Inborn Errors of Metabolism(IEM) Lecture 1

1. Inborn Errors of Metabolism(IEM)Lecture 1 SDK December 24, 2013

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” • 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. How do we can recognize “IEM” 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. Classification of IEM diseases 1 • Disorders of Carbohydrate Metabolism • Glycogen storage disease (Type 1= Von Gierke’s, Type 2- Pompe’s disease) • Disorders of amino acid metabolism • Phenylketonuria , • Maple syrup urine disease, • Glutaricacidemia type 1 • Disorders of fatty acid oxidation and mitochondrial metabolism • Disorders of organic acid metabolism – alkaptonuria • Disorders of porphyrin metabolism - acute intermittent porphyria SDK 2012

10. Classification of IEM diseases 2 • Disorders of purine or pyrimidine metabolism - Lesch-Nyhan syndrome • Disorders of steroid metabolism - congenital adrenal hyperplasia • Disorders of mitochondrial function - Kearns-Sayre syndrome • Disorders of peroxisomal function - Zellwegger’s Syndrome • X-linked Adrenoleukodystrophy • Lysosomal storage disorders - Mucopolysaccharidoses (X-linked Hunter’s, Hurler’s),Gaucherdisease,Tay-Sachs Disease SDK 2012

11. SCREEN ABLE IEM • Organic acidemia • Isovalericacidemia • HMG-CoAlyase deficiency • PropionicAcidemia • Methylmalonicacidemia and other • Urea cycle defects • Argininosuccinicaciduria and others • Amino acid disorders • Maple syrup urine disease • PKU • Homocystinuria • Carbohydrate disorders • Galactosemia SDK 2012

12. 1. Organic Acidemia • The term "organic acidemia" or "aciduria" applies to a group of disorders characterized by the excretion of non amino 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

13. Organic Acidemia • Most organic acidemias result from dysfunction of a specific step in amino acid catabolism, and are usually the result of deficient enzyme activity at that step. • The pathophysiology results from accumulation of precursors and deficiency of products of the affected pathway. SDK 2012

14. Organic Acidemia

15. Organic Acidemia

16. 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.

17. Laboratory findings • Metabolic acidosis • Hyperammonemia • Hypoglycemia • Lactic acidosis • Anemia, ± thrombocytopenia ± neutropenia • Other complication : pancreatitis, cardiomyopathy and recurrent infections. • Definite diagnosis. Urine organic acid analysis by mass spectrometry.

18. 1.1. IsovalericAcidemia • Isovalericacidemia is a disorder in which the body is unable to process certain proteins properly. • People with isovalericacidemia have inadequate levels of an enzyme isovaleryl-CoAdehydrogenase, that helps break down an amino acid called leucine. SDK 2012

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20. The IVD Gene • The IVD gene provides instructions for making enzyme isovaleryl-CoAdehydrogenase. • Cytogenetic Location: 15q14-q15 SDK 2012

21. Mutaation of the IVD gene • Mutations in the IVD gene (“isovaleryl-CoAdehydrogenase gene)causes isovalericacidemia • At least 25 mutations in the IVD gene have been identified in people with isovalericacidemia. • Some of these mutations disrupt the normal function of the enzyme, while other mutations prevent the cell from producing any functional enzyme.  SDK 2012

22. Mutaation of the IVD gene • As a result, the body is unable to break down leucine properly. • Defects in leucine processing allow several potentially harmful substances, including a compound called isovaleric acid, to build up to toxic levels in the body. • An accumulation of isovaleric acid causes people with isovalericacidemia to have a characteristic odor of sweaty feet. • The buildup of isovaleric acid and related compounds also damages the brain and nervous system, leading to poor feeding, lack of energy (lethargy) and seizures. SDK 2012

23. How do people inherit isovalericacidemia • This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. • The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. SDK 2012

24. 1.2. HMG-CoAlyase deficiency3-hydroxy-3-methylglutaryl-CoA lyase deficiency • 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (also known as HMG-CoAlyase deficiency) is an inherited disorder in which the body cannot process a particular protein building block (amino acid) called leucine. • Additionally, the disorder prevents the body from making ketones, which are used for energy during periods without food (fasting). SDK 2012

25. Signs and Symptoms • The signs and symptoms of HMG-CoAlyase deficiency usually appear within the first year of life. • The condition causes episodes of vomiting, diarrhea, dehydration, extreme tiredness (lethargy), and weak muscle tone (hypotonia). • During an episode, blood sugar levels can become dangerously low (hypoglycemia), and cause metabolic acidosis) • If untreated, the disorder can lead to breathing problems, convulsions, coma, and death. SDK 2012

26. How common is HMG-CoAlyase deficiency? • HMG-CoAlyase deficiency is a rare condition; • Most people diagnosed with this disorder have been from Saudi Arabia, Portugal and Spain. • This condition is inherited in an autosomal recessive pattern SDK 2012

