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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  • Metabolic Disorders Inborn Errors Of Metabolism*DR. ABDULLAH ALOMAIR

    MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.)

    Associate Professor of PediatricsConsultant PediatricianDepartment of Pediatrics

    PRESIDENT SAUDI PEDIATRIC ASSOCIATION

  • *

    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

  • Pathophysiology

    SINGLE GENE DEFECTS in synthesis or catabolism of proteins, carbohydrates, or fats.

    Defect in an ENZYME or TRANSPORT PROTEIN , which results in a block in a metabolic pathway.

  • Pathophysiology

    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.

  • Metabolic Disorders

    From history:

    Parental history :

    Consanguineous parents

    Previous unexplained neonatal deaths

    Particular ethnic group (in certain diseases) *Features suggestive of metabolic disorder :

  • Features suggestive of metabolic disorder : Metabolic DisordersExamination findings:

    Organomegaly (e.g. hepatomegaly)

    Cardiac disease

    Ocular involvement (e.g. cherry red spot)

    Skin manifestations

    Unusual odour

    Non-specific neurological findings

  • Neonatal and Post Neonatal Presentation

    Neonatal presentationNormal-appearing child at birth (some conditions are associated with dysmorphic features)poor feedinglethargyvomitingseizurescomaunusual odourhypoglycaemia, acidosis (in some defects) *

  • 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.

  • Newborn ScreeningPKU - in NICU even if not advanced to full feedsGalactosemiaHypothyroidismHemoglobinopathiesBiotinidase defic, CAH (21-OHase def), Maple syrup urine disease ( MSUD )

    - GUTHRIE TEST

  • Specific Tests:

    Direct biochemical assays of metabolites or their metabolic by-products, or of an enzymes function.

    DNA studies

    Neuro-radiology * PROCEDURES FOR DIAGNOSIC CONFIRMATIONNon Specific Tests:

    Blood glucose, ammonia, bicarbonate and PHPeripheral Blood smear WBC or bone marrow vacuolization , foam cells or granules.

    C.S.F. glycine , other amino acids , lactate.

  • * INBORN ERRORS OF AMINO ACID METABOLISM ASSOSIATED WITH ABNORMAL ODOR

  • Genetic:

    Establish diagnosis.

    Carrier testing.

    Pedigree analysis, risk counseling.

    Consideration of Prenatal diagnosis for pregnancies at risk.*MANAGEMENT OF IEM

  • Family counseling and support.

    Education to promote increased compliance with special form of therapy such as Protein restricted diet.

    Assessment of community resources and support groups. *PSYCHOSOCIAL , EDUCATIONAL , FAMILIAL MANAGEMENT OF IEM

  • TREATMENT OF GENETIC DISEASESModify environment, e.g., diet, drugsAvoid known environmental triggersBMTSurgical, correct or repair defect or organ transplantation

    Modify or replace defective gene product, megadose vitamin therapy or enzyme replacement

    Replace defective gene

    Correct altered DNA in defective gene

  • Galactosemia*

  • : Carbohydrates

    GalactosemiaEnzyme deficiency: Galactose-1-phosphate uridyl transferase deficiency.

    Rare . Autosomal recessive

    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. *

  • CYSTIC FIBROSIS

    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.

  • AMINO ACID DISORDERS

    Phenyl Ketonuria (PKU)

    *PhenylalanineTyrosine

    Hydroxylase

    PhenylalaninePhenyl ethylamine Phenyl pyruvic acid

  • Phenylketonuria PKU*

  • Hyperactivity, athetosis, vomiting.

    Blond.

    Seborric dermatitis or eczema skin.

    Hypertonia.

    Seizures.

    Severe mental retardation.

    Unpleasant odor of phenyl acetic acid.

    *PKU

    DIAGNOSISScreening : Guthrie Test.

    High Phenylalanine > 20 mg/dl.

    High Phenyl pyruvic acid.

    TREATMENT DIET.

    BH4 (Tetrahydrobiopterin).

