Inborn Errors of Metabolism(IEM) Lecture 2

1. Inborn Errors of Metabolism(IEM)Lecture 2 SDK December 18 2012

2. Objectives • Define Inborn error of metabolism • Identify the most common errors • Explains the mechanism of Inborn error of metabolism. • Explain the dietary plan for IEM SDK 2012

3. 1.Metabolic Storage Disorders SDK 2012

4. 1.1. Types of Metabolic Storage Disorders • Glycogen storage diseases (GSD) • Mucopolysaccharidosis (MPS) • Lysosomal storage diseases or lipidosis (LSD) • Peroxisomal diseases

5. 1.2. Glycogen storage diseases • These are inherited metabolic disorders that are characterized by deposition of abnormal quantities or types of glycogen. • There are 8 types of glycogen storage diseases SDK 2012

6. Type I (VonGierke's Disease): • Defective enzyme: glucose 6-phosphatase. • Organ affected: liver and kidney. • Glycogen in the affected organ: increased amount, normal structure. • Clinical features: massive enlargement of the liver. Failure to thrive. Sever hypoglycemia, ketosis, hyperuricemia, hyperlipidemia. • The blood glucose level does not increase on administration of epinephrine or glucagon SDK 2012

7. Glucosidase/Acid Maltase Type II= (Pompe Disease) Glycogen D- glucose 1-phosphate

8. 1.3. Galactosemia • Galactosemia is an inherited an autosomal- recessive disorder • deficiency in enzyme (galactose-1-phosphate uridyl transferase) that metabolize galactose • Galactosemia = high level of plasma galactose. SDK 2012

9. Blood tests Enzyme activity in RBCs (Normal range for Galactose-1-phosphate uridyltransferase activity is18.5 to 28.5 U/g Hb). Low blood sugar (hypoglycemia) Urine analysis Reducing substances accumulation (i.e. Galactose & Galactose-1-P) 1.4. Diagnosis & Treatment • Treatment • No pharmacological treatment is currently available • Sources of galactose (especially lactose) must be eliminated from the diet • All dairy products (chesses, yoghurt, ice cream), breast milk, infant formulas, sweeteners • Foods with > 10mg galactose/100g fresh weight must be avoided; dates, papaya, tomatoes, watermelon • Calcium and vitamin supplementation (vitamin D)

10. 2. Mucopolysaccharidosis (MPS) • Are inheritable storage diseases caused by a deficiency of lysosomal enzymes that degrade glycosaminoglycans (GAGs, previously called mucopolysaccharides such as dermatan sulfate, heparan sulfate and keratan sulfate . The MPSs are characterized by the • Intra lysosomal accumulation of GAGs, • Excessive urinary excretion of GAGs, • Variable degrees of progressive mental and physical deterioration • In severe forms, premature death. SDK 2012

11. 2.1.Mucopolysaccharidosis (MPS) • Types • Seven types Depending on the enzyme deficiency, the metabolism of • Dermatan sulfate, • Heparan sulfate, or • Keratan sulfate may be blocked alone or in combination. • Lysosomal accumulation of the GAGs eventually results in cell, vascular, tissue, and organ dysfunction. SDK 2012

12. Symptoms & signs Developmental delay. Behavioral dysfunction Coarse facial features Cloudy cornea Abdominal distension (Hepato-splenomegaly) Dysostosis multiplex (Scoliosis and gibbous deformity) Diagnosis Urine for MPS ( Heparan , Keratan , Dermatan) enzyme assay 2.2. Symptoms & signs (MPS)

13. Deficiency of iduronidase Accumulation of Dermatan sulfate and heparan sulfate Autosomal Recessive Clinical signs Developmental delay Coarse facial features & other somatic features(large tongue, prominent forehead, Cloudy cornea Hepatosplenomegaly joint stiffness, Hearing loss Hydrocephalus Kyphosis Diagnosis α-Iduronidase deficiency death before 10 yr of age 2.3. Type 1-Hurler syndrome(MPS-I)

14. 2.4. Type II-Hunters Syndrome • Deficiency of Iduronatesulfatase • Accumulation of Dermatan sulfate and heparan sulfate. • onset of disease usually between 2–4 yr of age • Death usually occurs between 10–15 yr of age • X-Linked recessive • Patients with the severe form of MPS II have major deletions or rearrangements of the IDS gene present o Xq28.

15. 2.5. Type IV- Morquio • Deficiency of Galactose-6-sulfatase. • Gene is on chromosome 16q24.3 • Autosomal recessive • Accumulation of Keratan sulfate Characterized • By significant, short-trunk dwarfism, • Fine corneal deposits, • A skeletal dysplasia that is distinct from other mucopolysaccharidoses, • Preservation of intelligence.

16. 3. Lysosomal Storage Diseases or Lipidosis • Lipid storage diseases (Lipidoses) are a group of diseases that arise from a deficiency of a specific lysosomalhydrolase with a resulting accumulation of the enzyme’s specific substrate. • Clinical symptoms of these disorders are mainly from accumulation of the substrates in various body organ-systems. • All are inherited in autosomal recessive fashion except for the X- linked Fabry’s disease.

