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Leukoencephalopathy with vanishing white matter

Reviewed May 2013

What is leukoencephalopathy with vanishing white matter?

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.

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.

How common is leukoencephalopathy with vanishing white matter?

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.

What genes are related to leukoencephalopathy with vanishing white matter?

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

The EIF2B1, EIF2B2, EIF2B3, EIF2B4 and EIF2B5 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.

Related Gene(s)

Changes in these genes are associated with leukoencephalopathy with vanishing white matter.

  • EIF2B1
  • EIF2B2
  • EIF2B3
  • EIF2B4
  • EIF2B5

How do people inherit leukoencephalopathy with vanishing white matter?

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.

Where can I find information about diagnosis or management of leukoencephalopathy with vanishing white matter?

These resources address the diagnosis or management of leukoencephalopathy with vanishing white matter and may include treatment providers.

  • Gene Review: Childhood Ataxia with Central Nervous System Hypomelination/Vanishing White Matter (http://www.ncbi.nlm.nih.gov/books/NBK1258)
  • Genetic Testing Registry: Leukoencephalopathy with vanishing white matter (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1858991)

You might also find information on the diagnosis or management of leukoencephalopathy with vanishing white matter in Educational resources (http://ghr.nlm.nih.gov/condition/leukoencephalopathy-with-vanishing-white-matter/show/Educational+resources) and Patient support (http://ghr.nlm.nih.gov/condition/leukoencephalopathy-with-vanishing-white-matter/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about leukoencephalopathy with vanishing white matter?

You may find the following resources about leukoencephalopathy with vanishing white matter helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for leukoencephalopathy with vanishing white matter?

  • CACH syndrome
  • childhood ataxia with central nervous system hypomyelination
  • Cree leukoencephalopathy
  • myelinosis centralis diffusa
  • vanishing white matter disease
  • vanishing white matter leukodystrophy

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about leukoencephalopathy with vanishing white matter?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/gard).

What glossary definitions help with understanding leukoencephalopathy with vanishing white matter?

ataxia ; autosomal ; autosomal recessive ; cell ; central nervous system ; comatose ; dysgenesis ; gene ; guanine ; imaging ; infection ; inherited ; injury ; lethargic ; leukodystrophy ; leukoencephalopathy ; magnetic resonance imaging ; motor ; nervous system ; nucleotide ; ovarian ; prevalence ; progression ; protein ; recessive ; spasticity ; stress ; syndrome ; synthesis ; trauma ; white matter

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://ghr.nlm.nih.gov/glossary).

References

  • Dietrich J, Lacagnina M, Gass D, Richfield E, Mayer-Pröschel M, Noble M, Torres C, Pröschel C. EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy. Nat Med. 2005 Mar;11(3):277-83. Epub 2005 Feb 20. (http://www.ncbi.nlm.nih.gov/pubmed/15723074?dopt=Abstract)
  • Fogli A, Boespflug-Tanguy O. The large spectrum of eIF2B-related diseases. Biochem Soc Trans. 2006 Feb;34(Pt 1):22-9. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16246171?dopt=Abstract)
  • Fogli A, Schiffmann R, Hugendubler L, Combes P, Bertini E, Rodriguez D, Kimball SR, Boespflug-Tanguy O. Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients. Eur J Hum Genet. 2004 Jul;12(7):561-6. (http://www.ncbi.nlm.nih.gov/pubmed/15054402?dopt=Abstract)
  • Gene Review: Childhood Ataxia with Central Nervous System Hypomelination/Vanishing White Matter (http://www.ncbi.nlm.nih.gov/books/NBK1258)
  • OMIM: LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER (http://omim.org/entry/603896)
  • Li W, Wang X, Van Der Knaap MS, Proud CG. Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways. Mol Cell Biol. 2004 Apr;24(8):3295-306. (http://www.ncbi.nlm.nih.gov/pubmed/15060152?dopt=Abstract)
  • Pavitt GD. eIF2B, a mediator of general and gene-specific translational control. Biochem Soc Trans. 2005 Dec;33(Pt 6):1487-92. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16246152?dopt=Abstract)
  • Pronk JC, van Kollenburg B, Scheper GC, van der Knaap MS. Vanishing white matter disease: a review with focus on its genetics. Ment Retard Dev Disabil Res Rev. 2006;12(2):123-8. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16807905?dopt=Abstract)
  • Scali O, Di Perri C, Federico A. The spectrum of mutations for the diagnosis of vanishing white matter disease. Neurol Sci. 2006 Sep;27(4):271-7. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16998732?dopt=Abstract)
  • Scheper GC, Proud CG, van der Knaap MS. Defective translation initiation causes vanishing of cerebral white matter. Trends Mol Med. 2006 Apr;12(4):159-66. Epub 2006 Mar 20. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16545608?dopt=Abstract)
  • Schiffmann R, Elroy-Stein O. Childhood ataxia with CNS hypomyelination/vanishing white matter disease--a common leukodystrophy caused by abnormal control of protein synthesis. Mol Genet Metab. 2006 May;88(1):7-15. Epub 2006 Jan 18. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16378743?dopt=Abstract)
  • Schiffmann R, Moller JR, Trapp BD, Shih HH, Farrer RG, Katz DA, Alger JR, Parker CC, Hauer PE, Kaneski CR, et al. Childhood ataxia with diffuse central nervous system hypomyelination. Ann Neurol. 1994 Mar;35(3):331-40. (http://www.ncbi.nlm.nih.gov/pubmed/8122885?dopt=Abstract)
  • van der Voorn JP, van Kollenburg B, Bertrand G, Van Haren K, Scheper GC, Powers JM, van der Knaap MS. The unfolded protein response in vanishing white matter disease. J Neuropathol Exp Neurol. 2005 Sep;64(9):770-5. (http://www.ncbi.nlm.nih.gov/pubmed/16141786?dopt=Abstract)
  • van Kollenburg B, van Dijk J, Garbern J, Thomas AA, Scheper GC, Powers JM, van der Knaap MS. Glia-specific activation of all pathways of the unfolded protein response in vanishing white matter disease. J Neuropathol Exp Neurol. 2006 Jul;65(7):707-15. (http://www.ncbi.nlm.nih.gov/pubmed/16825957?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: May 2013
Published: January 27, 2015