27. Genes related to HMG-CoAlyasedeficiency • Mutations in the HMGCL gene cause HMG-CoAlyase deficiency. • The HMGCL gene provides instructions for making an enzyme known as 3-hydroxymethyl-3-methylglutaryl-coenzyme A lyase (HMG-CoAlyase). • This enzyme plays a critical role in breaking down of leucine, • HMG-CoAlyase also produces ketones during the breakdown of fats. • Ketones: The brain use ketones for energy when the simple sugar glucose is not available during fasting. SDK 2012

28. Location of  HMGCL gene • Cytogenetic Location: 1p36.1-p35. • The HMGCL gene is located on the short (p) arm of chromosome 1 between positions 36.1 and 35. SDK 2012

29. Consequences of Mutation • If a mutation in the HMGCL gene reduces or eliminates the activity of HMG-CoAlyase, the body is unable to process leucine or make ketones properly. • When leucine is not processed normally, a buildup of chemical byproducts called organic acids can result in metabolic acidosis. • A shortage of ketones often leads to hypoglycemia. • Metabolic acidosis and hypoglycemia will damage brain, cells. SDK 2012

30. Consequences of Mutation • An important finding is hypoglycemia without significant ketoaciduria, reflecting the significance of 3hydroxy-3-methylglutaryl-CoAlyase to the synthesis of ketone bodies. • The hypoglycemia may be due to excessive consumption of glucose in the absence of the capacity to utilize an alternate fuel such as acetoacetate. • Patients must avoid fasting, which predisposes them both to developing hypoglycemia and, • by favoring the synthesis of ketones from fatty acids, to the accumulation of 3-hydroxy-3-methylglutaric acid. • Restriction of dietary protein and fat also may have a therapeutic role. SDK 2012

31. 1.3. Propionicacidemia • Propionicacidemia is an inherited disorder in which the body is unable to process Propionic acid.  • Propionicacidemia affects about 1 in 100,000 people in the United States. • The condition appears to be more common in the Inuit population of Greenland, some Amish communities, and Saudi Arabians. SDK 2012

32. Disease characteristics • Late-onset PA includes developmental regression, chronic vomiting, protein intolerance, failure to thrive, hypotonia, and occasionally basal ganglia infarction (resulting in dystonia and choreoathetosis) and cardiomyopathy. Affected children can have an acute decompensation that resembles the neonatal presentation and is precipitated by a catabolic stress such as infection, injury, or surgery. • Isolated cardiomyopathy and arrhythmia can be observed on rare occasion in the absence of clinical metabolic decompensation or neurocognitive deficits. • The spectrum of propionicacidemia (PA) ranges from neonatal-onset to late-onset disease. • Neonatal-onset PA, the most common form, is characterized by poor feeding, vomiting, and somnolence in the first days of life in a previously healthy infant, followed by lethargy, seizures, coma, and death. • It is frequently accompanied by metabolic acidosis with anion gap, ketonuria, hypoglycemia, hyperammonemia, and cytopenias. SDK 2012

33. Genes Related to PropionicAcidemia • PA is caused by deficiency of propionyl-CoAcarboxylase (PCC), the enzyme that catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA • Two genes the PCCA and PCCB genes code for this enzyme. • Mutations in the PCCA and PCCB genes cause propionicacidemia. SDK 2012

34. Mutations in the PCCA or PCCBgene • Mutations in the PCCA or PCCB gene disrupt the function of the enzyme and prevent the normal breakdown of these molecules. • As a result, a substance called propionyl-CoA and other potentially harmful compounds can build up to toxic levels in the body. • This buildup damages the brain and nervous system, causing the serious health problems associated with propionicacidemia. SDK 2012

35. Mutations in the PCCA gene • More than 45 mutations in the PCCA gene have been identified in people with propionicacidemia.  • These mutations include changes in single DNA building blocks (nucleotides) and insertions or deletions of genetic material in the PCCA gene.  • PCCA mutations prevent the production of functional propionyl-CoAcarboxylase or reduce the enzyme's activity. • The altered or missing enzyme is unable to process certain parts of proteins and lipids properly. SDK 2012

36. Where is the PCCA gene located? • Cytogenetic Location: 13q32. • The PCCA gene is located on the long (q) arm of chromosome 13 at position 32. • The PCCA gene provides instructions for making part of an enzyme called propionyl-CoAcarboxylase, specifically, the alpha subunit of this enzyme. • Six alpha subunits come together with six beta subunits (produced from the PCCB gene) to form a functioning enzyme. • The alpha subunit also includes a region for binding to the B vitamin biotin. SDK 2012

