🏷

Classifications

Harrison's Part

👪

Inheritance

1

Autosomal Dominant HP:0000006

MMERV is inherited in an autosomal dominant manner across multigenerational pedigrees segregating the heterozygous MYRF c.1208A>G (p.Gln403Arg) missense variant. Incomplete penetrance and variable expressivity are documented, with some heterozygous carriers experiencing only isolated childhood seizures without recurrent adult episodes or extensive white matter relapses.

Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE

Show evidence (3 references)

PMID:29265453 SUPPORT Human Clinical

"By filtering genes expressed in the corpus callosum, we identified a heterozygous c.1208A>G predicting p.Gln403Arg in the highly conserved DNA-binding domain in the myelin regulatory factor (MYRF) gene. We subsequently screened the coding regions of MYRF by Sanger sequencing in our cohort..."

Establishes heterozygous cosegregation of the MYRF c.1208A>G (p.Gln403Arg) variant across affected family members in two multiplex families consistent with autosomal dominant inheritance.

PMID:38155716 SUPPORT Human Clinical

"MYRF-related mild encephalopathy with reversible myelin vacuolization is a rare autosomal dominant genetic disease, with early clinical manifestations often being seizures."

Explicitly defines MMERV as an autosomal dominant genetic disorder.

PMID:38155716 SUPPORT Human Clinical

"It is noteworthy that only three patients (II-1 and IV-1 in family A and III-1 in Family C) in the study experienced multiple episodes. However, it is uncertain whether these episodes were triggered by predisposing factors or if other carriers had asymptomatic episodes."

Documents marked intrafamilial variable expressivity and potential incomplete penetrance across heterozygous MYRF c.1208A>G carriers within the three reported families.

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Pathophysiology

4

Impaired MYRF DNA-Binding Domain Transcriptional Activity

MYRF encodes an endoplasmic reticulum membrane-anchored precursor protein that undergoes intramolecular chaperone auto-processing (ICA) domain-mediated homotrimerization and autoproteolytic self-cleavage to release an active N-terminal transcription factor trimer that translocates to the nucleus. In MMERV, the recurrent heterozygous missense variant c.1208A>G (p.Gln403Arg) alters a highly conserved residue within the Ndt80-like DNA-binding domain of the cleaved N-terminal fragment, significantly diminishing its transcriptional activation of downstream myelin target genes.

oligodendrocyte CL:0000128

MYRF hgnc:1181

positive regulation of transcription by RNA polymerase II GO:0045944 ↓ DECREASED

DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981 ↓ DECREASED

central nervous system UBERON:0001017

Downstream

Compromised Oligodendrocyte Myelin Gene Transcription and Maintenance Reserve Reduced nuclear MYRF transcriptional activity decreases expression of core central nervous system myelin structural proteins, impairing oligodendrocyte myelin maintenance capacity.

Show evidence (3 references)

PMID:29265453 SUPPORT In Vitro

"Luciferase assay revealed that transcriptional activity of the N-terminal region of MYRF was significantly diminished by introducing the c.1208A>G variant."

Demonstrates functionally in vitro that the MMERV-associated c.1208A>G (p.Gln403Arg) variant in the DNA-binding domain reduces the transcriptional activation capacity of the N-terminal MYRF fragment.

PMID:23966832 SUPPORT BACKGROUND In Vitro

"Indeed, the intramolecular chaperone domain of MYRF facilitates its homo-oligomerization and proteolytically processes it into two halves. The N-terminal trimer, containing the DNA-binding domain, is released from the ER membrane and moves to the nucleus, where it exerts transcriptional effects."

Establishes the normal biochemical mechanism by which MYRF self-cleaves via its ICA domain into an active N-terminal homotrimeric transcription factor.

PMID:23966833 SUPPORT BACKGROUND In Vitro

"Using ChIP-Seq we show that the N-terminal cleavage product directly binds the enhancer regions of oligodendrocyte-specific and myelin genes. This binding occurs via a defined DNA-binding consensus sequence and strongly promotes the expression of target genes."

Confirms that nuclear translocation of the cleaved N-terminal MYRF fragment directly binds myelin gene enhancers to drive transcription.

Compromised Oligodendrocyte Myelin Gene Transcription and Maintenance Reserve

Mature oligodendrocytes require continuous MYRF transcriptional activity to sustain expression of major structural myelin genes (such as MBP, PLP1, MAG, and MOG) and preserve compact central nervous system myelin sheath integrity. Partial loss of MYRF transcriptional activity due to heterozygous missense variation permits normal baseline myelination and neurodevelopment but leaves mature oligodendrocytes with reduced homeostatic reserve for myelin maintenance and repair.

oligodendrocyte CL:0000128

myelin maintenance GO:0043217 ↓ DECREASED central nervous system myelination GO:0022010 ↓ DECREASED

white matter UBERON:0002316

Downstream

Acute Reversible Intramyelinic Edema and Myelin Vacuolization When challenged by a febrile viral infection ("second hit"), compromised oligodendrocyte myelin maintenance capacity fails to prevent intramyelinic fluid accumulation and myelin sheath vacuolization.

Show evidence (3 references)

PMID:29265453 SUPPORT Human Clinical

"MYRF is a transcriptional regulator that is necessary for oligodendrocyte differentiation and myelin maintenance. Functional defects of MYRF are likely to be causally associated with encephalopathy with extensive myelin vacuolization."

Establishes that MYRF transcriptional activity is required in oligodendrocytes to maintain CNS myelin and that functional MYRF defects underlie reversible myelin vacuolization.

PMID:23966833 SUPPORT BACKGROUND Model Organism

"Inducible ablation of Myrf in mature oligodendrocytes of the adult CNS also causes a rapid down-regulation of myelin gene expression followed by a gradual degeneration of CNS myelin [14]."

Demonstrates that ongoing MYRF activity in mature oligodendrocytes is continuously required to sustain myelin gene expression and prevent myelin breakdown in the adult CNS.

PMID:38155716 SUPPORT Human Clinical

"In mature oligodendrocytes, conditional knockdown of MYRF results in a dramatic downregulation of myelin gene expression and myelin damage (Wang et al., 2022). Mutations in the structural domain of this gene may have an impact on myelin transcription."

Confirms that MYRF activity in mature oligodendrocytes maintains CNS myelin gene expression and that domain mutations impair myelin transcription.

Acute Reversible Intramyelinic Edema and Myelin Vacuolization

During acute febrile or viral triggers, systemic inflammatory cytokines and metabolic stress act on vulnerable MYRF-deficient myelin sheaths, causing splitting of myelin lamellae and accumulation of fluid within intramyelinic spaces (intramyelinic edema / myelin vacuolization) across high-density commissural and deep cerebral white matter tracts, especially the corpus callosum (splenium) and bilateral centrum semiovale. Because axons and oligodendrocyte cell bodies remain viable, the intramyelinic fluid is reabsorbed as inflammation subsides, resulting in rapid and complete radiological resolution within one to two weeks.

oligodendrocyte CL:0000128

myelin maintenance GO:0043217 ⚠ ABNORMAL

corpus callosum UBERON:0002336 cerebral hemisphere white matter UBERON:0002437

Downstream

Leukoencephalopathy Extensive intramyelinic edema and myelin vacuolization produce diffuse symmetrical T2/FLAIR and diffusion-weighted imaging hyperintensity with reduced apparent diffusion coefficient across the corpus callosum and bilateral centrum semiovale.

Cerebral edema Intramyelinic fluid accumulation manifests on diffusion-weighted MRI and ADC mapping as extensive cytotoxic/intramyelinic cerebral white matter edema.

Transient Callosal and Deep White Matter Conduction Failure Acute intramyelinic edema in the corpus callosum and deep subcortical white matter transiently disrupts saltatory axonal conduction across interhemispheric and corticobulbar/corticospinal tracts.

Show evidence (3 references)

PMID:29265453 SUPPORT Human Clinical

"We examined a family in which the proband presented with a history of recurrent encephalopathy with extensive but reversible cerebral myelin vacuolization and neurological symptoms similar to those of MERS spanning 3 generations."

Establishes extensive reversible cerebral myelin vacuolization as the defining pathological substrate across affected family members.

PMID:35990002 SUPPORT Human Clinical

"In our patient, inflammatory responses were milder than those seen in patients with MIS-C, but caused cytotoxic edema in the entire CC and cerebral white matter. This may have been related to the vulnerability of myelin maintenance associated with the MYRF variant."

Confirms that viral inflammatory responses precipitate extensive cytotoxic edema across the entire corpus callosum and cerebral white matter due to MYRF-related myelin maintenance vulnerability.

PMID:41190523 SUPPORT Human Clinical

"In individuals with a pre‐existing, subclinical genetic vulnerability such as MYRF haploinsufficiency, the robust systemic inflammation and immune dysregulation following a viral infection (e.g., cytokine storms seen in COVID‐19 or influenza) can act as a “second hit” ... This may disrupt the..."

Provides mechanistic detail on how systemic viral inflammation acts as a second hit that overwhelms compromised MYRF myelin maintenance capacity, discussed in the context of an adjacent nonreversible MYRF leukoencephalopathy phenotype compared against MMERV.

