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Childhood Ataxia with Central Nervous System Hypomyelination/Vanishing White Matter

Synonyms: Leukoencephalopathy with Vanishing White Matter, CACH/VWM. Includes: EIF2B1-, EIF2B2-, EIF2B3-, EIF2B4-, and EIF2B5-Related Childhood Ataxia with Central Nervous System Hypomyelination/Vanishing White Matter

, MD, , PhD, , MD, PhD, and , MD, PhD.

Author Information
, MD
Institute of Metabolic Disease
Baylor Research Institute
Dallas, Texas
, PhD
Genetics, Reproduction, and Development Unit
Faculty of Medicine
UMR INSERM 1103 CNRS 6293
Clermont-Ferrand, France
, MD, PhD
Department of Child Neurology
VU University Medical Center
Amsterdam, The Netherlands
, MD, PhD
Reference Center for Leukodystrophies
Department of Child Neurology
Robert Debré University Hospital
University Paris Diderot- Sorbonne Cité
UMR INSERM 676
Paris, France

Initial Posting: ; Last Revision: August 9, 2012.

Summary

Disease characteristics. Childhood ataxia with central nervous system hypomyelination/vanishing white matter disease (CACH/VWM) is characterized by ataxia, spasticity, and variable optic atrophy. The phenotypic range includes a prenatal/congenital form, a subacute infantile form (onset age <1 year), an early childhood onset form (onset age 1-5 years), a late childhood /juvenile onset form (onset age 5-15 years), and an adult onset form. The prenatal/congenital form is characterized by severe encephalopathy. In the later onset forms initial motor and intellectual development is normal or mildly delayed followed by neurologic deterioration with a chronic progressive or subacute course. Chronic progressive decline can be exacerbated by rapid deterioration during febrile illnesses or following head trauma or major surgical procedures, or by acute psychological stresses such as extreme fright.

Diagnosis/testing. The diagnosis of CACH/VWM can be made with confidence in individuals with typical clinical findings, characteristic abnormalities on cranial MRI, and identifiable mutations in one of five genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5), encoding the five subunits of the eukaryotic translation initiation factor 2B (eIF2B). Mutations have been found in approximately 90% of individuals with CACH/VWM using sequence analysis or mutation scanning.

Management. Treatment of manifestations: Physical therapy and rehabilitation for motor dysfunction (mainly spasticity and ataxia); antiepileptic drugs for seizures.

Prevention of secondary complications: Prevention of infections and fever when possible through the use of vaccinations, low-dose maintenance antibiotics during winter, antibiotics for minor infections, and antipyretics for fever. For children, wearing a helmet outside helps minimize the effects of head trauma.

Surveillance: Close monitoring of neurologic status for several days following head trauma or surgical procedures with anesthesia.

Agents/circumstances to avoid: Contact sports, head trauma, stressful situations including high body temperature.

Genetic counseling. CACH/VWM is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutations in an affected relative have been identified.

Diagnosis

Clinical Diagnosis

The diagnosis of childhood ataxia with central nervous system hypomyelination/leukoencephalopathy with vanishing white matter (CACH/VWM) can be made with confidence in individuals with typical clinical findings, characteristic abnormalities on cranial MRI [van der Knaap et al 2006], and identifiable mutations in one of the five genes in which mutation is causative (EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5), encoding the five subunits of the eukaryotic translation initiation factor 2B (eIF2B) [Leegwater et al 2001, van der Knaap et al 2002].

Clinical findings

  • Antenatal/early-infantile forms are characterized by severe encephalopathy; oligohydramnios, intrauterine growth retardation, microcephaly, contractures, cataract, pancreatitis, hepatosplenomegaly, and renal hypoplasia may be present.
  • In all later onset forms initial motor and intellectual development is normal or mildly delayed.
  • Neurologic deterioration has a chronic progressive or subacute course. Episodes of subacute deterioration may follow minor infection or minor head trauma and may lead to lethargy or coma.
  • Clinical examination usually shows a combination of truncal and appendicular ataxia and spasticity with increased tendon reflexes. The peripheral nervous system is usually not involved.
  • Optic atrophy may develop.
  • Epilepsy may occur but is not the predominant sign of the disease except in an acute situation.
  • Intellectual abilities may be affected but not to the same degree as motor functions. Alteration in intellectual abilities associated with behavioral changes can be the initial symptom in adult onset forms.
  • Ovarian dysgenesis may be present as primary or secondary amenorrhea [Fogli et al 2003].

