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Gert C. Scheper - One of the best experts on this subject based on the ideXlab platform.
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Vanishing White Matter Disease (CACH syndrome)
Encyclopedia of the Neurological Sciences, 2014Co-Authors: Gert C. Scheper, M.s. Van Der KnaapAbstract:Vanishing White Matter Disease is an inherited disorder, most frequently affecting children, caused by mutations in the genes encoding the subunits of the eIF2B complex. This Disease is primarily diagnosed by magnetic resonance imaging (MRI). The diagnosis is confirmed when mutations are found in one of the eIF2B genes. Pathological hallmarks are foamy oligodendrocytes, dysmorphic astrocytes, and the presence of high numbers of glia progenitors that fail to mature. The selective involvement of the White Matter is unexplained, and a causal role for reduced eIF2B activity is debatable.
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defective glial maturation in vanishing White Matter Disease
Journal of Neuropathology and Experimental Neurology, 2011Co-Authors: Marianna Bugiani, Nienke L. Postma, Emiel Polder, Ilja Boor, Barbara Van Kollenburg, Carola G M Van Berkel, Ronald E Van Kesteren, Martha S Windrem, Elly M Hol, Gert C. ScheperAbstract:Vanishing White Matter (VWM) Disease is a genetic leukoencephalopathy linked to mutations in the eukaryotic translation initiation factor 2B. It is a Disease of infants, children, and adults who experience a slowly progressive neurologic deterioration with episodes of rapid clinical worsening triggered by stress and eventually leading to death. Characteristic neuropathologic findings include cystic degeneration of the White Matter with scarce reactive gliosis, dysmorphic astrocytes, and paucity of myelin despite an increase in oligodendrocytic density. To assess whether a defective maturation of macroglia may be responsible for the feeble gliosis and lack of myelin, weinvestigated the maturation status of astrocytes and oligodendrocytes in the brains of 8 VWM patients, 4 patients with other White Matter disorders and 6 age-matched controls with a combination of immunocytochemistry, histochemistry, scratch-wound assays, Western blot, and quantitative polymerase chain reaction. We observed increased proliferation and a defect in the maturation of VWM astrocytes. They show an anomalous composition of their intermediate filament network with predominance of the δ-isoform of the glial fibrillary acidic protein and an increase in the heat shock protein αB-crystallin, supporting the possibility that a deficiency in astrocyte function may contribute to the loss of White Matter in VWM. We also demonstrated a significant increase in numbers of premyelinating oligodendrocyte progenitors in VWM, which may explain the coexistence of oligodendrocytosis and myelin paucity in the patients' White Matter.
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Vanishing White Matter Disease Associated With Ptosis and Myoclonic Seizures
Journal of child neurology, 2010Co-Authors: Suvasini Sharma, Gert C. Scheper, Marjo S. Van Der Knaap, Ravindra Arya, K.n. Vykunta Raju, Atin Kumar, Sheffali GulatiAbstract:A 5-year-old boy who presented with progressive ataxia, neuroregression, and worsening with febrile illnesses is described. He also had myoclonic jerks and ptosis. His elder sister had died of a similar illness. Serial magnetic resonance imaging of the brain demonstrated extensive abnormality of the cerebral White Matter with rarefaction and cystic degeneration, suggestive of vanishing White Matter Disease. The patient was found to be compound heterozygous for 2 new mutations in the gene EIF2B5, confirming the diagnosis.
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Vanishing White Matter Disease associated with progressive macrocephaly.
