Organic acidemias are a group of disorders characterized by excess excretion of non-amino organic acids in urine due to defects in amino acid metabolism. Common presentations include acute overwhelming illness in neonates or recurrent metabolic crises in infants leading to developmental delay, seizures, and dystonia or choreoathetosis. Symptoms represent toxic encephalopathy and include lethargy, coma, vomiting, and seizures. Laboratory findings include metabolic acidosis, ketosis, and elevated organic acids in urine. Examples of organic acidemias with typical presentations are methylmalonic acidemia, propionic acidemia, and isovaleric acidemia.

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)