ORPHA: 135; DO: 0070373;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q24.3 | Leukoencephalopathy with vanishing white matter 2, with or without ovarian failure | 620312 | Autosomal recessive | 3 | EIF2B2 | 606454 |
A number sign (#) is used with this entry because of evidence that leukoencephalopathy with vanishing white matter-2 (VWM2) is caused by homozygous or compound heterozygous mutation in the EIF2B2 gene (606454) on chromosome 14q24.
Leukoencephalopathy with vanishing white matter-2 (VWM2) is a chronic and progressive autosomal recessive leukoencephalopathy characterized by neurologic deterioration with cerebellar ataxia, spasticity, and relatively mild mental decline. Severity ranges from onset at birth with death in infancy to mild cases with later and even adult onset. Initial development may be normal. Episodes of rapid deterioration occur following febrile infection or minor head trauma. Death occurs after a variable period usually of a few years to a few decades, usually following an episode of fever and coma. Affected females may have ovarian failure manifest as primary or secondary amenorrhea. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy are diagnostic and show a diffuse abnormality of the cerebral white matter beginning in the presymptomatic stage, with increasing amounts of the abnormal white matter vanishing and being replaced by cerebrospinal fluid; autopsy confirms these findings (summary by Leegwater et al., 2001, van der Knaap et al., 2003).
For a discussion of genetic heterogeneity of VWM, see 603896.
Leegwater et al. (2001) reported 2 distantly related patients (vwm63 and vwm203) with VWM and mutation in the EIF2B2 gene. The majority of the patients' ancestors originated from the same small area of the southern Netherlands.
Fogli et al. (2003) reported 2 unrelated patients (944 and 992) with mutation in the EIF2B2 gene who had white matter abnormalities observed on cerebral MRI and ovarian failure confirmed by findings of high basal gonadotrophin levels and low estrogen and progesterone levels. Both walked at age 12 months and had normal speech development but had school difficulties. Patient 944 was 33 years of age and had spasticity, gait instability at age 25 years with walker use by age 30, sphincter dysfunction at age 26, and optic atrophy with visual motor difficulties and vision loss after an acute episode at age 28 years. Menarche occurred at age 14 years, but she never acquired regular menstrual cycles. Secondary amenorrhea occurred at age 26 years, and atrophied ovaries were seen on ultrasonography. Her IQ was measured at 65 at age 30 years. Patient 992 was 16 years of age and had severe spasticity with gait instability by age 10 and walker use at age 16; dysarthria developed at age 14 years. She had primary amenorrhea, but no imaging of her ovaries had been performed. Her IQ had not been evaluated, but no deterioration had been observed. In this report Fogli et al. (2003) identified 8 patients from 7 families with the association of ovarian failure with white matter abnormalities.
Van der Knaap et al. (2003) described 3 sisters (patients 1-3), born of unrelated parents, with VWM and mutation in the EIF2B2 gene. In patient 1, decreased movements and oligohydramnios were noted late in gestation. Hypotonia and low body temperature were present after birth at 38 weeks' gestation, blood sugars were just below normal, and congenital dislocation of the hips was present. She was an irritable baby, and after 3 months of age her condition deteriorated, with intractable seizures, feeding difficulties, hypotonia, apathy, and finally coma and respiratory failure. On physical examination, she had hepatosplenomegaly, oil-droplet cataracts, hypotonia, and brisk reflexes. Liver biopsy revealed markedly increased smooth endoplasmic reticulum, decreased glycogen stores, and reactive Kupffer cells, but otherwise intact architecture. Patient 1 died at the age of 8 months, and her similarly affected sisters died at 4.5 and 5 months of age.
Matsukawa et al. (2011) reported a 56-year-old Japanese woman, born of consanguineous parents, with adult-onset leukoencephalopathy with vanishing white matter and mutation in the EIF2B2 gene. She had a history of amenorrhea and juvenile cataracts in her twenties, and developed progressive unsteadiness of the upper and lower limbs at age 43. Forgetfulness appeared at age 54.
The transmission pattern of VWM2 in the families reported by Leegwater et al. (2001) was consistent with autosomal recessive inheritance.
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.
In 2 distantly related individuals (vwm63 and vwm203) with VWM2, Leegwater et al. (2001) found homozygosity for an glu213-to-gly (E213G) mutation in the EIF2B2 gene (606454.0001). Heterozygosity for the same mutation was found in a patient from the United States (vwm206) who shared a part of the haplotype on 14q24 with the homozygous patients observed in Europe, suggesting a familial relationship. The second mutation predicted a V316D amino acid substitution (606454.0002). The Dutch patients with VWM due to the mutation in EIF2B2 came from the southern part of the Netherlands rather than the eastern part, where the patients with the T91A mutation in the EIF2B5 gene (603945.0001) lived.
In 2 patients with ovarioleukodystrophy, Fogli et al. (2003) identified compound heterozygosity for mutations in the EIF2B2 gene. Patient 992 carried the E213G mutation with an arg183 to ter mutation (R183X; 606454.0003) on the opposite allele. Patient 944 carried a ser171-to-phe mutation (S171F; 606454.0004) and a 6-bp deletion (ATGGCT)/2-bp insertion (TG) at nucleotide 607, resulting in a frameshift at met203 (606454.0005). The mutations were not found in a control group composed of 320 chromosomes of individuals from the same populations, which were of northern European and North African descent.
In 56-year-old Japanese woman, born of consanguineous parents, with adult-onset leukoencephalopathy with vanishing white matter, Matsukawa et al. (2011) identified a homozygous c.375T-A transversion in the EIF2B2 gene, resulting in a val85-to-glu (V85E; 606454.0006) substitution. She had a history of amenorrhea and juvenile cataracts in her twenties, and developed progressive unsteadiness of the upper and lower limbs at age 43. Forgetfulness appeared at age 54. In vitro functional expression studies showed that the GDP/GTP exchange activity of eIF2B containing mutant EIF2B2 was significantly decreased (20% decrease) compared to wildtype, although the decrease was not as much as observed in mutations associated with childhood-onset VWM. The findings suggested that mutations that result in residual eIF2B activity may be associated with a later age at disease onset.
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., Rodriguez, D., Eymard-Pierre, E., Bouhour, F., Labauge, P., Meaney, B. F., Zeesman, S., Kaneski, C. R., Schiffmann, R., Boespflug-Tanguy, O. Ovarian failure related to eukaryotic initiation factor 2B mutations. Am. J. Hum. Genet. 72: 1544-1550, 2003. [PubMed: 12707859] [Full Text: https://doi.org/10.1086/375404]
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]
Leegwater, P. A. J., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulders, J., Visser, A., Kersbergen, P., Mobach, D., Fonds, D., van Berkel, C. G. M., Lemmers, R. J. L. F., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. Nature Genet. 29: 383-388, 2001. [PubMed: 11704758] [Full Text: https://doi.org/10.1038/ng764]
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., van Berkel, C. G. M., Herms, J., van Coster, R., Baethmann, M., Naidu, S., Boltshauser, E., Willemsen, M. A. A. P., Plecko, B., Hoffmann, G. F., Proud, C. G., Scheper, G. C., Pronk, J. C. eIF2B-related disorders: antenatal onset and involvement of multiple organs. Am. J. Hum. Genet. 73: 1199-1207, 2003. [PubMed: 14566705] [Full Text: https://doi.org/10.1086/379524]