In conclusion, identification of this single case with null NOTCH3 mutation acting in a recessive manner argues in favor of the role, still questioned, of NOTCH3 hypomorphic mutations in white matter disease and implies the possible occurrence of null NOTCH3 recessive mutations in other patients, in particular among those displaying a severe, early-onset cavitating leukoencephalopathy. This evidence concerns the gene NOTCH3 and Leukoencephalopathy.