Transient Callosal and Deep White Matter Conduction Failure

Reversible intramyelinic edema across the corpus callosum, centrum semiovale, and frontoparietal subcortical white matter transiently impairs action potential propagation and network synchronization without causing irreversible axonal transection. This temporary white matter conduction block produces acute encephalopathy, confusion, delirium, seizures, dysarthria/speech dysfluency, and ataxia, all of which resolve as intramyelinic edema clears.

action potential propagation GO:0019227 ⚠ ABNORMAL

corpus callosum UBERON:0002336 cerebral hemisphere white matter UBERON:0002437

Downstream

Encephalopathy Widespread subcortical and callosal white matter conduction disturbance causes acute episodes of mild encephalopathy.

Confusion Disrupted interhemispheric and subcortical network conduction manifests clinically with acute confusion and impaired consciousness.

Delirium Acute diffuse callosal and subcortical white matter dysfunction can present with transient delirium during febrile episodes.

Seizure Acute cortical-subcortical network excitability changes during episodes of myelin vacuolization manifest as childhood or adult seizures.

Dysarthria Transient conduction block across callosal and corticobulbar white matter tracts produces acute dysarthria and loss of speech fluency.

Ataxia Transient involvement of deep cerebral and cerebellar-projecting white matter pathways produces episodic ataxia during acute attacks.

Show evidence (2 references)

PMID:38155716 SUPPORT Human Clinical

"The clinical manifestations of MMERV include seizures, impaired speech (such as lack of fluency, dysarthria, and language difficulties), recurrent episodes of impaired consciousness (confusion or delirium), spontaneous motor difficulties, and limb numbness (Imamura et al., 2010; Kurahashi et..."

Summarizes the spectrum of transient cortical and white-matter tract dysfunction episodes seen during acute MMERV relapses.

PMID:35990002 SUPPORT Human Clinical

"A follow-up MRI on the 10th day after onset demonstrated resolution of the previously noted abnormalities. She was discharged on the 11th day after onset with no neurological sequelae."

Demonstrates that clinical recovery of neurological conduction parallels rapid resolution of the callosal and subcortical white matter edema.

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Pathograph

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Phenotypes

8

Metabolism 1

Cerebral edema HP:0002181

Show evidence (1 reference)

PMID:35990002 SUPPORT Human Clinical

"In our patient, inflammatory responses were milder than those seen in patients with MIS-C, but caused cytotoxic edema in the entire CC and cerebral white matter. This may have been related to the vulnerability of myelin maintenance associated with the MYRF variant."

Characterizes acute episodes in MYRF p.Gln403Arg carriers by extensive cytotoxic edema across the entire corpus callosum and cerebral white matter.

Nervous System 7

Encephalopathy HP:0001298

Show evidence (2 references)

PMID:29265453 SUPPORT Human Clinical

"We examined a family in which the proband presented with a history of recurrent encephalopathy with extensive but reversible cerebral myelin vacuolization and neurological symptoms similar to those of MERS spanning 3 generations."

Establishes recurrent episodes of acute encephalopathy with reversible myelin vacuolization as the hallmark clinical presentation across multiple generations.

PMID:35990002 SUPPORT Human Clinical

"We report a 14-year-old girl with a heterozygous p. Gln403Arg variant in the MYRF gene, who had five episodes of encephalopathy. She experienced reduced consciousness, numbness in the arm, and impaired verbal communication from day 4 of SARS-CoV-2 infection."

Documents five recurrent episodes of acute encephalopathy in a pediatric carrier of the MYRF p.Gln403Arg variant.

Leukoencephalopathy HP:0002352

Show evidence (2 references)

PMID:38155716 SUPPORT Human Clinical

"Magnetic Resonance Imaging (MRI) of the brain showed abnormal intensities in bilateral white matter in the centrum semiovale and corpus callosum on diffusion-weighted, T2-weighted and apparent diffusion coefficient images."

Describes the characteristic bilateral centrum semiovale and corpus callosum white matter abnormalities on MRI during acute MMERV episodes.

PMID:29265453 SUPPORT Human Clinical

"We examined a family in which the proband presented with a history of recurrent encephalopathy with extensive but reversible cerebral myelin vacuolization and neurological symptoms similar to those of MERS spanning 3 generations."

Demonstrates that extensive reversible cerebral white matter myelin vacuolization is present across affected individuals during acute attacks.

Confusion HP:0001289

Show evidence (2 references)

PMID:38155716 SUPPORT Human Clinical

"The clinical manifestations of MMERV include seizures, impaired speech (such as lack of fluency, dysarthria, and language difficulties), recurrent episodes of impaired consciousness (confusion or delirium), spontaneous motor difficulties, and limb numbness (Imamura et al., 2010; Kurahashi et..."

Documents recurrent episodes of impaired consciousness including confusion across reported MMERV patients.

PMID:35990002 SUPPORT Human Clinical

"She experienced reduced consciousness, numbness in the arm, and impaired verbal communication from day 4 of SARS-CoV-2 infection."

Illustrates acute reduced consciousness at clinical relapse presentation.

Delirium HP:0031258

Show evidence (1 reference)

PMID:38155716 SUPPORT Human Clinical

"The clinical manifestations of MMERV include seizures, impaired speech (such as lack of fluency, dysarthria, and language difficulties), recurrent episodes of impaired consciousness (confusion or delirium), spontaneous motor difficulties, and limb numbness (Imamura et al., 2010; Kurahashi et..."

Identifies delirium as a recurring clinical feature of impaired consciousness in MMERV.

Seizure HP:0001250

Show evidence (1 reference)

PMID:38155716 SUPPORT Human Clinical

"MYRF-related mild encephalopathy with reversible myelin vacuolization is a rare autosomal dominant genetic disease, with early clinical manifestations often being seizures."

Establishes seizures as a common early clinical manifestation of MMERV.

Dysarthria HP:0001260

Show evidence (1 reference)

PMID:38155716 SUPPORT Human Clinical

"The clinical manifestations of MMERV include seizures, impaired speech (such as lack of fluency, dysarthria, and language difficulties), recurrent episodes of impaired consciousness (confusion or delirium), spontaneous motor difficulties, and limb numbness (Imamura et al., 2010; Kurahashi et..."

Documents dysarthria and impaired speech fluency as core clinical features of MMERV.

Ataxia HP:0001251

Show evidence (1 reference)

PMID:41190523 SUPPORT REVIEW SYNTHESIS Human Clinical

"Recurrent episodes of ataxia, dysarthria, impaired consciousness, seizures"

Summarizes in the literature review comparison table (Table 1) the characteristic recurrent ataxia, dysarthria, impaired consciousness, and seizures reported across the Kurahashi et al. (PMID:29265453) MMERV cohort carrying MYRF p.Gln403Arg.

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Genetic Associations

1

MYRF (Causal Germline Heterozygous Missense Variant)

Gene: MYRF hgnc:1181 gene page

Autosomal Dominant

Show evidence (2 references)

PMID:29265453 SUPPORT Human Clinical

"By filtering genes expressed in the corpus callosum, we identified a heterozygous c.1208A>G predicting p.Gln403Arg in the highly conserved DNA-binding domain in the myelin regulatory factor (MYRF) gene. We subsequently screened the coding regions of MYRF by Sanger sequencing in our cohort..."

Identifies the recurrent heterozygous MYRF c.1208A>G (p.Gln403Arg) DNA-binding domain variant across two unrelated multiplex families with MMERV.

PMID:38155716 SUPPORT Human Clinical

"Whole exome sequencing of the proband revealed a missense mutation (MYRF- Q403R) at codon 403 of the MYRF gene: c.1208A>G (p.Gln403Arg) (Figure 3), resulting in an amino acid change from glutamine to arginine."

Confirms the same recurrent MYRF c.1208A>G (p.Gln403Arg) variant in an independent Chinese family with MMERV.

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Medical Actions

2

Corticosteroid Therapy

Action: systemic corticosteroid therapy Ontology label: Systemic Corticosteroid Therapy NCIT:C122080

Short-course systemic corticosteroid therapy (such as intravenous methylprednisolone or dexamethasone) is frequently administered during acute episodes of MMERV to attenuate neuroinflammation and intramyelinic edema, with patients typically achieving complete clinical recovery within one week.

Mechanism Target:

INHIBITS Acute Reversible Intramyelinic Edema and Myelin Vacuolization — Systemic corticosteroids suppress acute inflammatory signaling and stabilize the blood-brain barrier during febrile relapses, accelerating resolution of intramyelinic edema.

Show evidence (1 reference)

PMID:38155716 SUPPORT Human Clinical

"Currently, the treatment options for MMERV are limited and based on hormonal steroids therapy with full recovery of symptoms within 1 week."

Documents that acute MMERV episodes are managed clinically with corticosteroid therapy followed by full symptom recovery within one week.

Show evidence (1 reference)

PMID:38155716 SUPPORT Human Clinical

"Currently, the treatment options for MMERV are limited and based on hormonal steroids therapy with full recovery of symptoms within 1 week."

Establishes hormonal steroid therapy as the primary acute medical treatment reported for MMERV episodes.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Genetic counseling and family cascade testing are indicated to identify asymptomatic or mildly affected heterozygous MYRF variant carriers, clarify autosomal dominant recurrence risk, and provide anticipatory guidance regarding febrile viral triggers.

Show evidence (1 reference)

PMID:38155716 SUPPORT Human Clinical

"Therefore, when MRI shows extensive myelin vacuolization, genetic analysis should be performed to determine the presence of MYRF variants to further diagnose the disease and guide eugenics in this family."

