Vanishing White Matter Disease in a Spanish Population

Abstract

Vanishing white matter (VWM) leukoencephalopathy is one of the most prevalent hereditary white matter diseases. It has been associated with mutations in genes encoding eukaryotic translation initiation factor (eIF2B). We have compiled a list of all the patients diagnosed with VWM in Spain; we found 21 children. The first clinical manifestation in all of them was spasticity, with severe ataxia in six patients, hemiparesis in one child, and dystonic movements in another. They suffered from progressive cognitive deterioration and nine of them had epilepsy too. In four children, we observed optic atrophy and three also had progressive macrocephaly, which is not common in VWM disease. The first two cases were diagnosed before the 1980s. Therefore, they were diagnosed by necropsy studies. The last 16 patients were diagnosed according to genetics: we found mutations in the genes eIF2B5 (13 cases), eIF2B3 (2 cases), and eIF2B4 (1 case). In our report, the second mutation in frequency was c.318A>T; patients with this mutation all followed a slow chronic course, both in homozygous and heterozygous states. Previously, there were no other reports to confirm this fact. We also found some mutations not described in previous reports: c.1090C>T in eIF2B4, c.314A>G in eIF2B5, and c.877C>T in eIF2B5.

Profile of Indian Children with Childhood Ataxia and Central Nervous System Hypomyelination/Vanishing White Matter Disease: A Single Center Experience from Southern India

“…All the cases in this series had motor predominant neuroregression, spasticity, and ataxia which are the cardinal clinical features of this disease which have been described similarly in other studies as well. Epilepsy in our series is higher than (►Table 3) that reported by Gungor et al and Turon-Vinas et al 19,20 The possible reason could be due to the smaller cohort of children in our series who had a chronic slowly progressive course compared with other studies. There is sufficient literature which describes a lower incidence of epilepsy in children with chronic slowly progressive course compared with acutely rapid course.…”

“…Ptosis, hemiparesis, dystonia, and chorea are other atypical clinical features reported in literature in CACH. 20 However, they were not observed in this series.…”

Astrocytes are central in the pathomechanisms of vanishing white matter

“…We bred the 2 single-mutant mouse strains into double mutants, with the expectation of obtaining a more severe VWM variant. Patients generally do not have more than 2 mutations in eIF2B, although a very small proportion of patients do, while still having the typical VWM phenotype (55). Indeed, the phenotypes of the different mutants differ only in severity, indicating the same underlying pathomechanisms across the strains.…”

Identification of Repurposable Cytoprotective Drugs in Vanishing White Matter Disease Patient-Derived cells

“…Steroids can regulate in ammation, mitochondrial function and apoptosis with neuroprotective effects in brain injury, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and stroke (30). Although glucocorticosteroids are a commonly administered class of drugs, an anecdotal study of corticosteroids on three VWMD patients did not identify bene ts and the patients were removed from this treatment due to potential clinical complications (31). Nonetheless, de azacort was included in our study as a representative glucocorticosteroid on the basis of fewer reports of adverse effects in the literature and its existing use in the clinic, including in children with muscular dystrophy (32,33).…”