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.

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

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. This cumbersome test measuring CSF asialotransferrin/total transferrin ratio is available on a research basis only.

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

View in own window

Gene Symbol	Proportion of CACH/VWM Attributed to Mutations in This Gene 1	Test Method	Mutations Detected	Mutation Detection Frequency by Gene and Test Method 2	Test Availability
EIF2B1	2%	Sequence analysis	Sequence variants 3	See footnotes 1, 4	Clinical
		Deletion / duplication analysis 5	Exonic or whole-gene deletions	Unknown; none reported 6
EIF2B2	13.6%	Sequence analysis	Sequence variants 3	See footnotes 1, 4	Clinical
		Deletion / duplication analysis 5	Exonic or whole-gene deletions	Unknown; none reported 6
EIF2B3	9.1%	Sequence analysis	Sequence variants 3	See footnotes 1, 4	Clinical
		Deletion / duplication analysis 5	Exonic or whole-gene deletions	Unknown; none reported 6
EIF2B4	10.6%	Sequence analysis	Sequence variants 3	See footnotes 1, 4	Clinical
		Deletion / duplication analysis 5	Exonic or whole-gene deletions	Unknown; none reported 6
EIF2B5	64.7%	Sequence analysis	Sequence variants 3	See footnotes 1, 4	Clinical
		Deletion / duplication analysis 5	Exonic or whole-gene deletions	Unknown; none reported 6
		Targeted mutation analysis	c.338G>A, c.584G>A	100% for the targeted variants 7

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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. See CMA.

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

• 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.

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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Thus far, all individuals with eIF2B-related disease have a leukodystrophy; no other phenotypes have been observed.

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]:

• In individuals homozygous for the p.Thr91Ala mutation in EIF2B5, the phenotype may vary from childhood onset to adults with no symptoms [Leegwater et al 2001].

• The neonatal onset form is characterized by a more diffuse encephalopathy with failure of development and serious seizures [van der Knaap et al 2003].

• Certain EIF2B5 homozygous mutations, such as p.Arg113His, never give rise to the infantile type [Fogli et al 2004a].

• Certain EIF2B5 mutations, such as p.Val309Leu, are predictably associated with severe disease [Fogli et al 2004a].

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].

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.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

Myelin Disorders Bioregistry Project
Phone: 202-476-6230
Email: myelin@cnmc.org
Web: www.myelindisorders.org

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.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 available on a clinical basis 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 available 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. See for a list of laboratories offering DNA banking.

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 available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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.

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

Abnormal gene product. See Molecular Genetic Pathogenesis.

