The large spectrum of eIF2B-related diseases

Abstract

eIF2B (eukaryotic initiation factor 2B) is a GEF (guanine nucleotide-exchange factor) that plays, with its substrate eIF2, a key regulatory role in the translation initiation phase of protein synthesis. The importance of correct control of eIF2 and eIF2B for normal physiology is underlined by the recent involvement of the five genes that encode the five eIF2B subunits in a severe autosomal recessive neurodegenerative disease, described in young children as CACH (childhood ataxia with central nervous system hypomyelination)/VWM (leukoencephalopathy with vanishing white matter) syndrome. The syndrome is characterized by episodes of rapid deterioration during febrile illnesses or following head trauma and symmetrical demyelination of the brain white matter with cavitation aspects, leading to a progressive vanishing of the white matter replaced by CSF (cerebrospinal fluid). However, a wide clinical spectrum has been observed in the 148 patients presently reported, from congenital forms with rapid death to adult-onset forms with slow mental decline and progressive motor dysfunction, sometimes associated with congenital eye abnormalities or ovariodysgenesis. So far, 77 different mutations in each of the five EIF2B genes (EIF2B1-5), encoding subunits eIF2Balpha-epsilon, have been found, with two-thirds affecting the eIF2Bepsilon subunit. The correlation found between the level of GEF activity of eIF2B in the mutated white blood cells and the age at disease onset suggests a direct role of the abnormal translation control in the pathophysiology of the disease.

Early Reduction of Total N-Acetyl-Aspartate-Compounds in Patients With Classical Vanishing White Matter Disease. A Long-Term Follow-Up MRS Study

“…They may impair the ability of the subunits to form holocomplexes, and diminish the nucleotide exchange activity, or reduce the ability of the catalytic domain of the ⑀ subunit to bind to the substrate, or actually enhance the binding (24). Another group reported a compromised generation of astrocytes positive for glial fibrillary acidic protein, thus raising the possibility of a functional deficiency (25,26). Certainly, the pathogenesis of VWM is still not fully understood (27).…”

Sensitivity and specificity of decreased CSF asialotransferrin for eIF2B-related disorder

“…2,8 However, eIF2B-related disorders are proving to have a much broader phenotype than originally reported. 9,10 The use of MRI or neuropathologic criteria to select patients with undetermined leukodystrophies for EIF2B1-5 gene analysis demonstrated the wide clinical spectrum of EIF2B1-5-mutated patients: from severe infantile cases such as Cree leukoencephalopathy 11 and congenital forms with rapid death, 12 to adult-onset forms with slow neurologic progression [13][14][15] and ovarian failure such as ovarioleukodystrophy. 16,17 Neonatal cases have been seen with severe encephalopathy and extraneurologic features such as cataracts, kidney hypoplasia, and ovarian dysgenesis.…”

Functional analysis of recently identified mutations in eukaryotic translation initiation factor 2Bɛ (eIF2Bɛ) identified in Chinese patients with vanishing white matter disease

“…29 Recently p.Arg113His in the e and p.Glu213Gly in the b subunits have been associated with milder phenotypes, and a relationship between severe phenotype with early infantile onset and p.Arg195His in the e has been found. 29,30 One hypothesis is that severe phenotypes occur in the presence of homozygotic mutations in highly conserved regions, with mutations in non-conserved amino acids leading to mild phenotype. However, the genotype-phenotype correlation is not consistent.…”