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Organic Acidemias Didactic Bb Day1 3 Jh


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Day 1, Third Lecture

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Organic Acidemias Didactic Bb Day1 3 Jh

  1. 1. Organic Acidemias Barbara K. Burton, MD Northwestern University Feinberg School of Medicine, Chicago, IL
  2. 2. Definition <ul><li>Group of disorders characterized by excretion of excess of non-amino organic acids in urine </li></ul><ul><li>Defects in amino acid metabolism distal to removal of the amino group and separated from the amino acid by a non-reversible reaction </li></ul><ul><li>Organic acids are low molecular weight substances </li></ul><ul><li>They have at least one carboxylic group and may have keto or hydroxy-groups (so water soluble compounds) </li></ul><ul><li>Their polar character enables rapid urinary excretion </li></ul>
  3. 3. <ul><li>“ Classic or typical” presentation: acute overwhelming illness; recurrent metabolic crises </li></ul><ul><li>Developmental delay with or without seizures </li></ul><ul><li>Static or progressive dystonia or choreoathetosis in early childhood </li></ul><ul><li>Abnormal odor of body or body fluids </li></ul>Clinical presentations of organic acidemias
  4. 4. <ul><li>What do the symptoms represent? - they represent a toxic encephalopathy </li></ul><ul><li>What are the typical symptoms? </li></ul><ul><ul><li>Lethargy progressing to coma </li></ul></ul><ul><ul><li>Poor feeding </li></ul></ul><ul><ul><li>Abnormal muscle tone </li></ul></ul><ul><ul><li>Respiratory distress </li></ul></ul><ul><ul><li>Vomiting </li></ul></ul><ul><ul><li>Seizures </li></ul></ul>“ Typical” presentations of organic acidemias
  5. 5. <ul><li>Age of onset is highly variable </li></ul><ul><li>Severity is highly variable </li></ul><ul><li>In the neonate, may be confused with a number of more common pediatric disorders such as sepsis, congenital heart disease, gastrointestinal disorders </li></ul><ul><li>In the older infant and child, may be misdiagnosed as an ingestion, gastroenteritis or CNS disorder </li></ul>“ Typical” presentations of organic acidemias
  6. 6. <ul><li>Metabolic acidosis (with increased anion gap) </li></ul><ul><li>Ketosis </li></ul><ul><li>Hyperammonemia </li></ul><ul><li>Hypoglycemia </li></ul><ul><li>Neutropenia </li></ul><ul><li>Thrombocytopenia </li></ul>Laboratory findings in organic acidemias
  7. 7. <ul><li>Urine organic acid analysis by GC/MS </li></ul><ul><li>Plasma amino acid analysis </li></ul><ul><li>Plasma acylcarnitine analysis profile </li></ul>Diagnosis of the organic acidemias
  8. 8. Examples of organic acidemias with a “typical” presentation <ul><li>Methylmalonic acidemia </li></ul><ul><li>Propionic acidemia </li></ul><ul><li>Isovaleric acidemia </li></ul><ul><li>Multiple carboxylase deficiency </li></ul><ul><li>3-ketothiolase deficiency </li></ul>
  9. 9. Biochemical pathway involved in methylmalonic and propionic acidemias NEXT >>
  10. 10. Methylmalonic acidemia NEXT >>
  11. 11. Methylmalonic acidemia <ul><li>The defect is in the enzyme methymalonyl CoA mutase </li></ul><ul><li>Adenosylcobalamin, the active form of vitamin B12 is a cofactor for the mutase enzyme </li></ul><ul><li>There are vitamin B12 responsive and non-responsive forms of MMA which are genetically distinct </li></ul><ul><li>IEM phenocopy: severe vitamin B12 deficiency </li></ul><ul><li>Defects in cobalamin synthesis and transport also result in methylmalonic acidemia and aciduria </li></ul>
  12. 12. <ul><li>Vitamin B12 responsiveness must be determined clinically </li></ul><ul><li>Renal disease is a common late complication </li></ul><ul><li>Pancreatitis is a common complication </li></ul><ul><li>Metabolic “stroke” producing choreoathetosis may occur </li></ul>Special clinical features of methylmalonic acidemia
  13. 13. <ul><li>Optic atrophy may be late complication </li></ul><ul><li>There is a “benign” form with lower level elevations of plasma and urine MMA; there is also a transient form detected by NBS which may persist for up to one year after birth </li></ul>Special clinical features of methylmalonic acidemia
