Table 3. Leukodystrophies caused by a primary astrocyte defect.

Leukodystrophy	Gene defect	Astrocyte-mediated pathological mechanisms	Clinical and histopathological featuresshared among cystic leukodystrophies
Alexander’s disease (AxD)	Mutations in the glial fibrillary acidicprotein (GFAP) gene (130)	Accumulation of Rosenthal fibers, abnormal GFAP polimerization, defects in proteasomal degradation and authophagy processes, decrease in glutamate trasporters	Macrocephaly, ataxia, spasticity, epilepsy, aggravation of clinical conditions after minor head trauma and infections; limited genotype-phenotype correlation. Swollen white matter, astrocyte vacuolation
Megalencephalic leukoencephalopathy with subcortical cysts (MLC)	Mutations in the MLC1 or HEPACAM gene (168,178)	Altered regulation of ion and fluid homeostasis and cell volume	Macrocephaly, ataxia, spasticity, mild cognitive decline, severe motor dysfunctions, epilepsy, subcortical cysts, aggravation of clinical conditions after minor head trauma. No genotype-phenotype correlation. Swollen white matter, astrocyte vacuolation
Vanishing white matter syndrome (VWM) or childhood ataxia with central nervous system hypomyelination (CACH)	Mutations in the Eukariotic Translation Initiation Factor 2 (EIF-2B) gene (187)	Astrocyte maturation defect, abnormal response to stress conditions	Ataxia, spasticity, loss of vision, severe motor dysfunctions, mild cognitive decline, epilepsy, aggravation of clinical symptoms after minor stress conditions. Limited genotype-phenotype correlation. Swollen white matter