Metabolic disorders 2019

Metabolic disorders

1. Metabolic Disorders Prof. Imran Iqbal Prof of Paediatrics (2003-2018) Prof of Pediatrics Emeritus, CHICH Multan, Pakistan

2. Inborn errors of metabolism A group of diseases caused by a defect in the activity of an enzyme that affect a wide variety of metabolic processes; defective processing or transport of amino acids, fatty acids, sugars or metals

3. 11 August 2019 Total slide. 132 4 Inborn Errors of Metabolism An inherited enzyme deficiency leading to the disruption of normal bodily metabolism Impaired formation of a product normally produced by the deficient enzyme Accumulation of a toxic substrate (compound acted upon by an enzyme in a chemical reaction)

4. 11 August 2019 Total slide. 132 5 What is a metabolic disease? Garrod’s hypothesis product deficiency substrate excess toxic metabolite A D B C

5. Our Genetic background Total genes 25000 in pairs Genetic disorders 7000

6. 11 August 2019 Total slide. 132 7 Genetic Basis of Inherited Disorders Point mutations, Insertions, Deletions, Missense Mutations and Rearrangements

7. 11 August 2019 Total slide. 132 8 Epidemiology and Inheritance Although each individual IEM is rare, cumulatively they occur ~ 1:5000 live births Majority of IEM follow an autosomal recessive mode of inheritance

8. 11 August 2019 Total slide. 132 9 Classification of Metabolic Diseases Small molecule disease Carbohydrate Protein Lipid Nucleic Acids Minerals Vitamins Organelle disease Lysosomes Mitochondria Peroxisomes Cytoplasm

9. Metobolic Disorders Aminoacid Metabolim Lipid Metabolism Carbohydrate Metabolism Mitochondrial Energy Metabolism Vitamin Metabolism Metal Transport Nucleic acid and Heme Metabolism Organelles – lysosomes , peroxisomes

10. Defects in Amino and Organic Acid Metabolism Defects in Carbohydrate Metabolism Errors in Fatty Acid Metabolism Defects in Cholesterol and Lipoprotein Metabolism Mucopolysaccharide and Glycolipid Disorders Defects in Nucleotide Metabolism Disorders in Metal Metabolism and Transport Porphyrias and Bilirubinemias Diseases Associated with Defective DNA Repair Metobolic Disorders

11. Categories of IEMs Disorders of protein metabolism (amino acidopathies, organic acidopathies , and urea cycle defects) Disorders of carbohydrate metabolism (eg, carbohydrate intolerance disorders , glycogen storage disorders, disorders of gluconeogenesis and glycogenolysis) Fatty acid oxidation defects Lysosomal storage disorders Mitochondrial disorders Peroxisomal disorders

12. Protein metabolism disorders Organic acidemias Aminoacidurias Urea cycle defects

13. Carbohydrate metabolism disorders Glycogen storage disease Galactosemia Fructose intolerance Glucose malabsorption

14. Fat metabolism disorders Hypertriglyceridemia Hyperlipidemia Fatty acid oxidation defects

15. Vitamin disorders Biotinidase deficiency

16. Mineral disorders Wilson disease Menkes disease Cystinosis

17. Wilson Disease (KF rings)

18. Endocrine disorders Primary congenital hypothyroidism Congenital adrenal hyperplasia

19. Hemoglobin disorders SS disease (sickle cell anemia) S, beta- thalassemia

20. Common amino acid metabolism disorders Phenylketonuria Tyrosinemia , type 1 Maple syrup urine disease Homocystinuria

21. 23 Hyperactivity, athetosis , vomiting. Blond. Seborric dermatitis or eczema skin. Hypertonia . Seizures. Severe mental retardation. Unpleasant odor of phenyl acetic acid. PKU CLINICAL FEATURES

22. 11 August 2019 Total slide. 132 24

23. 25 AMINO ACID DISORDERS Phenyl Ketonuria (PKU) Phenylalanine Tyrosine Hydroxylase Phenylalanine Phenyl ethylamine Phenyl pyruvic acid Phenyl pyruvic acid is what gives the urine its smell because its ketonic and acidic.

24. 26 Phenylketonuria PKU

25. Child with PKU – born before NBS Full expression of this genetic disease + gene mutation + environmental exposure

26. 11 August 2019 Total slide. 132 28 Defect here causes Type I Tyrosinemia Defect here causes alkaptonuria Catabolic pathway for phenylalanine and tyrosine Homogentisate dioxygenase Fumarylacetoacetate hydrolase

27. Tyrosinemia

28. 11 August 2019 Total slide. 132 30 abnormalities appear in the first month of life poor weight gain enlarged liver and spleen distended abdomen swelling of the legs increased tendency to bleeding, particularly nose bleeds Jaundice death from hepatic failure frequently occurs between three and nine months of age unless a liver transplantation is performed. Acute tyrosinemia

29. 11 August 2019 Total slide. 132 31 Normal urine Urine from patients with alkaptonuria Symptoms of alkaptonuria

30. 11 August 2019 Total slide. 132 32 Patients may display painless bluish darkening of the outer ears, nose and whites of the eyes. Longer term arthritis often occurs .

