Sensitivity and specificity of decreased CSF asialotransferrin for eIF2B-related disorder.
OBJECTIVE
This is a study estimating diagnostic accuracy of CSF asialotransferrin to transferrin ratio measurement in eIF2B related disorders by using clinical evaluation and EIF2B mutation analysis as the reference standard. eIF2B-related disorder is a relatively common leukodystrophy with broad phenotypic variation that is caused by mutations in any of the five EIF2B genes. There is a need for a simple and clinically valid screening tool for physicians evaluating patients with an unclassified leukodystrophy.


METHODS
CSF two-dimensional gel (2DG) electrophoresis analyses to measure asialotransferrin to transferrin ratios were performed in 60 subjects including 6 patients with documented EIF2B gene mutations, patients with other types of leukodystrophy, and patients with no leukodystrophy.


RESULTS
All six patients with mutation proven eIF2B-related disease showed low to nearly undetectable amounts of asialotransferrin in their CSF when compared to 54 unaffected controls by CSF 2DG analyses in this study. eIF2B-like patients, with clinically similar presentations but no mutations in EIF2B1-5, were distinguished from patients with mutations in EIF2B1-5 by this biomarker. Patients with mutations in EIF2B1-5 had asialotransferrin/transferrin ratio levels significantly different from the group as a whole (p < 0.001). Using 8% asialotransferrin/transferrin ratio as a cutoff, this biomarker has a 100% sensitivity (95% CI = 52-100%) and 94% specificity (95% CI = 84-99%).


CONCLUSIONS
Decreased asialotransferrin/transferrin ratio in the CSF of patients with eIF2B-related disorder is highly sensitive and specific. This rapid (<48 hours) and inexpensive diagnostic tool for eIF2B-related disorders has the potential to identify patients with likely eIF2B-related disorder for mutation analysis.
Vanderver
A
A
Children's National Medical Center, Children's Research Institute, Center for Genetic Medicine, Washington, DC 20010, USA. avanderv@cnmc.org
Hathout
Y
Y
Maletkovic
J
J
Gordon
E S
ES
Mintz
M
M
Timmons
M
M
Hoffman
E P
EP
Horzinski
L
L
Niel
F
F
Fogli
A
A
Boespflug-Tanguy
O
O
Schiffmann
R
R
D000328:Adult; D001212:Asialoglycoproteins / Q000134:cerebrospinal fluid* / Q000235:genetics*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002648:Child; D002675:Child, Preschool; D015140:Dementia, Vascular / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000235:genetics; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics*; D006801:Humans; D007223:Infant; D007965:Leukodystrophy, Globoid Cell / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000235:genetics; D009154:Mutation; D012680:Sensitivity and Specificity; D014168:Transferrin / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid / Q000235:genetics
D001212:Asialoglycoproteins; D015415:Biomarkers; D020717:Eukaryotic Initiation Factor-2B; D014168:Transferrin; C017031:asialotransferrins