17. SDK 2012

19. 3.1..Tay-Sachs Disease • Tay-Sachs Disease is rare autosomal recessive genetic disorder . • Genetic mutation on chromosome 15 • Lipid storage disorder that results from deficiency in -hexosaminidase A & Accumulation of GM2 in nerve cells of the brain • Different names are: • GM2gangliosidosis • Hexosaminidase A deficiency • Sphingolipidosis

20. 3.2.Tay-Sachs Disease

21. 3.3.Tay-Sachs Disease The accumulation of GM2 is toxic The lack of metabolism will cause the build up of GM2 The build up of GM2 causes the cell to burst [cell death]

22. 3.4. Symptoms • Loss of hearing • Physical and mental retardation • Seizures • Dementia • And most noticeably detected by the red dots it causes on the retina of an individuals eye

23. 3.5. Treatments • Enzyme replacement therapy • Replace with synthetic enzyme • Gene therapy • Replace defective genes • Substrate reduction therapy • Bypass the defect so GM2 can be metabolized

24. 3.6 FabryDisease • X-linked inborn error of metabolism • Deficient -Galactosidase A (-GAL A) enzyme activity • Progressive globo-triasyl-ceramide(GL-3) accumulation • multiple cell types and tissues -- end organ impairment • Cardiac complications • Stroke • Renal failure • Decreased lifespan

25. 3.7. Other Signs/Symptoms • Fatigue •  Growth, delayed puberty • Impaired fertility • Changes in joints and bones • Corneal opacity • Chronic bronchitis • Impaired social functioning & Depression •  Quality of life • Multiple variants of Acroparesthesia (pain in hands and feet)

26. 3.8.Skin Manifestations • Hypohidrosis or anhidrosis (decreased or no sweating) • Heat and cold intolerance • Angio-keratomas (reddish, purplish skin lesions ) caused by endothelial cells deposition with Globotrioasylceramide(GL-3)

27. 3.9.Diagnosis &Treatment of Fabry Disease • Provisional diagnosis • observation of symptoms and laboratory findings • family history/medical pedigree • Definitive diagnosis • enzyme assay in plasma, leukocytes, tears, or biopsied tissue • gene mutation analysis or linkage analysis Treatment: Enzyme replacement therapy

28. 4. Peroxisomal Disorder • Peroxisomal disorders are a group of genetically heterogeneous metabolic diseases that share dysfunction of peroxisomes. • Peroxisomes are cellular organelles that are an integral part of the metabolic pathway. • They participate in important peroxisome-specific metabolic pathways, such as beta-oxidation of very-long-chain fatty acids (VLCFA) and detoxification of hydrogen peroxide. • Peroxisomes are also involved in the production of cholesterol, bile acids,platelet activating factor [PAF] and plasmalogens, which contribute to a big part of the phospholipid content of the brain white matter.

29. 4.1. PeroxisomalDiseases Adrenoleukodystrophy: Deficiency in -oxidation of very long- chain fatty acids Zellweger syndrome: Defect in protein import, giving rise to “ghost peroxisomes”

30. 4.2.Zellweger syndrome • Cerebro-hepato-renal syndrome of Zellweger (Zellweger syndrome) is a peroxisomal disease that is biochemically characterized by abnormal accumulation of very long chain fatty acid. • most severe form of peroxisomal disorder due to errors in peroxisomal biogenesis or defects in maintaining peroxisomalintergrity. SDK 2012

31. 4.3.Genetics of Zellweger syndrome • Autosomal recessive. • There are at least 10, probably more, different human genes involved in peroxisome assembly. • Mutation of peroxisomal membrane protein-1 (PXMP1) on chromosome 1p22-21 and peroxisomal assembly factor-1 (PAF1) on chromosome 8q21.1 have been identified in patients with Zellweger syndrome. SDK 2012

32. 4.4. Genetics of X-linked Adrenoleukodystrophy • X-linked adrenoleukodystrophy is a peroxisomal disease with combined involvement of the CNS and the adrenal glands. • Characterized by lipid accumulation in the adrenal gland and testicular interstitial glands and inflammatory demyelinating lesions in the brain. • The ability to form coenzyme A derivatives of very long chain fatty acids (chain length over 22 carbon) is reduced. This lead to wide spread accumulation of very long chain fatty acid. SDK 2012

33. 4.5.X-linked Adrenoleukodystrophy • ALD gene is located on chromsome Xq28 that encodes an ATP-binding transpoter. • Mutations: A large number of mutations have been found, about half (54%)of them are missense mutations, • Half of the remaining half (25%) are frameshift mutation, the rest are nonsense (10%) and large deletions (7%). • A mutation hotspot is identified on exon 5. • ALD-protein: ALD gene expression is highest in adrenal glands, intermediate in brain, and almost undectable in liver. • ALDP is highly expressed in microglia, astrocytes, and endothelial cells; oligodendrocytes have little to none. SDK 2012

34. 4.6. Clinical Manifestations: Peroxisomal Disorder • Hypotonia. • Dysmorphia. • Psychomotor delay and seizures. • Hepatomegaly. • Abnormal eye findings such as retinitis pigmentosa or cataract. • Hearing impairment.

35. 4.7.Diagnosis & Treatment • Immunochemical studies for Peroxisomes. • Measures the level of very long chain fatty acids in plasma=  VLCFA level. • C.V.S. or/ aminocytes culture   Plasmalogens synthesis. Treatment • Supportive, multidisciplinary interventions. • Diet:  VLCFA,  phytanic acid (branched chain fatty acid present in dairy products) • Organ transplantation.

36. Summary • Inborn errors of metabolism (IEMs) individually are rare but collectively are common. Presentation can occur at any time, even in adulthood. • Diagnosis does not require extensive knowledge of biochemical pathways or individual metabolic diseases. • An understanding of the broad clinical manifestations of IEMs provides the basis for knowing when to consider the diagnosis. • Most important in making the diagnosis is a high index of suspicion. • Successful emergency treatment depends on prompt institution of therapy aimed at metabolic stabilization.

37. Thank You SDK 2012