Date Published: December 15, 2009
Publisher: Public Library of Science
Author(s): Laetitia Horzinski, Aurélia Huyghe, Marie-Céleste Cardoso, Céline Gonthier, Lemlih Ouchchane, Raphael Schiffmann, Pierre Blanc, Odile Boespflug-Tanguy, Anne Fogli, Antoni L. Andreu. http://doi.org/10.1371/journal.pone.0008318
Abstract: In 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.
Partial Text: 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 , , , . Disease severity is correlated with age at disease onset, with stress onset trigger or aggravating factors , . 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 , , ii) the infantile severe forms with disease onset <2 years and rapid fatal evolution , iii) the most severe antenatal forms responsible for fetal death , and iv) the milder forms with disease onset >5 years and restricted to slow cognitive impairment , .
Analysis of this extended cohort showed that eIF2B GEF activity measured in patients’ LLB distinguishes eIF2B-mutated patients from those with eIF2B-unrelated leukodystrophies with 100% positive predictive value (PPV) and 89% negative predictive value at ≤77.5% threshold. At this threshold, the assay systematically excludes patients without eIF2B mutations. Therefore, it represents an interesting screening tool to select patients for a direct sequencing of the EIF2B1-5 genes. For leukodystrophic patients with >77.5% GEF activity, the probability to find eIF2B mutations is 15% (7/45) and increases to 26.9% (7/26) if patients have clinical and/or MRI features typical to eIF2B-related disorder. Therefore, EIF2B1-5 sequencing is still indicated for patients who are clinically suspected of eIF2B-related disorder with GEF activity >77.5%, particularly in milder forms.