Emphasizes performing MYRF genetic analysis in affected families to confirm the diagnosis and guide family reproductive counseling.

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Environmental Factors

1

Febrile Viral Infections

Acute episodes of MMERV are characteristically precipitated by antecedent febrile infections—including influenza A, SARS-CoV-2, and other respiratory or systemic viral illnesses—in genetically susceptible MYRF variant carriers.

Show evidence (3 references)

PMID:38155716 SUPPORT Human Clinical

"Infectious diseases in children are a major triggering factor for MMERV (Imamura et al., 2010; Kurahashi et al., 2018; Saito et al., 2022)."

Identifies childhood infectious illnesses as a major precipitating factor for acute MMERV episodes.

PMID:35990002 SUPPORT Human Clinical

"Her medical history included five episodes of MERS, at the ages of 3, 6, 7, 8 and 9 years (Table 1). Three of these five episodes were associated with influenza A."

Documents recurrent acute episodes associated with influenza A and SARS-CoV-2 viral infections in a patient carrying the MYRF p.Gln403Arg variant.

PMID:41190523 SUPPORT Human Clinical

"In individuals with a pre‐existing, subclinical genetic vulnerability such as MYRF haploinsufficiency, the robust systemic inflammation and immune dysregulation following a viral infection (e.g., cytokine storms seen in COVID‐19 or influenza) can act as a “second hit” ... This may disrupt the..."

Articulates the general "second hit" mechanism by which systemic viral inflammation precipitates acute leukoencephalopathy in individuals with underlying MYRF genetic vulnerability, discussed in the context of an adjacent nonreversible MYRF leukoencephalopathy phenotype compared against MMERV.

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Diagnosis

2

MYRF Molecular Genetic Testing

Definitive diagnosis of MMERV requires molecular genetic testing (such as whole-exome sequencing, gene panel testing, or targeted Sanger sequencing) demonstrating a heterozygous pathogenic variant in MYRF, characteristically c.1208A>G (p.Gln403Arg), which differentiates familial MMERV from sporadic CLOCC/MERS and GJB1-related CMTX1.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:38155716 SUPPORT Human Clinical

"MYRF-related mild encephalopathy with reversible myelin vacuolization is a rare autosomal dominant genetic disease, with early clinical manifestations often being seizures. The definitive diagnosis of MMERV can be confirmed through genetic analysis."

Establishes that genetic analysis is required to confirm the definitive diagnosis of MMERV.

PMID:38155716 SUPPORT Human Clinical

"Whole exome sequencing of the proband revealed a missense mutation (MYRF- Q403R) at codon 403 of the MYRF gene: c.1208A>G (p.Gln403Arg) (Figure 3), resulting in an amino acid change from glutamine to arginine."

Demonstrates whole-exome sequencing detection of the recurrent MYRF c.1208A>G (p.Gln403Arg) variant to establish the diagnosis.

Brain Magnetic Resonance Imaging (MRI)

Acute-phase brain MRI with diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) mapping, and T2/FLAIR sequences identifies symmetrical diffusion restriction across the corpus callosum (particularly the splenium) and bilateral deep cerebral white matter (centrum semiovale), while follow-up MRI within one to two weeks demonstrates complete radiological resolution of the reversible myelin vacuolization lesions.

magnetic resonance imaging NCIT:C16809

Show evidence (2 references)

PMID:38155716 SUPPORT Human Clinical

"Magnetic Resonance Imaging (MRI) of the brain showed abnormal intensities in bilateral white matter in the centrum semiovale and corpus callosum on diffusion-weighted, T2-weighted and apparent diffusion coefficient images."

Documents the diagnostic neuroimaging pattern on DWI, T2-weighted, and ADC brain MRI sequences during acute episodes.

PMID:35990002 SUPPORT Human Clinical

"A follow-up MRI on the 10th day after onset demonstrated resolution of the previously noted abnormalities."

Demonstrates the diagnostic value of serial follow-up brain MRI in confirming rapid reversibility of the white matter lesions.

📊

Prevalence

1

Global (reported families and cases)

Cases In Literature Ultra Rare

Ultra-rare disorder with no established population prevalence rate. Reported cases in the literature comprise three familial MMERV pedigrees carrying the recurrent heterozygous MYRF c.1208A>G (p.Gln403Arg) variant summarized in the 2023 literature review—including the two multiplex Japanese families (nine affected individuals) originally described by Kurahashi et al.—as well as additional case reports such as the recurrent pediatric patient reported by Saito et al.

Show evidence (2 references)

PMID:38155716 SUPPORT Human Clinical

"Kurahashi (Kurahashi et al., 2018) identified this missense mutation in the MYRF gene through genetic testing of nine symptomatic individuals from two unrelated families. In one family, the pedigree showed an autosomal dominant mode of inheritance, while the other family was too small to..."

Summarizes the three reported familial MMERV pedigrees (including the nine symptomatic individuals across the first two families) carrying the recurrent MYRF c.1208A>G variant.

PMID:38155716 SUPPORT Human Clinical

"Currently, knowledge regarding MMERV has been based on two familial MMERV, which may be underdiagnosed due to limited awareness of the disease among clinicians and the fact that genetic testing technology is not yet fully available."

Confirms that prior to the third familial pedigree reported in 2023, published MMERV knowledge derived from two familial cohorts and that the condition is likely underdiagnosed.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Encephalitis/Encephalopathy, Mild, with Reversible Myelin Vacuolization:

Mild Encephalopathy with a Reversible Splenial Lesion (MERS / CLOCC)

Overlapping Features Cytotoxic lesions of the corpus callosum / mild encephalopathy with a reversible splenial lesion (CLOCC/MERS) is the primary clinical and radiological differential diagnosis for MMERV. Like MMERV, CLOCC/MERS is typically triggered by childhood viral infections and presents with mild encephalopathy, seizures, confusion, and reversible diffusion restriction in the corpus callosum (MERS type I) or both the corpus callosum and symmetric cerebral white matter (MERS type II). Whereas MERS type II is radiologically indistinguishable from acute MMERV, sporadic MERS cases do not harbor MYRF variants, making family history and MYRF genetic testing the definitive discriminators.

Distinguishing Features

Sporadic CLOCC/MERS lacks pathogenic MYRF variants (0/33 sporadic MERS cases carried MYRF mutations in the discovery cohort), whereas MMERV segregates autosomal dominant MYRF variants (characteristically c.1208A>G p.Gln403Arg) with frequent family history or recurrence.
MERS type I is confined to the corpus callosum (splenium), whereas MMERV characteristically involves extensive symmetrical subcortical/centrum semiovale white matter in addition to the corpus callosum (resembling MERS type II).

Show evidence (3 references)

PMID:38155716 SUPPORT Human Clinical

"CLOCC/MERS is the primary differential diagnosis for MMERV."

Explicitly identifies CLOCC/MERS as the primary differential diagnosis for MMERV.

PMID:38155716 SUPPORT Human Clinical

"In contrast, MMERV presents clinically indistinguishable from MERS type II. Therefore, when MRI shows extensive myelin vacuolization, genetic analysis should be performed to determine the presence of MYRF variants to further diagnose the disease and guide eugenics in this family."

Explains why MMERV mimics MERS type II on neuroimaging and why MYRF genetic analysis is required to distinguish the two conditions.

PMID:29265453 SUPPORT Human Clinical

"We subsequently screened the coding regions of MYRF by Sanger sequencing in our cohort comprised of 33 sporadic cases with MERS and 3 cases in another family with extensive myelin vacuolization, and identified the same heterozygous c.1208A>G in all affected members in the second family."

Demonstrates that 0 of 33 sporadic MERS cases carried pathogenic MYRF variants, whereas familial cases with extensive reversible myelin vacuolization shared the heterozygous MYRF c.1208A>G variant.

Charcot-Marie-Tooth Disease, X-Linked Dominant, 1 (CMTX1) Not Yet Curated MONDO:0010549

Overlapping Features GJB1-related X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) can present with recurrent, infection-triggered transient central nervous system leukoencephalopathy and reversible diffusion-weighted MRI lesions in the corpus callosum and deep cerebral white matter (centrum semiovale) that closely mimic MMERV. However, CMTX1 is caused by hemizygous or heterozygous variants in GJB1 (encoding connexin 32), typically features baseline peripheral demyelinating sensorimotor neuropathy and acute motor/sensory deficits rather than isolated seizures or impaired consciousness, and follows X-linked inheritance.

Distinguishing Features

Causal variant in GJB1 (X-linked inheritance) rather than MYRF (autosomal dominant inheritance).
Presence of chronic peripheral sensorimotor polyneuropathy and prominent acute motor/sensory deficits in CMTX1.

Show evidence (1 reference)

PMID:38155716 SUPPORT Human Clinical

"Additionally, CMTX1 can sometimes present as familial/recurrent transient leukoencephalopathy with reversible callosal and deep brain white matter lesions similar to MMERV. CMTX1 is caused by mutations in the GJB1 gene located on the X chromosome, which encodes connexin 32 (Cx32), a..."

Establishes CMTX1 as a key genetic differential diagnosis for recurrent reversible callosal and deep white matter leukoencephalopathy and distinguishes it by GJB1 etiology and peripheral nervous system involvement.

