Chapter 235.1

## Abstract

“Vanishing white matter” (VWM) is an autosomal recessively inherited disorder in which the basic defect resides in eukaryotic initiation factor 2B (eIF2B). The clinical onset and severity of VWM vary greatly. The classical form has an early-childhood onset, but onset can vary from antenatal and early-infantile onset at one end of the spectrum to late-adult onset at the other end. Age of onset is predictive of disease severity. The clinical and histopathologic manifestations of VWM are dominated by degeneration of the white matter of the central nervous system. Organs other than the brain are rarely affected, with the exception of the ovaries. In addition to a chronic progressive encephalopathy, there are typically episodes of rapid and major deterioration, provoked by stresses like febrile infections of minor head trauma. VWM is caused by mutations in any of the five genes EIF2B1-5, encoding the α-ϵ subunits of eIF2B. The reason for the selective vulnerability of the white matter of the central nervous system and, less consistently, the ovaries is poorly understood. Multiple hypotheses have been put forward, including the effects of inappropriate activation of the unfolded protein response in oligodendrocytes and astrocytes, differing cellular levels of eIF2B or eIF2/eIF2B ratios and aberrant control of translation of specific mRNAs.
1. “Vanishing white matter” (VWM) is an autosomal recessively inherited disorder in which the basic defect resides in eukaryotic initiation factor 2B (eIF2B). Another frequently used name for the disease is “childhood ataxia with central nervous system hypomyelination”(CACH). “Myelinopathia centralis diffusa” and “eIF2B-related disorder” are used less commonly. The clinical and histopathologic manifestations of VWM are dominated by degeneration of the white matter of the central nervous system. Peripheral nerves and organs other than the brain are rarely affected, with the exception of the ovaries.

2. The clinical onset and severity of VWM show great variation. The classical form of the disease has its onset between 2 and 6 years of life. Most patients die within a few years. More severe variants include those with antenatal and early-infantile onset. Patients with antenatal onset die within a few months after birth. Early infantile onset is generally associated with demise before age 2. Late childhood, adolescent and adult onset can allow survival for decades, although some patients do die unexpectedly within a few months or years.

3. In all variants a progressive encephalopathy dominates the clinical picture. In the classical form slow motor regression occurs, mainly due to cerebellar ataxia and to a lesser degree spasticity. Mental regression is less obvious. Typically, there are additional episodes of rapid deterioration, provoked by minor head trauma, febrile infections and acute fright. These episodes are characterized by rapid loss of motor skills, hypotonia, irritability, seizures, vomiting and somnolence. They may end in coma. Death or partial recovery follows. In the most severe variants, other organs than the brain may also be affected, with cataract, hepatosplenomegaly, kidney hypoplasia and pancreas abnormalities. In the later onset variants, the clinical presentation is more variable and can start with motor deterioration, seizures, complicated migraines, psychiatric symptoms and presenile dementia. The episodic deterioration is less obvious. In female patients of all ages, primary or secondary ovarian failure may occur, although it is only clinically manifest in patients after puberty.

4. MRI plays a pivotal role in the diagnosis of VWM, typically showing a diffuse abnormality of the cerebral white matter with evidence of progressive white matter rarefaction and cystic degeneration. This makes MRI a powerful tool in the diagnosis of VWM. Using genetic analysis as the “gold standard”, MRI criteria have 95% sensitivity and 94% specificity. In the most severe, and also in the mildest, variants, MRI findings may be atypical. Decreased CSF asialotransferrin could be used as a biomarker for VWM in cases with equivocal MRI findings.

5. VWM is caused by mutations in any of the five genes EIF2B1-5, encoding the α-ϵ subunits of eIF2B. Approximately 80% of the mutations are missense mutations. Patients with two mutations that totally abrogate the activity of eIF2B have not been reported. Most likely, residual eIF2B activity is indispensable for life. A few mutations occur relatively frequently, but many different mutations have been reported over the whole length of the five subunit proteins, with the exception of the N-termini of the β- and γ-subunits. Several mutations are known to be consistently associated with an early or late onset phenotype. After the mutations responsible for the disease have been found in a family, prenatal diagnosis is possible by genetic analysis in cultured amniotic fluid cells or chorionic villi.

6. eIF2B is required for the initiation of translation of all cytoplasmic mRNAs. It activates another initiation factor, eIF2, by facilitating the exchange of GDP for GTP on eIF2. A ternary complex consisting of eIF2, GTP and initiator methionyl-tRNA binds to the 40S ribosomal subunit; after this, the scanning of the mRNA for the AUG start codon begins. Upon encountering a start codon, recognized by the methionyl-tRNA, the GTP is hydrolyzed and eIF2 leaves as a complex with GDP. The guanine nucleotide exchange activity of eIF2B is required to regenerate active eIF2·GTP to allow new rounds of initiation. Regulation of the activity of eIF2B occurs mainly through the phosphorylation of the α-subunit of eIF2. When phosphorylated on its α-subunit, eIF2 binds eIF2B so tightly that it inhibits its activity, leading to a reduction or shut-down of protein synthesis. Down-regulation of eIF2B activity is part of the cellular stress response.

7. All known mutations lead to decreased eIF2B activity, as measured in samples from patients’ lymphoblasts and fibroblasts. Surprisingly, no evidence of a decrease in general protein synthesis, a defect in the regulation of protein synthesis, or alterations in proliferation and survival of these cells has been detected.

8. VWM is a cavitating orthochromatic leukoencephalopathy. Histopathology reveals that white matter oligodendrocytes and astrocytes bear the brunt of the disease. Increased numbers of oligodendrocytes are present around cystic areas and in less affected white matter. In these regions, oligodendrocytes display an abundant foamy cytoplasm, a feature which is considered characteristic of VWM. Tissue rarefaction is accompanied by a meager astrogliosis and astrocytes are dysmorphic with short blunt processes instead of the fine arborizations seen in activated normal astrocytes.

9. The reason for the selective vulnerability of the white matter of the central nervous system and, less consistently, the ovaries is poorly understood. Multiple hypotheses have been put forward, including the effects of inappropriate activation of the unfolded protein response in oligodendrocytes and astrocytes, differing cellular levels of eIF2B or eIF2/eIF2B ratios and aberrant control of translation of specific mRNAs.

10. There is no specific treatment for VWM. Avoidance of known stress factors, like febrile infections and minor head trauma is important, but not sufficient. Prevention of the disease is restricted to prenatal diagnosis and carrier identification in families with known risk.

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