Neuropediatrics, 2008Co-Authors: Mercedes Pineda, M.s. Van Der Knaap, A. R-palmero, M. Baquero, M. O'callaghan, A. Aracil, Gert C. ScheperAbstract:Vanishing White Matter Disease (VWM) is one of the most frequent inherited childhood leukoencephalopathies. Five genes have been implicated in this Disease ( EIF2B1-5), which encode the five subunits of translation initiation factor eIF2B. The Disease has an autosomal recessive mode of inheritance. The age of onset and clinical severity vary widely. The diagnosis is based on magnetic resonance imaging (MRI) findings and is confirmed by molecular studies. We describe an affected female patient with a common and a novel mutation of the EIF2B5 gene, who demonstrated a progressive neurological and radiological deterioration. An unusual feature was her striking macrocephaly. She had an early clinical onset at two years of age and is currently still alive at 26 years of age.
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Vanishing White Matter Disease: the first reported chinese patient.
Journal of child neurology, 2007Co-Authors: Sheila S. N. Wong, David C. K. Luk, Virginia Wong, Gert C. Scheper, Marjo S. Van Der KnaapAbstract:Vanishing White Matter Disease is a rare neurological Disease. The majority of patients reported are Caucasian individuals. We describe the first Chinese patient with typical clinical and radiological features genetically confirmed to have vanishing White Matter Disease for a mutation in EIF2B4, followed by a brief review of the Disease.
Marjo S. Van Der Knaap - One of the best experts on this subject based on the ideXlab platform.
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Towards understanding the underlying mechanism of vanishing White Matter Disease
Tijdschrift Voor Kindergeneeskunde, 2013Co-Authors: Lisanne E. Wisse, Marjo S. Van Der Knaap, Emiel Polder, M. Clair Van De Beek, Truus Em AbbinkAbstract:s ingediend voor het Amsterdam Kindersymposium 2013 117 Towards understanding the underlying mechanism of vanishing White Matter Disease Lisanne E. Wisse, Emiel Polder, M. Clair van de Beek, Marjo S. van der Knaap, Truus E.M. Abbink Department of Pediatrics, Center for Childhood White Matter Disorders, VUmc INTRODUCTION Vanishing White Matter Disease (VWM) is one of the most prevalent genetic childhood White Matter disorders. The Disease is characterized by ataxia and spasticity. Diagnosis is performed by MRI, which shows progressive White Matter degeneration, aggravated by stress, minor head trauma or fever. The lack of myelin and scar tissue formation in the aff ected area may result from a maturation defect in astrocytes and oligodendrocytes. VWM is caused by recessive mutations in the eukaryotic initiation factor 2B (eIF2B). This enzyme regulates the protein synthesis rate in every cell type and is regulated by various stressors, including heat shock. METHODS Our project aims to unravel the molecular mechanisms that underlie VWM. Although we have acquired increasing insights into the VWM brain pathology, it remains elusive how a defect in eIF2B causes a Disease that almost exclusively aff ects the White Matter. Aided by two clinically representative Disease models, we currently address two unresolved questions. Firstly, we investigate whether relative White Matter eIF2B levels deviate from those in other tissues using immunoblotting. Secondly, we address whether aberrant translation regulation of specifi c mRNAs in White Matter cells underlies VWM using polysomal profi ling and pulsed isotope labeling. In follow-up assays we will assess the functional importance of the observed diff erences between control and VWM tissues. RESULTS Preliminary results suggest that we can purify polysomes from brain cells and tissue from normal and VWM mice. CONCLUSION Two representative Disease models in combination with two robust genome-wide assays allow us to gain further insight into the Disease mechanism of VWM.