31. 11 August 2019 Total slide. 132 33 MSUD Clinical Manifestations Time Symptom/Sign 12-24 hours Maple syrup odor to cerumen Elevated BCAA 2-3 days Irritability, poor feeding Ketonuria 4-5 days Encephalopathy (lethargy, apnea, atypical movements 7-10 days Coma and respiratory failure

32. MSUD patient after liver transplant

33. 11 August 2019 Total slide. 132 35 Homocystinuria Defective activity of cystathionine synthase

34. 11 August 2019 Total slide. 132 36 Major phenotypic expression Ectopia lentis Vascular occlusive disease Malar flash Osteoporosis Accumulation of homocysteine and methionine

35. 11 August 2019 Total slide. 132 37

36. 11 August 2019 Total slide. 132 38

37. 11 August 2019 Total slide. 132 39 A family of homocystinuria

38. 11 August 2019 Total slide. 132 40 Albinism

39. 11 August 2019 Total slide. 132 41 Characteristics of albinism: Low Vision (20/50 to 20/800) Sensitivity to bright light and glare Rhythmic, involuntary eye movements Absent or decreased pigment in the skin and eye and sensitivity to sunburn that could lead to skin cancers or cataracts in later life "Slowness to see" in infancy

40. 11 August 2019 Total slide. 132 42 Characteristics of albinism: Farsighted, nearsighted, often with astigmatism Underdevelopment of the central retina Decreased pigment in the retina Inability of the eyes to work together Light colored eyes ranging from lavender to hazel, with the majority being blue

41. Cystinosis

42. Cystiene deposits in cornea

43. Organic acidemias Methylmalonic acidemia Propionic acidemia Isoveleric acidemia Glutaric acidemia 3-Methylglutaconic aciduria 2-Hydroxyglutaric aciduria

44. Urea Cycle disorders Ornithin transcarbnamylase deficiency Carbamyl phosphate synthetase deficiency Argininosuccinicaciduria Citrullinemia N-acetyl glutamate synthtase deficiency Arginase deficiency

45. Disorders of Fat Metabolism Defect in enzymes which allows transport of fatty acids into the mitochondria; specific to short-, medium- or long-chain fatty acids Fatty acids not utilized resulting in hypoglycemia, hyperammonemia , death MCADD most common Deficiencies of carnitine metabolism

46. © 2007 Thomson - Wadsworth

47. Disorders of fatty acid oxidation Carnitine uptake defect( carnitine transport defect ) Carnitine Palmitoyl Transferase I deficiency Short-chain acyl-CoA dehydrogenase deficiency Medium-chain acyl-CoA dehydrogenase deficiency Very long-chain acyl-CoA dehydrogenase deficiency Long-chain-L-3- hydroxyacyl-CoA dehydrogenase deficiency Trifunctional protein deficiency

48. Disorders of Cholestrol metabolism Hypercholestrolemia Hyperlipidemia Smith- Lemli - Opitz syndrome

49. Hypercholestrolemia

50. Disorders of carbohydrate intolerance Galactosemia Galactokinase deficiency Hereditary fructose intolerance UPD galactose epimerase deficeincy

51. Glycogenolysis (Glycogen Storage Diseases, GSD) Liver glycogen synthase deficiency (GSD 0) GSD I: von Gierke disease GSD II: Pompe disease GSD III: Cori/ Forbes disease GSD IV: Anderson disease GSD V: McArdle disease GSD VI: Hers disease GSD VII: Tarui disease Phosphorylase b kinases deficiency

52. Glycogen Storage Diseases GSD1 most commonly diagnosed Deficiency of enzyme glucose 6 phosphatase resulting in hypoglycemia Low blood glucose results in short periods of fasting (2-4 hours) Elevations in lipids, lactate, uric acid Hepatomegaly Chronic lactic acidosis, poor growth Osteoporotic bones, delayed bone age

53. Gluconeogenesis disorders Fructose 1,6-biphosphatase deficiency Pyruvate carboxylase deficiency Phosphoenolpyruvate carboxykinase deficiency Pyruvate dehydrogenase deficiency

54. Mitochondrial disorders Pyruvate carboxylase deficiency MELAS, MERRF, NARP K – S syndrome Pearson syndrome

55. Peroxisomal disorders Zellweger syndrome Adrenoleukodystrophy Hyperoxaluria type I ( alanine glyoxylate aminotransferase deficiency) Refsum disease ( phytanyoyl CoA hydroxylase deficiency )

56. 62 Hypotonia . Dysmorphia . Psychomotor delay and seizures. Hepatomegaly . Abnormal eye findings such as retinitis pigmentosa or cataract. Hearing impairment. PEROXISOMAL DISORDERS Clinical Manifestations :

57. Peroxisomal Disorders Zellweger Syndrome ( Cerebro - hepato -renal syndrome) Dysmorphic facies . Progressive degeneration of Brain/Liver/Kidney, Death ~6 mo after onset. When screening for PDs . obtain serum Very Long Chain Fatty Acids- VLCFAs

58. 64 Zellweger

59. Lipid storage disorders Mucopolysacchridosis Mucolipidosis Farber disease Fabry disease Lysosomal storage diseases

60. Farber Disease

61. Mucopolysaccharidoses (MPS) MPS I (Hurler, Hurler-Scheie, Scheie) MPS II (Hunter) MPS III (Sanfillippo) MPS IV (Morquio) MPS VII (Sly) MPS IX (Natowicz)

62. 68 Hurler’s In hurler : Nasal bridge is depressed , increase distance of philthrum , epicanthal folds, bossing of the head , thick eyebrows , upturn nostrils

63. Sphingolipidoses Gaucher disease Niemann -Pick disease Tay -Sachs Fabry disease Farber disease

64. Mucolipidosis Mucolipidoses type I ( Sialidosis ) Mucolipidoses type II (I-cell) Mucolipidoses type III (pseudo-Hurler) Mucolipidoses type V ( Sialolipidosis )

65. Thankyou