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.-In autosomal dominant disorders, the structural abnormality dominates over the chemical abnormality. -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. • 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.

6. Classification • Transient Hyperammonemia of Newborn • Inborn Errors of Metab: • Organic Acidemias • Fatty Acid Oxidation def • Urea Cycle Defects • Amino Acidurias • Non-ketotic Hyperglycinemia • Molybdenum Cofactor Deficiency • Sulfite Oxidase Deficiency • Metal Storage Disorders: • Cholesterol Disorders: • Leukodystrophies, other… • Krabbe disease • Mitochondrial Disorders • Glycogen Storage Disorders • Hyperinsulinism • Carbohydrate Disorders • Lysosomal Disorders • Mucopolysaccharidoses (X-linked Hunter’s, Hurler’s) • Gaucher disease • Tay-Sachs Disease • Peroxisomal Disorders • Zellwegger’s (Cerebro-Hepato-renal) • X-linked Adrenoleukodystrophy

7. Metabolic Disorders Due 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.

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

9. Metabolic Disorders Features suggestive of metabolic disorder : Examination findings: Organomegaly (e.g. hepatomegaly) in the absence of viral infection. Cardiac disease Ocular involvement (e.g. cherry red spot) Skin manifestations e.g. pigmentations. Unusual odour. Due to change in the chemicals of the urine. Non-specific neurological findings. In a non-meningitis child you have to think of metabolic disorders.

10. 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 is very dangerous, acidosis (in some defects)

11. Neonatal and Post Neonatal Presentation Post neonatal presentation • Encephalopathy without the presence of infection. • Developmental regression • Reye syndrome ( damage of the brain and liver eventually leading to encephalopathy). • Motor deficits • Seizures • Intermittent episodes of vomiting, acidosis, • hypoglycaemia and/or coma triggered by stress e.g. infections, surgery.

12. Newborn Screeningthe earlier its detected the fewer the complications • PKU - in NICU even if not advanced to full feeds • Galactosemia • Hypothyroidism • Hemoglobinopathies • Biotinidase defic, CAH (21-OH’ase def), • Maple syrup urine disease ( MSUD ) - GUTHRIE TEST: it’s a cheap test that requires only one drop of blood to check for multiple metabolic disorders. – MCQ اقراء عنه

13. 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. Amino acids shouldn’t be present in the CSF if its there it indicates a metabolic disorder. Bone marrow transplantation is a treatment of both inborn errors of metabolism Specific Tests: Direct biochemical assays of metabolites or their metabolic by-products, or of an enzyme’s function. DNA studies Neuro-radiology

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

16. They may come with flattened mid-face, indistinct philtrum, low nasal bridge and single palmar crease. Small chin is called micrognathia

18. Low-set ears: >1/3rd of the ears lower than the line connecting the 2 pupils. Low nasal bridge: common sign, which is also seen in Down.

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

20. 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.

21. 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

22. اولا : Galactosemia Examples of some metabolic disorders :

23. :Carbohydrates Galactosemia Enzyme deficiency: Galactose-1-phosphate uridyl transferase deficiency. It is a rare autosomal recessive. • Follows feeding with lactose containing (breast milk / formula) • Patient feeds poorly , have vomiting, jaundice, hepatomegaly and hepatic failure • Chronic liver disease • Cataracts • Developmental delay develop if condition is untreated., if they were given galactose free diet you will avoid the social and mental damage but they might complain of dyslexia.

24. ثانيا : CYSTIC FIBROSISexocrine disorder مهمه 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. It is diagnosed by sweat test: measuring the chloride concentration in the sweat

25. AMINO ACID DISORDERS Phenylalanine Phenylalanine Tyrosine Hydroxylase Phenyl ethylamine Phenyl pyruvic acid Phenyl pyruvic acid is what gives the urine its smell because its ketonic and acidic. ثالثا : Phenyl Ketonuria (PKU)

26. Phenylketonuria PKU • Remember : phenylalanine is an essential protein . • Phenyl ethylamine + phenylpyrunivic acid give the child bad smell and it toxic to the brain • babies with this condition present with melanin deficiency

27. 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.

28. PKU

29. رابعا : Albinism

30. Iris had fibrous tissue, and it’s colourless and is red due to vessels.

31. خامسا: Congenital adrenal hyperplasia • Congenital adrenal hyperplasia (CAH) refers to any of several autosomalrecessivediseases resulting from mutations of genes forenzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands (steroidogenesis).[1] • Most of these conditions involve excessive or deficient production of sex steroids and can alter development of primary or secondary sex characteristics in some affected infants, children, or adults. • Etiology : 21-hydroxylase deficiency MCQ

32. cont • Screening : • Currently, in the United States and over 40 other countries, every child born is screened for CAH at birth. This test will detect elevated levels of 17-hydroxy-progesterone (17-OHP). Detecting high levels of 17-OHP enables early detection of CAH. Newborns detected early enough can be placed on medication and live a relatively normal life.

33. cont • Treatment of all forms of CAH may include any of: • supplying enough glucocorticoid to reduce hyperplasia and overproduction of androgens or mineralocorticoids • providing replacement mineralocorticoid and extra salt if the person is deficient • providing replacement testosterone or estrogen at puberty if the person is deficient • additional treatments to optimize growth by delaying puberty or delaying bone maturation

34. سادسا : Homocystinuria Elevated homocystine levels affect collagen , result in a Marfanoid habitus, ectopia lentis but lens dislocation in homocystinemia is downward unlike in marfan its upward, mental retardation and strokes, its harmful to the bones and body. Araachnodyctly. Pt will have Lens abnormalities مهمه

35. 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

36. Homocystinuria

37. Amino acid disorders :سابعا : Urea cycle defects and hyperammonemia All present with lethargy, seizures, ketoacidosis, neutropenia, and hyperammonemia Ornithine carbamyl transferase (OTC) deficiency Carbamyl phosphate synthetase deficiency Citrullinemia Arginosuccinic Aciduria Argininemia Transient tyrosinemia of prematurity

38. 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)

39. 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 pyruvate dehydrogenase deficiency) • 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

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

41. ثامنا : 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 . • Carnitine is an endogenous metabolite but can be given as supplementations.

42. CARNITINE METABOLISM • Primary defects of carnitine transport manifest as Reye syndrome , cardiomyopathy or skeletal myopathy with hypotonia • Secondary carnitine deficiency is due to diet ( esp. I.V alimentation or ketogenic diet ) , renal losses , drug therapy ( esp. valproic acid) and other metabolic disorders ( esp. disorders of fatty acid oxidation and organic acidemias ) • Prognosis depends on the cause of the carnitine abnormality. • Free and esterified carnitine can be measured in blood. • Oral or I.V. L-carnitine is used in carnitine deficiency or lnsufficiency in doses of 25-100mg/kgm/day or higher.

43. 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.

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

45. ORGANIC ACIDEMIA

46. تاسعا : LYSOSOMAL STORAGE DISORDERS 1- Glycogen Storage Diseases 2- Sphingolipidoses common in eastern jews (Lipidoses And Mucolipidoses)  common in Ashkenazi Jews مهمه Pt present with cherry red spot in the eye + atrophic dick 3- Mucopolysaccharidoses

47. Lysosomal Storage Disease

48. Glycogen Storage Diseases

50. Principle Groups of Glycogen Storage Diseases