Delayed Clinical and Pathological Signs in Twitcher (Globoid Cell Leukodystrophy) Mice on a C57BL/6 × CAST/Ei Background

Abstract

Modifier genes may account for the phenotypic variability observed in the late-onset forms of globoid cell leukodystrophy (GCL) in humans. In order to begin a search for modifier genes, the effect of genetic background on the clinical and pathological manifestations of GCL was investigated in twitcher mice. Twitcher mice on a C57BL/6 × CAST/Ei background had an increased life span (61.4 ± 2.5 vs 37.0 ± 0.6 days), a delayed onset of tremor (24 vs 21 days), and a delayed decline in walking ability compared to C57BL/6 twitcher mice. Pathologically, C57BL/6 × CAST/Ei twitcher mice had fewer lectin-positive globoid cells, less gliosis, and a greater preservation of myelin compared to C57BL/6 twitcher mice under moribund conditions. Similar concentrations of psychosine, the toxic species that accumulates in GCL, were measured by tandem mass spectrometry between moribund C57BL/6 twitcher mice (286.5 pmol/mg protein), 40-day C57BL/6 × CAST/Ei twitcher mice (276.5 pmol/mg), and moribund C57BL/6 × CAST/Ei twitcher mice (247.0 pmol/mg), suggesting that the milder phenotype in CAST/Ei × C57BL/6 twitcher mice did not correlate with less psychosine. In summary, the introduction of modifier genes from the wild, inbred CAST/Ei strain had a phenotypic effect resulting in a significantly slower disease course.