{ }

Source YAML

click to show

name: Encephalitis/Encephalopathy, Mild, with Reversible Myelin Vacuolization
creation_date: "2026-10-14T00:00:00Z"
category: Mendelian
description: >-
  Encephalitis/encephalopathy, mild, with reversible myelin vacuolization
  (MMERV; MONDO:0020853; OMIM:618113) is an autosomal dominant neurological
  disorder caused by heterozygous missense variants in the N-terminal
  Ndt80-like DNA-binding domain of the myelin regulatory factor gene (MYRF),
  characteristically the recurrent c.1208A>G (p.Gln403Arg) variant. Affected
  individuals have normal baseline neurodevelopment and experience acute or
  recurrent episodes of mild encephalopathy—manifesting with impaired
  consciousness, confusion, delirium, seizures, dysarthria or speech fluency
  impairment, ataxia, and transient motor deficits—typically triggered by
  febrile viral infections in infancy, childhood, or young adulthood. Brain
  magnetic resonance imaging during acute episodes demonstrates extensive
  symmetrical diffusion restriction (hyperintensity on diffusion-weighted
  imaging with reduced apparent diffusion coefficient) and T2/FLAIR
  hyperintensity involving the corpus callosum (particularly the splenium) and
  bilateral deep cerebral white matter (centrum semiovale), reflecting
  intramyelinic edema and reversible myelin vacuolization. Clinical symptoms
  and neuroimaging abnormalities characteristically resolve within one to two
  weeks without permanent neurological sequelae, distinguishing classic MMERV
  from severe de novo MYRF loss-of-function syndromic conditions (cardiac-urogenital
  syndrome and nanophthalmos) and from nonreversible MYRF leukoencephalopathies.
disease_term:
  preferred_term: encephalitis/encephalopathy, mild, with reversible myelin vacuolization
  term:
    id: MONDO:0020853
    label: encephalitis/encephalopathy, mild, with reversible myelin vacuolization
parents:
- hereditary neurological disease
- encephalopathy
synonyms:
- MMERV
- MYRF-related mild encephalopathy with reversible myelin vacuolization
- familial mild encephalopathy with a reversible splenial lesion and extensive white matter involvement
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >-
    MMERV is inherited in an autosomal dominant manner across multigenerational
    pedigrees segregating the heterozygous MYRF c.1208A>G (p.Gln403Arg)
    missense variant. Incomplete penetrance and variable expressivity are
    documented, with some heterozygous carriers experiencing only isolated
    childhood seizures without recurrent adult episodes or extensive white
    matter relapses.
  evidence:
  - reference: PMID:29265453
    reference_title: "MYRF is associated with encephalopathy with reversible myelin vacuolization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By filtering genes expressed in the corpus callosum, we identified a heterozygous c.1208A>G predicting p.Gln403Arg in the highly conserved DNA-binding domain in the myelin regulatory factor (MYRF) gene. We subsequently screened the coding regions of MYRF by Sanger sequencing in our cohort comprised of 33 sporadic cases with MERS and 3 cases in another family with extensive myelin vacuolization, and identified the same heterozygous c.1208A>G in all affected members in the second family."
    explanation: >-
      Establishes heterozygous cosegregation of the MYRF c.1208A>G
      (p.Gln403Arg) variant across affected family members in two multiplex
      families consistent with autosomal dominant inheritance.
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYRF-related mild encephalopathy with reversible myelin vacuolization is a rare autosomal dominant genetic disease, with early clinical manifestations often being seizures."
    explanation: >-
      Explicitly defines MMERV as an autosomal dominant genetic disorder.
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is noteworthy that only three patients (II-1 and IV-1 in family A and III-1 in Family C) in the study experienced multiple episodes. However, it is uncertain whether these episodes were triggered by predisposing factors or if other carriers had asymptomatic episodes."
    explanation: >-
      Documents marked intrafamilial variable expressivity and potential
      incomplete penetrance across heterozygous MYRF c.1208A>G carriers within
      the three reported families.
prevalence:
- population: Global (reported families and cases)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Ultra-rare disorder with no established population prevalence rate. Reported
    cases in the literature comprise three familial MMERV pedigrees carrying the
    recurrent heterozygous MYRF c.1208A>G (p.Gln403Arg) variant summarized in
    the 2023 literature review—including the two multiplex Japanese families
    (nine affected individuals) originally described by Kurahashi et al.—as well
    as additional case reports such as the recurrent pediatric patient reported
    by Saito et al.
  evidence:
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kurahashi (Kurahashi et al., 2018) identified this missense mutation in the MYRF gene through genetic testing of nine symptomatic individuals from two unrelated families. In one family, the pedigree showed an autosomal dominant mode of inheritance, while the other family was too small to confirm. In all three familial cases of MMERV, carriers of this mutation showed normal psychomotor development under physiological, indicating relatively preserved MYRF function under normal conditions."
    explanation: >-
      Summarizes the three reported familial MMERV pedigrees (including the nine
      symptomatic individuals across the first two families) carrying the
      recurrent MYRF c.1208A>G variant.
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently, knowledge regarding MMERV has been based on two familial MMERV, which may be underdiagnosed due to limited awareness of the disease among clinicians and the fact that genetic testing technology is not yet fully available."
    explanation: >-
      Confirms that prior to the third familial pedigree reported in 2023,
      published MMERV knowledge derived from two familial cohorts and that the
      condition is likely underdiagnosed.
environmental:
- name: Febrile Viral Infections
  exposure_term:
    preferred_term: exposure to virus
    term:
      id: ECTO:3000001
      label: exposure to virus
  presence: Present
  notes: >-
    Acute episodes of MMERV are characteristically precipitated by antecedent
    febrile infections—including influenza A, SARS-CoV-2, and other respiratory
    or systemic viral illnesses—in genetically susceptible MYRF variant carriers.
  evidence:
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infectious diseases in children are a major triggering factor for MMERV (Imamura et al., 2010; Kurahashi et al., 2018; Saito et al., 2022)."
    explanation: >-
      Identifies childhood infectious illnesses as a major precipitating factor
      for acute MMERV episodes.
  - reference: PMID:35990002
    reference_title: "Case report: Mild encephalitis with a reversible splenial lesion associated with SARS-CoV-2 infection in a patient with MYRF variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her medical history included five episodes of MERS, at the ages of 3, 6, 7, 8 and 9 years (Table 1). Three of these five episodes were associated with influenza A."
    explanation: >-
      Documents recurrent acute episodes associated with influenza A and
      SARS-CoV-2 viral infections in a patient carrying the MYRF p.Gln403Arg
      variant.
  - reference: PMID:41190523
    reference_title: "Persistent Leukoencephalopathy Following H1N1 Infection Associated With a Novel MYRF Variant (p.Gly735Asp)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In individuals with a pre‐existing, subclinical genetic vulnerability such as MYRF haploinsufficiency, the robust systemic inflammation and immune dysregulation following a viral infection (e.g., cytokine storms seen in COVID‐19 or influenza) can act as a “second hit” ... This may disrupt the blood–brain barrier, promote neuroinflammation, and overwhelm the compromised myelin maintenance or repair capacity, thereby precipitating acute neurological disease"
    explanation: >-
      Articulates the general "second hit" mechanism by which systemic viral
      inflammation precipitates acute leukoencephalopathy in individuals with
      underlying MYRF genetic vulnerability, discussed in the context of an
      adjacent nonreversible MYRF leukoencephalopathy phenotype compared against
      MMERV.
pathophysiology:
- name: Impaired MYRF DNA-Binding Domain Transcriptional Activity
  description: >-
    MYRF encodes an endoplasmic reticulum membrane-anchored precursor protein
    that undergoes intramolecular chaperone auto-processing (ICA)
    domain-mediated homotrimerization and autoproteolytic self-cleavage to
    release an active N-terminal transcription factor trimer that translocates
    to the nucleus. In MMERV, the recurrent heterozygous missense variant
    c.1208A>G (p.Gln403Arg) alters a highly conserved residue within the
    Ndt80-like DNA-binding domain of the cleaved N-terminal fragment,
    significantly diminishing its transcriptional activation of downstream
    myelin target genes.
  genes:
  - preferred_term: MYRF
    term:
      id: hgnc:1181
      label: MYRF
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific
    modifier: DECREASED
    term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: positive regulation of transcription by RNA polymerase II
    modifier: DECREASED
    term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
  locations:
  - preferred_term: central nervous system
    term:
      id: UBERON:0001017
      label: central nervous system
  evidence:
  - reference: PMID:29265453
    reference_title: "MYRF is associated with encephalopathy with reversible myelin vacuolization."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Luciferase assay revealed that transcriptional activity of the N-terminal region of MYRF was significantly diminished by introducing the c.1208A>G variant."
    explanation: >-
      Demonstrates functionally in vitro that the MMERV-associated c.1208A>G
      (p.Gln403Arg) variant in the DNA-binding domain reduces the
      transcriptional activation capacity of the N-terminal MYRF fragment.
  - reference: PMID:23966832
    reference_title: "A Bacteriophage tailspike domain promotes self-cleavage of a human membrane-bound transcription factor, the myelin regulatory factor MYRF."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Indeed, the intramolecular chaperone domain of MYRF facilitates its homo-oligomerization and proteolytically processes it into two halves. The N-terminal trimer, containing the DNA-binding domain, is released from the ER membrane and moves to the nucleus, where it exerts transcriptional effects."
    explanation: >-
      Establishes the normal biochemical mechanism by which MYRF self-cleaves via its
      ICA domain into an active N-terminal homotrimeric transcription factor.
  - reference: PMID:23966833
    reference_title: "MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Using ChIP-Seq we show that the N-terminal cleavage product directly binds the enhancer regions of oligodendrocyte-specific and myelin genes. This binding occurs via a defined DNA-binding consensus sequence and strongly promotes the expression of target genes."
    explanation: >-
      Confirms that nuclear translocation of the cleaved N-terminal MYRF
      fragment directly binds myelin gene enhancers to drive transcription.
  downstream:
  - target: Compromised Oligodendrocyte Myelin Gene Transcription and Maintenance Reserve
    description: >-
      Reduced nuclear MYRF transcriptional activity decreases expression of core
      central nervous system myelin structural proteins, impairing oligodendrocyte
      myelin maintenance capacity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29265453
      reference_title: "MYRF is associated with encephalopathy with reversible myelin vacuolization."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Luciferase assay revealed that transcriptional activity of the N-terminal region of MYRF was significantly diminished by introducing the c.1208A>G variant."
      explanation: >-
        Links diminished N-terminal MYRF transcriptional activity directly to
        compromised oligodendrocyte myelin gene regulation and maintenance.
- name: Compromised Oligodendrocyte Myelin Gene Transcription and Maintenance Reserve
  description: >-
    Mature oligodendrocytes require continuous MYRF transcriptional activity to
    sustain expression of major structural myelin genes (such as MBP, PLP1, MAG,
