Childhood Ataxia with Central Nervous System Hypomyelination: EIF2B4 Gene Sequencing

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Condition Description

Childhood ataxia with central nervous system hypomyelination/vanishing white matter disease (CACH/VWM) is characterized by ataxia, spasticity, and variable optic atrophy. The phenotypes range from a prenatal/congenital 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. The prenatal/congenital form is characterized by severe encephalopathy. In the later-onset forms initial motor and mental 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.

The diagnosis of CACH/VWM can be made with confidence in individuals with typical clinical findings, characteristic abnormalities on cranial MRI (cerebral hemispheric white matter that is symmetrically and diffusely abnormal with a signal intensity close to or the same as cerebrospinal fluid), and identifiable mutations in one of five causative genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5) encoding the five subunits of the eucaryotic translation initiation factor, eIF2B. Mutations have been found in approximately 90% of individuals with CACH/VWM using sequence analysis or mutation scanning. Affected individuals are homozygotes or compound heterozygotes for mutations within the same gene. The percentage of mutations found in each gene is as follows: EIF2B1 4%, EIF2B2 15%, EIF2B3 7%, EIF2B4 17%, EIF2B5 57%. Intrafamilial variability exists. Heterozygotes (carriers) are asymptomatic. No clinical or MRI abnormalities have been found in carriers for mutations in EIF2B1-5.

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. "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.

Testing is available for each gene individually or as a panel.

Click here for the GeneTests summary on this condition.

Genes (1)


This test is indicated for:

  • Confirmation of a clinical/biochemical diagnosis of CACH/VWM
  • Carrier testing in adults with a family history of CACH/VWM


Next Generation Sequencing: In-solution hybridization of all coding exons is performed on the patient's genomic DNA. Although some deep intronic regions may also be analyzed, this assay is not meant to interrogate most promoter regions, deep intronic regions, or other regulatory elements, and does not detect single or multi-exon deletions or duplications. Direct sequencing of the captured regions is performed using next generation sequencing. The patient's gene sequences are then compared to a standard reference sequence. Potentially causative variants and areas of low coverage are Sanger-sequenced. Sequence variations are classified as pathogenic, likely pathogenic, benign, likely benign, or variants of unknown significance. Variants of unknown significance may require further studies of the patient and/or family members.


Clinical Sensitivity: Approximately 90% for EIF2B1-5 together. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient's biochemical phenotype.

Analytical Sensitivity: ~99%

Specimen Requirements

When sample fails to meet the acceptable criteria, please call 470.378.2200 and ask to speak with a laboratory genetic counselor (

Submit only 1 of the following specimen types

Preferred specimen type: Whole Blood

Type: Whole Blood

Specimen Requirements:

In EDTA (purple top) tube:
Infants (<2 years): 2-3 ml
Children (>2 years): 3-5 ml
Older Children & Adults: 5-10 ml

Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.

Type: Saliva

Specimen Requirements:

OrageneTM Saliva Collection kit (available through EGL) used according to manufacturer instructions.

Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.

Special Instructions

Submit copies of diagnostic biochemical test results with the sample, if appropriate. Contact the laboratory if further information is needed.

  • Deletion/Duplication analysis of the EIF2B4 gene is available by CGH array for those individuals in whom sequence analysis is negative.
  • Sequence and deletion/duplication analysis of each of the EIF2B1-5 genes is available individually or as a panel for carrier testing in those individuals with a partner who is a known carrier.
  • Custom diagnostic mutation analysis (KM) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
  • Prenatal testing is available to couples who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.

How to Order

Requisition Forms