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  • Updated 03.07.2020
  • Released 10.27.1999
  • Expires For CME 03.07.2023

Childhood ataxia with central nervous system hypomyelination

Introduction

This article includes discussion of childhood ataxia with central nervous system hypomyelination, CACH, myelinopathia centralis diffusa, and vanishing white matter disease,. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Mutations affecting the eukaryotic initiation factor 2B (eIF2B) cause one of the most common leukodystrophies, the autosomal recessive childhood ataxia with central nervous system hypomyelination (CACH), or vanishing white matter disease (VWM). Patients may develop a wide spectrum of neurologic abnormalities, from prenatal-onset white matter disease to juvenile- or adult-onset ataxia and dementia, sometimes with ovarian insufficiency. The pattern of diffuse white matter abnormalities on brain MRI and diffusion studies is often diagnostic. A knock-in mouse model of CACH/VWM, which shows a developmental white matter abnormality, is a promising new tool for the research of this devastating disease. Molecules that stabilize the eIF2B complex and normalize its activity are being developed. Symptomatic treatment such as deep brain stimulation may alleviate tremor.

Key points

• Childhood ataxia with CNS hypomyelination (or vanishing white matter disease) is a relatively common leukodystrophy in which most of the patients have a pathognomonic pattern of MRI and diffusion tensor imaging abnormalities.

• Patients with childhood ataxia with CNS hypomyelination have a usual susceptibility to mild head trauma, fever, and other stresses.

• Childhood ataxia with CNS hypomyelination can present at any age. A detailed quantitative natural history study has been published.

• eIF2B mutations are associated with likely mitochondrial dysfunction that affects astrocytes and oligodendrocytes.

• Molecules like ISRIB (integrated stress response inhibitor) correct the eIF2B deficiency in most mutants and are likely to be tried as therapy for central nervous system hypomyelination/vanishing white matter disease.

Historical note and terminology

Patients with childhood ataxia with central nervous system hypomyelination were first identified in 1992 (53). Similar patients were soon described (25; 62). This disorder is also known as "the vanishing white matter disease" (62; 63).

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