The effect of genotype on the natural history of eIF2B-related leukodystrophies

Fogli, Anne; Schiffmann, Raphael; Bertini, Enrico; Ughetto, Sylvie; Combes, Patricia; Eymard-Pierre, Éléonore; Kaneski, Christine R.; Pineda, Mari Carmen; Troncoso, Mónica; Uziel, Graziella; Surtees, Robert; Pugin, Déborah; Chaunu, Marie‐Pierre; Rodriguez, Diana; Boespflug‐Tanguy, Odile

doi:10.1212/01.wnl.0000123259.67815.db

Cited by 155 publications

(167 citation statements)

References 24 publications

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“…Our study confirms that VWM has an extremely broad phenotypic range and that age at onset is an important determinant of prognosis 15, 34. Patients with onset at <1 year consistently have a rapidly progressive disease and die within several months.…”

Section: Discussionsupporting

confidence: 82%

“…For all ages of onset, seizures and episodic deteriorations are important negative predictors of disease course, underlining the importance of seizure control and preventive measures such as avoiding head trauma, antibiotics, and antipyretics for all patients 7. The present study confirms the presence of a genotype–phenotype correlation 15, 33, 36…”

Section: Discussionsupporting

confidence: 79%

“…Additionally, natural history studies are valuable for insight into pathomechanisms, genotype–phenotype correlations, and setup of therapeutic trials. Natural history studies in VWM are scarce and rather small 13, 14, 15. We report results of a 12½‐year natural history study of VWM, focusing on occurrence of neurological signs in relation to age and disease duration, identification of prognostic factors, and assessment of dimensions of disability by 2 validated scales: Health Utilities Index (HUI) and Guy's Neurological Disability Scale (GNDS).…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 79%

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confidence: 99%

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Natural History of Vanishing White Matter

Hamilton

Lei

Vermeulen

et al. 2018

Annals of Neurology

173

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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.…”

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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“…It is reported that the disease severity is not correlated with either the type of the subunit mutated, or the position of the mutation within the protein. 29 Recently p.Arg113His in the e and p.Glu213Gly in the b subunits have been associated with milder phenotypes, and a relationship between severe phenotype with early infantile onset and p.Arg195His in the e has been found. 29,30 One hypothesis is that severe phenotypes occur in the presence of homozygotic mutations in highly conserved regions, with mutations in non-conserved amino acids leading to mild phenotype.…”

Section: Discussionmentioning

confidence: 99%