Alternative titles; symbols
ORPHA: 135, 157713, 157716, 157719, 99853, 99854; DO: 0070374;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q24.31 | Leukoencephalopathy with vanishing white matter 1, with or without ovarian failure | 603896 | Autosomal recessive | 3 | EIF2B1 | 606686 |
A number sign (#) is used with this entry because of evidence that leukoencephalopathy with vanishing white matter-1 (VWM1) is caused by homozygous or compound heterozygous mutation in the EIF2B1 gene (606686) on chromosome 12q24.
Leukoencephalopathy with vanishing white matter is an autosomal recessive neurologic disorder characterized by variable neurologic features, including progressive cerebellar ataxia, spasticity, and cognitive impairment associated with white matter lesions on brain imaging. Age at onset ranges from early infancy to adulthood. Rapid neurologic deterioration can occur following minor head trauma. Female mutation carriers may additionally develop ovarian failure, manifest as primary amenorrhea or as secondary amenorrhea lasting more than 6 months, associated with elevated gonadotropin levels at age less than 40 years (summary by Van der Knaap et al., 1998 and Schiffmann et al., 1997). The association of vanishing white matter leukodystrophy with ovarian failure had been referred to as 'ovarioleukodystrophy.'
Genetic Heterogeneity of Leukoencephalopathy with Vanishing White Matter
Leukoencephalopathy with vanishing white matter may be caused by mutations in any of the 5 genes encoding the subunits of the eukaryotic translation factor initiation factor 2B. VWM2 (620312) is caused by mutation in the EIF2B2 gene (606454) on chromosome 14q24; VWM3 (620313) is caused by mutation in the EIF2B3 gene (606273) on chromosome 1p34; VWM4 (620314) is caused by mutation in the EIF2B4 gene (606687) on chromosome 2p23; and VWM5 (620315) is caused by mutation in the EIF2B5 gene (603945) on chromosome 3q27.
Schiffmann et al. (1994) described 4 unrelated girls with progressive ataxic diplegia who had normal development until the ages of 1.5 to 5 years. A diffuse confluent abnormality of the white matter of the central nervous system was present on computed tomography and magnetic resonance scans obtained early in the course of the illness. Light and electron microscopy of open-brain biopsy specimens from 2 girls showed selective white matter abnormalities including hypomyelination, demyelination, and gliosis. Myelin-specific proteins in the subcortical white matter were of normal molecular size but were markedly reduced in quantity in both patients compared to control subjects. Lipid analysis revealed decreased levels of characteristic myelin lipids. When examined by magnetic resonance spectroscopic imaging, all patients showed a marked decrease of N-acetylaspartic acid, choline, and creatine in white matter only. The authors concluded that the magnetic resonance spectroscopic imaging profile was a unique diagnostic feature of this group of patients.
Van der Knaap et al. (1997) identified 9 children with a 'new' leukoencephalopathy with vanishing white matter. The 9 patients included 3 affected sib pairs; the age range was 3 to 19 years. The onset of the disease was in childhood and the course was chronic, progressive, and episodic. Episodes of deterioration followed infections and minor head traumas, and these could result in unexplained coma. In 8 patients with advanced disease, magnetic resonance imaging (MRI) revealed a diffuse cerebral hemispheric leukoencephalopathy in which increasing areas of the abnormal white matter had a signal intensity close to that of CSF on all pulse sequences. In 1 patient in the early stages of disease, initial MRI showed diffusely abnormal cerebral white matter which only reached the signal characteristics of CSF at a later stage. In the patients in whom the disease was advanced, magnetic resonance spectroscopy (MRS) of the white matter showed an almost complete disappearance of all normal signals and the presence of glucose and lactate compatible with the presence of mainly CSF and little brain tissue. Autopsy in 1 patient confirmed the presence of extensive cystic degeneration of the cerebral white matter with reactive change and a preserved cortex. The disease has an autosomal recessive mode of inheritance. One of the 9 patients who was not part of an affected sib pair had consanguineous parents.
Ovarian failure can be expressed as primary amenorrhea or as secondary amenorrhea lasting more than 6 months, associated with elevated gonadotropin levels at age less than 40 years. Schiffmann et al. (1997) described 4 patients with the unusual association of ovarian failure with white matter abnormalities observed on cerebral magnetic resonance imaging (MRI), a condition they termed ovarioleukodystrophy.
Van der Knaap et al. (1998) reported on phenotypic variation in leukoencephalopathy with vanishing white matter in 5 additional patients who met the diagnostic criteria for the disorder except for the age at onset. Four of the patients had onset in late childhood or adolescence, and one was presymptomatic in his early twenties. The course of the disease tended to be milder than in the patients with early childhood onset. Van der Knaap et al. (1998) concluded that later onset does occur in the disease of vanishing white matter and that both MRS and histopathology are compatible with a primary axonopathy rather than primary demyelination. Extensive metabolic investigation in these 5 patients and the 9 previously reported patients failed to determine an underlying cause.
