Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2003 Nov;73(5):1199-207.
doi: 10.1086/379524. Epub 2003 Oct 17.

eIF2B-related disorders: antenatal onset and involvement of multiple organs

Marjo S van der Knaap  1 , Carola G M van Berkel, Jochen Herms, Rudy van Coster, Martina Baethmann, Sakkubai Naidu, Eugen Boltshauser, Michèl A A P Willemsen, Barbara Plecko, Georg F Hoffmann, Christopher G Proud, Gert C Scheper, Jan C Pronk
Affiliations

eIF2B-related disorders: antenatal onset and involvement of multiple organs

Marjo S van der Knaap et al. Am J Hum Genet. 2003 Nov.

Abstract

Leukoencephalopathy with vanishing white matter, also called "childhood ataxia with central nervous system hypomyelination," is the first human disease related to mutations in any of the five genes encoding subunits of eukaryotic initiation factor eIF2B or any translation factor at all. eIF2B is essential in all cells of the body for protein synthesis and the regulation of this protein synthesis under different stress conditions. It is surprising that mutations in the eIF2B genes have been reported to lead to abnormalities of the white matter of the brain only, although it has been shown recently that ovarian failure may accompany the leukoencephalopathy. Another surprising observation is that the onset of the disease varies from early childhood to adulthood, with the exception of Cree leukoencephalopathy, a disease related to a particular mutation in one of the eIF2B genes, which invariably has its onset within the first year of life. We analyzed the eIF2B genes of nine patients with an antenatal- or early-infantile-onset encephalopathy and an early demise and found mutations in eight of the patients. In addition to signs of a serious encephalopathy, we found oligohydramnios, intrauterine growth retardation, cataracts, pancreatitis, hepatosplenomegaly, hypoplasia of the kidneys, and ovarian dysgenesis. Until now, no evidence had been found for a genotype-phenotype correlation, but the consistently severe phenotype in affected siblings among our patients and in Cree encephalopathy patients suggests an influence of the genotype on the phenotype.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Illustration of the variation in white matter abnormalities in patients with VWM/CACH. For this purpose, T2-weighted and FLAIR images of patient 3 at 3 mo (A and B, respectively) and patient 7 at 6 mo (C and D, respectively) are shown, as well as T2-weighted and FLAIR images of a normal infant at 4 mo (E and F, respectively). In patient 3, the transverse T2-weighted image (A) is normal for the age, except that the progress of myelination is insufficient. The myelin deposition should cause the internal capsule to have a low signal intensity (arrow in E), but it still has a high signal intensity throughout (arrow in A). The FLAIR image is shown at a slightly higher level, where areas of low signal intensity are seen within the cerebral white matter, indicative of rarefaction (B). Such areas are not seen on the FLAIR image of the normal infant (F). In patient 7, the cerebral white matter has too high a signal intensity on the T2-weighted image (C), higher than normal for unmyelinated white matter (E). The gyri are mildly broadened. The FLAIR image shows that a large part of the white matter has a lower signal intensity, consistent with rarefaction (D). A subtle stripe-like pattern is visible within the rarefied white matter (D).
Figure 2
Figure 2
Illustration of the degree of white matter volume loss. Transverse T2-weighted and sagittal T1-weighted images of patient 6, obtained at 6 d (A and B, respectively) and 5 mo (C and D, respectively), and transverse T2-weighted and sagittal T1-weighted images of a normal-term neonate (E and F, respectively) are shown. The first MRI in patient 6, obtained at 6 d, shows broadening of gyri (A) as compared to the width of gyri in a normal neonate (E). The cerebral white matter has a normal signal intensity for unmyelinated white matter on the T2-weighted image (compare A and E). The lateral ventricles are mildly dilated. The cerebellar vermis is on the small side (compare B and F). The T2-weighted image at 5 mo shows that an impressive atrophy of the cerebral white matter has occurred with enormous dilatation of the lateral ventricles (C). What remains of the white matter now has too high a signal intensity, even for unmyelinated white matter. The sagittal image shows marked atrophy of the cerebellum (D). Also the pons is flatter than normal. These images are reproduced from the work of Boltshauser et al. (2002) with permission.
Figure 3
Figure 3
Examples of conserved residues in eIF2B involved in severe forms of VWM. A, Alignment of the sequence containing Gly200 (box) of human eIF2Bβ with corresponding sequences of eIF2Bβ of the indicated species and with the corresponding sequences of human eIF2Bα and eIF2Bδ. Residues conserved among all three human subunits and eIF2Bβ of all species are indicated in gray. B, Alignment of the region surrounding Tyr495 in human eIF2Bɛ with the corresponding sequences of eIF2Bɛ in other species. The conserved tyrosine is indicated by the box; residues that are conserved in at least five species are indicated in gray.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

Electronic-Database Information

    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for VWM and Wolcott-Rallison syndrome)
    1. VU University Medical Center site, http://www.vumc.nl/whitematter

References

    1. Barkovich AJ, Kjos BO, Jackson DE, Norman D (1988) Normal maturation of the neonatal and infant brain: MR imaging at 1.5 T. Radiology 166:173–180 - PubMed
    1. Bin-Abbas B, Al-Mulhim A, Al-Ashwal A (2002) Wolcott-Rallison syndrome in two siblings with isolated central hypothyroidism. Am J Med Genet 111:187–190 - PubMed
    1. Black DN, Booth F, Watters GV, Andermann E, Dumont C, Halliday WC, Hoogstraten J, Kabay ME, Kaplan P, Meagher-Villemure K, Michaud J, O’Gorman G (1988) Leukoencephalopathy among native Indian infants in northern Quebec and Manitoba. Ann Neurol 24:490–496 - PubMed
    1. Boltshauser E, Barth PG, Troost D, Martin E, Stallmach T (2002) “Vanishing white matter” and ovarian dysgenesis in an infant with cerebro-oculo-facio-skeletal phenotype. Neuropediatrics 33:57–62 - PubMed
    1. Brück W, Herms J, Brockmann K, Schulz-Schaeffer W, Hanefeld F (2001) Myelinopathia centralis diffusa (vanishing white matter disease): evidence of apoptotic oligodendrocyte degeneration in early lesion development. Ann Neurol 50:532–536 - PubMed

Publication types

MeSH terms

Substances