A Japanese girl with an early-infantile onset vanishing white matter disease resembling Cree leukoencephalopathy

Vanishing white matter disease (VWM)/childhood ataxia with central hypomyelination (CACH) is an autosomal recessive leukoencephalopathy caused by mutations in one of five genes, EIF2B1-5, encoding the 5 subunits of eukaryotic translation initiation factor 2B (eIF2B). The classical phenotype is characterized by early childhood onset and chronic progressive neurological deterioration with cerebellar ataxia, spasticity, optic atrophy and epilepsy. However, the onset of disease varies from antenatal period to adulthood. Cree leukoencephalopathy (CLE) is a severe variant of VWM and caused by a homozygous mutation (R195H) in the EIF2B5 gene. The patient reported in this study developed lethargy, vomiting and seizure 3days after an oral poliovirus vaccination at the age of 4months. She presented with rapid neurological deterioration within a month of onset. Brain MRI showed abnormal white matter intensity. Whole-exome sequencing identified two heterozygous mutations in the EIF2B5 gene: a known mutation, c.584G>A (R195H, which is homozygous in CLE), and a novel mutation, c.1223T>C (I408T, which resides in the "I-patch"). Mutations in the "I-patch" encoded region of eIF2Bε may be related to an early-infantile onset phenotype. This patient exhibits an early-infantile onset and progressive disease course resembling CLE, suggesting a severe functional disruption of eIF2Bε caused by R195H as well as by I408T mutations.