Phenotypic variation in leukoencephalopathy with vanishing white matter

Knaap, Marjo S. van der; Kamphorst, W.; Barth, Peter; Kraaijeveld, C. L.; Gut, E.; Valk, J.

doi:10.1212/wnl.51.2.540

Cited by 205 publications

(242 citation statements)

References 10 publications

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“…Age of onset is inversely related to clinical severity 2. Clinically, VWM is characterized by chronic neurological decline with additional episodes of rapid, severe deterioration provoked by stressors like febrile infections and minor head trauma, which may end in coma and death 3, 4, 5, 6. As yet, no curative treatment is available.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 99%

“…U‐fibers, corpus callosum, internal capsule, and brainstem are better preserved 5, 6, 12. Considering the degree of cerebral white matter damage, reactive astrogliosis is disproportionately meager 13, 14.…”

Section: Introductionmentioning

confidence: 99%

Axonal abnormalities in vanishing white matter

Klok

Bugiani

Vries

et al. 2018

Ann Clin Transl Neurol

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“…The symptoms of the disease can begin shortly after birth or in adulthood. The phenotypic variation is very wide and the most common features include neurological deterioration, optic atrophy, seizures, coma, and death 3, 4, 5. VWM disease is diagnosed on the basis of the clinical symptoms in combination with MRI results and molecular testing 6.…”

Section: Introductionmentioning

confidence: 99%

Diabetic ketoacidosis in vanishing white matter

Alamri

Mutairi

Alothman

et al. 2016

Clinical Case Reports

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“…Vanishing white matter (VWM; Online Mendelian Inheritance in Man database 603896) 1, 2, 3 is one of the more prevalent leukodystrophies 4. It is caused by recessive mutations in any of the genes EIF2B1–5.…”

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confidence: 99%

“…No curative treatment is available 7. Although VWM was initially recognized as a disorder of young children,1, 2, 8 it has become apparent that disease onset and severity vary widely, from antenatal or early infantile onset disease with rapid demise9, 10, 11 to adult onset slow disease 3, 12…”

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confidence: 99%

Natural History of Vanishing White Matter

Hamilton

Lei

Vermeulen

et al. 2018

Annals of Neurology

173

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ObjectiveTo comprehensively describe the natural history of vanishing white matter (VWM), aiming at improving counseling of patients/families and providing natural history data for future therapeutic trials.MethodsWe performed a longitudinal multicenter study among 296 genetically confirmed VWM patients. Clinical information was obtained via disease‐specific clinical questionnaire, Health Utilities Index and Guy's Neurological Disability Scale assessments, and chart review.ResultsFirst disease signs occurred at a median age of 3 years (mode = 2 years, range = before birth to 54 years); 60% of patients were symptomatic before the age of 4 years. The nature of the first signs varied for different ages of onset. Overall, motor problems were the most common presenting sign, especially in children. Adolescent and adult onset patients were more likely to exhibit cognitive problems early after disease onset. One hundred two patients were deceased. Multivariate Cox regression analysis revealed a positive relation between age at onset and both preservation of ambulation and survival. Absence of stress‐provoked episodes and absence of seizures predicted more favorable outcome. In patients with onset before 4 years, earlier onset was associated with more severe disability and higher mortality. For onset from 4 years on, disease course was generally milder, with a wide variation in severity. There were no significant differences for sex or for the 5 eIF2B gene groups. The results confirm the presence of a genotype–phenotype correlation.InterpretationThe VWM disease spectrum consists of a continuum with extremely wide variability. Age at onset is a strong predictor for disease course. Ann Neurol 2018;84:274–288

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Phenotypic variation in leukoencephalopathy with vanishing white matter

Abstract: Later onset does occur in the disease of vanishing white matter, and both MRS and histopathology are compatible with a primary axonopathy rather than primary demyelination.

Cited by 205 publications

References 10 publications

Axonal abnormalities in vanishing white matter

Axonal abnormalities in vanishing white matter

Diabetic ketoacidosis in vanishing white matter

Natural History of Vanishing White Matter

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