Inborn Errors of Metabolism(IEM) Lecture 2 SDK December SDK December

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 20122

3 1.Metabolic Storage Disorders

1.1. Types of Metabolic Storage Disorders 1.Glycogen storage diseases (GSD) 2.Mucopolysaccharidosis (MPS) 3.Lysosomal storage diseases or lipidosis (LSD) 4.Peroxisomal 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 5SDK Glycogen storage diseases

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 6SDK 2012

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

 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 Galactosemia

1.4. Diagnosis & Treatment Blood tests – Enzyme activity in RBCs ( Normal range for Galactose-1-phosphate uridyl transferase activity is18.5 to 28.5 U/g Hb). – Low blood sugar (hypoglycemia) Urine analysis – Reducing substances accumulation (i.e. Galactose & Galactose-1-P) 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) 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)

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 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 Mucopolysaccharidosis (MPS)

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)

 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)

2.4. Type II-Hunters Syndrome  Deficiency of Iduronate sulfatase  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.

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.

3. Lysosomal Storage Diseases or Lipidosis  Lipid storage diseases (Lipidoses) are a group of diseases that arise from a deficiency of a specific lysosomal hydrolase 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.

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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: – G M2 gangliosidosis – Hexosaminidase A deficiency – Sphingolipidosis

3.2.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] 3.3.Tay-Sachs Disease

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

3.5. Treatments  Enzyme replacement therapy  Replace with synthetic enzyme  Gene therapy  Replace defective genes  Substrate reduction therapy  Bypass the defect so G M2 can be metabolized

3.6 Fabry Disease  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

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)

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 Globo trioasylceramide(GL-3)

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

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. 4. Peroxisomal Disorder

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

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 peroxisomal intergrity. SDK

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

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

 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 X-linked Adrenoleukodystrophy

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

 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 1.Supportive, multidisciplinary interventions. 2.Diet:  VLCFA,  phytanic acid (branched chain fatty acid present in dairy products) 3.Organ transplantation. 4.7.Diagnosis & Treatment

 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. Summary

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