MRI findings

  • The cerebral hemispheric white matter is symmetrically and diffusely abnormal.
  • The abnormal white matter has a signal intensity close to or the same as cerebrospinal fluid (CSF) on T1-weighted (Figure 1), T2-weighted (Figure 2), and fluid-attenuated inversion recovery (FLAIR) (Figure 3) images.
  • On T1-weighted and FLAIR images, a fine meshwork of remaining tissue strands is usually visible within the areas of CSF-like white matter, with a typical radiating appearance on sagittal and coronal images and a dot-like pattern in the centrum semiovale on the transverse images (Figure 4) [van der Knaap et al 2002, van der Knaap et al 2006].
  • The MRI abnormalities are present in all affected individuals regardless of age of onset and are even present in asymptomatic at-risk sibs of a proband. Over time, increasing amounts of white matter vanish and are replaced with CSF; cystic breakdown of the white matter is seen on proton density or FLAIR images [van der Knaap et al 2006]. Cerebellar atrophy varies from mild to severe and primarily involves the vermis.
  • Supratentorial cortico-subcortical atrophy can be observed in adult onset forms with slow progression. Cranial CT scan is of limited use and usually shows diffuse and symmetric hypodensity of the cerebral hemispheric white matter with no calcifications.
MRI of an individual with the classic form of CACH
Figure 1

Figure

MRI of an individual with the classic form of CACH
Figure 1. Diffuse hypointensity of the white matter on T1-weighted images
Figure 2. Increased signal intensity in the same white matter area on T2-weighted images
Figure 3. Secondary (more...)

Figure 4

Figure

Figure 4. Parasagittal T1-weighted MRI image of an individual with CACH shows diffuse hypointensity of the white matter interrupted by a typical meshwork of remaining tissue strands radiating across the abnormal white matter.

Testing

Routine laboratory tests, including CSF analysis, are normal.

Research testing

  • Eukaryotic translation initiation factor 2B (eIF2B) guanine exchange factor (GEF) activity measured in lymphoblastoid cell lines from affected individuals was found to be lower in most persons with mutations in EIF2B1 through EIF2B5 than in control subjects [Fogli et al 2004b]. eIF2B GEF activity assays in lymphoblastoid cell lines from 63 affected persons presenting with different clinical forms and EIF2B mutations showed a significantly decreased GEF activity in cells from EIF2B mutated individuals with 100% specificity and 89% sensitivity when the activity threshold was set at 77.5% of normal [Horzinski et al 2009]. In the early infantile form of the disease (onset age <3 years) the GEF activity was below the threshold of 77.5% of normal. Persons with late onset disease and a wide variety of mutations (Table 1) had higher GEF activity that overlapped with the normal range. A significant decrease of GEF activity has also been reported in the 8/8 EIF2B -mutated lymphoblastoid cell lines and 3/4 fibroblast cell lines analyzed by Liu et al [2011]. However, no correlation between eIF2B GEF activity and disease severity was found in this study. The findings were substantiated by similar results in transfected HEK293 cells [Liu et al 2011]. Thus it can be concluded that if decreased activity is found, CACH/VWM is the most likely diagnosis; but if normal or increased activity is found, CACH/VWM cannot be ruled out.
  • The CSF asialotransferrin/total transferrin ratio was found to be low in persons with genetically confirmed CACH/VWM, a finding that can help identify those likely to have mutations in any of the five genes encoding the eIF2B subunits detected on sequence analysis. Note: This test is cumbersome and may not be generally available.

