Alternative titles; symbols
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q12.2 | Encephalitis/encephalopathy, mild, with reversible myelin vacuolization | 618113 | Autosomal dominant | 3 | MYRF | 608329 |
A number sign (#) is used with this entry because of evidence that mild encephalitis/encephalopathy with reversible myelin vacuolization (MMERV) is caused by heterozygous mutation in the MYRF gene (608329) on chromosome 11q12.
MMERV is an episodic acute reversible encephalopathy that occurs in children and is frequently associated with a trigger, such as a febrile illness. Affected individuals have impaired consciousness, delirious behavior, and/or seizures with lip smacking or eye deviation. These changes are associated with white matter lesions in the brain that often occur in the splenium of the corpus callosum, but may occur in surrounding areas. The acute phase of the disorder can be treated with steroids, and most patients make a full neurologic recovery between episodes with no sequelae (summary by Kurahashi et al., 2018).
Kurahashi et al. (2018) reported 2 unrelated Japanese families with onset of episodic encephalopathy in childhood. There were 4 definitely affected individuals from the 2 families. Five additional members from 1 family had a history suggestive of the disorder, although brain imaging was not performed. The proband in family A developed seizures at age 32 months, followed by repeated episodes of altered consciousness in the following few years, but had no neurologic sequelae at 106 months of age. Brain imaging showed signal abnormalities in the corpus callosum and white matter consistent with myelin changes. Family history revealed several additional family members with a history of single similar events in childhood, including speech difficulties, seizures, and abnormal behavior. None had permanent neurologic sequelae. In family B, 3 sisters had a similar disorder between 2 and 9 years of age. Their mother was also affected at age 6. Brain imaging in the sisters showed white matter vacuolization abnormalities in the corpus callosum and surrounding areas, all of which resolved in days to a week. Family B had previously been reported by Imamura et al. (2010).
The transmission pattern of MMERV in the families reported by Kurahashi et al. (2018) was consistent with autosomal dominant inheritance.
In 9 patients from 2 unrelated Japanese families with MMERV, Kurahashi et al. (2018) identified a heterozygous missense mutation in the MYRF gene (Q403R; 608329.0001). The mutation, which was found by whole-exome sequencing in the first family and confirmed by Sanger sequencing in both families, segregated with the disorder in both families. Haplotype analysis suggested a founder effect. In vitro functional expression studies using a luciferase reporter showed that the mutation resulted in significantly decreased transcriptional activity. Since all patients had normal psychomotor development even after recurrent episodes, Kurahashi et al. (2018) suggested that the function of the MYRF variant is relatively preserved under normal circumstances, but is insufficient during increased physiologic demands, such as infection. Direct sequencing of the MYRF gene in 33 individuals with sporadic MMERV did not identify any pathogenic variants.
Koenning et al. (2012) found that genetic ablation of the Mrf (Myrf) gene in mature oligodendrocytes in adult mice resulted in a delayed and severe demyelination. The mice had impaired motor skill learning. The demyelination was accompanied by microglial/macrophage infiltration, axonal damage, and decreased expression of myelin genes. However, over time, there was some evidence of remyelination. The findings demonstrated that ongoing expression of Mrf within the adult central nervous system is critical to maintain mature oligodendrocyte identity and the integrity of myelin.
Imamura, T., Takanashi, J., Yasugi, J., Terada, H., Nishimura, A. Sisters with clinically mild encephalopathy with a reversible splenial lesion (MERS)-like features; familial MERS? J. Neurol. Sci. 290: 153-156, 2010. [PubMed: 20042198] [Full Text: https://doi.org/10.1016/j.jns.2009.12.004]
Koenning, M., Jackson, S., Hay, C. M., Faux, C., Kilpatrick, T. J., Willingham, M., Emery, B. Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS. J. Neurosci. 32: 12528-12542, 2012. [PubMed: 22956843] [Full Text: https://doi.org/10.1523/JNEUROSCI.1069-12.2012]
Kurahashi, H., Azuma, Y., Masuda, A., Okuno, T., Nakahara, E., Imamura, T., Saitoh, M., Mizuguchi, M., Shimizu, T., Ohno, K., Okumura, A. MYRF is associated with encephalopathy with reversible myelin vacuolization. Ann. Neurol. 83: 98-106, 2018. [PubMed: 29265453] [Full Text: https://doi.org/10.1002/ana.25125]