MYRF is associated with encephalopathy with reversible myelin vacuolization

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Myelin vacuolization is associated with several forms of disorders affecting white matter of the brain. It is triggered by variable pathologic mechanisms, and clinical manifestation is reversible in some patients. Several forms of reversible myelin vacuolization have been reported in association with genetic etiology. X‐Linked Charcot–Marie–Tooth disease (CMT) X1 is caused by pathogenic variants in GJB1,1 and transient white matter lesion has been reported in children and adults with CMTX1.2 Megalencephalic leukoencephalopathy with subcortical cysts (MLC) 2B is caused by dominant variants in GLIALCAM.3 In MLC2B patients with the remitting clinical phenotype, improvement and normalization of white matter abnormalities have been reported.5
Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) is a subtype of acute encephalopathy characterized by a transient white matter lesion suggesting myelin vacuolization.6 Central nervous system (CNS) symptoms in children with MERS are impaired consciousness and/or delirious behavior lasting for several days.6 Brain lesions observed in MERS patients are characterized by transiently reduced diffusion in the splenium of the corpus callosum, which usually disappears within 1 week. Brain lesions sometimes extend to the entire corpus callosum and bilateral subcortical white matter in the centrum semiovale.9 Familial cases of MERS have been reported, suggesting the presence of genetic factors.12
We examined familial cases of encephalopathy with extensive but reversible cerebral myelin vacuolization including splenium in which the proband had a history of recurrent reversible myelin vacuolization spanning 3 generations. All the affected individuals showed CNS symptoms similar to those of MERS. To explore the responsible gene, we performed whole‐exome sequencing in the family. By focusing on rare nonsynonymous variants in genes expressed in the CNS, especially in the white matter, we identified a single nucleotide variant (SNV) in the MYRF gene in all affected family members. We also sequenced the MYRF gene in another family that was previously described as familial MERS12 and 33 additional patients with sporadic MERS. Here, we report the clinical and genetic features of these patients.
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