Molecular Genetic Testing

Genes. The five genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5) that encode the five subunits of the eukaryotic translation initiation factor eIF2B are the genes in which mutations are known to cause CACH/VWM. In an affected individual both alleles are mutated in any one of the involved genes.

Evidence for locus heterogeneity. Approximately 10% of families with CACH/VWM diagnosed by MRI and clinical criteria do not have an identifiable mutation on sequence analysis of EIF2B1- EIF2B5, suggesting the possibility of causative mutations in other genes.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Childhood Ataxia with Central Nervous System Hypomyelination/Vanishing White Matter

Gene SymbolProportion of CACH/VWM Attributed to Mutations in This Gene 1Test MethodMutations DetectedMutation Detection Frequency by Gene and Test Method 2
EIF2B1 2%Sequence analysisSequence variants 3See footnotes 1, 4
Deletion / duplication analysis 5Exonic or whole-gene deletionsUnknown; none reported 6
EIF2B213.6%Sequence analysisSequence variants 3See footnotes 1, 4
Deletion / duplication analysis 5Exonic or whole-gene deletionsUnknown; none reported 6
EIF2B39.1%Sequence analysisSequence variants 3See footnotes 1, 4
Deletion / duplication analysis 5Exonic or whole-gene deletionsUnknown; none reported 6
EIF2B410.6%Sequence analysisSequence variants 3See footnotes 1, 4
Deletion / duplication analysis 5Exonic or whole-gene deletionsUnknown; none reported 6
EIF2B564.7%Sequence analysisSequence variants 3See footnotes 1, 4
Deletion / duplication analysis 5Exonic or whole-gene deletionsUnknown; none reported 6
Targeted mutation analysisc.338G>A, c.584G>A100% for the targeted variants 7

1. In individuals with MRI-confirmed CACH/VWM, mutation detection frequency for all five genes together is ~90% by sequence analysis/mutation scanning [Leegwater et al 2001, van der Knaap et al 2002, van der Knaap et al 2003, Fogli et al 2004a, Ohtake et al 2004, Ohlenbusch et al 2005, Vermeulen et al 2005, Federico et al 2006, Fogli & Boespflug-Tanguy 2006, Kaczorowska et al 2006, Mierzewska et al 2006, Pronk et al 2006, Ramaswamy et al 2006, Scali et al 2006, Denier et al 2007, Huntsman et al 2007, Matsui et al 2007, Passemard et al 2007, Riecker et al 2007, Damon-Perriere et al 2008, Fontenelle et al 2008, Horzinski et al 2008, Jansen et al 2008, Maletkovic et al 2008, Mathis et al 2008, Peter et al 2008, Pineda et al 2008, Labauge et al 2009, Wu et al 2009].

2. The ability of the test method used to detect a mutation that is present in the indicated gene

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected.

4. Approximately 90% of mutations are missense [Fogli et al 2004a]. Affected individuals are homozygotes or compound heterozygotes for mutations within the same gene. Mutations have been found in affected individuals of all ethnic origins [Leegwater et al 2001, Fogli et al 2002b, van der Knaap et al 2002, Fogli et al 2004a].

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. No deletions or duplications involving EIF2B1, EIF2B2, EIF2B3, EIF2B4, or EIF2B5 have been reported as causative of CACH/VWM. Therefore, the mutation detection rate is unknown and may be very low.

7. Targeted mutations may vary by laboratory.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm the diagnosis in a proband

Single gene testing

  • Molecular genetic testing (in order) of EIF2B5, EIF2B2, EIF2B4, EIFB3, and EIF2B1 is recommended. Sequencing of the coding sequence and associated splice sites must be performed.
  • Deletion/duplication analysis would also be useful to perform particularly in individuals with clinical CACH/VWM in whom direct sequencing has failed to identify mutations.

Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having CACH/VWM is use of a multi-gene panel. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Childhood ataxia with central nervous system hypomyelination/vanishing white matter disease (CACH/VWM) phenotypes range from a congenital or early infantile form to a subacute infantile form (onset age <1 year), an early childhood onset form (onset age 1-5 years), a late childhood/juvenile onset form (onset age 5-15 years), and an adult onset form [Fogli & Boespflug-Tanguy 2006]. Both the childhood and juvenile forms have been observed in sibs [Leegwater et al 2001]; the infantile and juvenile/adult forms have never been observed within the same family.

