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Organic Acidemias Didactic Bb Day1 3 Jh


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Day 1, Third Lecture

Day 1, Third Lecture

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    • 1. Organic Acidemias Barbara K. Burton, MD Northwestern University Feinberg School of Medicine, Chicago, IL
    • 2. Definition
      • Group of disorders characterized by excretion of excess of non-amino organic acids in urine
      • Defects in amino acid metabolism distal to removal of the amino group and separated from the amino acid by a non-reversible reaction
      • Organic acids are low molecular weight substances
      • They have at least one carboxylic group and may have keto or hydroxy-groups (so water soluble compounds)
      • Their polar character enables rapid urinary excretion
    • 3.
      • “ Classic or typical” presentation: acute overwhelming illness; recurrent metabolic crises
      • Developmental delay with or without seizures
      • Static or progressive dystonia or choreoathetosis in early childhood
      • Abnormal odor of body or body fluids
      Clinical presentations of organic acidemias
    • 4.
      • What do the symptoms represent? - they represent a toxic encephalopathy
      • What are the typical symptoms?
        • Lethargy progressing to coma
        • Poor feeding
        • Abnormal muscle tone
        • Respiratory distress
        • Vomiting
        • Seizures
      “ Typical” presentations of organic acidemias
    • 5.
      • Age of onset is highly variable
      • Severity is highly variable
      • In the neonate, may be confused with a number of more common pediatric disorders such as sepsis, congenital heart disease, gastrointestinal disorders
      • In the older infant and child, may be misdiagnosed as an ingestion, gastroenteritis or CNS disorder
      “ Typical” presentations of organic acidemias
    • 6.
      • Metabolic acidosis (with increased anion gap)
      • Ketosis
      • Hyperammonemia
      • Hypoglycemia
      • Neutropenia
      • Thrombocytopenia
      Laboratory findings in organic acidemias
    • 7.
      • Urine organic acid analysis by GC/MS
      • Plasma amino acid analysis
      • Plasma acylcarnitine analysis profile
      Diagnosis of the organic acidemias
    • 8. Examples of organic acidemias with a “typical” presentation
      • Methylmalonic acidemia
      • Propionic acidemia
      • Isovaleric acidemia
      • Multiple carboxylase deficiency
      • 3-ketothiolase deficiency
    • 9. Biochemical pathway involved in methylmalonic and propionic acidemias NEXT >>
    • 10. Methylmalonic acidemia NEXT >>
    • 11. Methylmalonic acidemia
      • The defect is in the enzyme methymalonyl CoA mutase
      • Adenosylcobalamin, the active form of vitamin B12 is a cofactor for the mutase enzyme
      • There are vitamin B12 responsive and non-responsive forms of MMA which are genetically distinct
      • IEM phenocopy: severe vitamin B12 deficiency
      • Defects in cobalamin synthesis and transport also result in methylmalonic acidemia and aciduria
    • 12.
      • Vitamin B12 responsiveness must be determined clinically
      • Renal disease is a common late complication
      • Pancreatitis is a common complication
      • Metabolic “stroke” producing choreoathetosis may occur
      Special clinical features of methylmalonic acidemia
    • 13.
      • Optic atrophy may be late complication
      • 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
      Special clinical features of methylmalonic acidemia
    • 14. Propionic acidemia
      • Enzymatic block: Propionyl-CoA carboxylase (PCC)
      • Biotin is the PCC Coenzyme
    • 15. Propionic acidemia NEXT >>
    • 16. Special clinical features of propionic acidemia
      • Although biotin is a cofactor for PCC, there are no biotin-responsive patients with PA
      • Recurrent pancreatitis is a common complication
      • Cardiomyopathy is a common complication and a common cause of death; the etiology is unclear
      • Optic atrophy has been reported like in MMA in a significant number of patients
      • Metabolic stroke involving basal ganglia may occur (acute or progressive extrapyramidal syndrome)
    • 17. Isovaleric acidemia
      • Enzymatic defect: Isovaleryl-CoA dehydrogenase
      NEXT >>
    • 18. Special clinical features of isovaleric acidemia
      • Highly variable, but in general, patients tend to have a better prognosis than do those with MMA or PA
      • Special sweaty feet odor of urine and sweat is a very distinctive sign (also observed in glutaric aciduria type II)
      • 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
    • 19.
      • Also referred to as beta-ketothiolase deficiency
      • Relatively common disorder
      • Presents with acute episodes of ketoacidosis accompanying intercurrent illnesses; patients are typically normal between episodes
      • Hypoglycemia and moderate hyperammonemia may occur
      Mitochondrial acetoacetyl CoA thiolase deficiency
    • 20. Developmental delay with/or without seizures
      • Examples of organic acidemias that can present in this way:
        • Cobalamin synthetic defects
        • Biotinidase deficiency
        • Methylmalonic acidemia
        • Propionic acidemia
        • Isovaleric acidemia
    • 21. Static or progressive dystonia or choreoathetosis
      • The most important disorder presenting in this way is glutaric aciduria type I
      • Acute dystonia can rarely be a presenting sign of MMA or PA
      • L-2-hydroxyglutaric aciduria
    • 22. Clinical features of glutaric aciduria type 1
      • Macrocephaly at birth in about half of affected infants
      • 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
      • Episodes may be recurrent but most disability is felt to be the result of a single episode of acute striatal necrosis
    • 23.
      • Highly suggestive brain CT scan and MRI findings: frontotemporal atrophy, delayed myelination, high signal intensities in the dentate nucleus
      • Laboratory findings may include hypoglycemia and metabolic acidosis although they are rarely profound
      Clinical features of glutaric aciduria type 1
    • 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. Abnormal odor in organic acidemias
      • Isovaleric acidemia (sweaty feet: isovaleric)
      • Glutaric aciduria type II (sweaty feet: isovaleric)
      • Trimethylaminuria (fish: trimethylamine)
      • Dimethylglycinuria (fish: dimethylglycine)
      • Maple syrup urine disease (maple syrup:3hydroxy ileu)
      • Tyrosinemia type I (boiled cabbage: ketomethylthiobutyric)