37. PCCBpropionylCoAcarboxylase, beta polypeptide • The PCCB gene provides instructions for making part of an enzyme called propionyl-CoAcarboxylase, specifically, the beta subunit of this enzyme. • Six beta subunits come together with six alpha subunits (produced from the PCCA gene) to form a functioning enzyme. SDK 2012

38. Where is the PCCB gene located? • Cytogenetic Location: 3q21-q22 • The PCCB gene is located on the long (q) arm of chromosome 3 between positions 21 and 22. SDK 2012

39.  Mutations in the PCCB gene • More than 55 mutations in the PCCB gene have been identified in people with propionicacidemia. • These mutations include changes in single DNA building blocks (nucleotides) and insertions or deletions of genetic material in the PCCB gene. • PCCB mutations prevent the production of functional propionyl-CoAcarboxylase or reduce the enzyme's activity. The altered or missing enzyme prevents certain parts of proteins and lipids from being broken down properly. • As a result, propionyl-CoA and other potentially toxic compounds can build up to toxic levels in the body. • This buildup damages the brain and nervous system, causing the serious health problems associated with propionicacidemia. SDK 2012

40. How do people inherit propionicacidemia • This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. • The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. SDK 2012

41. 1.4. MethylmalonicAcidemia • Methylmalonicacidemia is an inherited disorder in which the body is unable to process certain proteins and fats (lipids) properly. • The effects of methylmalonicacidemia, which usually appear in early infancy, vary from mild to life-threatening. • Affected infants can experience vomiting, dehydration, weak muscle tone (hypotonia), developmental delay, excessive tiredness (lethargy), an enlarged liver (hepatomegaly), and failure to gain weight and grow at the expected rate (failure to thrive). • Long-term complications can include feeding problems, intellectual disability, chronic kidney disease, and inflammation of the pancreas (pancreatitis). • Without treatment, this disorder can lead to coma and death in some cases. SDK 2012

42. Methylmalonicacidemia • Isolated methylmalonicacidemia/aciduria is caused by complete or partial deficiency of the enzyme methylmalonyl-CoAmutase. • This condition occurs in an estimated 1 in 50,000 to 100,000 people. SDK 2012

43. Genes are Related to MethylmalonicAcidemia • Mutations in the MUT, MMAA, MMAB, MMADHC, and MCEE genes cause methylmalonicacidemia.  • About 60 percent of methylmalonicacidemia cases are caused by mutations in the MUT gene “methylmalonylCoAmutase.” • This gene provides instructions for making an enzyme called methylmalonylCoAmutase. • This enzyme works with vitamin B12 (also called cobalamin) to break down several protein building blocks (amino acids), certain lipids, and cholesterol. • Mutations in the MUT gene alter the enzyme's structure or reduce the amount of the enzyme, which prevents these molecules from being broken down properly. • As a result, a substance called methylmalonylCoA and other potentially toxic compounds can accumulate in the body's organs and tissues, causing the signs and symptoms of methylmalonicacidemia. SDK 2012

44. Where is the MUT gene located? • Cytogenetic Location: 6p12.3 • The MUT gene is located on the short (p) arm of chromosome 6 at position 12.3. SDK 2012

45. MMAA, MMAB, or MMADHC gene • Some cases of methylmalonicacidemia are caused by mutations in the MMAA, MMAB, or MMADHCgene. • Proteins produced from the MMAA, MMAB, and MMADHC genes are needed for the proper function of methylmalonylCoAmutase. • Mutations that affect proteins produced from these three genes can impair the activity of methylmalonylCoAmutase, leading to methylmalonicacidemia. SDK 2012

46. MCEE Gene • A few other cases of methylmalonicacidemia are caused by mutations in the MCEE gene. • This gene provides instructions for producing an enzyme called methylmalonylCoAepimerase. • Like methylmalonylCoAmutase, this enzyme also plays a role in the breakdown of amino acids, certain lipids, and cholesterol. • Disruption in the function of methylmalonylCoAepimerase leads to a mild form of methylmalonicacidemia. SDK 2012

47. 2. MSUD Maple syrup urine disease

48. 2. Maple syrup urine disease(MSUD) • MSUD is an inherited disorder in which the body is unable to process certain protein building blocks (amino acids) properly. • Occurs in infants within the first few days of birth • Results in mental retardation/death • The condition gets its name from the distinctive sweet odor of affected infants' urine. • The condition is characterized by poor feeding, vomiting, lack of energy (lethargy), and developmental delay. • If untreated, maple syrup urine disease can lead to seizures, coma, and death.

49. 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 • This condition is inherited in an autosomal recessive pattern,

50. What genes are affected? • Autosomal recessive • BCKDHA (chr 19) • Branched chain ketoacid dehydrogenase • BCKDHB (chr 6) • DBT (chr 1) • DLT (chr 7)