Literature Cited

1. Biancheri R, Rossi A, Di Rocco M, Filocamo M, Pronk JC, van der Knaap MS, Tortori-Donati P. Leukoencephalopathy with vanishing white matter: an adult onset case. Neurology. 2003;61:1818–9. [PubMed: 14694060]
2. Bugiani M, Boor I, van Kollenburg B, Postma N, Polder E, van Berkel C, van Kesteren RE, Windrem MS, Hol EM, Scheper GC, Goldman SA, van der Knaap MS. Defective Glial Maturation in Vanishing White Matter Disease. J Neuropathol Exp Neurol. 2011;70:69–82. [PubMed: 21157376]
3. Damon-Perriere N, Menegon P, Anne O, Boespflug-Tanguy O, Niel F, Creveaux I, Dousset V, Brochet B, Goizet C. Intra-familial phenotypic heterogeneity in adult onset vanishing white matter disease. Clinical Neurology and Neurosurgery. 2008;110:1068–71. [PubMed: 18845387]
4. DeLonlay-Debeney P, von Kleist-Retzow JC, Hertz-Pannier L, Peudenier S, Cormier-Daire V, Berquin P, Chretien D, Rotig A, Saudubray JM, Baraton J, Brunelle F, Rustin P, van der Knaap MS, Munnich A. Cerebral white matter disease in children may be caused by mitochondrial respiratory chain deficiency. J Pediatr. 2000;136:209–14. [PubMed: 10657827]
5. Denier C, Orgibet A, Roffi F, Jouvent E, Buhl C, Niel F, Boespflug-Tanguy O, Said G, Ducreux D. Adult-onset vanishing white matter leukoencephalopathy presenting as psychosis. Neurology. 2007;68:1538–9. [PubMed: 17470759]
6. Federico A, Scali O, Stromillo ML, Di Perri C, Bianchi S, Sicurelli F, De Stefano N, Malandrini A, Dotti MT. Peripheral neuropathy in vanishing white matter disease with a novel EIF2B5 mutation. Neurology. 2006;67:353–5. [PubMed: 16864840]
7. Fogli A, Boespflug-Tanguy O. The large spectrum of eIF2B-related diseases. Biochem Soc Trans. 2006;34:22–9. [PubMed: 16246171]
8. Fogli A, Dionisi-Vici C, Deodato F, Bartuli A, Boespflug-Tanguy O, Bertini E. A severe variant of childhood ataxia with central hypomyelination/vanishing white matter leukoencephalopathy related to EIF21B5 mutation. Neurology. 2002a;59:1966–8. [PubMed: 12499492]
9. Fogli A, Rodriguez D, Eymard-Pierre E, Bouhour F, Labauge P, Meaney BF, Zeesman S, Kaneski CR, Schiffmann R, Boespflug-Tanguy O. Ovarian failure related to eukaryotic initiation factor 2B mutations. Am J Hum Genet. 2003;72:1544–50. [PMC free article: PMC1180314] [PubMed: 12707859]
10. Fogli A, Schiffmann R, Bertini E, Ughetto S, Combes P, Eymard-Pierre E, Kaneski CR, Pineda M, Troncoso M, Uziel G, Surtees R, Pugin D, Chaunu MP, Rodriguez D, Boespflug-Tanguy O. The effect of genotype on the natural history of eIF2B-related leukodystrophies. Neurology. 2004a;62:1509–17. [PubMed: 15136673]
11. 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. 2004b;12:561–6. [PubMed: 15054402]
12. Fogli A, Wong K, Eymard-Pierre E, Wenger J, Bouffard JP, Goldin E, Black DN, Boespflug-Tanguy O, Schiffmann R. Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus. Ann Neurol. 2002b;52:506–10. [PubMed: 12325082]
13. Fontenelle LM, Scheper GC, Brandão L, van der Knaap MS. Atypical presentation of vanishing white matter disease. Arq Neuropsiquiatr. 2008;66:549–51. [PubMed: 18813718]
14. Francalanci P, Eymard-Pierre E, Dionisi-Vici C, Boldrini R, Piemonte F, Virgili R, Fariello G, Bosman C, Santorelli FM, Boespflug-Tanguy O, Bertini E. Fatal infantile leukodystrophy: a severe variant of CACH/VWM syndrome, allelic to chromosome 3q27. Neurology. 2001;57:265–70. [PubMed: 11468311]
