metabolic disorders inborn errors of metabolism
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DESCRIPTIONMetabolic 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
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
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.
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.
Parental history :
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)
Ocular involvement (e.g. cherry red spot)
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
Direct biochemical assays of metabolites or their metabolic by-products, or of an enzymes function.
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
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
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. *
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)
PhenylalaninePhenyl ethylamine Phenyl pyruvic acid
Hyperactivity, athetosis, vomiting.
Seborric dermatitis or eczema skin.
Severe mental retardation.
Unpleasant odor of phenyl acetic acid.
DIAGNOSISScreening : Guthrie Test.
High Phenylalanine > 20 mg/dl.
High Phenyl pyruvic acid.
L dopa and 5- hydroxytryptophan.CLINICAL FEATURES
HomocystinuriaElevated homocystine levels affect collagen , result in a Marfanoid habitus, ectopia lentis, mental retardation and strokes*
High methionine and homocystine.
High dose of B6 and Folic Acid.Low methionine and high cystine diet,Betain (trimethylglycine)
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
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 .
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
Methyl malonic Acidemia.
Multiple carboxylase deficiency.
Ketothiolase deficiency .
Methyl malonyl COA mutase.
Propionyl COA Carboxylase.
Malfunction of all carboxylase.
2 methylacetyl COA thiolase def.
Thrombocytopenia , neutropenia.
Hydration / alkali.
Calories to catabolic state.
Low protein diet.
LYSOSOMAL STORAGE DISORDERS
Glycogen Storage Diseases
Sphingolipidoses (Lipidoses And Mucolipidoses)
*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
Enlarged, fatty liver; hypoglycemia when fasting
Hepatomegaly; slowed growth; hypoglycema; hyperlipidemia
Same as in von Gierke's disease but may be less severe; neutropenia
Enlarged liver and heart, muscle weakness
Enlarged liver or cirrhosis; low blood sugar levels; muscle damage and heart damage in some people
Glycogen branching enzyme
Cirrhosis in juvenile type; muscle damage and CHF
Muscle glycogen phosphorylase
Muscle cramps or weakness during physical activity
Liver glycogen phosphorlyase
Enlarged liver; often no symptoms
Muscle cramps durin