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Hyaluronan accumulation and arrested oligodendrocyte progenitor maturation in vanishing White Matter Disease
Brain, 2013Co-Authors: Marianna Bugiani, Marjo S. Van Der Knaap, Nienke L. Postma, Emiel Polder, Nikki Dieleman, Peter G. Scheffer, Fraser J. Sim, Ilja BoorAbstract:Vanishing White Matter Disease is a genetic leukoencephalopathy caused by mutations in eukaryotic translation initiation factor 2B. Patients experience a slowly progressive neurological deterioration with episodes of rapid clinical worsening triggered by stress. The Disease may occur at any age and leads to early death. Characteristic neuropathological findings include cystic degeneration of the White Matter with feeble, if any, reactive gliosis, dysmorphic astrocytes and paucity of myelin despite an increase in oligodendrocytic density. These features have been linked to a maturation defect of astrocytes and oligodendrocytes. However, the nature of the link between glial immaturity and the observed neuropathological features is unclear. We hypothesized that the defects in maturation and function of astrocytes and oligodendrocytes are related. Brain tissue of seven patients with genetically proven vanishing White Matter Disease was investigated using immunohistochemistry, western blotting, quantitative polymerase chain reaction and size exclusion chromatography. The results were compared with those obtained from normal brain tissue of age-matched controls, from chronic demyelinated multiple sclerosis lesions and from other genetic and acquired White Matter disorders. We found that the White Matter of patients with vanishing White Matter Disease is enriched in CD44-expressing astrocyte precursor cells and accumulates the glycosaminoglycan hyaluronan. Hyaluronan is a major component of the extracellular matrix, and CD44 is a hyaluronan receptor. We found that a high molecular weight form of hyaluronan is overabundant, especially in the most severely affected areas. Comparison between the more severely affected frontal White Matter and the relatively spared cerebellum confirms that high molecular weight hyaluronan accumulation is more pronounced in the frontal White Matter than in the cerebellum. High molecular weight hyaluronan is known to inhibit astrocyte and oligodendrocyte precursor maturation and can explain the arrested glial progenitor maturation observed in vanishing White Matter Disease. In conclusion, high molecular weight species of hyaluronan accumulate in the White Matter of patients with vanishing White Matter Disease, and by inhibiting glial maturation and proper function, they may be a major determinant of the White Matter pathology and lack of repair. * Abbreviations : eIF : eukaryotic translation initiation factor GFAP : glial fibrillary acidic protein HABP : hyaluronan-binding protein VWM : vanishing White Matter Disease
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Hyaluronan accumulation and arrested oligodendrocyte progenitor maturation in vanishing White Matter Disease.
Brain : a journal of neurology, 2013Co-Authors: Marianna Bugiani, Marjo S. Van Der Knaap, Emiel Polder, Nikki Dieleman, Peter G. Scheffer, Fraser J. Sim, Nienke Postma, Ilja BoorAbstract:Vanishing White Matter Disease is a genetic leukoencephalopathy caused by mutations in eukaryotic translation initiation factor 2B. Patients experience a slowly progressive neurological deterioration with episodes of rapid clinical worsening triggered by stress. The Disease may occur at any age and leads to early death. Characteristic neuropathological findings include cystic degeneration of the White Matter with feeble, if any, reactive gliosis, dysmorphic astrocytes and paucity of myelin despite an increase in oligodendrocytic density. These features have been linked to a maturation defect of astrocytes and oligodendrocytes. However, the nature of the link between glial immaturity and the observed neuropathological features is unclear. We hypothesized that the defects in maturation and function of astrocytes and oligodendrocytes are related. Brain tissue of seven patients with genetically proven vanishing White Matter Disease was investigated using immunohistochemistry, western blotting, quantitative polymerase chain reaction and size exclusion chromatography. The results were compared with those obtained from normal brain tissue of age-matched controls, from chronic demyelinated multiple sclerosis lesions and from other genetic and acquired White Matter disorders. We found that the White Matter of patients with vanishing White Matter Disease is enriched in CD44-expressing astrocyte precursor cells and accumulates the glycosaminoglycan hyaluronan. Hyaluronan is a major component of the extracellular matrix, and CD44 is a hyaluronan receptor. We found that a high molecular weight form of hyaluronan is overabundant, especially in the most severely affected areas. Comparison between the more severely affected frontal White Matter and the relatively spared cerebellum confirms that high molecular weight hyaluronan accumulation is more pronounced in the frontal White Matter than in the cerebellum. High molecular weight hyaluronan is known to inhibit astrocyte and oligodendrocyte precursor maturation and can explain the arrested glial progenitor maturation observed in vanishing White Matter Disease. In conclusion, high molecular weight species of hyaluronan accumulate in the White Matter of patients with vanishing White Matter Disease, and by inhibiting glial maturation and proper function, they may be a major determinant of the White Matter pathology and lack of repair.
