ORPHA: 135; DO: 0070371;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p23.3 | Leukoencephalopathy with vanishing white matter 4, with or without ovarian failure | 620314 | Autosomal recessive | 3 | EIF2B4 | 606687 |
A number sign (#) is used with this entry because of evidence that leukoencephalopathy with vanishing white matter-4 (VWM4) is caused by homozygous or compound heterozygous mutation in the EIF2B4 gene (606687) on chromosome 2p23.
Leukoencephalopathy with vanishing white matter-4 (VWM4) is a chronic and progressive autosomal recessive leukoencephalopathy characterized by neurologic deterioration with cerebellar ataxia, spasticity, and relatively mild mental decline. Onset is usually in childhood; early development may be normal. Female patients may experience ovarian failure. 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 van der Knaap et al., 2002 and Fogli et al., 2003).
For a discussion of genetic heterogeneity of VWM, see 603896.
Van der Knaap et al. (2002) identified 2 patients, vwm239 and vwm244, with leukoencephalopathy with vanishing white matter and mutation in the EIF2B4 gene.
Fogli et al. (2003) described 2 sisters (family 941) with leukoencephalopathy with vanishing white matter and mutation in the EIF2B4 gene. Patient 1, aged 23 years old, had had delayed walking (18 months of age) and speech as well as school difficulties. She experienced gait instability at age 10 years but did not require a walker. Her IQ was measured at 77 at age 15 and 79 at age 23. Patient 2, aged 24 years, walked at age 12 months and had normal speech, but had experienced school difficulties. She developed gait instability at age 15, required a walker at age 16, and had dysarthria and sphincter disturbances at age 20. Her IQ was measured at 60 and 66 at age 16 and 24 years, respectively. Both sisters had spasticity, optic atrophy, and visual motor difficulties, and patient 1 had fine motor difficulties. Patient 1 had primary amenorrhea, and patient 2 had secondary amenorrhea; ultrasonography revealed atrophied ovaries in both. Both patients had cerebral atrophy involving the cerebral cortex, hemispheric white matter (with ventricular dilatation), and corpus callosum. Abnormal signal within the abnormal white matter on FLAIR sequence imaging was extensive in the frontal white matter of patient 2. These patients had been described as patients 1 and 2, respectively, by Schiffmann et al. (1997).
Van der Knaap et al. (2003) reported 8 patients with antenatal- or early-infantile-onset encephalopathy, early demise, and EIF2B mutations. Three of the patients carried mutations in the EIF2B4 gene. A brother (patient 4) and sister (patient 5) had fetal growth retardation, oligohydramnios, and microcephaly noted at birth. Their clinical course deteriorated with feeding difficulties, vomiting, apathy, axial hypotonia, hypertonia and hyperreflexia of the extremities, seizures, and ultimately, apneic events. Ultrasound revealed hypoplastic kidneys. The patients died at 3.5 and 4 months of age, respectively. Patient 6, previously reported by Boltshauser et al. (2002), had a history of growth retardation and oligohydramnios noted at 31 weeks' gestation. She was born at 38 weeks' gestation with microcephaly, bilateral cataracts, and mild contractures. Her clinical course was significant for impaired swallowing, failure to thrive, myoclonic convulsions, and absence of psychomotor development. Aspiration pneumonia led to death at age 10 months. Autopsy revealed ovarian dysgenesis. Brain MRIs revealed abnormal signal in cerebral hemispheric white matter with a higher T2 signal intensity than normal for unmyelinated white matter. In patients 5 and 6, the lateral ventricles became highly dilated with age because of pronounced white matter atrophy as well as striking cerebellar atrophy.
Gungor et al. (2015) described a 12-month-old Turkish boy with intractable seizures since 3 months of age. Electroencephalogram (EEG) was initially normal but eventually demonstrated voltage suppression in both hemispheres and sharp spike-slow-wave complexes in the right hemisphere. Initial MRI at 3.5 months of age showed mild cerebral and cerebellar white matter involvement on T-2 weighted images, and 3 months later showed diffuse white matter hyperintensity and cerebral atrophy. Severe mental and motor retardation developed. By 12 months of age, MRI demonstrated cerebellar atrophy and rarefaction in the cerebral white matter. A diagnosis of vanishing white matter disease was made. Family history was significant for an elder brother who had a history of hypotonia, feeding difficulties, and seizures and died at age 7 months.
