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

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.

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

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

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.