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Adult-onset vanishing White Matter Disease due to a novel EIF2B3 mutation.
Archives of neurology, 2012Co-Authors: Roberta La Piana, Adeline Vanderver, Bernard Brais, Marjo S. Van Der Knaap, Louise Roux, Donatella Tampieri, Geneviève BernardAbstract:Objective To report a novel mutation in the gene EIF2B3 responsible for a late-onset form of vanishing White Matter Disease. Design Case report. Setting University teaching hospital. Patient A 29-year-old pregnant woman with a history of premature ovarian failure and hemiplegic migraines presented with a 10-week history of progressive confusion and headaches. Magnetic resonance imaging of the brain revealed a diffuse leukoencephalopathy. Results Sequencing of the exons and intron boundaries of EIF2B3 uncovered 2 missense mutations: c.260C>T (p.Ala87Val) and c.272G>A (p.Arg91His). To our knowledge, the latter missense mutation has never been previously reported. Conclusion This is the second report of adult-onset vanishing White Matter Disease due to mutations in EIF2B3 and the first report of the c.272G>A (p.Arg91His) missense mutation.
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Vanishing White Matter Disease Associated With Ptosis and Myoclonic Seizures
Journal of child neurology, 2010Co-Authors: Suvasini Sharma, Gert C. Scheper, Marjo S. Van Der Knaap, Ravindra Arya, K.n. Vykunta Raju, Atin Kumar, Sheffali GulatiAbstract:A 5-year-old boy who presented with progressive ataxia, neuroregression, and worsening with febrile illnesses is described. He also had myoclonic jerks and ptosis. His elder sister had died of a similar illness. Serial magnetic resonance imaging of the brain demonstrated extensive abnormality of the cerebral White Matter with rarefaction and cystic degeneration, suggestive of vanishing White Matter Disease. The patient was found to be compound heterozygous for 2 new mutations in the gene EIF2B5, confirming the diagnosis.
Juan Bilbao - One of the best experts on this subject based on the ideXlab platform.
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Understanding White Matter Disease: imaging-pathological correlations in vascular cognitive impairment.
Stroke, 2008Co-Authors: Sandra Black, Fuqiang Gao, Juan BilbaoAbstract:Most strokes are covert and observed incidentally on brain scans, but their presence increases risk of overt stroke and dementia. Amyloid angiopathy, associated with Alzheimer Disease (AD) causes stroke, and when even small strokes coexist with AD, they lower the threshold for dementia. Diffuse ischemic White Matter Disease impairs executive functioning, information processing speed, and gait. Neuroimaging techniques, such as tissue segmentation, Diffusion Tensor Imaging, MR Spectroscopy, functional MRI and amyloid PET, probe microstructural integrity, molecular biology, and activation patterns, providing new insights into brain-behavior relationships. MR-pathological studies of periventricular hyperintensity (leukoaraiosis) in aging and dementia reveal arteriolar tortuosity, reduced vessel density, and occlusive venous collagenosis which causes venous insufficiency and vasogenic edema. Activated microglia, oligodendroglial apoptosis, clasmatodendritic astrocytosis, and upregulated hypoxia-markers are seen on immunohistochemistry. Further research is needed to understand and treat this chronic subcortical vascular Disease, which is epidemic in our aging population.
Ilja Boor - One of the best experts on this subject based on the ideXlab platform.
