Impaired eIF2B activity in ligodendrocytes contributes to VWMD pathogenesis

Abstract

Vanishing white matter disease (VWMD, MIM #603896), also known as childhood ataxia with central nervous system (CNS) hypomyelination (CACH), is an inherited autosomal-recessive leukodystrophy (van der Knaap et al., 2006). The neurological signs of VWMD, such as cerebellar ataxia and spasticity, usually begin in late infancy or early childhood. VWMD is chronic and progressive, with additional episodes of rapid deterioration after febrile infection or minor head trauma. Most patients die within a few years of disease onset. VWMD patients display cystic cavitations of the white matter in the CNS. In contrast, the CNS gray matter and the other organs are generally spared. The grossly affected white matter shows profound myelin loss. Oligodendrocytes are predominantly affected in VWMD, which exhibit characteristic foamy morphology. Although oligodendrocyte numbers are decreased in the severely affected white matter, the numbers are increased in the less affected areas. Moreover, apoptotic oligodendrocytes are observed in the white matter of VWMD patients. Additionally, a recent study suggests that the myelinating function of oligodendrocytes is suppressed in VWMD patients (Bugiani et al., 2013).