White Matter Disease in a Toddler With New-Onset Seizures

This 19-month-old boy with tetralogy of Fallot, repaired at age 6 months, and mild gross motor and language developmental delays presented with new-onset generalized tonic-clonic seizures. Following a brief postictal state, he returned to baseline. Neurological examination was unremarkable. Initial imaging showed diffuse, confluent T2 white matter hyperintensity with associated diffusion restriction and T1 hypointensity. Follow-up imaging at 25 months (Figure 1) revealed progression involving the central corpus callosum. Differential diagnosis for leukodystrophy with diffuse white matter involvement is broad and includes vanishing white matter disease, metachromatic leukodystrophy, and certain mitochondrial disorders. A leukodystrophy gene panel demonstrated homozygous pathogenic sequence variants in EIF2B3, establishing a diagnosis of vanishing white matter disease 3 (VWM3).

VWM is an inherited leukodystrophy that most commonly presents in early childhood with motor deficits following a provoking event (e.g., febrile illness) [1]. VWM3 is caused by biallelic pathogenic variants in the EIF2B3 gene, which encodes a subunit of the enzyme eukaryotic initiation factor 2B (eIF2B). Pathogenic variants in any of the subunit genes lead to reduction in eIF2B activity, causing aberrant activation of the cellular response to physiologic stressors and downstream white matter pathology [2]. Unprovoked seizures and lack of motor manifestations are not typical initial presenting features in this age group [3]. Three-years after his VWM diagnosis, he was also diagnosed with autism.

Olivia Viscuso: conceptualization, writing – original draft, writing – review and editing, resources. Bhairav Patel: conceptualization, writing – review and editing; visualization. James B. Gibson: writing – review and editing. Louisa G. Keith: resources, supervision, writing – review and editing, writing – original draft, conceptualization.

Written consent for publication of clinical details and images was obtained from the patient's legal guardian.

The authors declare no conflicts of interest.