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Hyaluronan accumulation and arrested oligodendrocyte progenitor maturation in vanishing White Matter Disease
Brain, 2013Co-Authors: Marianna Bugiani, Marjo S. Van Der Knaap, Nienke L. Postma, Emiel Polder, Nikki Dieleman, Peter G. Scheffer, Fraser J. Sim, Ilja BoorAbstract:Vanishing White Matter Disease is a genetic leukoencephalopathy caused by mutations in eukaryotic translation initiation factor 2B. Patients experience a slowly progressive neurological deterioration with episodes of rapid clinical worsening triggered by stress. The Disease may occur at any age and leads to early death. Characteristic neuropathological findings include cystic degeneration of the White Matter with feeble, if any, reactive gliosis, dysmorphic astrocytes and paucity of myelin despite an increase in oligodendrocytic density. These features have been linked to a maturation defect of astrocytes and oligodendrocytes. However, the nature of the link between glial immaturity and the observed neuropathological features is unclear. We hypothesized that the defects in maturation and function of astrocytes and oligodendrocytes are related. Brain tissue of seven patients with genetically proven vanishing White Matter Disease was investigated using immunohistochemistry, western blotting, quantitative polymerase chain reaction and size exclusion chromatography. The results were compared with those obtained from normal brain tissue of age-matched controls, from chronic demyelinated multiple sclerosis lesions and from other genetic and acquired White Matter disorders. We found that the White Matter of patients with vanishing White Matter Disease is enriched in CD44-expressing astrocyte precursor cells and accumulates the glycosaminoglycan hyaluronan. Hyaluronan is a major component of the extracellular matrix, and CD44 is a hyaluronan receptor. We found that a high molecular weight form of hyaluronan is overabundant, especially in the most severely affected areas. Comparison between the more severely affected frontal White Matter and the relatively spared cerebellum confirms that high molecular weight hyaluronan accumulation is more pronounced in the frontal White Matter than in the cerebellum. High molecular weight hyaluronan is known to inhibit astrocyte and oligodendrocyte precursor maturation and can explain the arrested glial progenitor maturation observed in vanishing White Matter Disease. In conclusion, high molecular weight species of hyaluronan accumulate in the White Matter of patients with vanishing White Matter Disease, and by inhibiting glial maturation and proper function, they may be a major determinant of the White Matter pathology and lack of repair. * Abbreviations : eIF : eukaryotic translation initiation factor GFAP : glial fibrillary acidic protein HABP : hyaluronan-binding protein VWM : vanishing White Matter Disease
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Hyaluronan accumulation and arrested oligodendrocyte progenitor maturation in vanishing White Matter Disease.
Brain : a journal of neurology, 2013Co-Authors: Marianna Bugiani, Marjo S. Van Der Knaap, Emiel Polder, Nikki Dieleman, Peter G. Scheffer, Fraser J. Sim, Nienke Postma, Ilja BoorAbstract:Vanishing White Matter Disease is a genetic leukoencephalopathy caused by mutations in eukaryotic translation initiation factor 2B. Patients experience a slowly progressive neurological deterioration with episodes of rapid clinical worsening triggered by stress. The Disease may occur at any age and leads to early death. Characteristic neuropathological findings include cystic degeneration of the White Matter with feeble, if any, reactive gliosis, dysmorphic astrocytes and paucity of myelin despite an increase in oligodendrocytic density. These features have been linked to a maturation defect of astrocytes and oligodendrocytes. However, the nature of the link between glial immaturity and the observed neuropathological features is unclear. We hypothesized that the defects in maturation and function of astrocytes and oligodendrocytes are related. Brain tissue of seven patients with genetically proven vanishing White Matter Disease was investigated using immunohistochemistry, western blotting, quantitative polymerase chain reaction and size exclusion chromatography. The results were compared with those obtained from normal brain tissue of age-matched controls, from chronic demyelinated multiple sclerosis lesions and from other genetic and acquired White Matter disorders. We found that the White Matter of patients with vanishing White Matter Disease is enriched in CD44-expressing astrocyte precursor cells and accumulates the glycosaminoglycan hyaluronan. Hyaluronan is a major component of the extracellular matrix, and CD44 is a hyaluronan receptor. We found that a high molecular weight form of hyaluronan is overabundant, especially in the most severely affected areas. Comparison between the more severely affected frontal White Matter and the relatively spared cerebellum confirms that high molecular weight hyaluronan accumulation is more pronounced in the frontal White Matter than in the cerebellum. High molecular weight hyaluronan is known to inhibit astrocyte and oligodendrocyte precursor maturation and can explain the arrested glial progenitor maturation observed in vanishing White Matter Disease. In conclusion, high molecular weight species of hyaluronan accumulate in the White Matter of patients with vanishing White Matter Disease, and by inhibiting glial maturation and proper function, they may be a major determinant of the White Matter pathology and lack of repair.
