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CHAPTER SUMMARY

“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.

  • “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.

  • 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.

  • 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 ...

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