Childhood ataxia withcentral 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 earlychildhood-onset form (onset age 1-5 years), a late childhood-/juvenile-onsetform (onset age 5-15 years), and an adult-onset form. The prenatal/congenital form is characterized by severe encephalopathy. In the later-onset formsinitial motor and mental development is normal or mildly delayed followed byneurologic deterioration with a chronic progressive or subacute course. Chronicprogressive decline can be exacerbated by rapid deterioration during febrileillnesses or following head trauma or major surgical procedures, or by acutepsychological stresses such as extreme fright.
The diagnosis of CACH/VWMcan be made with confidence in individuals with typical clinical findings,characteristic abnormalities on cranial MRI (cerebral hemispheric white matterthat is symmetrically and diffusely abnormal with a signal intensity close toor the same as cerebrospinal fluid), and identifiable mutations in one of fivecausative 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% ofindividuals with CACH/VWM using sequence analysis or mutation scanning. Affected individuals are homozygotes or compound heterozygotes for mutations within thesame gene.The percentage of mutations found in each gene is as follows: EIF2B1 4%, EIF2B2 15%, EIF2B3 7%, EIF2B4 17%, EIF2B5 57%. Intrafamilialvariability exists. Heterozygotes (carriers) areasymptomatic. No clinical or MRI abnormalities have been found in carriers formutations in EIF2B1-5.
The prevalence of CACH/VWMis not known; it is considered one of the most common leukodystrophies. In astudy of unclassified leukodystrophies in childhood, CACH/VWM was the mostcommon. "Cree leukoencephalopathy," described in the native NorthAmerican Cree and Chippewayan indigenous population, is now recognized to bethe same as the infantile form of CACH/VWM.
Testing is available foreach gene individually or as a panel.
Click here for the GeneTests summary on this condition.
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
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%
Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Orangene™ Saliva Collection Kit used according to manufacturer instructions. Please contact EGL for a Saliva Collection Kit for patients that cannot provide a blood sample.
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
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 EIF2B2 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.