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

Abstract

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 Copyright © 2008 eIF2B, composed of five subunits (eIF2Bα, eIF2Bβ, eIF2Bγ, eIF2Bδ, eIF2Bε), is encoded by five different genes (EIF2B1-5) with a total of 57 exons, making gene sequencing expensive and time consuming. Mutations have been found in all five genes and in multiple different exons. 6,25 The great number of individual mutations has confounded efforts at simplifying mutation analysis in suspected eIF2B-related cases, requiring in many cases the sequencing of all five genes to exclude a diagnosis.Efforts to establish a screening tool to streamline the diagnosis of eIF2B-related disorders have included CSF glycine levels, 26 measuring guanine nucleotide exchange factor activity of eIF2B in lymphoblasts (GEF activity), 27 and most recently, decreased CSF asialotransferrin to transferrin ratio. 28 Detection of CSF asialotransferrin to transferrin ratio by 2DG analysis has the advantage of being technologically simple, rapid (<48 hours), inexpensive, and highly sensitive. In this study, we focus on establishing the diagnostic accuracy of 2 DG analysis of CSF asialotransferrin to transferrin ratio for the diagnosis of eIF2B-related disorders. Current diagnosis is based on clinical evaluation followed by confirmation of eIF2B mutation, and this approach will be used as the reference standard. . CSF samples were studied in 60 subjects (figure 1): 6 patient...

Characterization of transferrin glycopeptide structures in human cerebrospinal fluid

“…Actually, detection of asialo-Tf in the blood may be an indication of carbohydrate deficient glycoprotein syndrome often associated with alcohol abuse [12] or other congenital disorders of glycosylation known as CDG disorders [5, 13]. Inversely, absence of asialo-Tf in the CSF is abnormal and could indicate a serious neurological disorder, as we have previously demonstrated in patients with Vanishing White Matter (VWM) disease, a type of leukodystrophy characterized by deterioration of the white matter in the brain [14, 15]. The exact role of asialo-transferrin in the central nervous system is not well understood at present but it represents up to 30% of total circulating Tf in the CSF.…”

The potential of mass spectrometry to study iron-containing proteins used in clinical diagnosis

“…through nose and ears), but there are not studies of this clinical application by MS so far. However, Vanderver et al [94] reported a deficiency of S 0 in CSF from patients with childhood-onset ataxia and central hypomyelination (CACH) using MALDI-TOF/TOF MS and Nanospray FT-MS measurements. This finding opens to the use of S 0 as a potential clinical diagnostic biomarker.…”

Acute‐phase proteins investigation based on lectins affinity capture prior to 2‐DE separation: Application to serum from multiple sclerosis patients

“…Instructive examples are those of sepsis and/or acute pancreatitis [3,4], myocardial infarction [5,6], ANCA-associated systemic vasculitis [7], Alzheimer [8,9], Parkinson [10], childhood-onset ataxia and central nervous system hypo-myelination (CACH/VWM) disease [11], alcohol abuse [12] and glycosyl-transferases dysfunctions [13].…”