Elsevier

The Lancet Neurology

Volume 5, Issue 5, May 2006, Pages 413-423
The Lancet Neurology

Review
Vanishing white matter disease

https://doi.org/10.1016/S1474-4422(06)70440-9Get rights and content

Summary

Vanishing white matter disease (VWM) is one of the most prevalent inherited childhood leucoencephalopathies. The classical phenotype is characterised by early childhood onset of chronic neurological deterioration, dominated by cerebellar ataxia. VWM is unusual because of its clinically evident sensitivity to febrile infections, minor head trauma, and acute fright, which may cause rapid neurological deterioration and unexplained coma. Most patients die a few years after onset. The phenotypic variation is extremely wide, including antenatal onset and early demise and adult-onset, slowly progressive disease. MRI findings are diagnostic in almost all patients and are indicative of vanishing of the cerebral white matter. The basic defect of this striking disease resides in either one of the five subunits of eukaryotic translation initiation factor eIF2B. eIF2B is essential in all cells of the body for protein synthesis and its regulation under different stress conditions. Although the defect is in housekeeping genes, oligodendrocytes and astrocytes are predominantly affected, whereas other cell types are surprisingly spared. Recently, undue activation of the unfolded-protein response has emerged as important in the pathophysiology of VWM, but the selective vulnerability of glia for defects in eIF2B is poorly understood.

Introduction

Vanishing white matter disease (VWM; Online Mendelian Inheritance in Man number 306896), also called childhood ataxia with central hypomyelination, is one of the most prevalent inherited childhood white matter disorders.1 It was initially recognised as a devastating brain disorder affecting young children.2, 3, 4 However, in the past few years it has become apparent that the disease has an extremely wide phenotypic variation and may affect people of all ages.5, 6, 7 A characteristic clinical feature of VWM is that, in addition to the chronic progressive disease course, there are episodes of rapid and major neurological deterioration provoked by stresses, such as fever and minor head trauma.4, 5 VWM is caused by mutation in any of the five genes encoding the subunits of eukaryotic translation initiation factor eIF2B.8, 9 Because of the almost exclusive involvement of the white matter of the brain, it is unexpected that the basic defect is in housekeeping genes.

Section snippets

History

The first description of the disease that we found was from 1962, when Eicke described the neuropathological findings in a 36-year-old woman who presented at age 31 years with gait difficulties and secondary amenorrhoea.10 The clinical disease course was chronic progressive with episodes of rapid deterioration after minor physical trauma. At autopsy, a diffuse, cystic destruction of the cerebral white matter was found. Around the cystic areas, a dense “network” of oligodendrocytes was seen.

Epidemiology

VWM is one of the most prevalent inherited childhood white-matter disorders,1 although its exact incidence has not been determined. The disease seems to be particularly common in white populations,9 although no systematic study to assess the incidence in different populations has been done.

Classical phenotype

The classical and most common variant has its onset in childhood, at age 2–6 years.2, 3, 4 The disease is characterised by chronic progressive neurological deterioration with cerebellar ataxia, usually less prominent spasticity and relatively mild mental decline.2, 3, 4 Optic atrophy with loss of vision may occur, but not in all patients.3 Epilepsy is common in VWM but is usually mild. Characteristically, there are additional episodes of major and rapid deterioration following minor head trauma

Pathology

On macroscopic examination the cerebral white matter varies from gelatinous to cystic to frankly cavitary.4, 5, 18, 34, 35 The frontoparietal white matter, particularly deep and periventricular, seems to be more commonly involved with relative sparing of the temporal lobe, optic system, corpus callosum, anterior commissure, and internal capsule; the subcortical arcuate fibres also tend to be spared, but not consistently.4, 5, 18, 34, 35

Microscopically, the grossly affected white matter shows

Genetics

In the late 1990s, a genetic linkage study was done with exclusively MRI criteria4, 5 to select patients eligible for this study. Most genetic linkage studies assume that only one gene is associated with the disease under investigation (genetic homogeneity). The investigators circumvented the problem of possible genetic heterogeneity by focusing on Dutch patients.37, 38 They established linkage with chromosome 3q27 and showed that most Dutch patients shared a haplotype in the candidate region,

Pathophysiology

Multiple so-called eukaryotic initiation factors (eIFs) are involved in the initiation of translation of mRNAs into polypeptides.42 The guanine nucleotide exchange factor eIF2B plays a key part among them.42 A crucial step in translation initiation is the formation of a ternary complex, which consists of initiation factor eIF2, GTP, and initiator methionyl-transfer RNA (Met-tRNAi), which binds to the ribosome (figure 9).43 Upon recognition of the start codon of the mRNA, the eIF2-bound GTP is

Management

There is no specific treatment for VWM. Avoidance of stress situations known to provoke deterioration in VWM patients is essential. Liberal use of antibiotics and antipyretics, vaccinations, and abstinence of contact sports are simple but important measures. However, they are not sufficient to prevent onset or progression of the disease. The most important consequence of research findings of the last 5 years probably is that prenatal diagnosis has become available for families as soon as the

Conclusions

VWM is an intriguing disease, both from a clinical and molecular perspective. It is the first disease known to involve a translation initiation factor, eIF2B. It is surprising that although the basic defect of VWM involves housekeeping genes, the white matter of the brain is almost exclusively affected. Within the white matter, glia (both astrocytes and oligodendrocytes) are predominantly affected. They show morphological abnormalities and lack of function, leading to insufficient myelin

Search strategy and selection criteria

References for this review were identified by searches of MEDLINE between 1969 and February 2006 and references from relevant articles. Numerous articles were also identified through searches of our files. The search terms used were “vanishing white matter”, “CACH”, “translation initiation”, “eIF2B”, “eIF2”, “unfolded protein response”, “upstream open reading frame”, “internal ribosomal entry site”, “ATF4”, and “CHOP”.

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