15. Horzinski L, Gonthier C, Rodriguez D, Scherer C, Boespflug-Tanguy O, Fogli A. Exon deletion in the non catalytic domain of eIF2Bε due to a splice site mutation leads to infantile forms of CACH/VWM with severe decrease of eIF2B GEF activity. Ann Hum Genet. 2008;72:410–5. [PubMed: 18294360]
16. Horzinski L, Huyghe A, Cardoso MC, Gonthier C, Ouchchane L, Schiffmann R, Blanc P, Boespflug-Tanguy O, Fogli A. Eukaryotic initiation factor 2B (eIF2B) GEF activity as a diagnostic tool for EIF2B-related disorders. PLoS One. 2009;4:e8318. [PMC free article: PMC2789406] [PubMed: 20016818]
17. Horzinski L, Kantor L, Huyghe A, Schiffmann R, Elroy-Stein O, Boespflug-Tanguy O, Fogli A. Evaluation of the endoplasmic reticulum-stress response in eIF2B-mutated lymphocytes and lymphoblasts from CACH/VWM patients. BMC Neurol. 2010;10:94. [PMC free article: PMC2967530] [PubMed: 20958979]
18. Huntsman RJ, Seshia S, Lowry N, Lemire EG, Harder SL. Peripheral neuropathy in a child with Cree leukodystrophy. J Child Neurol. 2007;22:766–8. [PubMed: 17641267]
19. Jansen AC, Andermann E, Niel F, Creveaux I, Boespflug-Tanguy O, Andermann F. Leucoencephalopathy with vanishing white mater may cause progressive myoclonus epilepsy. Epilepsia. 2008;49:910–3. [PubMed: 18266750]
20. Kaczorowska M, Kuczynski D, Jurkiewicz E, Scheper GC, van der Knaap MS, Jozwiak S. Acute fright induces onset of symptoms in vanishing white matter disease-case report. Eur J Paediatr Neurol. 2006;10:192–3. [PubMed: 16952472]
21. Kantor L, Harding HP, Ron D, Schiffmann R, Kaneski CR, Kimball SR, Elroy-Stein O. Heightened stress response in primary fibroblasts expressingmutant eIF2B genes from CACH/VWM leukodystrophy patients. Hum Genet. 2005;118:99–106. [PubMed: 16041584]
22. Kantor L, Pinchasi D, Mintz M, Hathout Y, Vanderver A, Elroy-Stein O. A point mutation in translation initiation factor 2B leads to a continuous hyper stress state in oligodendroglial-derived cells. PLoS ONE. 2008;3:e3783. [PMC free article: PMC2583043] [PubMed: 19023445]
23. Labauge P, Horzinski L, Ayrignac X, Blanc P, Vukusic S, Rodriguez D, Mauguiere F, Peter L, Goizet C, Bouhour F, Denier C, Confavreux C, Obadia M, Blanc F, de Sèze J, Fogli A, Boespflug-Tanguy O. Natural history of adult-onset eIF2B-related disorders: a multi-centric survey of 16 cases. Brain. 2009;132:2161–9. [PubMed: 19625339]
24. Leegwater PA, Vermeulen G, Konst AA, Naidu S, Mulders J, Visser A, Kersbergen P, Mobach D, Fonds D, van Berkel CG, Lemmers RJ, Frants RR, Oudejans CB, Schutgens RB, Pronk JC, van der Knaap MS. Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. Nat Genet. 2001;29:383–8. [PubMed: 11704758]
25. 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;24:3295–306. [PMC free article: PMC381664] [PubMed: 15060152]
26. Liu AR, van der Lei HD, Wang X, Wortham NC, Tang H, van Berkel CG, Mufunde TA, Huang W, van der Knaap MS, Scheper GC, Proud CG. Severity of Vanishing White Matter disease does not correlate with deficits in eIF2B activity or the integrity of eIF2B complexes. Hum Mutat. 2011 [PubMed: 21560189]
27. Maletkovic J, Schiffmann R, Gorospe F, Gordon ES, Mintz M, Hoffman EP, Alper G, Lynch DR, Singhal BS, Harding C, Amartino H, Brown CM, Chan A, Renaud D, Geraghty M, Jensen L, Senbil N, Kadom N, Nazarian J, Feng Y, Wang Z, Hartka T, Morizono H, Vanderver A. Genetic and clinical heterogeneity in eIF2B-related disorder. J Child Neurol. 2008;23:205–15. [PubMed: 18263758]