    and MOG) and preserve compact central nervous system myelin sheath integrity.
    Partial loss of MYRF transcriptional activity due to heterozygous missense
    variation permits normal baseline myelination and neurodevelopment but leaves
    mature oligodendrocytes with reduced homeostatic reserve for myelin
    maintenance and repair.
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: myelin maintenance
    modifier: DECREASED
    term:
      id: GO:0043217
      label: myelin maintenance
  - preferred_term: central nervous system myelination
    modifier: DECREASED
    term:
      id: GO:0022010
      label: central nervous system myelination
  locations:
  - preferred_term: white matter
    term:
      id: UBERON:0002316
      label: white matter
  evidence:
  - reference: PMID:29265453
    reference_title: "MYRF is associated with encephalopathy with reversible myelin vacuolization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYRF is a transcriptional regulator that is necessary for oligodendrocyte differentiation and myelin maintenance. Functional defects of MYRF are likely to be causally associated with encephalopathy with extensive myelin vacuolization."
    explanation: >-
      Establishes that MYRF transcriptional activity is required in
      oligodendrocytes to maintain CNS myelin and that functional MYRF defects
      underlie reversible myelin vacuolization.
  - reference: PMID:23966833
    reference_title: "MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "Inducible ablation of Myrf in mature oligodendrocytes of the adult CNS also causes a rapid down-regulation of myelin gene expression followed by a gradual degeneration of CNS myelin [14]."
    explanation: >-
      Demonstrates that ongoing MYRF activity in mature oligodendrocytes is
      continuously required to sustain myelin gene expression and prevent myelin
      breakdown in the adult CNS.
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In mature oligodendrocytes, conditional knockdown of MYRF results in a dramatic downregulation of myelin gene expression and myelin damage (Wang et al., 2022). Mutations in the structural domain of this gene may have an impact on myelin transcription."
    explanation: >-
      Confirms that MYRF activity in mature oligodendrocytes maintains CNS
      myelin gene expression and that domain mutations impair myelin
      transcription.
  downstream:
  - target: Acute Reversible Intramyelinic Edema and Myelin Vacuolization
    description: >-
      When challenged by a febrile viral infection ("second hit"), compromised
      oligodendrocyte myelin maintenance capacity fails to prevent intramyelinic
      fluid accumulation and myelin sheath vacuolization.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38155716
      reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "However, under pathological conditions such as infection, MYRF function is further impaired or fails to increase the transcriptional rate of myelin. This leads to myelin fragmentation and subsequent phagocytosis by activated microglia/macrophages in the white matter (Koenning et al., 2012), resulting in associated neurological symptoms and rapid, reversible severe demyelination manifestations on neuroimaging."
      explanation: >-
        Directly connects infection-triggered failure to upregulate MYRF myelin
        transcription to acute reversible white matter lesions.
- name: Acute Reversible Intramyelinic Edema and Myelin Vacuolization
  description: >-
    During acute febrile or viral triggers, systemic inflammatory cytokines and
    metabolic stress act on vulnerable MYRF-deficient myelin sheaths, causing
    splitting of myelin lamellae and accumulation of fluid within intramyelinic
    spaces (intramyelinic edema / myelin vacuolization) across high-density
    commissural and deep cerebral white matter tracts, especially the corpus
    callosum (splenium) and bilateral centrum semiovale. Because axons and
    oligodendrocyte cell bodies remain viable, the intramyelinic fluid is
    reabsorbed as inflammation subsides, resulting in rapid and complete
    radiological resolution within one to two weeks.
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: myelin maintenance
    modifier: ABNORMAL
    term:
      id: GO:0043217
      label: myelin maintenance
  locations:
  - preferred_term: corpus callosum
    term:
      id: UBERON:0002336
      label: corpus callosum
  - preferred_term: cerebral hemisphere white matter
    term:
      id: UBERON:0002437
      label: cerebral hemisphere white matter
  evidence:
  - reference: PMID:29265453
    reference_title: "MYRF is associated with encephalopathy with reversible myelin vacuolization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We examined a family in which the proband presented with a history of recurrent encephalopathy with extensive but reversible cerebral myelin vacuolization and neurological symptoms similar to those of MERS spanning 3 generations."
    explanation: >-
      Establishes extensive reversible cerebral myelin vacuolization as the
      defining pathological substrate across affected family members.
  - reference: PMID:35990002
    reference_title: "Case report: Mild encephalitis with a reversible splenial lesion associated with SARS-CoV-2 infection in a patient with MYRF variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our patient, inflammatory responses were milder than those seen in patients with MIS-C, but caused cytotoxic edema in the entire CC and cerebral white matter. This may have been related to the vulnerability of myelin maintenance associated with the MYRF variant."
    explanation: >-
      Confirms that viral inflammatory responses precipitate extensive cytotoxic
      edema across the entire corpus callosum and cerebral white matter due to
      MYRF-related myelin maintenance vulnerability.
  - reference: PMID:41190523
    reference_title: "Persistent Leukoencephalopathy Following H1N1 Infection Associated With a Novel MYRF Variant (p.Gly735Asp)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In individuals with a pre‐existing, subclinical genetic vulnerability such as MYRF haploinsufficiency, the robust systemic inflammation and immune dysregulation following a viral infection (e.g., cytokine storms seen in COVID‐19 or influenza) can act as a “second hit” ... This may disrupt the blood–brain barrier, promote neuroinflammation, and overwhelm the compromised myelin maintenance or repair capacity, thereby precipitating acute neurological disease"
    explanation: >-
      Provides mechanistic detail on how systemic viral inflammation acts as a
      second hit that overwhelms compromised MYRF myelin maintenance capacity,
      discussed in the context of an adjacent nonreversible MYRF
      leukoencephalopathy phenotype compared against MMERV.
  downstream:
  - target: Leukoencephalopathy
    description: >-
      Extensive intramyelinic edema and myelin vacuolization produce diffuse
      symmetrical T2/FLAIR and diffusion-weighted imaging hyperintensity with
      reduced apparent diffusion coefficient across the corpus callosum and
      bilateral centrum semiovale.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38155716
      reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Initially, Brain MRI showed abnormal intensities in bilateral white matter in the centrum semiovale and corpus callosum on diffusion-weighted, T2-weighted and apparent diffusion coefficient images, consistent with an acute demyelinating lesion (Figure 2). These extensive lesions have generally returned to normal within 1 week. Therefore, the presence of extensive myelin vacuolation on MRI should prompt consideration of the MYRF variant."
      explanation: >-
        Demonstrates that reversible myelin vacuolization manifests
        radiologically as extensive centrum semiovale and corpus callosum
        leukoencephalopathy on diffusion-weighted MRI.
  - target: Cerebral edema
    description: >-
      Intramyelinic fluid accumulation manifests on diffusion-weighted MRI and
      ADC mapping as extensive cytotoxic/intramyelinic cerebral white matter
      edema.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35990002
      reference_title: "Case report: Mild encephalitis with a reversible splenial lesion associated with SARS-CoV-2 infection in a patient with MYRF variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In our patient, inflammatory responses were milder than those seen in patients with MIS-C, but caused cytotoxic edema in the entire CC and cerebral white matter. This may have been related to the vulnerability of myelin maintenance associated with the MYRF variant."
      explanation: >-
        Directly links MYRF-related myelin maintenance vulnerability to
        extensive cytotoxic edema across the corpus callosum and cerebral white
        matter.
  - target: Transient Callosal and Deep White Matter Conduction Failure
    description: >-
      Acute intramyelinic edema in the corpus callosum and deep subcortical
      white matter transiently disrupts saltatory axonal conduction across
      interhemispheric and corticobulbar/corticospinal tracts.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38155716
      reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Demyelination of the corpus callosum can lead to bilateral hemispheric disconnection, resulting in disruption of higher cortical functions. Previous reports have described patients with the MYRF variant who exhibited extensive white matter lesions involving the entire corpus callosum, surpassing the extent of lesions observed in our case. Correspondingly, these patients displayed more severe symptoms, including profound impairment of consciousness, compared to the current case."
      explanation: >-
        Connects callosal and deep white matter myelin lesions directly to
        interhemispheric disconnection and higher cortical conduction
        dysfunction.
- name: Transient Callosal and Deep White Matter Conduction Failure
  description: >-
    Reversible intramyelinic edema across the corpus callosum, centrum
    semiovale, and frontoparietal subcortical white matter transiently impairs
    action potential propagation and network synchronization without causing
    irreversible axonal transection. This temporary white matter conduction
    block produces acute encephalopathy, confusion, delirium, seizures,
    dysarthria/speech dysfluency, and ataxia, all of which resolve as
    intramyelinic edema clears.
  biological_processes:
  - preferred_term: action potential propagation
    modifier: ABNORMAL
    term:
      id: GO:0019227
      label: neuronal action potential propagation
  locations:
  - preferred_term: corpus callosum
    term:
      id: UBERON:0002336
      label: corpus callosum
  - preferred_term: cerebral hemisphere white matter
    term:
      id: UBERON:0002437
      label: cerebral hemisphere white matter
  evidence:
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical manifestations of MMERV include seizures, impaired speech (such as lack of fluency, dysarthria, and language difficulties), recurrent episodes of impaired consciousness (confusion or delirium), spontaneous motor difficulties, and limb numbness (Imamura et al., 2010; Kurahashi et al., 2018; Saito et al., 2022)."
    explanation: >-
      Summarizes the spectrum of transient cortical and white-matter tract
      dysfunction episodes seen during acute MMERV relapses.
  - reference: PMID:35990002
    reference_title: "Case report: Mild encephalitis with a reversible splenial lesion associated with SARS-CoV-2 infection in a patient with MYRF variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A follow-up MRI on the 10th day after onset demonstrated resolution of the previously noted abnormalities. She was discharged on the 11th day after onset with no neurological sequelae."
    explanation: >-
      Demonstrates that clinical recovery of neurological conduction parallels
      rapid resolution of the callosal and subcortical white matter edema.
  downstream:
  - target: Encephalopathy
    description: >-
      Widespread subcortical and callosal white matter conduction disturbance
      causes acute episodes of mild encephalopathy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29265453
      reference_title: "MYRF is associated with encephalopathy with reversible myelin vacuolization."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We examined a family in which the proband presented with a history of recurrent encephalopathy with extensive but reversible cerebral myelin vacuolization and neurological symptoms similar to those of MERS spanning 3 generations."
      explanation: >-
        Links the reversible cerebral myelin vacuolization lesions directly to
