Substrate reduction intervention by L-cycloserine in twitcher mice (globoid cell leukodystrophy) on a B6;CAST/Ei...

Globoid cell leukodystrophy (GCL) is usually a fatal demyelinating disease caused by mutations in galactosylceramidase, which normally recycles galactosylceramide, a predominant glycolipid of myelin, and psychosine. The initial pathology is thought to be due to the accumulation of psychosine in myelin-forming cells leading to their death. In this study, substrate reduction therapy using L-cycloserine, an inhibitor of 3-ketodihydrosphingosine synthase, was examined in twitcher mice on a C57BL/6xCAST/Ei (B6;CAST/Ei) background, which mimics a late onset variant of GCL. A graded dose regimen of L-cycloserine initiated before the onset of symptoms increased the lifespan by approximately 45% and delayed the onset of weight loss while the administration of L-cycloserine beginning after the onset of symptoms had no effect. Despite the pronounced effect for the early treatment regimen, B6;CAST/Ei twitcher mice still displayed a progressive disease leading to an early death.