ORPHA: 135; DO: 0070372;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p34.1 | Leukoencephalopathy with vanishing white matter 3, with or without ovarian failure | 620313 | Autosomal recessive | 3 | EIF2B3 | 606273 |
A number sign (#) is used with this entry because of evidence that leukoencephalopathy with vanishing white matter-3 (VWM3) is caused by homozygosity or compound heterozygosity for mutation in the EIF2B3 gene (606273) on chromosome 1p34.
Leukoencephalopathy with vanishing white matter-3 (VWM3) is an autosomal recessive leukoencephalopathy characterized by progressive cerebellar ataxia, spasticity, and mental decline. The course is chronic and progressive, with episodes of rapid deterioration following minor head trauma. Affected females may have amenorrhea. Magnetic resonance imaging (MRI) reveals diffuse leukoencephalopathy with lesions having cerebrospinal fluid (CSF)-like signals (summary by Matsukawa et al., 2011).
For a discussion of genetic heterogeneity of VWM, see 603896.
Van der Knaap et al. (2002) studied 2 patients (vwm91 and vwm47) with leukoencephalopathy with vanishing white matter and mutation in the EIF2B3 gene. In both patients, MRI showed symmetrically and diffusely abnormal cerebral hemispheric white matter, signal intensity of part or all of the abnormal white matter close to or the same as cerebrospinal fluid (CSF) on T2-weighted and either proton density or FLAIR images, and a fine meshwork of remaining tissue strands visible within the areas of CSF-like white matter.
Wu et al. (2009) reported 5 children (patients 7-11) with VWM and mutation in the EIF2B3 gene. Four had normal development before disease onset, and the fifth patient had been mildly delayed. Motor signs were the presenting symptoms in all. Four had moderate to severe motor difficulties (either ambulating with assistance or confined to wheelchair or bed) by age 6 years; the fifth child had mild motor difficulties and could ambulate without assistance, with ataxia or gait disturbance. Cognitive difficulties were mild or moderate. The most severely affected patient had seizures and dysarthria. The disorder was noted to be progressive in all.
Matsukawa et al. (2011) reported a 30-year-old Japanese woman (patient 3) with adult-onset leukoencephalopathy with vanishing white matter and mutation in the EIF2B3 gene. She developed secondary amenorrhea at age 28 years, left hemianopia at age 29, and weakness in her left leg after a fall. T1- and T2-weighted MRI showed diffuse hypointense and hyperintense lesions, respectively, in cerebral white matter. Some of the white matter lesions adjacent to the lateral ventricles showed signal intensities identical to those of CSF on FLAIR imaging.
Ghezzi et al. (2012) described a 66-year-old woman with adult-onset vanishing white matter disease and mutation in the EIF2B3 gene. She had a 5-year history of progressive gait impairment and behavioral and cognitive disturbances. She had experienced a rapid worsening of her clinical condition in the 10 days prior to evaluation. Neurologic examination demonstrated lower limb hypertonia, spastic paraparesis, brisk reflexes, positive Babinski sign in her right foot, and ideomotor apraxia. Her medical history was significant for premature ovarian failure at age 24 years, subclinical hypothyroidism, and late-onset diabetes. A brain MRI showed symmetric diffuse signal abnormality in the hemispheric white matter in T2-weighted images, sparing the U fibers. Cortical and subcortical atrophy was also present. Adult-onset vanishing white matter disease was diagnosed.
The transmission pattern of VWM3 in the families reported by Wu et al. (2009) was consistent with autosomal recessive inheritance.
Van der Knaap et al. (2002) identified mutations in the EIF2B3 gene in 2 patients (vwm91 and vwm47) with vanishing white matter. Patient vwm91 was compound heterozygous for a missense mutation (R225Q; 606273.0001) and a 2-bp deletion (606273.0002). Patient vwm47 was homozygous for an ala87-to-val substitution (A87V; 606273.0003).
Wu et al. (2009) identified an ile346-to-thr substitution (I346T; 606273.0004) in the EIF2B3 gene in 4 unrelated Chinese patients with vanishing white matter. Two patients carried the mutation in homozygosity, 1 in compound heterozygosity, and in 1 patient a second mutation could not be identified.
In a 30-year-old Japanese woman (patient 3), born of consanguineous parents, with adult-onset leukoencephalopathy with vanishing white matter, Matsukawa et al. (2011) identified a homozygous c.80T-A transversion in the EIF2B3 gene, resulting in a leu27-to-gln (L27Q) substitution.
