Inborn Errors of Metabolism(IEM) Lecture 1 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

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. 3SDK 2012 Inborn Errors of Metabolism

 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 4SDK 2012

Common Presentation of “IEM” Diseases  Acute life threatening illness  Encephalopathy - Lethargy, Irritability, Coma  Vomiting  Respiratory Distress  Seizures, Hypertonia/ hypotonia  Hepatomegaly (enlarged liver)  Hepatic dysfunction / jaundice  Odour, Failure to thrive  Hiccoughs  Mental retardation, Macro/Microcephaly.  Coarse facial features/dysmorphia.  Developmental regression.  Myopathy / Cardiomyopathy. 5SDK 2012

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 tests  Glucose, Electrolytes, BUN (blood urea nitrogen), Creatinine – Lactate, Ammonia, Bilirubin, LFT – Amino acids, Organic acids, Reducing subst. 6SDK 2012

IEM associated with abnormal Urine odor Urine OdorInborn Error of Metabolism Sweaty feetGultaric Academia Maple syrupMaple Syrup urine disease Boiled cabbageHyper-methioninemia Mousy or mustyPhenylketonuria Rotten fishTrimethyl 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

SDK 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 Disorders 4.1. 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.

Metabolism of PA SDK

 Hyperactivity, athetosis, vomiting.  Blond.  Seborric dermatitis or eczema skin.  Hypertonia.  Seizures.  Severe mental retardation.  Unpleasant odor of phenyl acetic acid Clinical features of PKU

4.2. Alkaptonuria SDK

4.3. Albinism SDK

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 SDK

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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

Thank You SDK