  14. 14. Propionic acidemia <ul><li>Enzymatic block: Propionyl-CoA carboxylase (PCC) </li></ul><ul><li>Biotin is the PCC Coenzyme </li></ul>
  15. 15. Propionic acidemia NEXT >>
  16. 16. Special clinical features of propionic acidemia <ul><li>Although biotin is a cofactor for PCC, there are no biotin-responsive patients with PA </li></ul><ul><li>Recurrent pancreatitis is a common complication </li></ul><ul><li>Cardiomyopathy is a common complication and a common cause of death; the etiology is unclear </li></ul><ul><li>Optic atrophy has been reported like in MMA in a significant number of patients </li></ul><ul><li>Metabolic stroke involving basal ganglia may occur (acute or progressive extrapyramidal syndrome) </li></ul>
  17. 17. Isovaleric acidemia <ul><li>Enzymatic defect: Isovaleryl-CoA dehydrogenase </li></ul>NEXT >>
  18. 18. Special clinical features of isovaleric acidemia <ul><li>Highly variable, but in general, patients tend to have a better prognosis than do those with MMA or PA </li></ul><ul><li>Special sweaty feet odor of urine and sweat is a very distinctive sign (also observed in glutaric aciduria type II) </li></ul><ul><li>There is a mild, presumably asymptomatic form that has been frequently detected since newborn screening began with MS/MS. It is associated with lower levels of urinary metabolites and with a defined mutation </li></ul>
  19. 19. <ul><li>Also referred to as beta-ketothiolase deficiency </li></ul><ul><li>Relatively common disorder </li></ul><ul><li>Presents with acute episodes of ketoacidosis accompanying intercurrent illnesses; patients are typically normal between episodes </li></ul><ul><li>Hypoglycemia and moderate hyperammonemia may occur </li></ul>Mitochondrial acetoacetyl CoA thiolase deficiency
  20. 20. Developmental delay with/or without seizures <ul><li>Examples of organic acidemias that can present in this way: </li></ul><ul><ul><li>Cobalamin synthetic defects </li></ul></ul><ul><ul><li>Biotinidase deficiency </li></ul></ul><ul><ul><li>Methylmalonic acidemia </li></ul></ul><ul><ul><li>Propionic acidemia </li></ul></ul><ul><ul><li>Isovaleric acidemia </li></ul></ul>
  21. 21. Static or progressive dystonia or choreoathetosis <ul><li>The most important disorder presenting in this way is glutaric aciduria type I </li></ul><ul><li>Acute dystonia can rarely be a presenting sign of MMA or PA </li></ul><ul><li>L-2-hydroxyglutaric aciduria </li></ul>
  22. 22. Clinical features of glutaric aciduria type 1 <ul><li>Macrocephaly at birth in about half of affected infants </li></ul><ul><li>Acute encephalopathic crisis at 3-18 months, often but not always precipitated by intercurrent illness. Results in dystonia, choreoathetosis, significant motor disabilities, although cognitive abilities are often preserved </li></ul><ul><li>Episodes may be recurrent but most disability is felt to be the result of a single episode of acute striatal necrosis </li></ul>
  23. 23. <ul><li>Highly suggestive brain CT scan and MRI findings: frontotemporal atrophy, delayed myelination, high signal intensities in the dentate nucleus </li></ul><ul><li>Laboratory findings may include hypoglycemia and metabolic acidosis although they are rarely profound </li></ul>Clinical features of glutaric aciduria type 1
  24. 24. Glutaric aciduria type 1 – MRI Findings (text from image) Job name: MRDD Job #:4906-079-6 175LnScrn Folder: H2/H8 05/069/Goodman – fig #04 100% FINAL SIZE: 26,9x35,9
  25. 25. Abnormal odor in organic acidemias <ul><li>Isovaleric acidemia (sweaty feet: isovaleric) </li></ul><ul><li>Glutaric aciduria type II (sweaty feet: isovaleric) </li></ul><ul><li>Trimethylaminuria (fish: trimethylamine) </li></ul><ul><li>Dimethylglycinuria (fish: dimethylglycine) </li></ul><ul><li>Maple syrup urine disease (maple syrup:3hydroxy ileu) </li></ul><ul><li>Tyrosinemia type I (boiled cabbage: ketomethylthiobutyric) </li></ul>