title: Defective glial maturation in vanishing white matter disease.
abstract: Vanishing white matter (VWM) disease is a genetic leukoencephalopathy linked to mutations in the eukaryotic translation initiation factor 2B. It is a disease of infants, children, and adults who experience a slowly progressive neurologic deterioration with episodes of rapid clinical worsening triggered by stress and eventually leading to death. Characteristic neuropathologic findings include cystic degeneration of the white matter with scarce reactive gliosis, dysmorphic astrocytes, and paucity of myelin despite an increase in oligodendrocytic density. To assess whether a defective maturation of macroglia may be responsible for the feeble gliosis and lack of myelin, weinvestigated the maturation status of astrocytes and oligodendrocytes in the brains of 8 VWM patients, 4 patients with other white matter disorders and 6 age-matched controls with a combination of immunocytochemistry, histochemistry, scratch-wound assays, Western blot, and quantitative polymerase chain reaction. We observed increased proliferation and a defect in the maturation of VWM astrocytes. They show an anomalous composition of their intermediate filament network with predominance of the δ-isoform of the glial fibrillary acidic protein and an increase in the heat shock protein αB-crystallin, supporting the possibility that a deficiency in astrocyte function may contribute to the loss of white matter in VWM. We also demonstrated a significant increase in numbers of premyelinating oligodendrocyte progenitors in VWM, which may explain the coexistence of oligodendrocytosis and myelin paucity in the patients' white matter.
authors.affiliation: Department of Pediatrics/Child Neurology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Marianna
authors.initials: M
authors.lastname: Bugiani
authors.forename: Ilja
authors.initials: I
authors.lastname: Boor
authors.forename: Barbara
authors.initials: B
authors.lastname: van Kollenburg
authors.forename: Nienke
authors.initials: N
authors.lastname: Postma
authors.forename: Emiel
authors.initials: E
authors.lastname: Polder
authors.forename: Carola
authors.initials: C
authors.lastname: van Berkel
authors.forename: Ronald E
authors.initials: RE
authors.lastname: van Kesteren
authors.forename: Martha S
authors.initials: MS
authors.lastname: Windrem
authors.forename: Elly M
authors.initials: EM
authors.lastname: Hol
authors.forename: Gert C
authors.initials: GC
authors.lastname: Scheper
authors.forename: Steven A
authors.initials: SA
authors.lastname: Goldman
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002454:Cell Differentiation / Q000502:physiology; D049108:Cell Enlargement; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D056784:Leukoencephalopathies / Q000473:pathology*; D008875:Middle Aged; D009413:Nerve Fibers, Myelinated / Q000473:pathology*; D009457:Neuroglia / Q000473:pathology*; D055815:Young Adult