inborn errors of metabolism(iem) lecture 1
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Inborn Errors of Metabolism(IEM) Lecture 1. SDK December 18 2012. 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. Inborn Errors of Metabolism. - PowerPoint PPT PresentationTRANSCRIPT
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