The Unfolded Protein Response in Vanishing White Matter Disease

Voorn, J. Patrick van der; Kollenburg, Barbara van; Bertrand, Gesina A.M.; Haren, Keith Van; Scheper, Gert C.; Powers, James M.; Knaap, Marjo S. van der

doi:10.1097/01.jnen.0000178446.41595.3a

Cited by 98 publications

(79 citation statements)

References 32 publications

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“…40,42 In the brain of patients with EIF2B mutations, oligodendrocytes have been reported with a foamy aspect consistent with the presence of material rich in glycoproteins. 43 Increasing evidence supports an exaggerated ER stress response with abnormal activation of the unfolded protein response in EIF2B-mutated cells with abnormal protein synthesis and cellular homeostasis 20,[44][45][46][47][48] in particular in oligodendrocytes and astrocytes of the white matter from affected patients. 46 Hence, we hypothesize that the decrease of CSF asialotransferrin to transferrin ratio in patients with eIF2B-related disorders may be due to reduced de novo secretion from these cells.…”

Section: Discussionmentioning

confidence: 99%

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

Vanderver¹,

Hathout²,

Maletkovic³

et al. 2008

Neurology

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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...

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Section: Discussionmentioning

confidence: 99%

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

Vanderver¹,

Hathout²,

Maletkovic³

et al. 2008

Neurology

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“…White matter astrocytes and oligodendrocytes are selectively affected 11, 14, 15, 22. Recent studies indicate that astrocyte dysfunction is primary and oligodendrocyte dysfunction secondary 16, 23.…”

Section: Introductionmentioning

confidence: 99%

Axonal abnormalities in vanishing white matter

Klok

Bugiani

Vries

et al. 2018

Ann Clin Transl Neurol

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ObjectiveWe aimed to study the occurrence and development of axonal pathology and the influence of astrocytes in vanishing white matter.MethodsAxons and myelin were analyzed using electron microscopy and immunohistochemistry on Eif2b4 and Eif2b5 single‐ and double‐mutant mice and patient brain tissue. In addition, astrocyte‐forebrain co‐culture studies were performed.ResultsIn the corpus callosum of Eif2b5‐mutant mice, myelin sheath thickness, axonal diameter, and G‐ratio developed normally up to 4 months. At 7 months, however, axons had become thinner, while in control mice axonal diameters had increased further. Myelin sheath thickness remained close to normal, resulting in an abnormally low G‐ratio in Eif2b5‐mutant mice. In more severely affected Eif2b4‐Eif2b5 double‐mutants, similar abnormalities were already present at 4 months, while in milder affected Eif2b4 mutants, few abnormalities were observed at 7 months. Additionally, from 2 months onward an increased percentage of thin, unmyelinated axons and increased axonal density were present in Eif2b5‐mutant mice. Co‐cultures showed that Eif2b5 mutant astrocytes induced increased axonal density, also in control forebrain tissue, and that control astrocytes induced normal axonal density, also in mutant forebrain tissue. In vanishing white matter patient brains, axons and myelin sheaths were thinner than normal in moderately and severely affected white matter. In mutant mice and patients, signs of axonal transport defects and cytoskeletal abnormalities were minimal.InterpretationIn vanishing white matter, axons are initially normal and atrophy later. Astrocytes are central in this process. If therapy becomes available, axonal pathology may be prevented with early intervention.

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“…Early histopathological work discussed hypomyelination versus demyelination (1,3,28), while the observation of a commensurate degeneration of axons and myelin sheaths in cerebral WM prompted the hypothesis of a primary axonopathy (3). More recent studies, however, point toward a primary glial dysfunction which predominantly affects astrocytes and the myelin-producing oligodendrocytes (27,29,30). Phosphorous MRS of patients with childhood ataxia with diffuse central nervous system hypomyelination revealed abnormal cerebral concentrations of high-energy phosphates…”

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confidence: 99%

Early Reduction of Total N-Acetyl-Aspartate-Compounds in Patients With Classical Vanishing White Matter Disease. A Long-Term Follow-Up MRS Study

et al. 2008

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ABSTRACT:The neuropathology of vanishing white matter (VWM) disease is characterized by a loss of white matter (WM). Although recent histopathological studies suggest a primary glial dysfunction, the purpose of this work was to assess the extent of axonal involvement in VWM using long-term follow-up proton MR spectroscopy. White and gray matter of nine children with genetically proven VWM and late infancy/early childhood onset were investigated with short-echo time, single-voxel proton MR spectroscopy over up to 8 years starting as early as less than 2 years after the onset of symptoms (5 patients). Total N-acetyl-aspartate (Ϫ51% from normal control), creatine and phosphocreatine (Ϫ47%), and myo-inositol (Ϫ49%) were reduced in WM at early disease stages. Cholinecontaining compounds were less severely decreased (Ϫ31%). Follow-up investigations revealed progressive reduction of all metabolites in WM. In gray matter, no distinct changes were detected at early stages. Later total N-acetyl-aspartate decreased slightly (Ϫ22%). Assuming the metabolite alterations to primarily reflect changes in cellular composition, the observed pattern indicates early axonal involvement or loss as well as relatively enhanced turnover of myelin. These early stages are followed by a complete cellular loss in cerebral WM. V anishing white matter (VWM) disease (MIM 603836)-also known as myelinopathia centralis diffusa and childhood ataxia with diffuse central nervous system hypomyelination-was first separated from the vast group of unknown leukoencephalopathies in the early 90s (1,2). The MR imaging (MRI) and MR spectroscopy (MRS) features of VWM are unique and therefore considered diagnostic. MRI characteristically reveals bilaterally symmetric, diffuse involvement of cerebral white matter (WM) at the onset of symptoms and progressive cystic degeneration into an appearance like cerebrospinal fluid (CSF) over the course of the disease (3). Proton MRS shows a reduction of all WM metabolites except for the presence of lactate (Lac) and glucose (Glc) in concentrations typical for CSF (1,4,5).Several phenotypic variations have been described encompassing i) rapidly fatal variants with antenatal onset and involvement of multiple organs, ii) onset in early infancy before 2 years of age (6 -10), iii) a classical form with onset in late infancy/early childhood followed by a relapsingremitting/chronic progression over half a decade (1,2,11-15), iv) juvenile onset cases with a protracted progression over 1-2 decades (3), and v) mild adolescence/adult forms, in females often associated with ovarian failure (16 -22).The mode of inheritance is autosomal recessive. Mutations in each of the five subunits ␣-⑀ of the eucaryotic translation initiation factor 2B (eIF2B) have been found to cause the disease in most patients (23). eIF2B plays an essential role for initiation and regulation of cell protein synthesis. There is growing evidence that the mutations cause a decrease in eIF2B activity by different mechanisms and to a different extent. They may impai...

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The Unfolded Protein Response in Vanishing White Matter Disease

Cited by 98 publications

References 32 publications

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

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

Axonal abnormalities in vanishing white matter

Early Reduction of Total N-Acetyl-Aspartate-Compounds in Patients With Classical Vanishing White Matter Disease. A Long-Term Follow-Up MRS Study

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