Metabolic defects that produce organic acid accumulation may directly affect neuronal and muscle metabolism when the defect is located in a major metabolic pathway.  Such defects often produce severe encephalopathies. The cytochrome chain is the final common pathway for glial and neuronal oxidative metabolism.  Electron transport chain defects are increasingly identified in the group of mitochondrial encephalomyopathies.  In many disorders, organic acid accumulation results in secondary mitochondrial dysfunction. Many organic acids and especially fatty acids are mitochondrial toxins producing both uncoupling and inhibition of oxidative phosphorylation. Although organic acids are generally weak acids, accumulation may exceed tissue buffering capacity. Most enzymatic reactions are pH-sensitive, and a reduction of intracellular or intramitochondrial pH will render many metabolic steps inefficient. Such mechanisms are proposed to underlie the neurotoxicity accompanying lactic acid accumulation.

As most of these abnormal metabolites are concentrated in the urine, a quantitative urinary organic acid screen evaluated by gas chromatography-mass spectrometry is the test of choice. While most of the organic acidemias are inherited disorders of amino acid metabolism and fatty acid oxidation, onset of clinical signs can be at an early age or in adulthood. Persistent lactic acidemia or metabolic acidosis may be found. This category of metabolic disorders should be considered when clinical signs persist and another diagnosis is not reached

CLINICAL EXAMPLES OF ABNORMAL ORGANIC ACID SCREENS

Case 1.  A 6 year-old Staffordshire bull terrier presented for progressive neurologic signs including seizures.  Related dogs had similar clinical signs including behavior changes, tonic-clonic seizures, ataxia and tremors.  As a specific cause for seizure activity was not identified, a urine organic acid screen was performed.  Markedly excessive excretion of 2-OHglutaric acid was identified. L-2-OHglutaric aciduria has now been established as a genetic disease in this breed (Abramson et al, J Vet Intern  Med 2003;17:551-556) and a DNA based test currently available (See January 2006 Case of the Month).

Case 2.  A 6 year-old male Sheltie was evaluated for progressive generalized seizures. Between episodes of seizures the dog was not normal and appeared to have ataxia. As a specific cause for seizure activity was not identified, a urine organic acid screen was performed.  Propionylglycine and other glycine conjugates  including tiglyglycine and 2-Mebutyryl-glycine were markedly elevated. This pattern of organic acid excretion is highly suggestive of propionic acidemia, an error in protein metabolism. In humans, with a complete enzyme defect, an early onset of severe symptoms is described. An adult onset with partial enzyme deficiencies and milder disease is also reported.  Propionic acidemia has not yet been reported in dogs.

Case 3. A 3 year- old female-spayed DSH was presented with a 4 month history of polyphagia, voluminous stools, severe muscle wasting and intermittent generalized weakness.  There was no evidence of renal or liver disease. However, the cat had a severe metabolic acidosis (blood pH 6.9). A urine organic acid screen was performed.  Marked excretion of lactic acid and milder excretion of the ketones 3-hydroxybutyric and acetoacetic acids were found. A final  diagnosis of D-lactic acidosis secondary to exocrine pancreatic insufficiency was made (Packer et al, J Vet Intern Med 2005;19:106-110).