Clinical And Pathologic Characterization

In our initial paper describing this mutant mouse model, we reported that they had undetectable SCAD activity, which agreed metabolically with the urinary organic acid results and the genetic marker results. In addition, upon fasting the blood glucose of these mice would drop to approximately half of normal control values and their serum glycine concentrations would also decrease to two thirds of normal.3 We speculated that the glycine was being lost in the urine due to the abnormally high amounts of butyrylglycine being excreted. We also did carnitine loading experiments and found that these mice were not carnitine deficient, perhaps because they were excreting excess butyryl-CoA as butyrylglycine via glycine conjugation rather than as butyrylcarnitine.3 We did, however, find excessive muscle butyrylcarnitine in the mutants and trace to no detectable amounts of muscle butyrylcarnitine in the controls. The mutant mice develop severe fatty liver with fasting, as well as excessive fat in the liver without fasting as compared to normal controls. Immunoprecipitation studies later showed that there was no detectable SCAD antigen produced in multiple tissues.8

Clinically, these mutants have remained consistently normal.3 We have challenged them with fasting,3 medium-chain triglyceride loading,3 as well as, sodium butyrate loading, sodium benzoate and salicylate loading in an attempt to overload the glycine conjugation pathway. We have also fed them a high fat diet (40% fat) composed of butter fat with a relatively high short-chain fatty acid content. Even after consuming this diet for over a month, these mice showed no clinical signs of disease with fasting. Pathological characteristics include predominately fatty liver and kidney3,9 ultrastructural studies demonstrated swollen, disorganized mitochondria in hepatocytes from fasted mutants with the appearance of a grade II change as described for children with swollen mitochondria associated with Reye Syndrome.9 There was also depletion of hepatocyte glycogen stores.

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