28. Mathis S, Scheper GC, Baumann N, Petit E, Gil R, van der Knaap MS, Neau JP. The ovarioleukodystrophy. Clin Neurol Neurosurg. 2008;110:1035–7. [PubMed: 18678442]
29. Matsui M, Mizutani K, Ohtake H, Miki Y, Ishizu K, Fukuyama H, Shimohata T, Onodera O, Nishizawa M, Takayama Y, Shibasaki H. Novel mutation in EIF2B gene in a case of adult-onset leukoencephalopathy with vanishing white matter. Eur Neurol. 2007;57:57–8. [PubMed: 17119336]
30. Mierzewska H, van der Knaap MS, Scheper GC, Jurkiewicz E, Schmidt-Sidor B, Szymanska K. Leukoencephalopathy with vanishing white matter due to homozygous EIF2B2 gene mutation. First Polish cases. Folia Neuropathologica. 2006;44:144–8. [PubMed: 16823698]
31. Ohlenbusch A, Henneke M, Brockmann K, Goerg M, Hanefeld F, Kohlschütter A, Gärtner J. Identification of ten novel mutations in patients with eIF2B-related disorders. Hum Mutat. 2005;25:411. [PubMed: 15776425]
32. Ohtake H, Shimohata T, Terajima K, Kimura T, Jo R, Kaseda R, Iizuka O, Takano M, Akaiwa Y, Goto H, Kobayashi H, Sugai T, Muratake T, Hosoki T, Shioiri T, Okamoto K, Onodera O, Tanaka K, Someya T, Nakada T, Tsuji S. Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2B5. Neurology. 2004;62:1601–3. [PubMed: 15136690]
33. Passemard S, Gelot A, Fogli A, N'Guyen S, Barnerias C, Niel F, Doummar D, Arbues AS, Mignot C, de Villemeur TB, Ponsot G, Boespflug-Tanguy O, Rodriguez D. Progressive megalencephaly due to specific EIF2Bepsilon mutations in two unrelated families. Neurology. 2007;69:400–2. [PubMed: 17646634]
34. Peter L, Niel F, Catenoix H, Jung J, Demarquay G, Petiot P, Rudigoz RC, Boespflug-Tanguy O, Ryvlin P, Mauguière F. Acute neurological deterioration in ovarioleukodystrophy related to EIF2B mutations: pregnancy with oocyte donation is a potentially precipitating factor. Eur J Neurol. 2008;15:94–97. [PubMed: 18005052]
35. Pineda M, Palmero A, Baquero M, O’Callaghan M, Aracil A, van der Knaap MS, Scheper GC. Vanishing white matter disease associated with progressive macrocephaly. Neuropediatrics. 2008;39:29–32. [PubMed: 18504679]
36. 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;12:123–8. [PubMed: 16807905]
37. Ramaswamy V, Chan AK, Kolski H. Vanishing white matter disease with periodic (paroxysmal) hemiparesis. Pediatr Neurol. 2006;35:65–8. [PubMed: 16814090]
38. Richardson JP, Mohammad SS, Pavitt GD. Mutations causing childhood ataxia with central nervous system hypomyelination reduce eukaryotic initiation factor 2B complex formation and activity. Mol Cell Biol. 2004;24:2352–63. [PMC free article: PMC355856] [PubMed: 14993275]
39. Riecker A, Nägele T, Henneke M, Schöls L. Late onset vanishing white matter disease. J Neurol. 2007;254:544–5. [PubMed: 17401526]
40. Rodriguez D, Gelot A, della Gaspera B, Robain O, Ponsot G, Sarlieve LL, Ghandour S, Pompidou A, Dautigny A, Aubourg P, Pham-Dinh D. Increased density of oligodendrocytes in childhood ataxia with diffuse central hypomyelination (CACH) syndrome: neuropathological and biochemical study of two cases. Acta Neuropathol (Berl). 1999;97:469–80. [PubMed: 10334484]
41. Scali O, Di Perri C, Federico A. The spectrum of mutations for the diagnosis of vanishing white matter disease. Neurol Sci. 2006;27:271–7. [PubMed: 16998732]
42. 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;35:331–40. [PubMed: 8122885]
43. Schiffmann R, Tedeschi G, Kinkel RP, Trapp BD, Frank JA, Kaneski CR, Brady RO, Barton NW, Nelson L, Yanovski JA. Leukodystrophy in patients with ovarian dysgenesis. Ann Neurol. 1997;41:654–61. [PubMed: 9153528]
