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NEUROLOGY 2008;70:2226-2232
© 2008 American Academy of Neurology

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

A. Vanderver, MD, Y. Hathout, PhD, J. Maletkovic, MD, E. S. Gordon, MS, M. Mintz, PhD, M. Timmons, MD, E. P. Hoffman, PhD, L. Horzinski, F. Niel, A. Fogli, MD, O. Boespflug-Tanguy, MD and R. Schiffmann, MD

From Children’s National Medical Center (A.V., Y.H., J.M., E.S.G., M.M., E.P.H.), Children’s Research Institute, Center for Genetic Medicine, Washington, DC; Developmental and Metabolic Neurology Branch (DMNB) (M.T., R.S.), National Institute of Neurologic Disorders and Stroke (NINDS)/National Institutes of Health (NIH), Bethesda, MD; INSERM (L.H., A.F., O.B.-T.), Faculté de Médecine, Clermont-Ferrand; CHU (F.N.), Biochimie Médicale, Clermont-Ferrand; and CHU (O.B.-T.), Génétique Médicale, Clermont-Ferrand, France.

Address correspondence and reprint requests to Dr. Adeline Vanderver, Children’s National Medical Center, 111 Michigan Ave., NW, Washington, DC 20010 avanderv{at}cnmc.org

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%).

Conclusion: 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.

Abbreviations: 2DG = two-dimensional gel; CACH = hood onset ataxia with CNS hypomyelination; FLAIR = fluid-attenuated inversion recovery; LR = likelihood ratio; VWM = vanishing white matter.

Supported in part by Children’s Health Research Center, NIH supported K12HD001399, by grants from the NIH (HD-P30-40677 Child Health Research Career Development Award; 1P30HD40677-01 Mental Retardation and Developmental Disabilities Research Center), by the Parson family foundation, and the intramural program of the National Institute of Neurological Disorders and Stroke. The participation of O.B.-T. and A. F. was supported by a grant from the European Leukodystrophy Association.

Disclosure: Drs. Vanderver and Hathout have a patent pending for asialotransferrin as a biomarker in eIF2B related disorders. The other authors report no disclosures.

Received July 23, 2007. Accepted in final form February 27, 2008.






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