        recurrent episodes of acute encephalopathy.
  - target: Confusion
    description: >-
      Disrupted interhemispheric and subcortical network conduction manifests
      clinically with acute confusion and impaired consciousness.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38155716
      reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The clinical manifestations of MMERV include seizures, impaired speech (such as lack of fluency, dysarthria, and language difficulties), recurrent episodes of impaired consciousness (confusion or delirium), spontaneous motor difficulties, and limb numbness (Imamura et al., 2010; Kurahashi et al., 2018; Saito et al., 2022)."
      explanation: >-
        Documents recurrent episodes of confusion and impaired consciousness as
        core clinical manifestations of MMERV.
  - target: Delirium
    description: >-
      Acute diffuse callosal and subcortical white matter dysfunction can
      present with transient delirium during febrile episodes.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38155716
      reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The clinical manifestations of MMERV include seizures, impaired speech (such as lack of fluency, dysarthria, and language difficulties), recurrent episodes of impaired consciousness (confusion or delirium), spontaneous motor difficulties, and limb numbness (Imamura et al., 2010; Kurahashi et al., 2018; Saito et al., 2022)."
      explanation: >-
        Establishes delirium as a recognized presentation of impaired
        consciousness during acute MMERV episodes.
  - target: Seizure
    description: >-
      Acute cortical-subcortical network excitability changes during episodes
      of myelin vacuolization manifest as childhood or adult seizures.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38155716
      reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "MYRF-related mild encephalopathy with reversible myelin vacuolization is a rare autosomal dominant genetic disease, with early clinical manifestations often being seizures."
      explanation: >-
        Identifies seizures as a frequent early clinical manifestation of MMERV.
  - target: Dysarthria
    description: >-
      Transient conduction block across callosal and corticobulbar white matter
      tracts produces acute dysarthria and loss of speech fluency.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38155716
      reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The patient had a sudden onset of recurrent episodes of impaired speech fluency at the age of 19, which lasted for several hours and then resolved spontaneously."
      explanation: >-
        Documents recurrent reversible speech fluency impairment as a primary
        adult presentation of MMERV in the proband.
  - target: Ataxia
    description: >-
      Transient involvement of deep cerebral and cerebellar-projecting white
      matter pathways produces episodic ataxia during acute attacks.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41190523
      reference_title: "Persistent Leukoencephalopathy Following H1N1 Infection Associated With a Novel MYRF Variant (p.Gly735Asp)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Recurrent episodes of ataxia, dysarthria, impaired consciousness, seizures"
      explanation: >-
        Summarizes in the literature review comparison table (Table 1) the
        characteristic clinical features—including recurrent ataxia—of the
        Kurahashi et al. (PMID:29265453) MMERV cohort carrying MYRF p.Gln403Arg.
phenotypes:
- name: Encephalopathy
  category: Neurological
  diagnostic: true
  description: >-
    Acute or recurrent episodes of mild encephalopathy triggered by febrile
    illnesses, typically resolving completely within one to two weeks without
    residual cognitive or motor decline.
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:29265453
    reference_title: "MYRF is associated with encephalopathy with reversible myelin vacuolization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We examined a family in which the proband presented with a history of recurrent encephalopathy with extensive but reversible cerebral myelin vacuolization and neurological symptoms similar to those of MERS spanning 3 generations."
    explanation: >-
      Establishes recurrent episodes of acute encephalopathy with reversible
      myelin vacuolization as the hallmark clinical presentation across
      multiple generations.
  - reference: PMID:35990002
    reference_title: "Case report: Mild encephalitis with a reversible splenial lesion associated with SARS-CoV-2 infection in a patient with MYRF variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a 14-year-old girl with a heterozygous p. Gln403Arg variant in the MYRF gene, who had five episodes of encephalopathy. She experienced reduced consciousness, numbness in the arm, and impaired verbal communication from day 4 of SARS-CoV-2 infection."
    explanation: >-
      Documents five recurrent episodes of acute encephalopathy in a pediatric
      carrier of the MYRF p.Gln403Arg variant.
- name: Leukoencephalopathy
  category: Neurological
  diagnostic: true
  description: >-
    Extensive symmetrical diffusion-weighted and T2/FLAIR hyperintensity with
    reduced apparent diffusion coefficient in the corpus callosum (especially
    the splenium) and bilateral deep cerebral white matter (centrum semiovale)
    during acute MMERV attacks, with complete radiological resolution on
    follow-up imaging.
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  evidence:
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic Resonance Imaging (MRI) of the brain showed abnormal intensities in bilateral white matter in the centrum semiovale and corpus callosum on diffusion-weighted, T2-weighted and apparent diffusion coefficient images."
    explanation: >-
      Describes the characteristic bilateral centrum semiovale and corpus
      callosum white matter abnormalities on MRI during acute MMERV episodes.
  - reference: PMID:29265453
    reference_title: "MYRF is associated with encephalopathy with reversible myelin vacuolization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We examined a family in which the proband presented with a history of recurrent encephalopathy with extensive but reversible cerebral myelin vacuolization and neurological symptoms similar to those of MERS spanning 3 generations."
    explanation: >-
      Demonstrates that extensive reversible cerebral white matter myelin
      vacuolization is present across affected individuals during acute
      attacks.
- name: Cerebral edema
  category: Neurological
  diagnostic: true
  description: >-
    Extensive reversible intramyelinic white matter edema involving the corpus
    callosum and bilateral cerebral hemispheres demonstrated by diffusion
    restriction (high DWI signal and low ADC values) during acute febrile
    episodes.
  phenotype_term:
    preferred_term: Cerebral edema
    term:
      id: HP:0002181
      label: Cerebral edema
  evidence:
  - reference: PMID:35990002
    reference_title: "Case report: Mild encephalitis with a reversible splenial lesion associated with SARS-CoV-2 infection in a patient with MYRF variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our patient, inflammatory responses were milder than those seen in patients with MIS-C, but caused cytotoxic edema in the entire CC and cerebral white matter. This may have been related to the vulnerability of myelin maintenance associated with the MYRF variant."
    explanation: >-
      Characterizes acute episodes in MYRF p.Gln403Arg carriers by extensive
      cytotoxic edema across the entire corpus callosum and cerebral white
      matter.
- name: Confusion
  category: Neurological
  description: >-
    Recurrent episodes of acute confusion, drowsiness, and impaired
    consciousness accompanying febrile or afebrile relapses.
  phenotype_term:
    preferred_term: Confusion
    term:
      id: HP:0001289
      label: Confusion
  evidence:
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical manifestations of MMERV include seizures, impaired speech (such as lack of fluency, dysarthria, and language difficulties), recurrent episodes of impaired consciousness (confusion or delirium), spontaneous motor difficulties, and limb numbness (Imamura et al., 2010; Kurahashi et al., 2018; Saito et al., 2022)."
    explanation: >-
      Documents recurrent episodes of impaired consciousness including confusion
      across reported MMERV patients.
  - reference: PMID:35990002
    reference_title: "Case report: Mild encephalitis with a reversible splenial lesion associated with SARS-CoV-2 infection in a patient with MYRF variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She experienced reduced consciousness, numbness in the arm, and impaired verbal communication from day 4 of SARS-CoV-2 infection."
    explanation: >-
      Illustrates acute reduced consciousness at clinical relapse presentation.
- name: Delirium
  category: Neurological
  description: >-
    Transient delirium and acute confusional state occurring during febrile
    encephalopathy episodes.
  phenotype_term:
    preferred_term: Delirium
    term:
      id: HP:0031258
      label: Delirium
  evidence:
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical manifestations of MMERV include seizures, impaired speech (such as lack of fluency, dysarthria, and language difficulties), recurrent episodes of impaired consciousness (confusion or delirium), spontaneous motor difficulties, and limb numbness (Imamura et al., 2010; Kurahashi et al., 2018; Saito et al., 2022)."
    explanation: >-
      Identifies delirium as a recurring clinical feature of impaired
      consciousness in MMERV.
- name: Seizure
  category: Neurological
  description: >-
    Childhood febrile or afebrile seizures and episodic seizures during acute
    encephalopathic relapses, often representing the earliest clinical
    manifestation of MMERV.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYRF-related mild encephalopathy with reversible myelin vacuolization is a rare autosomal dominant genetic disease, with early clinical manifestations often being seizures."
    explanation: >-
      Establishes seizures as a common early clinical manifestation of MMERV.
- name: Dysarthria
  category: Neurological
  description: >-
    Acute transient dysarthria, slurred speech, or loss of speech fluency during
    relapses, which may present with or without accompanying fever in adult
    patients.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical manifestations of MMERV include seizures, impaired speech (such as lack of fluency, dysarthria, and language difficulties), recurrent episodes of impaired consciousness (confusion or delirium), spontaneous motor difficulties, and limb numbness (Imamura et al., 2010; Kurahashi et al., 2018; Saito et al., 2022)."
    explanation: >-
      Documents dysarthria and impaired speech fluency as core clinical features
      of MMERV.
- name: Ataxia
  category: Neurological
  description: >-
    Episodic gait or limb ataxia occurring during acute reversible myelin
    vacuolization attacks.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:41190523
    reference_title: "Persistent Leukoencephalopathy Following H1N1 Infection Associated With a Novel MYRF Variant (p.Gly735Asp)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Recurrent episodes of ataxia, dysarthria, impaired consciousness, seizures"
    explanation: >-
      Summarizes in the literature review comparison table (Table 1) the
      characteristic recurrent ataxia, dysarthria, impaired consciousness, and
      seizures reported across the Kurahashi et al. (PMID:29265453) MMERV cohort
      carrying MYRF p.Gln403Arg.
genetic:
- name: MYRF
  association: Causal Germline Heterozygous Missense Variant
  gene_term:
    preferred_term: MYRF
    term:
      id: hgnc:1181
      label: MYRF
  inheritance:
  - name: Autosomal Dominant
  features: >-
    Classic MMERV is caused by the recurrent heterozygous missense variant
    c.1208A>G (p.Gln403Arg) in the conserved Ndt80-like DNA-binding domain of
    MYRF, which partially reduces transcriptional activation of the cleaved
    N-terminal fragment without causing the developmental cardiac-urogenital
    defects seen with truncating or complete loss-of-function MYRF alleles.
  evidence:
  - reference: PMID:29265453
