Natural history of adult-onset eIF2B-related disorders: a multi-centric survey of 16 cases

Abstract

Mutations in one of the five eukaryotic initiation factor 2B genes (EIF2B1-5) were first described in childhood ataxia with cerebral hypomyelination--vanishing white matter syndrome. The syndrome is characterized by (i) cerebellar and pyramidal signs in children aged 2-5 years; (ii) extensive cavitating leucoencephalopathy; and (iii) episodes of rapid deterioration following stress. Since then a broad clinical spectrum from congenital to adult-onset forms has been reported, leading to the concept of eIF2B-related disorders. Our aim was to describe clinical and brain magnetic resonance imaging characteristics, genetic findings and natural history of patients with adult-onset eIF2B-related disorders (after age 16). The inclusion criteria were based on the presence of eIF2B mutations and a disease onset after the age of 16 years. One patient with an asymptomatic diagnosis (age 16 years) was also included. Clinical and magnetic resonance findings were retrospectively recorded in all patients. All patients were examined to assess clinical evolution, using functional, pyramidal, cerebellar and cognitive scales. This multi-centric study included 16 patients from 14 families. A sex ratio imbalance was noted (male/female = 3/13). The mean age of onset was 31.1 years (range 16-62). Initial symptoms were neurologic (n = 11), psychiatric (n = 2) and ovarian failure (n = 2). Onset of the symptoms was linked to a precipitating factor in 13% of cases that included minor head trauma and delivery. During follow-up (mean: 11.2 years, range 2-22 years) 12.5% of the patients died. Of the 14 survivors, 62% showed a decline in their cognitive functions, and 79% were severely handicapped or bedridden. One case remained asymptomatic. Stress worsened clinical symptoms in 38% of the patients. Magnetic resonance imaging findings consist of constant cerebral atrophy, extensive cystic leucoencephalopathy (81%), corpus callosum (69%) and cerebellar (38%) T2-weighted hyperintensities. All families except one showed mutations in the EIF2B5 gene. The recurrent p.Arg113His-eIF2Bepsilon mutation was found in 79% of the 14 eIF2B-mutated families, mainly at a homozygous state. The family with a mutation in EIF2B2 had the relatively prevalent p.Glu213Gly mutation. eIF2B-related disorder is probably underestimated as an adult-onset inherited leucoencephalopathy. In this late-onset form, presentation ranges from neurologic symptoms to psychiatric manifestations or primary ovarian failure. Cerebral atrophy is constant, whereas the typical vanishing of the white matter can be absent. Functional and/or cognitive prognosis remains severe. Molecular diagnosis is facilitated for these forms by the screening of the two recurrent p.Arg113His-eIF2Bepsilon and p.Glu213Gly-eIF2Bbeta mutations, positive in 86% of cases.

Natural History of Vanishing White Matter

“…Prior studies have pointed to sex‐related differences among VWM patients, such as the male:female imbalance among adolescent/adult onset patients and possible differences in disease severity 13, 14, 33. Our study did not confirm consistent clinical differences between males and females.…”

“…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).…”

Astrocytes are central in the pathomechanisms of vanishing white matter

“…The most common form has its onset between 2 and 6 years of age; death occurs within a few years (1). Adult-onset VWM is characterized by slowly progressive encephalopathy and death after several decades (4). Apart from ovarian failure, extracerebral organs are not affected in patients with onset after infancy.…”

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

“…This change is best shown by proton density and fluid-attenuated inversion recovery (FLAIR) images. In the series of Labauge, cystic changes included the corpus callosum [11]. Contrast enhancement has never been reported.…”

“…Cognitive decline or behavioral problems may be the presenting symptom in adult-onset forms of the disease [11,12]. Since 1998, milder variants of the disease with an adolescent or adult onset have been identified [5].…”