When exome analysis is the key for your patient with cognitive decline: a case report

Vanishing white matter (VWM) disease is a leukodystrophy caused by mutations in EIF2B1-5 genes, which impair cellular stress responses and protein synthesis regulation, leading to astrocytic dysfunction and white matter degeneration. While typically a pediatric condition, adult-onset cases are increasingly recognized. We report a 39-year-old Brazilian woman with a six-year history of progressive cognitive decline, gait impairment, and rapid deterioration following an infection. Neurological examination revealed spastic tetraparesis and severe cognitive impairment. Brain magnetic resonance imaging (MRI) showed diffuse white matter abnormalities with cystic degeneration. Whole-exome sequencing identified a homozygous EIF2B3 c.260C>T (p.Ala87Val) variant, previously associated with a founder effect in Quebec but not reported in Brazil. This case highlights the phenotypic variability of VWM, stress-triggered exacerbations, and the importance of genetic testing in adult patients with cognitive decline. It also expands the genotypic diversity of VWM in Brazil and underscores the need for multidisciplinary care.