Natural History of Vanishing White Matter.

OBJECTIVE: To 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. METHODS: We 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. RESULTS: First 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. INTERPRETATION: The 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.

Restricted diffusion in vanishing white matter.

OBJECTIVE: To investigate the occurrence of restricted diffusion in vanishing white matter, the affected structures,the time of occurrence in the disease course, and the histopathologic correlate. DESIGN: Retrospective observational study. PATIENTS: Forty-six patients with vanishing white matter. SETTING: VU University Medical Center. MAIN OUTCOME MEASURES: We evaluated all available diffusion-weighted imaging studies in our database and recorded the areas that displayed restricted diffusion in 1 or more patients. We measured the mean apparent diffusion coefficients of these areas in all patients and used the putamen for internal quality control. We recorded age and disease duration during magnetic resonance imaging, and we obtained a magnetic resonance image of a postmortem vanishing white matter brain slice and subsequently performed histopathologic stainings. RESULTS: Areas with decreased apparent diffusion coefficient values were found in the U fibers (n=21 patients), cerebellar white matter (n=18), middle cerebellar peduncle(n=8), pyramids (n=8), genu (n=8) or splenium (n=9) of the corpus callosum, and posterior limb of the internal capsule(n=10). Overall, patients showing restricted diffusion(n=32)were younger and had shorter disease duration. Histopathologic analysis of the brain slice revealed that regions with restricted diffusion had a higher cell density. CONCLUSION: In vanishing white matter, restricted diffusion can be found in relatively spared regions with high cellularity particularly in young patients with short disease duration.

Late onset vanishing white matter disease presenting with learning difficulties.

BACKGROUND: Vanishing white matter is an inherited leukoencephalopathy with typical childhood onset. Late onset forms are rare and may present with an extended range of phenotypes. Case report We present a patient born to consanguineous parents who developed learning disabilities by the age of 16 years. At the age of 25 she had a focal motor seizure with subsequent hemiparesis. After an extensive investigation she was diagnosed and treated as multiple sclerosis. There was progressive memory and planning impairment and, six years later, Sjögren syndrome with central nervous system involvement was diagnosed. For six months she was treated with cyclophosphamide, without any improvement. The next two years she had major clinical deterioration following infections. A homozygous mutation was identified in the EIF2B5 gene at the age of 33, and she died a year later. CONCLUSIONS: VWM leukoencephalopathy is still largely recognized as a pediatric disorder, with many adult neurologists being unfamiliar with the late onset presentations. We wish to draw attention into these forms, avoiding submitting these patients to extensive workup and unnecessary treatments.

Severity of vanishing white matter disease does not correlate with deficits in eIF2B activity or the integrity of eIF2B complexes.

Autosomal recessive mutations in eukaryotic initiation factor 2B (eIF2B) cause leukoencephalopathy vanishing white matter with a wide clinical spectrum. eIF2B comprises five subunits (α-ε; genes EIF2B1, 2, 3, 4 and 5) and is the guanine nucleotide-exchange factor (GEF) for eIF2. It plays a key role in protein synthesis. Here, we have studied the functional effects of selected VWM mutations in EIF2B2-5 by coexpressing mutated and wild-type subunits in human cells. The observed functional effects are very diverse, including defects in eIF2B complex integrity; binding to the regulatory α-subunit; substrate binding; and GEF activity. Activity data for recombinant eIF2B complexes agree closely with those for patient-derived cells with the same mutations. Some mutations do not affect these parameters even though they cause severe disease. These findings are important for three reasons; they demonstrate that measuring eIF2B activity in patients' cells has limited value as a diagnostic test; they imply that severe disease can result from alterations in eIF2B function other than defects in complex integrity, substrate binding or GEF activity, and last, the diversity of functional effects of VWM mutations implies that seeking agents to manage or treat VWM should focus on downstream effectors of eIF2B, not restoring eIF2B activity.