Kanbayashi et al. (2015) identified a 59-year-old Japanese woman who presented with gait unsteadiness and forgetfulness at age 56. She had no history of episodic neurologic deterioration evoked by stresses. Her childhood development was described as normal and she had no history of ovarian failure. Neurologic examination revealed spastic paraparesis, increased bilateral patellar tendon reflexes, and bilateral extensor Babinski signs. She scored 16 on the Mini-Mental State Examination (MMSE), indicative of cognitive impairment. The Wechsler Adult Intelligence Scale third edition (WAIS-III) revealed a full-scale IQ of 60. Brain MRI revealed symmetric diffuse high-intensity lesions in the deep white matter on T-2 weighted images. The lesions in the deep frontal white matter had CSF-like signals on fluid-attenuated inversion recovery (FLAIR) images. Adult-onset VWM disease was diagnosed.
Goyal et al. (2023) described a 52-year-old woman with a 2-year history of slowly progressive right foot drag, a 1-year history of bladder urgency, and a 6-month history of right-sided abnormal limb posturing and behavioral disturbances. She had a high-grade fever 2 months prior to presentation. Following the febrile illness, she became incontinent and bedridden. She had a history of premature menopause at age 35 years. On physical examination, she had contractures and bilateral spasticity. Cognitive examination revealed perseveration, repetition, and echolalia. Brain MRI demonstrated diffuse white matter involvement with radiating strips of preserved white matter. Cysts were present in both anterior frontal regions and thinning of the corpus callosum was noted. Based on clinical and imaging characteristics, the diagnosis of adult-onset VWM was made.
The transmission pattern of VWM4 in family 941 reported by Fogli et al. (2003) was consistent with autosomal recessive inheritance.
In 2 patients with leukoencephalopathy with vanishing white matter (vwm239 and vwm244), van der Knaap et al. (2002) identified mutations in the EIF2B4 gene. Patient vwm239 was compound heterozygous for 2 missense mutations in exon 11 (R357Q, 606687.0001 and R374C, 606687.0002), and patient vwm244 was compound heterozygous for a splice site mutation in intron 11 (606687.0003) and a missense mutation in exon 7 (A228V; 606687.0004).
In 2 sisters with vanishing white matter leukodystrophy and ovarian failure, Fogli et al. (2003) detected compound heterozygosity for missense mutations in the EIF2B4 gene: C465R (606687.0005) and Y489H (606687.0006).
In 3 patients with antenatal-onset encephalopathy, van der Knaap et al. (2003) performed mutation analysis of the EIF2B1-EIF2B5 genes and detected different novel homozygous missense mutations in EIF2B4: R483W (606687.0007) in sib patients 4 and 5, and A391D (606687.0008) in patient 6.
In a 12-month old Turkish boy with intractable seizures and VWM disease, Gungor et al. (2015) detected a homozygous missense mutation (R374C; 606687.0002) in exon 11 in the EIF2B4 gene.
By Sanger sequencing of all 5 EIF2B subunit genes, Kanbayashi et al. (2015) found compound heterozygosity for novel missense mutations in the EIF2B4 gene (M206T, 606687.0009 and I318V, 606687.0010) in a 59-year-old Japanese woman with adult-onset VWM disease.
In a 52-year-old Indian woman with adult-onset VWM disease, Goyal et al. (2023) detected a homozygous missense mutation in exon 12 of the EIF2B4 gene. Specific details of the mutation were not provided.
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.
Boltshauser, E., Barth, P. G., Troost, D., Martin, E., Stallmach, T. 'Vanishing white matter' and ovarian dysgenesis in an infant with cerebro-oculo-facio-skeletal phenotype. Neuropediatrics 33: 57-62, 2002. [PubMed: 12075484] [Full Text: https://doi.org/10.1055/s-2002-32363]
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]
Goyal, S., Mudabbir, M., Taallapalli, A. V. R., Nashi, S., Kulkarni, G. B. Vanishing white matter leukodystrophy due to novel EIF2B4 mutation in an adult female. J Neurosci Rural Pract 14: 191-193, 2023. [PubMed: 36891084] [Full Text: https://doi.org/10.25259/JNRP-2022-2-48]
Gungor, O., Ozkaya, A. K., Hirfanoglu, T., Dilber, C., Aydin, K. A rare mutation in EIF2B4 gene in an epileptic child with vanishing white matter disease: a case report. Genet. Counsel. 26: 41-46, 2015. [PubMed: 26043506]
Kanbayashi, T., Saito, F., Matsukawa, T., Oba, H., Hokkoku, K., Hatanaka, Y., Tsuji, S., Sonoo, M. Adult-onset vanishing white matter disease with novel missense mutations in a subunit of translational regulator, EIF2B4. Clin. Genet. 88: 401-403, 2015. [PubMed: 25600065] [Full Text: https://doi.org/10.1111/cge.12554]
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]
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]
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]