Rodriguez et al. (1999) reported neuropathologic, biochemical, and molecular studies of 2 patients, ages 6 and 10 years, who had died of complications of childhood ataxia with diffuse central nervous system hypomyelination. At autopsy, both had severe cavitating orthochromatic leukodystrophy without atrophy, predominating in hemispheric white matter. The severity of white matter lesions contrasted with the paucity of myelin breakdown products and astroglial and microglial reactions. Within the white matter, there was an increase in oligodendrocytes. Myelin protein and lipid content were reduced. In 1 case, there was a decreased amount of proteolipid protein (PLP1; 300401) demonstrated by Western blot, but Southern blot analysis of the PLP1 gene, as well as sequencing of the coding region of the PLP1 gene, were unremarkable.
Verghese et al. (2002) reported 2 sisters who presented with primary amenorrhea and behavior problems at ages greater than 30 years, with subsequent neurologic deterioration, white matter abnormalities detected during cerebral MRI, and pigmented orthochromatic leukodystrophy (POLD) observed at autopsy. Genetic analysis was not performed.
Ohlenbusch et al. (2005) described 2 sisters, ages 25 and 21 years (patients 3252 and 3253, respectively) with a moderate form of VWM and mutation in the EIF2B1 gene. Cognitive and behavioral issues were the presenting signs in both at ages 17 and 10 years, respectively; impaired intellectual development had been present before disease onset. Disability was scored as moderate; both were able to walk with assistance. Ovarian failure was present in both.
Shimada et al. (2015) reported a 61-year-old Japanese woman (patient 1) with VWM and mutation in the EIF2B1 gene. She presented with neurologic symptoms with gait disturbances at age 29 years. She also had mild cognitive impairment (IQ of 66), motor incoordination, spasticity, and seizures. Brain imaging showed nonspecific white matter abnormalities. The disorder was progressive, and she was bedridden at the time of the report.
Zhang et al. (2015) reported a 2-year-old Chinese girl (case 29) with early-childhood onset of leukoencephalopathy with vanishing white matter and mutation in the EIF2B1 gene. She had seizures, episodic aggravation, and progressive significant loss of motor function on follow-up about a year later.
Tedeschi et al. (1995) studied a group of 6 patients (4 unrelated girls and 2 brothers from 5 families) with CACH by proton magnetic resonance spectroscopic imaging. Relative to controls, there was a decrease in the signal intensity of N-acetylaspartate, choline, and creatine throughout the white matter in all 6 patients. Tedeschi et al. (1995) identified lactate signals in white matter in 3 of the children with advanced disease. The degree of white matter involvement was not homogeneous over the entire patient group, but did correlate with clinical presentation. No abnormalities were detected in the gray matter. Tedeschi et al. (1995) concluded that this syndrome is secondary to a metabolic defect causing hypomyelination, axonal degeneration, and, in the most compromised cases, accumulation of lactate.
Van der Knaap et al. (1998) proposed the following diagnostic criteria for vanishing white matter: (1) initial motor and mental development is normal or mildly delayed; (2) neurologic deterioration has a chronic progressive and episodic course, and episodes of deterioration may follow minor infection and minor head trauma and may lead to lethargy or coma; (3) neurologic signs consist mainly of cerebellar ataxia and spasticity; optic atrophy may develop, but is not obligatory; epilepsy may occur, but is not the predominant sign of the disease; mental abilities may also be affected, but not to the same degree as the motor functions; and (4) MRI may indicate symmetric involvement of the cerebral hemispheric white matter, and part or all of the white matter has a signal intensity close to or the same as CSF on proton-density, T2-weighted, T1-weighted, and FLAIR images, and cerebellar atrophy varies from mild to severe and primarily involves the vermis. Magnetic resonance spectroscopy can be used to obtain additional evidence for the diagnosis. White matter spectra show a serious decrease or almost complete disappearance of all normal signals and presence of some lactate and glucose. The initial report of vanishing white matter leukoencephalopathy was a report by Hanefeld et al. (1993) of 3 cases with unique features on MRI and proton MRS.
The transmission pattern of VWM1 in the family of patients 3252 and 3253 reported by Ohlenbusch et al. (2005) was consistent with autosomal recessive inheritance.
In a patient with VWM, van der Knaap et al. (2002) found compound heterozygosity for 2 mutations in the EIF2B1 gene (606686.0001 and 606686.0002).
In 2 sisters with a moderate form of VWM, Ohlenbusch et al. (2005) identified a homozygous missense mutation in the EIF2B1 gene (V183F; 606686.0003).
In a patient with leukoencephalopathy with vanishing white matter, Maletkovic et al. (2008) identified compound heterozygous mutations in the EIF2B1 gene (606686.0005 and 606686.0006). The patient was 1 of 15 VWM patients with mutations in 1 of the EIF2B genes. The authors noted that mutations in the EIF2B1 gene account for only approximately 4% of all reported mutations and are found in approximately 1% of patients with EIF2B-related disorders in previous studies.
Leegwater et al. (2001) and van der Knaap et al. (2002) showed that leukoencephalopathy with vanishing white matter may be caused by mutation in any of the 5 subunits of translation initiation factor eIF2B.
