Inborn Errors of Metabolism(IEM)Lecture 2

SDK

December 18 2012

SDK 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

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

SDK 2012 5

• 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

1.2. 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

Type II= (Pompe Disease)

Glucosidase/Acid Maltase

Glycogen D- glucose 1-phosphate

SDK 2012 8

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.

1.3. 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)

SDK 2012 10

• 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.

2. Mucopolysaccharidosis (MPS)

SDK 2012 11

• 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.

2.1.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.

SDK 2012 17

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:– GM2 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 GM2 can be metabolized

3.6 Fabry DiseaseX-linked inborn error of metabolismDeficient -Galactosidase A (-GAL A) enzyme

activityProgressive globo-triasyl-ceramide (GL-3)

accumulation– multiple cell types and tissues -- end organ impairment

Cardiac complicationsStrokeRenal failureDecreased 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”

SDK 2012 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 peroxisomal

intergrity.

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

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.

4.5.X-linked Adrenoleukodystrophy

Hypotonia. Dysmorphia. Psychomotor delay and seizures. Hepatomegaly. Abnormal eye findings such as retinitis pigmentosa

or cataract. Hearing impairment.

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.

Treatment1. 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

SDK 2012 37

Thank You