    L dopa and 5- hydroxytryptophan.CLINICAL FEATURES

  • *PKU

  • Albinism*

  • HomocystinuriaElevated homocystine levels affect collagen , result in a Marfanoid habitus, ectopia lentis, mental retardation and strokes*

  • METHIONINE CYSTATHIONINE*HomocystinuriaCysathionine

    Synthatase

    DIAGNOSIS:

    High methionine and homocystine.

    TREATMENT:

    High dose of B6 and Folic Acid.Low methionine and high cystine diet,Betain (trimethylglycine)

  • Homocystinuria*

  • Amino acid disorders :Urea cycle defects and hyperammonemia All present with lethargy, seizures, ketoacidosis, neutropenia, and hyperammonemia

    Ornithine carbamyl transferase (OTC) deficiencyCarbamyl phosphate synthetase deficiencyCitrullinemiaArginosuccinic AciduriaArgininemiaTransient tyrosinemia of prematurity

  • First Steps in Metabolic Therapy for IEMReduce precursor substrate load

    Provide caloric support

    Provide fluid support

    Remove metabolites via dialysis

    Divert metabolites

    Supplement with cofactor(s)

  • 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 .

    CARNITINE METABOLISM

  • Important IEM Treatment supplements:Carnitine for elimination of Organic Acid through creation of carnitine esters. Sodium Benzoate, phenylacetate and phenylbutyrate for Hyperammonemia elimination.

  • 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

  • ORGANIC ACIDEMIADisorder

    Methyl malonic Acidemia.

    Propionic Acidemia.

    Multiple carboxylase deficiency.

    Ketothiolase deficiency .

    Enzyme

    Methyl malonyl COA mutase.

    Propionyl COA Carboxylase.

    Malfunction of all carboxylase.

    2 methylacetyl COA thiolase def.

    *

  • ORGANIC ACIDEMIA

    Clinical Features

    Vomiting, ketosis.

    Thrombocytopenia , neutropenia.

    Osteoporosis.

    Mental retardation.Treatment

    Hydration / alkali.

    Calories to catabolic state.

    Exchange transfusion.

    Low protein diet.

    *

  • ORGANIC ACIDEMIA*

  • LYSOSOMAL STORAGE DISORDERS

    Glycogen Storage Diseases

    Sphingolipidoses (Lipidoses And Mucolipidoses)

    Mucopolysaccharidoses

    *

  • *Lysosomal Storage Disease

    DiseaseEnzyme Defiency Major Accumulating MetaboliteGlycogenosisType II (Pompe disease)GlucosidaseGlycogenSphingolipidosesGM1 gangliosidoses

    GM2 gangliosidoses Tay-Sachs disease Gaucher disease Niemann-Pick disease-galactosidase

    Hexosaminidase AGlucocerebrosidaseSphingomyelinaseGM1 gangliosides, galactose-containing oligosaccharides

    GM2 gangliosideGlucocerebrosideSphingomyelinMucopolysaccharidoses MPS I H (Hurler)

    MPS II (Hunter)(X-linked recessive)-L-Iduronidase

    L-Iduronosulfate sulfataseHeparan sulfateDermatan sulfate

    Heparan sulfateDermatan sulfate

  • Glycogen Storage Diseases

  • Name

    Enzyme

    Symptoms

    Type O

    Glycogen synthetase

    Enlarged, fatty liver; hypoglycemia when fasting

    von Gierke

    (Type IA)

    Glucose-6-phosphatase

    Hepatomegaly; slowed growth; hypoglycema; hyperlipidemia

    Type IB

    G-6-P translocase

    Same as in von Gierke's disease but may be less severe; neutropenia

    Pompe

    (Type II)

    Acid maltase

    Enlarged liver and heart, muscle weakness

    Forbe (Cori)

    (Type III)

    Glycogen debrancher

    Enlarged liver or cirrhosis; low blood sugar levels; muscle damage and heart damage in some people

    Andersen

    (Type IV)

    Glycogen branching enzyme

    Cirrhosis in juvenile type; muscle damage and CHF

    McArdle's

    (Type V)

    Muscle glycogen phosphorylase

    Muscle cramps or weakness during physical activity

    Her

    (Type VI)

    Liver glycogen phosphorlyase

    Enlarged liver; often no symptoms

    Tarui

    (Type VII)

    Muscle phosphofructokinase

    Muscle cramps durin

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