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Leukoencephalopathy with vanishing white matter
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Condition

Leukoencephalopathy with vanishing white matter

Leukoencephalopathy with vanishing white matter is a progressive genetic disorder that deteriorates the central nervous system's white matter, leading to motor difficulties and vulnerability to physiological stress.

Overview

Leukoencephalopathy with vanishing white matter is a progressive disorder that mainly affects the brain and spinal cord (central nervous system). This disorder causes deterioration of the central nervous system's white matter, which consists of nerve fibers covered by myelin. Myelin is the fatty substance that insulates and protects nerves.

Symptoms

In most cases, people with leukoencephalopathy with vanishing white matter show no signs or symptoms of the disorder at birth. Affected children may have slightly delayed development of motor skills such as crawling or walking. During early childhood, most affected individuals begin to develop motor symptoms, including abnormal muscle stiffness (spasticity) and difficulty with coordinating movements (ataxia). There may also be some deterioration of mental functioning, but this is not usually as pronounced as the motor symptoms. Some affected females may have abnormal development of the ovaries (ovarian dysgenesis). Specific changes in the brain as seen using magnetic resonance imaging (MRI) are characteristic of leukoencephalopathy with vanishing white matter, and may be visible before the onset of symptoms.

While childhood onset is the most common form of leukoencephalopathy with vanishing white matter, some severe forms are apparent at birth. A severe, early-onset form seen among the Cree and Chippewayan populations of Quebec and Manitoba is called Cree leukoencephalopathy. Milder forms may not become evident until adolescence or adulthood, when behavioral or psychiatric problems may be the first signs of the disease. Some females with milder forms of leukoencephalopathy with vanishing white matter who survive to adolescence exhibit ovarian dysfunction. This variant of the disorder is called ovarioleukodystrophy.

Progression of leukoencephalopathy with vanishing white matter is generally uneven, with periods of relative stability interrupted by episodes of rapid decline. People with this disorder are particularly vulnerable to stresses such as infection, mild head trauma or other injury, or even extreme fright. These stresses may trigger the first symptoms of the condition or worsen existing symptoms, and can cause affected individuals to become lethargic or comatose.

Frequency

The prevalence of leukoencephalopathy with vanishing white matter is unknown. Although it is a rare disorder, it is believed to be one of the most common inherited diseases that affect the white matter.

Causes

Mutations in the EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5 genes cause leukoencephalopathy with vanishing white matter.

These genes provide instructions for making the five parts (subunits) of a protein called eIF2B. The eIF2B protein helps regulate overall protein production (synthesis) in the cell by interacting with another protein, eIF2. The eIF2 protein is called an initiation factor because it is involved in starting (initiating) protein synthesis. Proper regulation of protein synthesis is vital for ensuring that the correct levels of protein are available for the cell to cope with changing conditions. For example, cells must synthesize protein much faster if they are multiplying than if they are in a resting state.

Mutations have been identified in all five of the genes from which the eIF2B protein is produced, although most of these mutations (about 65 percent) occur in the EIF2B5 gene. These mutations cause partial loss of eIF2B function in various ways. For example, they may impair the ability of one of the protein subunits to form a complex with the others, or make it more difficult for the protein to attach to the initiation factor.

Partial loss of eIF2B function makes it more difficult for the body's cells to regulate protein synthesis and deal with changing conditions and stress. Researchers believe that cells in the white matter may be particularly affected by an abnormal response to stress, resulting in the signs and symptoms of leukoencephalopathy with vanishing white matter.

Associated Genes

  • EIF2B1
  • EIF2B2
  • EIF2B3
  • EIF2B4
  • EIF2B5

Inheritance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Other Names for This Condition

  • CACH syndrome
  • Childhood ataxia with central nervous system hypomyelination
  • Cree leukoencephalopathy
  • Myelinosis centralis diffusa
  • Vanishing white matter disease
  • Vanishing white matter leukodystrophy

Frequently Asked Questions

Diagnosis typically involves a combination of clinical symptoms and characteristic findings on a brain magnetic resonance imaging (MRI) scan. The MRI is key, as it can show specific changes in the white matter, sometimes even before symptoms appear. "Vanishing white matter" refers to the progressive loss of the brain's white matter, which is made of nerve fibers insulated by myelin. On MRI, this appears as areas of abnormally low signal intensity, indicating the replacement of healthy white matter with cerebrospinal fluid-filled cysts, giving the appearance of the white matter "vanishing." Genetic testing can confirm mutations in the genes responsible for the disorder.
Individuals with Leukoencephalopathy with vanishing white matter are highly vulnerable to physiological stress, which can trigger a rapid worsening of symptoms or even lead to coma. Common stressors include infections (even mild ones), fever, minor head trauma, sudden fright, or extreme emotional stress. Management involves promptly treating infections, controlling fever, avoiding head injuries, and minimizing situations that cause significant emotional distress. Close monitoring and proactive care during illness are crucial.
While motor delays like difficulty crawling or walking are common early signs, other symptoms can emerge. In early childhood, these include abnormal muscle stiffness (spasticity) and problems with coordination (ataxia). Some deterioration of mental functioning may also occur, though motor symptoms are usually more pronounced. In some affected females, abnormal development of the ovaries (ovarian dysgenesis) can be a sign. Milder forms in adolescence or adulthood may first present with behavioral or psychiatric problems.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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