INTRODUCTION AND HISTORY
Vanishing white matter disease (VWM; MIM #603896), also known as childhood ataxia with central nervous system hypomyelination, leukoencephalopathy with vanishing white matter, and Cree leukoencephalopathy, is a chronic and progressive white matter disorder, often exacerbated by infection or head trauma.
Scattered neuropathologic case reports beginning in the 1960s were the earliest descriptions of the disease [1-8]. In 1988, a study from Canada described a severe infantile leukodystrophy in three Cree Indian villages termed "Cree leukoencephalopathy" , a condition that is now recognized as a phenotypic variant of VWM . However, VWM was not recognized as a clinical syndrome until the 1990s.
- A 1993 study from Germany described three children with normal early development who rapidly declined with progressive ataxia and spasticity, followed later by bulbar symptoms, optic atrophy, and seizures; brain magnetic resonance imaging (MRI) showed a diffuse hypodensity of the white matter similar to the signal of the ventricles .
- A 1994 report from the United States described four unrelated patients with progressive ataxic diplegia that was named "childhood ataxia with diffuse central nervous system hypomyelination" .
- In 1997, a study from the Netherlands described a cohort of nine children, including three affected sibling pairs, who had similar clinical, radiographic, and pathologic characteristics and were diagnosed with a "new leukoencephalopathy with vanishing white matter" .
Later studies have revealed the genetic underpinnings and the phenotypic variability of VWM, as described below.
Inheritance of VWM is autosomal recessive. Mutations in any of the five genes that encode subunits of the eukaryotic translation initiation factor eIF2B are the cause of VWM and its phenotypic variants [10,14].