Inborn Errors of Metabolism(IEM) Lecture 1

1. Inborn Errors of Metabolism(IEM)Lecture 1 SDK December 18 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. Inborn Errors of Metabolism • 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. SDK 2012

4. Problems arise due to • 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 SDK 2012

5. 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. SDK 2012

6. 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. SDK 2012

7. IEM associated with abnormal Urine odor

8. Genetic Characteristic & Mode of Inheritance • 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

9. Small molecule disease Carbohydrate Amino acid /Protein Lipid Nucleic Acids Organelle disease Lysosomes Mitochondria Peroxisomes Cytoplasm Classification of diseases due to IEM

10. Screen able IEM • Organic acidemia • PropionicAcidemia • Methylmalonicacidemia • Urea cycle defects • Argininosuccinicaciduria and others • Amino acid disorders • Maple syrup urine disease • PKU • Homocystinuria • Carbohydrate disorders • Galactosemia SDK 2012

11. 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

12. Organic Acidemia

13. Clinical presentationsOrganic Acidemia, • 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.

14. Laboratory findings • Metabolic acidosis • Hyperammonemia • Hypoglycemia • Lactic acidosis • Anemia, ± thrombocytopenia ± neutropenia • Definite diagnosis. Urine organic acid analysis by mass spectrometry.

15. 2. Maple syrup urine disease

16. 2. Maple syrup urine disease(MSUD) • Inherited disease • Occurs in infants within the first few days of birth • Results in mental retardation/death

17. 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

18. What genes are affected? • Autosomal recessive • deficiency of BCKDHA (chr 19) • Branched chain ketoacid Dehydrogenase

19. 3. Urea Cycle Defects. • causes hyperammonemia but without acidosis • Others causes of hyperammonemia without acidosis: • liver impairment • Generalized Infections

20. SDK 2012

21. Clinical Findings in Urea Cycle Defects

22. Argininosuccinatelyase 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

23. 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.

24. Metabolism of PA SDK 2012

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

26. 4.2. Alkaptonuria SDK 2012

27. 4.3. Albinism SDK 2012

28. 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 2012

29. SDK 2012

30. Homocystinuria (CBS def) • Mental retardation • Ectopialentis • Skeletal abnormalities • Thromboembolism

31. Summary • 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.

32. Thank You SDK 2012