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.

Regulation of protein synthesis in lymphoblasts from vanishing white matter patients.

Leukoencephalopathy with vanishing white matter (VWM) is an inherited childhood white matter disorder, caused by mutations in the genes encoding eukaryotic initiation factor 2B (eIF2B). The present study showed that, while the eIF2B activity was reduced in VWM lymphoblasts, the expression levels of the eIF2B subunits were similar to control lymphoblast lines. The mutations in eIF2B did not affect the interaction with eIF2. Strikingly, no apparent differences for the regulation of protein synthesis, measured by [35S]-methionine incorporation, were found between control and VWM lymphoblasts. Western blotting showed that, in some VWM cells, exposure to heat shock caused a decrease in the expression of specific eIF2B subunits. Most importantly, the increase in phosphorylation of eIF2alpha in response to heat shock was lower in VWM lymphoblasts than in control cells. These findings could form part of the explanation for the episodes of rapid and severe deterioration in VWM patients that are precipitated by febrile infections.

Fright is a provoking factor in vanishing white matter disease.

Leukoencephalopathy with vanishing white matter is an inherited disorder with a chronic progressive disease course and additional episodes of rapid neurological deterioration. These episodes typically are provoked by febrile infections or minor head trauma. We report on two patients who experienced an episode of rapid neurological deterioration after a fright.

Pattern of white matter abnormalities at MR imaging: use of polymerase chain reaction testing of Guthrie cards to link pattern with congenital cytomegalovirus infection.

PURPOSE: To define a magnetic resonance (MR) imaging pattern suggestive of congenital cytomegalovirus (CMV) infection by using polymerase chain reaction (PCR) testing to detect CMV DNA in neonatal blood on Guthrie cards for validation. MATERIALS AND METHODS: On the basis of findings in eight patients with documented congenital CMV infection, the authors developed MR imaging inclusion criteria, including multifocal lesions predominantly located in the deep parietal white matter. If gyral abnormalities were present, white matter lesions were either multifocal or diffuse. The criteria were applied to 152 patients with static leukoencephalopathy of unknown etiology. Guthrie cards for 22 of the 43 patients fulfilling the MR imaging criteria, 20 patients not fulfilling them, and 300 control subjects were analyzed. Fisher exact testing was used to evaluate the association between MR imaging characteristics and CMV status, and backward elimination linear discriminant analysis was used to identify MR imaging characteristics predictive of CMV infection in addition to the initial criteria. RESULTS: PCR test results were positive in 12 of 22 patients suspected of having congenital CMV infection, in no patient not suspected of having infection (P <.001), and in two of 300 control subjects (negative predictive value [NPV] of MR imaging criteria, 100% [95% CI: 83%, 100%]; positive predictive value [PPV], 55% [95% CI: 32%, 76%]). The most important additional MR imaging finding predicting a positive PCR result was abnormality of the anterior part of the temporal lobe, including abnormal white matter, cysts, and enlargement of inferior horns. Including this finding in the MR imaging criteria enhanced the PPV (89%; 95% CI: 52%, 99%) at the expense of the NPV (88%; 95% CI: 72%, 97%). CONCLUSION: In patients with static encephalopathy, an MR imaging pattern of multifocal lesions predominantly involving deep parietal white matter, with or without gyral abnormalities, is predictive of congenital CMV infection. When gyral abnormalities are present, leukoencephalopathy may also be diffuse. The presence of abnormalities in the anterior part of the temporal lobe increases the likelihood that CMV infection is present.