Neurology. The neurologic signs include ataxia, spasticity, and variable optic atrophy. In the early onset forms, the encephalopathy is severe, seizures are often a predominant clinical feature and decline is rapid and followed quickly by death; in the later onset forms, decline is usually slower and milder [van der Knaap et al 2002]. Chronic progressive decline can be exacerbated by rapid deterioration during febrile illness or following minor head trauma or fright [Vermeulen et al 2005, Kaczorowska et al 2006].

Ovarian failure. While the juvenile and adult forms are often associated with primary or secondary ovarian failure, a syndrome referred to as "ovarioleukodystrophy" [Schiffmann et al 1997, Fogli et al 2003], ovarian dysgenesis may occur in any of the forms regardless of age of onset [van der Knaap et al 2003]; it has been found at autopsy in infantile and childhood cases. Because the affected individuals were prepubertal, the ovarian dysgenesis was clinically not manifest.

Antenatal form. The antenatal onset form presents in the third trimester of pregnancy with oligohydramnios and decreased fetal movement [van der Knaap et al 2003]. Clinical features that may be noted soon after birth include feeding difficulties, vomiting, hypotonia, mild contractures, and cataract (sometimes oil droplet cataract) and microcephaly. Apathy, intractable seizures, and finally apneic spells and coma follow. Other organ involvement can include hepatosplenomegaly, renal hypoplasia, pancreatitis, and ovarian dysgenesis.

The clinical course is rapidly and relentlessly downhill; the adverse effect of stress factors is less clear. So far, all infants with neonatal presentation have died within the first year of life [van der Knaap et al 2003].

Infantile form. A rapidly fatal severe form of CACH/VWM is characterized by onset in the first year of life and death a few months later [Francalanci et al 2001, Fogli et al 2002a, Fogli et al 2002b]. Two sisters described by Francalanci et al [2001] developed irritability, stupor, and rapid loss of motor abilities following an intercurrent infection at age ten to 11 months and died at age 21 months.

Another infantile-onset phenotype was described as "Cree leukoencephalopathy" because of its occurrence in the native North American Cree and Chippewayan indigenous population [Fogli et al 2002b]. Infants typically have hypotonia followed by sudden onset of seizures (age 3-6 months), spasticity, rapid breathing, vomiting (often with fever), developmental regression, blindness, lethargy, and cessation of head growth, with death by age two years.

Early childhood onset form. Initially most children develop normally; some have mild motor or speech delay. New-onset ataxia is the most common initial symptom between ages one and five years. Some children develop dysmetric tremor or become comatose spontaneously or acutely following mild head trauma or febrile illness [Schiffmann et al 1994, van der Knaap et al 1997].

Subsequently, generally progressive deterioration results in increasing difficulty in walking, tremor, spasticity with hyperreflexia, dysarthria, and seizures. Once a child becomes nonambulatory, the clinical course may remain stable for several years. Swallowing difficulties and optic atrophy develop late in the disease.

Head circumference is usually normal; however, severe progressive megalencephaly occurring after age two years has been reported [Passemard et al 2007]; microcephaly has also been observed. The peripheral nervous system is usually normal, although predominantly sensory nerve involvement has been reported in recent cases [Federico et al 2006, Huntsman et al 2007]. Intellectual abilities are relatively preserved.

The time course of disease progression varies from individual to individual even within the same family, ranging from rapid progression with death occurring one to five years after onset to very slow progression with death occurring many years after onset.

Late childhood/juvenile onset form. Children develop symptoms between ages five and 15 years. They often have a more slowly progressive spastic diplegia, relative sparing of cognitive ability, and likely long-term survival with long periods of stability and even improvement of motor function [Schiffmann et al 1994, van der Knaap et al 1998]. However, rapid progression and death after a few months have also been described [van der Knaap et al 1998].

