Abstract
BackgroundIn recent years, the phenotypes of leukodystrophies linked to mutations in the eukaryotic initiation factor 2B genes have been extended, classically called CACH/VWM (Childhood ataxia with cntral hypomyélination/vanishing white matter disorder). The large clinical spectrum observed from the more severe antenatal forms responsible for fetal death to milder adult forms with an onset after 16 years old and restricted to slow cognitive impairment have lead to the concept of eIF2B-related disorders. The typical MRI pattern with a diffuse CSF-like aspect of the cerebral white matter can lack particularly in the adult forms whereas an increasing number of patients with clinical and MRI criteria for CACH/VWM disease but without eIF2B mutations are found. Then we propose the use of biochemical markers to help in this difficult diagnosis. The biochemical diagnosis of eIF2B-related disorder is difficult as no marker, except the recently described asialotransferrin/transferrin ratio measured in cerebrospinal fluid, has been proposed and validated until now. Decreased eIF2B GEF activity has been previously reported in lymphoblastoid cell lines from 30 eIF2B-mutated patients. Our objective was to evaluate further the utility of this marker and to validate eIF2B GEF activity in a larger cohort as a specific diagnostic test for eIF2B-related disorders.Methodology/Principal FindingsWe performed eIF2B GEF activity assays in cells from 63 patients presenting with different clinical forms and eIF2B mutations in comparison to controls but also to patients with defined leukodystrophies or CACH/VWM-like diseases without eIF2B mutations. We found a significant decrease of GEF activity in cells from eIF2B-mutated patients with 100% specificity and 89% sensitivity when the activity threshold was set at ≤77.5%.ConclusionThese results validate the measurement of eIF2B GEF activity in patients' transformed-lymphocytes as an important tool for the diagnosis of eIF2B-related disorders.
Highlights
Mutations in the EIF2B1-5 genes (OMIM 606686, 606454, 606273, 606687, 603945) encoding the subunits of the ubiquitously expressed eukaryotic initiation factor 2B have been reported in a group of clinically heterogeneous leukodystrophies termed Eukaryotic Initiation Factor 2B (eIF2B)-related disorders [1,2,3,4]
A large clinical spectrum is observed and several distinct forms have been proposed: i) the classical childhood ataxia with central hypomyelination/vanishing white matter disease (CACH/VWM, OMIM 603896), with progressive neurological deterioration between age 2-5 years [1,3], ii) the infantile severe forms with disease onset,2 years and rapid fatal evolution [7], iii) the most severe antenatal forms responsible for fetal death [8], and iv) the milder forms with disease onset .5 years and restricted to slow cognitive impairment [6,9]
MRI can lack in the adult forms whereas an increasing number of patients with clinical and MRI criteria for CACH/VWM disease but without EIF2B1-5 genes mutations (CACH/VWM-like) are found, underlining the necessity to have biochemical markers to help in the diagnosis process and in the selection of patients eligible for EIF2B1-5 direct sequencing
Summary
Mutations in the EIF2B1-5 genes (OMIM 606686, 606454, 606273, 606687, 603945) encoding the subunits of the ubiquitously expressed eukaryotic initiation factor 2B (eIF2B) have been reported in a group of clinically heterogeneous leukodystrophies termed eIF2B-related disorders [1,2,3,4]. A large clinical spectrum is observed and several distinct forms have been proposed: i) the classical childhood ataxia with central hypomyelination/vanishing white matter disease (CACH/VWM, OMIM 603896), with progressive neurological deterioration between age 2-5 years [1,3], ii) the infantile severe forms with disease onset ,2 years and rapid fatal evolution [7], iii) the most severe antenatal forms responsible for fetal death [8], and iv) the milder forms with disease onset .5 years and restricted to slow cognitive impairment [6,9]. The typical MRI pattern with a diffuse CSF-like aspect of the cerebral white matter can lack in the adult forms whereas an increasing number of patients with clinical and MRI criteria for CACH/VWM disease but without eIF2B mutations are found. Our objective was to evaluate further the utility of this marker and to validate eIF2B GEF activity in a larger cohort as a specific diagnostic test for eIF2B-related disorders
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