Vanishing white matter disease (VWMD) is one of the most prevalent hereditary white matter diseases. It is also known as childhood ataxia with central hypomyelination (CACH) and was first described by Van der Knaap et al in 1996.

It typically appears in a previously healthy child and produces a progressive neurological deterioration with some acute exacerbations secondary to infections, cranial trauma, or acute fright. Typical signs and symptoms comprise an initial motor deterioration, with pyramidal signs and cerebellar ataxia and a cognitive impairment which is less evident and appears later. There can be epileptic seizures, tremor, dystonia, or chorea and can also produce optic atrophy and progressive macrocephaly.

The most frequent clinical forms of the disease have their onset during childhood: the early childhood-onset appears before five years of age, and the late childhood-onset between ages five and fifteen. The disease may have a chronic progressive course or an acute form, and it is difficult to predict the evolution that each patient will follow even though some efforts to find a correlation between genotype and phenotype have been made. It is also worth noting that the evolution can be different even among affected members of the same family.

MRI images show important diffuse abnormalities of the signal on T1 and T2 of almost all the cerebral white matter, sparing the U fibers, with progressive rarefaction and cystic degeneration that leads to its complete disappearance. Even in the end-stage, when almost all white matter is cystic,  atrophy is usually mild if any.

On proton density and FLAIR images, within the rarified and cystic white-matter, a stripe-like pattern can be found, which represent remaining tissue strands.

Proton magnetic-resonance spectroscopy shows normal signals at the beginning but they progressively disappear and a spectrum similar to that of cerebrospinal fluid (CSF) can be recognised.

Genetic studies have proved an association between this disease and molecular mutations in five genes (eIF2B1-5) encoding the five subunits of eukaryotic translation initiation factor eIF2B (eIF2Ba-e), with the mutations in eIF2B5 being the most frequent ones.

EIF2B is responsible for initiating mRNA translation to polypeptides, and therefore it is essential to protein synthesis. It is also known that cells are prepared for protein synthesis inhibition in stress situations, to save energy and to prevent denatured proteins from accumulating. Under stress, eIF2B is inactivated, and therefore mRNA translation cannot begin. It has been reported that mutations in the genes encoding eIF2B could affect protein synthesis inhibition, rendering the cell more vulnerable to stress. Since this situation affects oligodendrocytes, which are the responsible cells for myelin synthesis, eIF2B mutations would end in an alteration of myelin production.

To date no curative treatment has been found. What seems to be effective is the prevention of the acute deterioration, avoiding cranial trauma and treating infection aggressively. Nevertheless, chronic progression is unavoidable.

Dr Turón-Viñas is author of the recently published paper Vanishing White Matter Disease in a Spanish Population, available for download now in Journal of Central Nervous System Disease.

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