title: Eukaryotic initiation factor 2B (eIF2B) GEF activity as a diagnostic tool for EIF2B-related disorders.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  We 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 < or =77.5%.
  
  
  CONCLUSIONS
  These results validate the measurement of eIF2B GEF activity in patients' transformed-lymphocytes as an important tool for the diagnosis of eIF2B-related disorders.
authors.affiliation: INSERM U931-CNRS 6247- Université Clermont, GReD, Clermont-Ferrand, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Horzinski
authors.forename: Aurélia
authors.initials: A
authors.lastname: Huyghe
authors.forename: Marie-Céleste
authors.initials: MC
authors.lastname: Cardoso
authors.forename: Céline
authors.initials: C
authors.lastname: Gonthier
authors.forename: Lemlih
authors.initials: L
authors.lastname: Ouchchane
authors.forename: Raphael
authors.initials: R
authors.lastname: Schiffmann
authors.forename: Pierre
authors.initials: P
authors.lastname: Blanc
authors.forename: Odile
authors.initials: O
authors.lastname: Boespflug-Tanguy
authors.forename: Anne
authors.initials: A
authors.lastname: Fogli
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000375:Aging / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000175:diagnosis* / Q000235:genetics; D006801:Humans; D007223:Infant; D008214:Lymphocytes / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D012372:ROC Curve; D055815:Young Adult
chemical_list: D020717:Eukaryotic Initiation Factor-2B; D020662:Guanine Nucleotide Exchange Factors