    reference_title: "MYRF is associated with encephalopathy with reversible myelin vacuolization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By filtering genes expressed in the corpus callosum, we identified a heterozygous c.1208A>G predicting p.Gln403Arg in the highly conserved DNA-binding domain in the myelin regulatory factor (MYRF) gene. We subsequently screened the coding regions of MYRF by Sanger sequencing in our cohort comprised of 33 sporadic cases with MERS and 3 cases in another family with extensive myelin vacuolization, and identified the same heterozygous c.1208A>G in all affected members in the second family."
    explanation: >-
      Identifies the recurrent heterozygous MYRF c.1208A>G (p.Gln403Arg)
      DNA-binding domain variant across two unrelated multiplex families with
      MMERV.
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing of the proband revealed a missense mutation (MYRF- Q403R) at codon 403 of the MYRF gene: c.1208A>G (p.Gln403Arg) (Figure 3), resulting in an amino acid change from glutamine to arginine."
    explanation: >-
      Confirms the same recurrent MYRF c.1208A>G (p.Gln403Arg) variant in an
      independent Chinese family with MMERV.
diagnosis:
- name: MYRF Molecular Genetic Testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Definitive diagnosis of MMERV requires molecular genetic testing (such as
    whole-exome sequencing, gene panel testing, or targeted Sanger sequencing)
    demonstrating a heterozygous pathogenic variant in MYRF, characteristically
    c.1208A>G (p.Gln403Arg), which differentiates familial MMERV from sporadic
    CLOCC/MERS and GJB1-related CMTX1.
  evidence:
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYRF-related mild encephalopathy with reversible myelin vacuolization is a rare autosomal dominant genetic disease, with early clinical manifestations often being seizures. The definitive diagnosis of MMERV can be confirmed through genetic analysis."
    explanation: >-
      Establishes that genetic analysis is required to confirm the definitive
      diagnosis of MMERV.
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing of the proband revealed a missense mutation (MYRF- Q403R) at codon 403 of the MYRF gene: c.1208A>G (p.Gln403Arg) (Figure 3), resulting in an amino acid change from glutamine to arginine."
    explanation: >-
      Demonstrates whole-exome sequencing detection of the recurrent MYRF
      c.1208A>G (p.Gln403Arg) variant to establish the diagnosis.
- name: Brain Magnetic Resonance Imaging (MRI)
  diagnosis_term:
    preferred_term: magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  description: >-
    Acute-phase brain MRI with diffusion-weighted imaging (DWI), apparent
    diffusion coefficient (ADC) mapping, and T2/FLAIR sequences identifies
    symmetrical diffusion restriction across the corpus callosum (particularly
    the splenium) and bilateral deep cerebral white matter (centrum semiovale),
    while follow-up MRI within one to two weeks demonstrates complete
    radiological resolution of the reversible myelin vacuolization lesions.
  evidence:
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic Resonance Imaging (MRI) of the brain showed abnormal intensities in bilateral white matter in the centrum semiovale and corpus callosum on diffusion-weighted, T2-weighted and apparent diffusion coefficient images."
    explanation: >-
      Documents the diagnostic neuroimaging pattern on DWI, T2-weighted, and ADC
      brain MRI sequences during acute episodes.
  - reference: PMID:35990002
    reference_title: "Case report: Mild encephalitis with a reversible splenial lesion associated with SARS-CoV-2 infection in a patient with MYRF variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A follow-up MRI on the 10th day after onset demonstrated resolution of the previously noted abnormalities."
    explanation: >-
      Demonstrates the diagnostic value of serial follow-up brain MRI in
      confirming rapid reversibility of the white matter lesions.
treatments:
- name: Corticosteroid Therapy
  description: >-
    Short-course systemic corticosteroid therapy (such as intravenous
    methylprednisolone or dexamethasone) is frequently administered during acute
    episodes of MMERV to attenuate neuroinflammation and intramyelinic edema,
    with patients typically achieving complete clinical recovery within one
    week.
  treatment_term:
    preferred_term: systemic corticosteroid therapy
    term:
      id: NCIT:C122080
      label: Systemic Corticosteroid Therapy
  target_mechanisms:
  - target: Acute Reversible Intramyelinic Edema and Myelin Vacuolization
    treatment_effect: INHIBITS
    description: >-
      Systemic corticosteroids suppress acute inflammatory signaling and
      stabilize the blood-brain barrier during febrile relapses, accelerating
      resolution of intramyelinic edema.
    evidence:
    - reference: PMID:38155716
      reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Currently, the treatment options for MMERV are limited and based on hormonal steroids therapy with full recovery of symptoms within 1 week."
      explanation: >-
        Documents that acute MMERV episodes are managed clinically with
        corticosteroid therapy followed by full symptom recovery within one
        week.
  evidence:
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently, the treatment options for MMERV are limited and based on hormonal steroids therapy with full recovery of symptoms within 1 week."
    explanation: >-
      Establishes hormonal steroid therapy as the primary acute medical
      treatment reported for MMERV episodes.
- name: Genetic Counseling
  description: >-
    Genetic counseling and family cascade testing are indicated to identify
    asymptomatic or mildly affected heterozygous MYRF variant carriers, clarify
    autosomal dominant recurrence risk, and provide anticipatory guidance
    regarding febrile viral triggers.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, when MRI shows extensive myelin vacuolization, genetic analysis should be performed to determine the presence of MYRF variants to further diagnose the disease and guide eugenics in this family."
    explanation: >-
      Emphasizes performing MYRF genetic analysis in affected families to
      confirm the diagnosis and guide family reproductive counseling.
differential_diagnoses:
- name: Mild Encephalopathy with a Reversible Splenial Lesion (MERS / CLOCC)
  description: >-
    Cytotoxic lesions of the corpus callosum / mild encephalopathy with a
    reversible splenial lesion (CLOCC/MERS) is the primary clinical and
    radiological differential diagnosis for MMERV. Like MMERV, CLOCC/MERS is
    typically triggered by childhood viral infections and presents with mild
    encephalopathy, seizures, confusion, and reversible diffusion restriction in
    the corpus callosum (MERS type I) or both the corpus callosum and symmetric
    cerebral white matter (MERS type II). Whereas MERS type II is
    radiologically indistinguishable from acute MMERV, sporadic MERS cases do
    not harbor MYRF variants, making family history and MYRF genetic testing the
    definitive discriminators.
  distinguishing_features:
  - Sporadic CLOCC/MERS lacks pathogenic MYRF variants (0/33 sporadic MERS cases carried MYRF mutations in the discovery cohort), whereas MMERV segregates autosomal dominant MYRF variants (characteristically c.1208A>G p.Gln403Arg) with frequent family history or recurrence.
  - MERS type I is confined to the corpus callosum (splenium), whereas MMERV characteristically involves extensive symmetrical subcortical/centrum semiovale white matter in addition to the corpus callosum (resembling MERS type II).
  evidence:
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CLOCC/MERS is the primary differential diagnosis for MMERV."
    explanation: >-
      Explicitly identifies CLOCC/MERS as the primary differential diagnosis for
      MMERV.
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, MMERV presents clinically indistinguishable from MERS type II. Therefore, when MRI shows extensive myelin vacuolization, genetic analysis should be performed to determine the presence of MYRF variants to further diagnose the disease and guide eugenics in this family."
    explanation: >-
      Explains why MMERV mimics MERS type II on neuroimaging and why MYRF
      genetic analysis is required to distinguish the two conditions.
  - reference: PMID:29265453
    reference_title: "MYRF is associated with encephalopathy with reversible myelin vacuolization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We subsequently screened the coding regions of MYRF by Sanger sequencing in our cohort comprised of 33 sporadic cases with MERS and 3 cases in another family with extensive myelin vacuolization, and identified the same heterozygous c.1208A>G in all affected members in the second family."
    explanation: >-
      Demonstrates that 0 of 33 sporadic MERS cases carried pathogenic MYRF
      variants, whereas familial cases with extensive reversible myelin
      vacuolization shared the heterozygous MYRF c.1208A>G variant.
- name: Charcot-Marie-Tooth Disease, X-Linked Dominant, 1 (CMTX1)
  disease_term:
    preferred_term: Charcot-Marie-Tooth disease X-linked dominant 1
    term:
      id: MONDO:0010549
      label: Charcot-Marie-Tooth disease X-linked dominant 1
  description: >-
    GJB1-related X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) can present
    with recurrent, infection-triggered transient central nervous system
    leukoencephalopathy and reversible diffusion-weighted MRI lesions in the
    corpus callosum and deep cerebral white matter (centrum semiovale) that
    closely mimic MMERV. However, CMTX1 is caused by hemizygous or heterozygous
    variants in GJB1 (encoding connexin 32), typically features baseline
    peripheral demyelinating sensorimotor neuropathy and acute motor/sensory
    deficits rather than isolated seizures or impaired consciousness, and follows
    X-linked inheritance.
  distinguishing_features:
  - Causal variant in GJB1 (X-linked inheritance) rather than MYRF (autosomal dominant inheritance).
  - Presence of chronic peripheral sensorimotor polyneuropathy and prominent acute motor/sensory deficits in CMTX1.
  evidence:
  - reference: PMID:38155716
    reference_title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, CMTX1 can sometimes present as familial/recurrent transient leukoencephalopathy with reversible callosal and deep brain white matter lesions similar to MMERV. CMTX1 is caused by mutations in the GJB1 gene located on the X chromosome, which encodes connexin 32 (Cx32), a myelin-associated protein involved in the formation of gap junctions."
    explanation: >-
      Establishes CMTX1 as a key genetic differential diagnosis for recurrent
      reversible callosal and deep white matter leukoencephalopathy and
      distinguishes it by GJB1 etiology and peripheral nervous system
      involvement.
notes: >-
  Genotype-phenotype correlation at the MYRF locus reflects both variant-specific
  functional severity and domain localization. MYRF is broadly expressed during
  embryonic development (heart, diaphragm, lungs, urogenital tract, and eye) as
  well as postnatally in differentiated CNS oligodendrocytes. De novo
  loss-of-function or severe DNA-binding/autoproteolytic variants cause
  cardiac-urogenital syndrome (CUGS; MONDO:0032702) or C-terminal syndromic
  nanophthalmos, whereas the hypomorphic missense variant p.Gln403Arg in MMERV
  retains sufficient residual transcriptional activity for normal embryonic
  organogenesis and baseline development while compromising stress-induced myelin
  homeostasis in mature oligodendrocytes. Additionally, a distinct allelic
  autosomal dominant virus-triggered MYRF leukoencephalopathy caused by
  c.2204G>A (p.Gly735Asp) in the C-terminal ICA/peptidase S74 domain has been
  reported (PMID:41190523); unlike classic p.Gln403Arg MMERV, the p.Gly735Asp
  phenotype presented with persistent, nonreversible white matter lesions on
  two-year follow-up MRI and minimal corpus callosum involvement.
references:
- reference: PMID:23966832
  title: "A Bacteriophage tailspike domain promotes self-cleavage of a human membrane-bound transcription factor, the myelin regulatory factor MYRF."
  findings: []
- reference: PMID:23966833
  title: "MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes."
  findings: []
- reference: PMID:29265453
  title: "MYRF is associated with encephalopathy with reversible myelin vacuolization."
  findings: []
- reference: PMID:35990002
  title: "Case report: Mild encephalitis with a reversible splenial lesion associated with SARS-CoV-2 infection in a patient with MYRF variant."
  findings: []
- reference: PMID:38155716
  title: "MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review."
  findings: []
- reference: PMID:41190523
  title: "Persistent Leukoencephalopathy Following H1N1 Infection Associated With a Novel MYRF Variant (p.Gly735Asp)."
  findings: []

