Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter

Knaap, Marjo S. van der; Leegwater, P.A.J.; Könst, Andrea A.M.; Visser, Allerdien; Naidu, Sakkubai; Oudejans, Cees B.M.; Schutgens, R. B. H.; Pronk, Jan C.

doi:10.1002/ana.10112

Cited by 333 publications

(237 citation statements)

References 22 publications

(38 reference statements)

Supporting

Mentioning

225

Contrasting

Unclassified

Order By: Relevance

“…VWM is caused by mutations in the genes encoding the five subunits of the eukaryotic translation initiation factor 2B (eIF2B), EIF2B1 through EIF2B5 7, 8. eIF2B is an enzyme complex essential for translation of mRNAs into proteins and central in downregulating the rate of translation under different stress conditions 9.…”

Section: Introductionmentioning

confidence: 99%

Axonal abnormalities in vanishing white matter

Klok

Bugiani

Vries

et al. 2018

Ann Clin Transl Neurol

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

Axonal abnormalities in vanishing white matter

Klok

Bugiani

Vries

et al. 2018

Ann Clin Transl Neurol

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is caused by recessive mutations in any of the genes EIF2B1–5. 5, 6 Patients typically have normal early development, followed by chronic neurological deterioration and additionally stress‐provoked episodes of rapid decline 2. No curative treatment is available 7.…”

mentioning

confidence: 99%

Natural History of Vanishing White Matter

Hamilton

Lei

Vermeulen

et al. 2018

Annals of Neurology

Self Cite

173

View full text Add to dashboard Cite

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

show abstract

“…There are identifiable mutations in five causative genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5) encoding the five subunits of eucaryotic translation initiation factor 2B (EIF2B) in 90% of individuals [8]. A broad clinical spectrum from congenital to adult-onset forms has been described [5,9].…”

Section: Introductionmentioning

confidence: 99%

Childhood Ataxia With Central Nervous System Hypomyelination: A Report of First Two Cases With Juvenile and Adult - Onset Forms in a Turkish Family

Kenangil

2012

J Neurol Res

View full text Add to dashboard Cite

Childhood ataxia with central nervous system hypomyelination (CACH)) is an inherited autosomal recessive white matter disease which is also known as leukoencephalopathy with vanishing white matter (VWM). Ataxia and spasticity are the predominant symptoms of the disease. It is a progressive disease with exacerbations. Manyetic resonance imaging (MRI) is diagnostic with diffuse white matter abnormalities. It can be seen at all ages but adult forms are rare. We report here the first two cases of juvenile and adult-onset forms of the disease in Turkey. They are two sisters with age of 21 and 25 who presented us with gait difficulty and spasticity. They had seizures and also the typical MRI findings of CACH. We should consider it in the differential diagnosis of gait difficulty, ataxia and spasticity in adult patients.

show abstract

Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter

Cited by 333 publications

References 22 publications

Axonal abnormalities in vanishing white matter

Axonal abnormalities in vanishing white matter

Natural History of Vanishing White Matter

Childhood Ataxia With Central Nervous System Hypomyelination: A Report of First Two Cases With Juvenile and Adult - Onset Forms in a Turkish Family

Contact Info

Product

Resources

About