44. van der Knaap MS, Barth PG, Gabreels FJ, Franzoni E, Begeer JH, Stroink H, Rotteveel JJ, Valk J. A new leukoencephalopathy with vanishing white matter. Neurology. 1997;48:845–55. [PubMed: 9109866]
45. van der Knaap MS, Kamphorst W, Barth PG, Kraaijeveld CL, Gut E, Valk J. Phenotypic variation in leukoencephalopathy with vanishing white matter. Neurology. 1998;51:540–7. [PubMed: 9710032]
46. van der Knaap MS, Leegwater PA, Konst AA, Visser A, Naidu S, Oudejans CB, Schutgens RB, Pronk JC. Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. Ann Neurol. 2002;51:264–70. [PubMed: 11835386]
47. van der Knaap MS, Leegwater PA, van Berkel CG, Brenner C, Storey E, Di Rocco M, Salvi F, Pronk JC. Arg113His mutation in eIF2Bepsilon as cause of leukoencephalopathy in adults. Neurology. 2004;62:1598–600. [PubMed: 15136689]
48. van der Knaap MS, Pronk JC, Scheper GC. Vanishing white matter disease. Lancet Neurol. 2006;5:413–23. [PubMed: 16632312]
49. van der Knaap MS, van Berkel CG, Herms J, van Coster R, Baethmann M, Naidu S, Boltshauser E, Willemsen MA, Plecko B, Hoffmann GF, Proud CG, Scheper GC, Pronk JC. eIF2B-related disorders: antenatal onset and involvement of multiple organs. Am J Hum Genet. 2003;73:1199–207. [PMC free article: PMC1180499] [PubMed: 14566705]
50. van der Knaap MS, Breiter SN, Naidu S, Hart AA, Valk J. Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach. Radiology. 1999;213:121–33. [PubMed: 10540652]
51. van der Lei HD, van Berkel CG, van Wieringen WN, Brenner C, Feigenbaum A, Mercimek-Mahmutoglu S, Philippart M, Tatli B, Wassmer E, Scheper GC, van der Knaap MS. Genotype-phenotype correlation in vanishing white matter disease. Neurology. 2010;75:1555–9. [PubMed: 20975056]
52. 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;64:770–5. [PubMed: 16141786]
53. Van Haren K, van der Voorn JP, Peterson DR, van der Knaap MS, Powers JM. The life and death of oligodendrocytes in vanishing white matter disease. J Neuropathol Exp Neurol. 2004;63:618–30. [PubMed: 15217090]
54. van Kollenburg B, Thomas AA, Vermeulen G, Bertrand GA, van Berkel CG, Pronk JC, Proud CG, van der Knaap MS, Scheper GC. Regulation of protein synthesis in lymphoblasts from vanishing white matter patients. Neurobiol Dis. 2006a;21:496–504. [PubMed: 16185887]
55. 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. 2006b;65:707–15. [PubMed: 16825957]
56. Vermeulen G, Seidl R, Mercimek-Mahmutoglu S, Rotteveel JJ, Scheper GC, van der Knaap MS. Fright is a provoking factor in vanishing white matter disease. Ann Neurol. 2005;57:560–3. [PubMed: 15786451]
57. Wong K, Armstrong RC, Gyure KA, Morrison AL, Rodriguez D, Matalon R, Johnson AB, Wollmann R, Gilbert E, Le TQ, Bradley CA, Crutchfield K, Schiffmann R. Foamy cells with oligodendroglial phenotype in childhood ataxia with diffuse central nervous system hypomyelination syndrome. Acta Neuropathol (Berl). 2000;100:635–46. [PubMed: 11078215]
58. Wu Y, Pan Y, Du L, Wang J, Gu Q, Gao Z, Li Z, Leng X, Qin J, Wu X, Jiang Y. Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease. J Hum Genet. 2009;54:74–7. [PubMed: 19158808]

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 Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 235.1. New York, NY: McGraw-Hill; 2012. Available at www.ommbid.com. Accessed 5-21-12.

Revision History

• 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