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defective glial maturation in vanishing White Matter Disease
Journal of Neuropathology and Experimental Neurology, 2011Co-Authors: Marianna Bugiani, Nienke L. Postma, Emiel Polder, Ilja Boor, Barbara Van Kollenburg, Carola G M Van Berkel, Ronald E Van Kesteren, Martha S Windrem, Elly M Hol, Gert C. ScheperAbstract:Vanishing White Matter (VWM) Disease is a genetic leukoencephalopathy linked to mutations in the eukaryotic translation initiation factor 2B. It is a Disease of infants, children, and adults who experience a slowly progressive neurologic deterioration with episodes of rapid clinical worsening triggered by stress and eventually leading to death. Characteristic neuropathologic findings include cystic degeneration of the White Matter with scarce reactive gliosis, dysmorphic astrocytes, and paucity of myelin despite an increase in oligodendrocytic density. To assess whether a defective maturation of macroglia may be responsible for the feeble gliosis and lack of myelin, weinvestigated the maturation status of astrocytes and oligodendrocytes in the brains of 8 VWM patients, 4 patients with other White Matter disorders and 6 age-matched controls with a combination of immunocytochemistry, histochemistry, scratch-wound assays, Western blot, and quantitative polymerase chain reaction. We observed increased proliferation and a defect in the maturation of VWM astrocytes. They show an anomalous composition of their intermediate filament network with predominance of the δ-isoform of the glial fibrillary acidic protein and an increase in the heat shock protein αB-crystallin, supporting the possibility that a deficiency in astrocyte function may contribute to the loss of White Matter in VWM. We also demonstrated a significant increase in numbers of premyelinating oligodendrocyte progenitors in VWM, which may explain the coexistence of oligodendrocytosis and myelin paucity in the patients' White Matter.
Sandra Black - One of the best experts on this subject based on the ideXlab platform.
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Understanding White Matter Disease: imaging-pathological correlations in vascular cognitive impairment.
Stroke, 2008Co-Authors: Sandra Black, Fuqiang Gao, Juan BilbaoAbstract:Most strokes are covert and observed incidentally on brain scans, but their presence increases risk of overt stroke and dementia. Amyloid angiopathy, associated with Alzheimer Disease (AD) causes stroke, and when even small strokes coexist with AD, they lower the threshold for dementia. Diffuse ischemic White Matter Disease impairs executive functioning, information processing speed, and gait. Neuroimaging techniques, such as tissue segmentation, Diffusion Tensor Imaging, MR Spectroscopy, functional MRI and amyloid PET, probe microstructural integrity, molecular biology, and activation patterns, providing new insights into brain-behavior relationships. MR-pathological studies of periventricular hyperintensity (leukoaraiosis) in aging and dementia reveal arteriolar tortuosity, reduced vessel density, and occlusive venous collagenosis which causes venous insufficiency and vasogenic edema. Activated microglia, oligodendroglial apoptosis, clasmatodendritic astrocytosis, and upregulated hypoxia-markers are seen on immunohistochemistry. Further research is needed to understand and treat this chronic subcortical vascular Disease, which is epidemic in our aging population.
