Rare Pediatrics News

Disease Profile

Leukoencephalopathy with vanishing white matter

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Childhood

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ICD-10

E75.2

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Childhood ataxia with diffuse central nervous system hypomyelination; CACH syndrome; CACH/VWM syndrome;

Categories

Congenital and Genetic Diseases

Summary

Leukoencephalopathy with vanishing white matter is a progressive disorder that mainly affects the central nervous system (CNS). This disorder causes deterioration of white matter, which consists of nerve fibers covered by myelin (the substance that protects the nerves). Most affected people begin to have signs and symptoms during childhood, but symptoms may first become apparent anywhere from before birth to adulthood. Symptoms may include difficulty coordinating movements (ataxia); muscle stiffness (spasticity); and optic atrophy. Symptoms may worsen rapidly with episodes of fever, after head trauma, or with other stresses on the body. This disorder may be caused by mutations in any of 5 genes and is inherited in an autosomal recessive manner. There is no specific treatment, and prognosis seems to correlate with the age of onset, the earliest forms being more severe.[1][2][3]

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
30%-79% of people have these symptoms
Juvenile onset
Signs and symptoms begin before 15 years of age
0003621
Macrocephaly
Increased size of skull
Large head
Large head circumference

[ more ]

0000256
5%-29% of people have these symptoms
Blindness
0000618
Percent of people who have these symptoms is not available through HPO
Autosomal recessive inheritance
0000007
Cerebral hypomyelination
0006808
Cessation of head growth
Head stopped growing
0004485
CNS demyelination
0007305
Decreased circulating progesterone
Decreased serum progesterone
0008233
Delusions
0000746
Developmental regression
Loss of developmental milestones
Mental deterioration in childhood

[ more ]

0002376
Dysarthria
Difficulty articulating speech
0001260
Emotional lability
Emotional instability
0000712
Fever
0001945
Gait disturbance
Abnormal gait
Abnormal walk
Impaired gait

[ more ]

0001288
Generalized hypotonia
Decreased muscle tone
Low muscle tone

[ more ]

0001290
Gliosis
0002171
Lethargy
0001254
Leukoencephalopathy
0002352
Memory impairment
Forgetfulness
Memory loss
Memory problems
Poor memory

[ more ]

0002354
Muscular hypotonia
Low or weak muscle tone
0001252
Optic atrophy
0000648
Personality changes
Personality change
0000751
Premature ovarian insufficiency
Early menopause
Premature menopause
Premature ovarian failure

[ more ]

0008209
Primary amenorrhea
0000786
Primary gonadal insufficiency
0008193
Secondary amenorrhea
Previous menstrual periods stop
0000869
Seizure
0001250
Spasticity
Involuntary muscle stiffness, contraction, or spasm
0001257
Unsteady gait
Unsteady walk
0002317

Cause

Leukoencephalopathy with vanishing white matter is a genetic condition caused by mutations in any of 5 genes EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5. These genes give the body instructions to make the five parts (subunits) of a protein called eIF2B. This protein helps regulate overall production of protein in cells (protein synthesis). Proper regulation of protein synthesis ensures that the correct levels of protein are available for cells to cope with changing conditions and stress.

Mutations in any of these 5 genes results in partial loss of eIF2B function, making it more difficult for 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, thus causing the signs and symptoms of this condition.[1]

Approximately 90% of affected people have been found to have mutations in one of these 5 genes. Approximately 10% of families who have been diagnosed by MRI and clinical features do not have an identifiable mutation, suggesting that additional genes may also be responsible for the condition.[2]

Diagnosis

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

    Treatment

    Treatment for leukoencephalopathy with vanishing white matter is supportive, aiming to alleviate symptoms. Management may include physical therapy and rehabilitation for motor dysfunction (mainly spasticity and ataxia); and antiseizure medications for seizures.[2]

    Infections and fevers should be prevented when possible through the use of vaccinations; low-dose maintenance antibiotics during winter months; antibiotics for minor infections; and antipyretics (fever-reducing medications) for fever. For children, wearing a helmet outside can help minimize the effects of head trauma. Contact sports, head trauma, and stressful situations (including high body temperature) should be avoided.[2]

    More detailed information about the management of leukoencephalopathy with vanishing white matter is available on the GeneReviews Web site.

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Providing General Support

      Learn more

      These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

      Where to Start

      • MedlinePlus Genetics contains information on Leukoencephalopathy with vanishing white matter. This website is maintained by the National Library of Medicine.

        In-Depth Information

        • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
        • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
        • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
        • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
          Orphanet
          Orphanet
        • PubMed is a searchable database of medical literature and lists journal articles that discuss Leukoencephalopathy with vanishing white matter. Click on the link to view a sample search on this topic.

          References

          1. Leukoencephalopathy with vanishing white matter. Genetics Home Reference. May, 2013; https://ghr.nlm.nih.gov/condition/leukoencephalopathy-with-vanishing-white-matter.
          2. Raphael Schiffmann, Anne Fogli, Marjo S van der Knaap, and Odile Boespflug-Tanguy. Childhood Ataxia with Central Nervous System Hypomyelination/Vanishing White Matter. GeneReviews. August 9, 2012; https://www.ncbi.nlm.nih.gov/books/NBK1258/.
          3. Odile Boespflug-Tanguy, Anne Fogli, Pierre Labauge, Florence Niel Buetschi, and Diana Rodriguez. CACH syndrome. Orphanet. September, 2007; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=135.

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