Inborn Errors of Metabolism(IEM)Lecture 1

SDK

December 18 2012

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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

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• Is a large group of hereditary biochemical diseases in which specific gene mutation cause abnormal or missing proteins that lead to alter function.

• Class of congenital disorders caused by an inherited defect in a single specific enzyme that results in a disturbance or abnormality in a specific metabolic pathway.

• Inborn errors of metabolism are now often referred to as – Congenital metabolic diseases or– Inherited metabolic diseases.

Inborn Errors of Metabolism

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Accumulation of substances which are toxic or obstruct with normal function

The effects of reduced ability to synthesize essential compounds.It leads to organ dysfunction ( brain, liver, muscle, eye, bone

etc ) and damage and if left untreated

Problems arise due to

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Common Presentation of “IEM” Diseases Acute life threatening illness

Encephalopathy - Lethargy, Irritability, ComaVomitingRespiratory DistressSeizures, Hypertonia/ hypotoniaHepatomegaly (enlarged liver)Hepatic dysfunction / jaundiceOdour, Failure to thriveHiccoughs

Mental retardation, Macro/Microcephaly. Coarse facial features/dysmorphia. Developmental regression. Myopathy / Cardiomyopathy.

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How do we can recognize “IEM”

Index of suspicion Any full-term infant who has no

Antecedent maternal fever or PROM (premature rupture of the membranes)

and who is sick enough to need a blood culture or LP, one should think for other possibilities and proceed with a few simple lab tests.

Simple laboratory testsGlucose, Electrolytes, BUN (blood urea nitrogen), Creatinine– Lactate, Ammonia, Bilirubin, LFT– Amino acids, Organic acids, Reducing subst.

IEM associated with abnormal Urine odor

Urine Odor Inborn Error of Metabolism

Sweaty feet Gultaric Academia

Maple syrup Maple Syrup urine disease

Boiled cabbage Hyper-methioninemia

Mousy or musty Phenylketonuria

Rotten fish Trimethyl aminuria

IEM are usually Autosomal recessive. Consanguinity is always relatively common. Some are X-linked recessive condition including

Adrenoleukodystrophy Agammaglobulinemia Fabry’s disease Granulomatous disease Hunter’s Syndrome Lesch – Nyhan Syndrome Menke’s Syndrome

A few inherited as Autosomal dominant trait including: Porphyria, Hyperlipedemia Hereditary angioedema

Genetic Characteristic & Mode of Inheritance

Classification of diseases due to IEM

• Small molecule disease– Carbohydrate– Amino acid /Protein– Lipid– Nucleic Acids

• Organelle disease– Lysosomes–Mitochondria– Peroxisomes– Cytoplasm

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Screen able IEM

• Organic acidemia– Propionic Acidemia – Methylmalonic acidemia

• Urea cycle defects– Argininosuccinic aciduria and others

• Amino acid disorders– Maple syrup urine disease– PKU – Homocystinuria

• Carbohydrate disorders– Galactosemia

1. Organic Acidemia

• The term "organic acidemia" or "aciduria" applies to a group

of disorders characterized by the excretion of organic acids

in urine.

Organic refer to amino acids and certain odd-chained fatty acids.

•  Well at birth and for the first few days of life.

• Toxic encephalopathy.

• All are autosomal recessive, the commonest MMA, MSUD

Organic Acidemia

Disorder Distinctive features

Propionic acidemia Ketosis, acidosis, hyperammonemia neutropenia

Isovaleric acidemia Sweaty feet odor, acidosis

Methylmalonic acidemia Ketosis, acidosis, hyperammonemia neutropenia

HMG-CoA lyase deficiency Reye syndrome, acidosis hyperammonemia, hypoglycemia, no

ketosis

Ketothiolase deficiency Acidosis, ketosis, hypoglycemia

Glutaric acidemia type I No acidosis; basal ganglia injury with movement disorder

• Signs of Toxic encephalopathy includes :

– Vomiting, poor feeding, neurologic symptoms such as

seizures and abnormal tone, and lethargy progressing to

coma.

– May attributed to sepsis or neonatal asphyxia.

Clinical presentations Organic Acidemia,

• Metabolic acidosis

• Hyperammonemia

• Hypoglycemia

• Lactic acidosis

• Anemia, ± thrombocytopenia ± neutropenia

• Definite diagnosis. Urine organic acid analysis by mass

spectrometry.

Laboratory findings

2. Maple syrup urine disease

• Inherited disease• Occurs in infants within the first few days of

birth• Results in mental retardation/death

2. Maple syrup urine disease(MSUD)

MSUD

• Urine has “burning sugar/maple syrup” odor• Symptoms

– Vomiting, dehydration, lethargy, seizures, pancreatitis

• Unable to process amino acids– Leucine, isoleucine, valine– Products build up, as well as their toxic by-products in blood

and urine

-If untreated, will lead to death, coma, neurological decline

What genes are affected?

• Autosomal recessive• deficiency of BCKDHA

(chr 19) – Branched chain ketoacid

Dehydrogenase

• causes hyperammonemia but without acidosis

• Others causes of hyperammonemia without acidosis:

liver impairment Generalized Infections

3. Urea Cycle Defects.

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Disorder Distinctive features

Carbamoyl phosphate synthetase I (CPS I) deficiency

Variable presentation

Ornithine transcarbamoylase (OTC) deficiency X-linked dominant disorder

Argininosuccinate synthase deficiency Variable presentation

Argininosuccinate lyase deficiency Elevated LFT & hepatomegaly

Arginase deficiency MR-DD, progressive spastic diplegia, choreoathetotic

Clinical Findings in Urea Cycle Defects

Argininosuccinate lyase deficiency (ASA)

• Initial clinical presentation, Sepsis-like features CNS depression ( i.e. decreased feeding, lethargy, apnea, seizure, coma) – Hyperammonemia ( recurrent)– No acidosis or hypoglycemia– Hepatomegaly

4. Amino Acid Disorders4.1. Phenylketonuria

• Autosomal Recessive Disorder.• Inherited error of metabolism caused by

deficiency in the enzyme phenylalanine hydroxylase (PAH).–Mutation in both alleles of the gene for the enzyme.– Chromosome 12.– Recessive allele carried by 1 out of every 60

individuals.

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Metabolism of PA

Hyperactivity, athetosis, vomiting.

Blond.

Seborric dermatitis or eczema skin.

Hypertonia.

Seizures.

Severe mental retardation.

Unpleasant odor of phenyl acetic acid

Clinical features of PKU

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4.2. Alkaptonuria

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4.3. Albinism

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4.4 Homocystinuria

homocysteine is an intermediate in the metabolism of methionine to cysteine but can also be used to reform methionine.

homocystine is formed by joining 2 homocysteines

homocysteine is linked to both folate and vitamin B12 metabolism

excessive accumulation of homocystine leads to homocystinuria and is caused by decreased metabolism of homocysteine through either its link to

folate Metabolism or through its link to cysteine formation

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Homocystinuria (CBS def)

• Mental retardation

• Ectopia lentis

• Skeletal abnormalities

• Thromboembolism

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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Thank You