Metabolic Disorders Inborn Errors Of Metabolism

1. 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

2. 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

3. Pathophysiology • SINGLE GENE DEFECTSin synthesis or catabolism of proteins, carbohydrates, or fats. • Defect in an ENZYME or TRANSPORT PROTEIN, which results in a block in a metabolic pathway.

4. Pathophysiology • EFFECTS : - toxic ACCUMULATION of substrates before the block, - intermediates fromALTERNATIVE pathways - defects inENERGY 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.

7. Metabolic Disorders Features suggestive of metabolic disorder : From history: Parental history : Consanguineous parents Previous unexplained neonatal deaths Particular ethnic group (in certain diseases)

8. Metabolic Disorders Features suggestive of metabolic disorder : Examination findings: Organomegaly (e.g. hepatomegaly) Cardiac disease Ocular involvement (e.g. cherry red spot) Skin manifestations Unusual odour Non-specific neurological findings

9. Neonatal and Post Neonatal Presentation Neonatal presentation Normal-appearing child at birth (some conditions are associated with dysmorphic features) • poor feeding • lethargy • vomiting • seizures • coma • unusual odour • hypoglycaemia, acidosis (in some defects)

10. Neonatal and Post Neonatal Presentation Post neonatal presentation • Encephalopathy • Developmental regression • Reye syndrome • Motor deficits • Seizures • Intermittent episodes of vomiting, acidosis, • hypoglycaemia and/or coma triggered by stress e.g. infections, surgery.

11. Newborn Screening • PKU - in NICU even if not advanced to full feeds • Galactosemia • Hypothyroidism • Hemoglobinopathies • Biotinidasedefic, CAH (21-OH’ase def), • Maple syrup urine disease ( MSUD ) - GUTHRIE TEST

12. PROCEDURES FOR DIAGNOSIC CONFIRMATION Non – Specific Tests: • Blood glucose, ammonia, bicarbonate and PH • Peripheral Blood smear – WBC or bone marrow vacuolization , foam cells or granules. • C.S.F. glycine , other amino acids , lactate. Specific Tests: • Direct biochemical assays of metabolites or their metabolic by-products, or of an enzyme’s function. • DNA studies • Neuro-radiology

13. INBORN ERRORS OF AMINO ACID METABOLISM ASSOSIATED WITH ABNORMAL ODOR

25. MANAGEMENT OF IEM Genetic: Establish diagnosis. Carrier testing. Pedigree analysis, risk counseling. Consideration of Prenatal diagnosis for pregnancies at risk.

26. MANAGEMENT OF IEM PSYCHOSOCIAL , EDUCATIONAL , FAMILIAL • 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.

27. TREATMENT OF GENETIC DISEASES Modify environment, e.g., diet, drugs Avoid known environmental triggers BMT Surgical, 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

28. Galactosemia

29. :Carbohydrates Galactosemia Enzyme 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 failure • Chronic liver disease • Cataracts • Developmental delay develop if condition is untreated.

30. CYSTIC FIBROSISCause : 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.

31. AMINO ACID DISORDERS Phenylalanine Phenylalanine Tyrosine Hydroxylase Phenyl ethylamine Phenyl pyruvic acid Phenyl Ketonuria (PKU)

32. Phenylketonuria PKU

33. PKU DIAGNOSIS CLINICAL FEATURES • Screening : Guthrie Test. • High Phenylalanine > 20 mg/dl. • High Phenyl pyruvic acid. TREATMENT • DIET. • BH4 (Tetrahydrobiopterin). • L – dopa and 5- hydroxytryptophan. • Hyperactivity, athetosis, vomiting. • Blond. • Seborric dermatitis or eczema skin. • Hypertonia. • Seizures. • Severe mental retardation. • Unpleasant odor of phenyl acetic acid.

34. PKU

35. Albinism

38. Homocystinuria Elevated homocystine levels affect collagen , result in a Marfanoid habitus, ectopia lentis, mental retardation and strokes

39. Homocystinuria Cysathionine Synthatase • DIAGNOSIS: • High methionine and homocystine. • TREATMENT: • High dose of B6 and Folic Acid. • Low methionine and high cystine diet, • Betain (trimethylglycine) METHIONINECYSTATHIONINE

40. Homocystinuria

41. Amino acid disorders :Urea cycle defects and hyperammonemia All present with lethargy, seizures, ketoacidosis, neutropenia, and hyperammonemia Ornithinecarbamyltransferase (OTC) deficiency Carbamyl phosphate synthetase deficiency Citrullinemia ArginosuccinicAciduria Argininemia Transient tyrosinemia of prematurity

42. First Steps in Metabolic Therapy for IEM Reduce precursor substrate load Provide caloric support Provide fluid support Remove metabolites via dialysis Divert metabolites Supplement with cofactor(s)

43. CARNITINE METABOLISM • 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 .

44. Important IEM Treatment supplements: Carnitine for elimination of Organic Acid through creation of carnitineesters. Sodium Benzoate, phenylacetate and phenylbutyrate for Hyperammonemiaelimination.

45. Therapeutic Measures for IEM • D/C oral intake temporarily • Usually IVF’s with glucose to give 12-15 mg/kg/min glu and at least 60 kcal/kg to prevent catabolism (may worsen PDH) • Bicarb/citrateCarnitine/glycine • Na Benzoate/arginine/citrulline • Dialysis--not exchange transfusion • Vitamins--often given in cocktails after labs drawn before dx is known • Biotin, B6, B12, riboflavin, thiamine, folate

46. ORGANIC ACIDEMIA Disorder • 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.

47. ORGANIC ACIDEMIA Clinical Features Treatment • Vomiting, ketosis. • Thrombocytopenia , neutropenia. • Osteoporosis. • Mental retardation. • Hydration / alkali. • Calories to  catabolic state. • Exchange transfusion. • Low protein diet.

48. ORGANIC ACIDEMIA

49. LYSOSOMAL STORAGE DISORDERS Glycogen Storage Diseases Sphingolipidoses (Lipidoses And Mucolipidoses) Mucopolysaccharidoses

50. Lysosomal Storage Disease