Adult onset form. Behavioral problems associated with cognitive decline are frequently reported before neurologic symptoms appear [Labauge et al 2009]. Acute, transient neurologic symptoms (optic neuritis, hemiparesis) or severe headache, as well as primary or secondary amenorrhea in females, can be the presenting symptoms.

Asymptomatic and symptomatic adults with two mutations in one of the genes and a typically affected sibling have also been described [Leegwater et al 2001, Biancheri et al 2003, Ohtake et al 2004, van der Knaap et al 2004].

Neuropathologic findings in general are a "cavitating orthochromatic leukodystrophy with rarity of myelin breakdown and relative sparing of axons” [Fogli et al 2002b]. Vacuolation and cavitation of the white matter are diffuse, giving a spongiform appearance. Cerebral and cerebellar myelin is markedly diminished, whereas the spinal cord is relatively spared. Oligodendrocytes are increased in number [Rodriguez et al 1999, van Haren et al 2004], whereas astrocytes are decreased, especially in the severe infantile form [Francalanci et al 2001]. The hallmark is the presence of oligodendrocytes with "foamy" cytoplasm and markedly hypotrophic and sometimes atypical astrocytes [Wong et al 2000]. The white matter astrocytes and oligodendrocytes are immature and are, in fact, astrocyte and oligodendrocyte precursor cells, explaining the lack of myelin production and scarce gliosis [Bugiani et al 2011].

Genotype-Phenotype Correlations

Although intrafamilial variability exists, correlation between certain homozygous mutations and age of onset and disease severity has been described [Fogli et al 2004a, van der Lei et al 2010]:

Penetrance

Some adults who are homozygous or compound heterozygous for two disease-causing mutations in the same gene may be asymptomatic for prolonged periods of time [van der Knaap et al 2004].

Nomenclature

"Cree leukoencephalopathy," described in the native North American Cree and Chippewayan indigenous population, is now recognized to be the same as the infantile form of CACH/VWM [Fogli et al 2002b].

Prevalence

The prevalence of CACH/VWM is not known; it is considered one of the most common leukodystrophies. In a study of unclassified leukodystrophies in childhood, CACH/VWM was the most common [van der Knaap et al 1999].

In some countries, the incidence of CACH/VWM is close to that of metachromatic leukodystrophy (see Arylsulfatase A Deficiency) [van der Knaap, personal communication].

Differential Diagnosis

Other disorders affecting the white matter diffusely during childhood to consider, with their distinguishing MRI findings:

  • X-linked adrenoleukodystrophy, metachromatic leukodystrophy, Krabbe disease, and Canavan disease. In the cerebral form of X-linked adrenoleukodystrophy and the other three disorders, MRI shows extensive or diffuse cerebral white matter changes but as a rule no cystic degeneration.
  • Alexander disease. In this condition white matter signal changes have a frontal predominance. The cystic degeneration may affect the subcortical or deep white matter. Basal ganglia and thalamic abnormalities are frequently present. Contrast enhancement of characteristic structures often facilitates the diagnosis. The diagnosis can be established with molecular genetic testing.
  • Megalencephalic leukoencephalopathy with subcortical cysts (MLC), characterized by diffusely abnormal and mildly swollen cerebral hemispheric white matter that does not show signs of diffuse rarefaction or cystic degeneration. Subcortical cysts are almost always present in the anterior temporal area and often in other regions. The cysts are best seen on proton density and FLAIR. The diagnosis can usually be established with molecular genetic testing.
  • Mitochondrial disorders, including deficiencies of pyruvate dehydrogenase and pyruvate carboxylase. MRI abnormalities similar to those seen in CACH/VWM with prominent and diffuse white matter rarefaction and cystic degeneration may be seen in mitochondrial disorders [DeLonlay-Debeney et al 2000].
  • PLP1-related disorders (Pelizaeus Merzbacher disease and X-linked spastic paraplegia type 2). Diffuse hyperintensity of the white matter on T2-weighted images is also observed in leukodystrophies with primary hypomyelination, such as the PLP1-related disorders; however, these disorders have a normal or nearly normal white matter signal on T1-weighted images and CT scan. In addition, central nerve conduction evaluated with evoked potentials is always severely affected even at an early stage of the disease.
  • CADASIL, lamin B1 mutations, or acquired white matter disorders such as multiple sclerosis need to be considered in individuals with adult-onset CACH/VWM; however, the early, constant, diffuse, symmetric alteration of the white matter on MRI in eIF2B-related disorders is distinctive.

