OBJECTIVE: To comprehensively describe the natural history of Vanishing White Matter (VWM), aiming at improving counseling of patients/families and providing natural history data for future therapeutic trials.
METHODS: We performed a longitudinal multicenter study among 296 genetically confirmed VWM patients. Clinical information was obtained via disease-specific clinical questionnaire, Health Utilities Index (HUI) and Guy's Neurological Disability Scale (GNDS) assessments and chart review.
RESULTS: First disease signs occurred at median age of 3 years (mode 2 years, range before birth - 54 years); 60% of patients were symptomatic before age of 4 years. The nature of the first signs varied for different ages of onset. Overall, motor problems were the most common presenting sign, especially in children. Adolescent and adult onset patients were more likely to exhibit cognitive problems early after disease onset. 102 patients were deceased. Multivariable Cox regression analysis revealed a positive relation between age of onset and both preservation of ambulation and survival. Absence of stress-provoked episodes and absence of seizures predicted more favorable outcome. In patients with onset before 4 years, earlier onset was associated with more severe disability and higher mortality. For onset from 4 years on, disease course was generally milder, with a wide variation in severity. There were no significant differences for sex or for the five eIF2B gene groups. The results confirm the presence of a genotype-phenotype correlation.
INTERPRETATION: The VWM disease spectrum consists of a continuum with extreme wide variability. Age of onset is a strong predictor for disease course. This article is protected by copyright. All rights reserved.