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]
Hanefeld, F., Holzbach, U., Kruse, B., Wilichowski, E., Christen, H. J., Frahm, J. Diffuse white matter disease in three children: an encephalopathy with unique features on magnetic resonance imaging and proton magnetic resonance spectroscopy. Neuropediatrics 24: 244-248, 1993. [PubMed: 8309512] [Full Text: https://doi.org/10.1055/s-2008-1071551]
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]
Maletkovic, J., Schiffmann, R., Gorospe, J. R., Gordon, E. S., Mintz, M., Hoffman, E. P., Alper, G., Lynch, D. R., Singhal, B. S., Harding, C., Amartino, H., Brown, C. M., and 12 others. Genetic and clinical heterogeneity in eIF2B-related disorder. J. Child Neurol. 23: 205-215, 2008. [PubMed: 18263758] [Full Text: https://doi.org/10.1177/0883073807308705]
Ohlenbusch, A., Henneke, M., Brockmann, K., Goerg, M., Hanefeld, F., Kohlschutter, A., Gartner, J. Identification of ten novel mutations in patients with eIF2B-related disorders. Hum. Mutat. 25: 411, 2005. [PubMed: 15776425] [Full Text: https://doi.org/10.1002/humu.9325]
Rodriguez, D., Gelot, A., della Gaspera, B., Robain, O., Ponsot, G., Sarlieve, L. L., 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 studies of two cases. Acta Neuropath. 97: 469-480, 1999. [PubMed: 10334484] [Full Text: https://doi.org/10.1007/s004010051016]
Schiffmann, R., Moller, J. R.., Trapp, B. D., Shih, H. H.-L., Farrer, R. G., Katz, D. A., Alger, J. R., Parker, C. C., Hauer, P. E., Kaneski, C. R., Heiss, J. D., Kaye, E. M., Quarles, R. H., Brady, R. O., Barton, N. W. Childhood ataxia with diffuse central nervous system hypomyelination. Ann. Neurol. 35: 331-340, 1994. [PubMed: 8122885] [Full Text: https://doi.org/10.1002/ana.410350314]
Schiffmann, R., Tedeschi, G., Kinkel, R. P., Trapp, B. D., Frank, J. A., Kaneski, C. R., Brady, R. O., Burton, N. W., Nelson, L., Yanovski, J. A. Leukodystrophy in patients with ovarian dysgenesis. Ann. Neurol. 41: 654-661, 1997. [PubMed: 9153528] [Full Text: https://doi.org/10.1002/ana.410410515]
Shimada, S., Shimojima, K., Sangu, N., Hoshino, A., Hachiya, Y., Ohto, T., Hashi, Y., Nishida, K., Mitani, M., Kinjo, S., Tsurusaki, Y., Matsumoto, N., Morimoto, M., Yamamoto, T. Mutations in the genes encoding eukaryotic translation initiation factor 2B in Japanese patients with vanishing white matter disease. Brain Dev. 37: 960-966, 2015. [PubMed: 25843247] [Full Text: https://doi.org/10.1016/j.braindev.2015.03.003]
Tedeschi, G., Schiffmann, R., Barton, N. W., Shih, H. H.-L., Gospe, S. M., Jr., Brady, R. O., Alger, J. R., Di Chiro, G. Proton magnetic resonance spectroscopic imaging in childhood ataxia with diffuse central nervous system hypomyelination. Neurology 45: 1526-1532, 1995. [PubMed: 7644053] [Full Text: https://doi.org/10.1212/wnl.45.8.1526]
van der Knaap, M. S., Barth, P. G., Gabreels, F. J. M., Franzoni, E., Begeer, J. H., Stroink, H., Rotteveel, J. J., Valk, J. A new leukoencephalopathy with vanishing white matter. Neurology 48: 845-855, 1997. [PubMed: 9109866] [Full Text: https://doi.org/10.1212/wnl.48.4.845]
van der Knaap, M. S., Kamphorst, W., Barth, P. G., Kraaijeveld, C. L., Gut, E., Valk, J. Phenotypic variation in leukoencephalopathy with vanishing white matter. Neurology 51: 540-547, 1998. [PubMed: 9710032] [Full Text: https://doi.org/10.1212/wnl.51.2.540]
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]
Verghese, J., Weidenheim, K., Malik, S., Rapin, I. Adult onset pigmentary orthochromatic leukodystrophy with ovarian dysgenesis. Europ. J. Neurol. 9: 663-670, 2002. [PubMed: 12453083] [Full Text: https://doi.org/10.1046/j.1468-1331.2002.00469.x]
Zhang, H., Dai, L., Chen, N., Zang, L., Leng, X., Du, L., Wang, J., Jiang, Y., Zhang, F., Wu, X., Wu, Y. Fifteen novel EIF2B1-5 mutations identified in Chinese children with leukoencephalopathy with vanishing white matter and a long term follow-up. PLoS One 10: e0118001, 2015. Note: Electronic Article. [PubMed: 25761052] [Full Text: https://doi.org/10.1371/journal.pone.0118001]