Further studies are needed to determine if white matter disorders described as orthochromatic leukodystrophies are related to CACH/VWM.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to CACH/VWM, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with childhood ataxia with central nervous system hypomyelination/vanishing white matter disease (CACH/VWM), the following evaluations are recommended:

  • Brain MRI
  • Ophthalmologic examination
  • Neurologic examination
  • Physical therapy/occupational therapy assessment as needed
  • Medical genetics consultation

Treatment of Manifestations

The following are appropriate:

  • Physical therapy and rehabilitation for motor dysfunction (mainly spasticity and ataxia)
  • Ankle-foot orthotics in individuals with hypotonia and weakness of ankle dorsiflexors
  • Antiepileptic drugs for treatment of seizures and abnormalities of behavior and mood

Prevention of Secondary Complications

Considering the known adverse effect of fever, it is important to prevent infections and fever as much as possible (e.g., through the use of vaccinations, including anti-flu vaccination); low-dose maintenance antibiotics during winter time, antibiotics for minor infections, and antipyretics for fever are appropriate. For children, wearing a helmet outside helps minimize the effects of possible head trauma.

Surveillance

Close surveillance for several days following head trauma or major surgical procedure with anesthesia is indicated because neurologic deterioration (presumably stress related) may follow.

Agents/Circumstances to Avoid

Avoid the following:

  • Contact sports and other activities with a high risk of head trauma
  • Stressful emotional and physical situations (e.g., extreme temperatures)

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

In general, corticosteriods and intravenous gamma globulin are not effective in the treatment of CACH/VWM. Corticosteriods have been used with inconsistent results in acute situations, including intractable status epilepticus.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Childhood ataxia with central nervous system hypomyelination/vanishing white matter disease (CACH/VWM) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore each carry a disease-causing allele.
  • Heterozygotes (carriers) are asymptomatic. No clinical or MRI abnormalities have been found in carriers for mutations in EIF2B1-EIF2B5.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Age of onset of neurologic signs can differ from one individual to another within the same family. Therefore, a neurologically asymptomatic sib of an affected individual may be homozygous for the mutation and at high risk of developing the disease. The large majority (if not all) of apparently asymptomatic individuals seem to have the diffuse white matter abnormalities characteristic of the syndrome on head MRI, and may have very mild learning, cognitive, or behavioral disabilities.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic. No clinical or MRI abnormalities have been found in carriers for mutations in EIF2B1-EIF2B5.

Offspring of a proband. The offspring of an individual with CACH/VWM are obligate heterozygotes (carriers) for a disease-causing mutation in EIF2B1-EIF2B5.

Other family members of a proband. Sibs of the proband's parents are at increased risk of being carriers.

Carrier Detection

Carrier testing for at-risk family members is possible once the mutations have been identified in the proband.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of an affected individual and to young adults who are affected or at risk, or are carriers.

Testing of at-risk asymptomatic individuals. Testing of at-risk asymptomatic individuals for CACH/VWM is possible using the techniques described in Molecular Genetic Testing. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. When testing at-risk individuals for CACH/VWM, an affected family member should be tested first to confirm the molecular diagnosis in the family.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified in an affected family member.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk
  • European Leukodystrophy Association (ELA)
    2, rue Mi-les-Vignes
    B.P. 61024
    Laxou Cedex 54521
    France
    Phone: 03833093 34
    Fax: 03833000 68
    Email: ela@ela-asso.com
  • United Leukodystrophy Foundation (ULF)
    2304 Highland Drive
    Sycamore IL 60178
    Phone: 800-728-5483 (toll-free)
    Fax: 815-895-2432
    Email: office@ulf.org
  • Myelin Disorders Bioregistry Project
    Email: myelindisorders@cnmc.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Childhood Ataxia with Central Nervous System Hypomelination/Vanishing White Matter: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Childhood Ataxia with Central Nervous System Hypomelination/Vanishing White Matter (View All in OMIM)

