatal adrenoleuko-</p><p>dystrophy, infantile refsum disease)</p><p>Jaundice Prominent</p><p>Galactosemia</p><p>Hereditary fructose intolerance</p><p>Menkes kinky hair syndrome</p><p>1-antitrypsin deficiency</p><p>Hypoglycemia (Nonketotic): Fatty acid oxidation defects (MCAD, LCAD, </p><p>carnitine palmityl transferase, infantile form)</p><p>Cardiomegaly</p><p>Glycogen storage disease (type II phosphorylase kinase b deficiency18)</p><p>Fatty acid oxidation defects (LCAD)</p><p>Hepatomegaly (Fatty): Fatty acid oxidation defects (MCAD, LCAD)</p><p>Skeletal Muscle Weakness: Fatty acid oxidation defects (LCAD, SCAD, </p><p>multiple acyl-CoA dehydrogenase</p></li><li><p> Clinical Symptomatology of Inborn Errors of Metabolism (IEM) in the Neonate or Infant</p><p>Symptoms indicating possibility of an IEM (one or all)</p><p>Infant becomes acutely ill after period of normal behavior and feeding; </p><p>this may occur within hours or weeks</p><p>Neonate or infant with seizures and/or hypotonia, especially if seizures </p><p>are intractable</p><p>Neonate or infant with an unusual odor</p><p>Symptoms indicating strong possibility of an IEM, particularly when coupled </p><p>with the above symptoms</p><p>Persistent or recurrent vomiting</p><p>Failure to thrive (failure to gain weight or weight loss)</p><p>Apnea or respiratory distress (tachypnea)</p><p>Jaundice or hepatomegaly</p><p>Lethargy</p><p>Coma (particularly intermittent)</p><p>Unexplained hemorrhage</p><p>Family history of neonatal deaths, or of similar illness, especially in </p><p>siblings</p><p>Parental consanguinity</p><p>Sepsis (particularly Escherichia coli)</p></li><li><p>Laboratory Assessment of Neonates </p><p>Suspected of Having an </p><p>Inborn Error of Metabolism</p><p>Routine Studies</p><p>Special Studies</p><p>Blood lactate and </p><p> pyruvate</p><p>Complete blood count</p><p> and differential</p><p>Plasma amino acids</p><p>Plasma ammonia </p><p> Plasma carnitine</p><p>Plasma glucose</p><p>Urine amino acids</p><p>Plasma electrolytes and </p><p> blood pH</p><p>Urine organic acids</p><p>Urine ketones</p><p>Urine-reducing </p><p> substances</p></li><li><p>ClassificationTransient Hyperammonemia of NewbornInborn Errors of Metab:Organic Acidemias Fatty Acid Oxidation defUrea Cycle DefectsAmino AciduriasNon-ketotic HyperglycinemiaMolybdenum Cofactor Deficiency Sulfite Oxidase DeficiencyMetal Storage Disorders:Cholesterol Disorders:Leukodystrophies, otherKrabbe diseaseMitochondrial Disorders Glycogen Storage DisordersHyperinsulinismCarbohydrate DisordersLysosomal DisordersMucopolysaccharidoses (X-linked Hunters, Hurlers)Gaucher diseaseTay-Sachs DiseasePeroxisomal DisordersZellweggers (Cerebro-Hepato-renal)X-linked Adrenoleukodystrophy</p></li><li><p>Diagnosis:Immunochemical studies for Peroxisomes. V. Long Chain FA ( VLCFA ) level.Chor. Vill. Samp. or/ amniocytes culture Plasmalogens synthesis.</p><p>* PEROXISOMAL DISORDERS Treatment:Supportive, multidisciplinary interventions.Diet: VLCFA, phytanic acid.Organ transplantation. </p></li><li><p> Peroxisomal Disorders GROUP II : PERSOXISOMAL ENZYME DEFECTS *GROUP I : BIOGENSIS OF PEROXISOMEGROUP III : POSITIVE PEROXISOMES BUT MULTIPLE DEFECTIVE ENZYMEZellweger syndrome (cerebrohepatorenal syndrome).Neonatal adrenoleukodystrophy.Infantile Refsum disease.Hyperpipecolic acidemia.Refsum disease.X - linked Adreno-Leuko-Dystrophy.Pseudo Zellweger syndrome.Hyperoxaluria.etc.Zellweger Like.Pseudo infantile Refsum disease.Rhizomelic chondro-dysplasia punctata</p></li><li><p>Mitochondrial Syndromes Presenting in Childhood to Adult*</p><p>SyndromeMost Common Clinical PresentationOther Cliical FeaturesMt DNA DefectMELAS: myopathy, encephalopathy, lactic acidosis and stroke-like episodesStroke-like episodes in the first and second decade of life often associated with migraine headache, blood lactate De...</p></li></ul>