In a 66-year old woman with adult-onset vanishing white matter disease, Ghezzi et al. (2012) identified homozygosity for a missense mutation (A87V; 606273.0003) in EIF2B3.
Fogli et al. (2004) measured the guanine nucleotide exchange factor (GEF) activity of EIF2B in transformed lymphocytes from 30 patients with leukoencephalopathies with homozygous or compound heterozygous mutations in EIF2B2, EIF2B3, EIF2B4, and EIF2B5 compared to 10 unaffected heterozygotes and 22 controls with no EIF2B mutation. A significant decrease of 20 to 70% in GEF activity was observed in all mutated cells, and the extent of the decrease correlated with age at onset of disease. Fogli et al. (2004) suggested that a deficiency in GEF activity underlies the encephalopathy in EIF2B-related disease.
Fogli et al. (2004) found that 68 (87%) of 78 families with MRI criteria of leukodystrophy had a mutation in 4 of the EIF2B genes. Forty-two families (62%) had a mutation in the EIF2B5 gene, and 71% had the arg113-to-his mutation (R113H; 603945.0004). Thirteen families (19%), 10 families (15%), and 3 families (4%) had mutations in the EIF2B2, EIF2B4, and EIF2B3 genes, respectively. No mutations were identified in the EIF2B1 gene. Disease onset ranged from 4 months to 30 years of age, with a mean of 3.9 years, and disease severity ranged from no neurologic signs in 2 to death in 24 individuals; there was no correlation between type of mutated gene and the age at onset or disease severity. However, the EIF2B5 R113H mutation and the EIF2B2 glu213-to-gly mutation (E213G; 606454.0001) were significantly associated with milder phenotypes.
Fogli, A., Schiffmann, R., Bertini, E., Ughetto, S., Combes, P., Eymard-Pierre, E., Kaneski, C. R., Pineda, M., Troncoso, M., Uziel, G., Surtees, R., Pugin, D., Chaunu, M. P., Rodriguez, D., Boespflug-Tanguy, O. The effect of genotype on the natural history of eIF2B-related leukodystrophies. Neurology 62: 1509-1517, 2004. [PubMed: 15136673] [Full Text: https://doi.org/10.1212/01.wnl.0000123259.67815.db]
Fogli, A., Schiffmann, R., Hugendubler, L., Combes, P., Bertini, E., Rodriguez, D., Kimball, S. R., Boespflug-Tanguy, O. Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients. Europ. J. Hum. Genet. 12: 561-566, 2004. [PubMed: 15054402] [Full Text: https://doi.org/10.1038/sj.ejhg.5201189]
Ghezzi, L., Scarpini, E., Rango, M., Arighi, A., Bassi, M. T., Tenderini, E., De Riz, M., Jacini, F., Fumagalli, G. G., Pietroboni, A. M., Galimberti, D., Bresolin, N. A 66-year-old patient with vanishing white matter disease due to the p.Ala87Val EIF2B3 mutation. Neurology 79: 2077-2078, 2012. [PubMed: 23115207] [Full Text: https://doi.org/10.1212/WNL.0b013e3182749edc]
Matsukawa, T., Wang, X., Liu, R., Wortham, N. C., Onuki, Y., Kubota, A., Hida, A., Kowa, H., Fukuda, Y., Ishiura, H., Mitsui, J., Takahashi, Y., Aoki, S., Takizawa, S., Shimizu, J., Goto, J., Proud, C. G., Tsuji, S. Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5. Neurogenetics 12: 259-261, 2011. [PubMed: 21484434] [Full Text: https://doi.org/10.1007/s10048-011-0284-7]
van der Knaap, M. S., Leegwater, P. A. J., Konst, A. A. M., Visser, A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C. Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. Ann. Neurol. 51: 264-270, 2002. [PubMed: 11835386] [Full Text: https://doi.org/10.1002/ana.10112]
Wu, Y., Pan, Y., Du, L., Wang, J., Gu, Q., Gao, Z., Li, J., Leng, X., Qin, J., Wu, X., Jiang, Y. Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease. J. Hum. Genet. 54: 74-77, 2009. [PubMed: 19158808] [Full Text: https://doi.org/10.1038/jhg.2008.10]