603896LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER; VWM
603945EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 5; EIF2B5
606273EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 3; EIF2B3
606454EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 2; EIF2B2
606686EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 1; EIF2B1
606687EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 4; EIF2B4

Molecular Genetic Pathogenesis

The eukaryotic translation initiation factor eIF2B is composed of five subunits. Its function is to convert protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex, allowing the formation of the 43S complex, precursor of protein translation initiation. It is not yet understood why a defect in eIF2B, a ubiquitous protein complex, affects predominantly the brain white matter. The crucial role of eIF2B as regulator of protein synthesis under stress conditions could explain the neurologic deterioration during or after head trauma and fever [Leegwater et al 2001].

Yeast with null mutations for any of the five genes EIF2B1-EIF2B5 are not viable. Mutations that completely abolish eIF2B activity are probably lethal in the homozygous state in humans; this explains why nonsense mutations are rare and only observed in compound heterozygotes in association with a missense mutation [Leegwater et al 2001, Fogli et al 2002b, van der Knaap et al 2002]. Mutations in EIF2B1-EIF2B5 were shown to decrease the guanine exchange factor (GEF) activity in vitro in yeast and mammalian cellular models. This reduction in activity results from aberrant protein folding, leading to an impaired ability to form functional eIF2B complexes that bind substrate normally [Li et al 2004, Richardson et al 2004, van Kollenburg et al 2006a]. The decrease in GEF activity leads to enhanced translation of specific mRNA of proteins, similar to the situation that occurs when a cell is under stress. Decreased GEF activity of 20%-77% of normal was also found in lymphoblasts of most affected individuals but was normal in obligate heterozygotes [Fogli et al 2004b, Horzinski et al 2009] and some patients [Horzinski et al 2009, Liu et al 2011]. Hyper-induction of ATF4-mediated ER-stress response is variably found in eIF2B-mutated cells [Kantor et al 2005, Kantor et al 2008, Horzinski et al 2010] or brain [van der Voorn et al 2005, van Kollenburg et al 2006b].

Normal allelic variants. See Table 2 (pdf) for exon number and cDNA length of each gene.

Pathologic allelic variants. See Table 3 (pdf) for a listing and frequency of selected pathologic allelic variants of each gene.

Table 4. Selected EIF2B5 Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.271A>Gp.Thr91AlaNM_003907​.2
NP_003898​.2
c.338G>Ap.Arg113His
c.584G>Ap.Arg195His
c.925G>Cp.Val309Leu

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. See Table 5 (pdf) for a description of protein subunits.

Abnormal gene product. See Molecular Genetic Pathogenesis.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

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Suggested Reading

  1. Scheper GC, Proud CG, van der Knaap MS. Defective translation initiation causes vanishing of cerebral white matter. Trends Mol Med. 2006;12:159–66. [PubMed: 16545608]
  2. 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;88:7–15. [PubMed: 16378743]
  3. van der Knaap MS, Bugiani M, Boor I, Proud CG, Scheper GC. Vanishing white matter. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 235.1. New York, NY: McGraw-Hill; 2012. Available online. Accessed 5-21-12.

Chapter Notes

Revision History

  • 9 August 2012 (cd) Revision: multi-gene panel for this disorder now listed in the GeneTests™ Laboratory Directory
  • 24 May 2012 (me) Comprehensive update posted live
  • 9 February 2010 (me) Comprehensive update posted live
  • 30 July 2007 (me) Comprehensive update posted to live Web site
  • 20 February 2003 (me) Review posted to live Web site
  • 19 November 2002 (pb) Original submission
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