📚

References & Deep Research

References

6

PMID:23966832

A Bacteriophage tailspike domain promotes self-cleavage of a human membrane-bound transcription factor, the myelin regulatory factor MYRF.

No top-level findings curated for this source.

PMID:23966833

MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes.

No top-level findings curated for this source.

PMID:29265453

MYRF is associated with encephalopathy with reversible myelin vacuolization.

No top-level findings curated for this source.

PMID:35990002

Case report: Mild encephalitis with a reversible splenial lesion associated with SARS-CoV-2 infection in a patient with MYRF variant.

No top-level findings curated for this source.

PMID:38155716

MYRF-related mild encephalopathy with reversible myelin vacuolization: a case report and literature review.

No top-level findings curated for this source.

PMID:41190523

Persistent Leukoencephalopathy Following H1N1 Infection Associated With a Novel MYRF Variant (p.Gly735Asp).

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Claude Code ▸

Encephalitis/Encephalopathy, Mild, with Reversible Myelin Vacuolization (MMERV): Research Report

claude-haiku-4-5-20251001, claude-opus-5-5 8 citations 2026-10-14T15:52:22.237539

Encephalitis/Encephalopathy, Mild, with Reversible Myelin Vacuolization (MMERV): Research Report

MONDO:0020853 · OMIM #618113 · Gene: MYRF (OMIM *608329; hgnc:1181)

Scope: Fewer than 20 genotyped patients have been published. The quotes below marked "verified" were read in this session from the repository's local reference cache (references_cache/) or from OMIM. I have not checked PMIDs marked "unverified". Run just fetch-reference on them before citing. The PubMed and OLS MCP servers need authorization in claude.ai connector settings and were not available, so no new ontology lookups were made. Every CURIE below either already appears in kb/disorders/Encephalitis_Encephalopathy_Mild_With_Reversible_Myelin_Vacuolization.yaml or is marked as a suggestion to be looked up.

1. Disease Information

Overview. MMERV is an autosomal dominant disorder. It causes repeated or single episodes of acute, mild encephalopathy, usually triggered by fever or infection, in people whose development is otherwise normal. During an episode, MRI shows extensive symmetric restricted diffusion in the corpus callosum (especially the splenium) and the deep cerebral white matter. The lesions and the symptoms resolve within days to about 2 weeks. The disorder lies on the same clinical spectrum as sporadic MERS (mild encephalitis/encephalopathy with a reversible splenial lesion), but it is familial and the white matter involvement is more extensive.

OMIM summary (verified via OMIM mirror): MMERV is an "episodic acute reversible encephalopathy that occurs in children and is frequently associated with a trigger, such as a febrile illness."

Identifiers | System | ID | |---|---| | MONDO | MONDO:0020853 | | OMIM (phenotype) | #618113 | | OMIM (gene) | *608329 (MYRF); allelic variant .0001 = Q403R | | MedGen | C4722446 | | KEGG Disease | H02489 | | Orphanet / ICD-10 / ICD-11 | No specific code found. ICD-10 G93.4 (other and unspecified encephalopathy) or G93.40 is the nearest generic code. |

Synonyms: MMERV; MYRF-related mild encephalopathy with reversible myelin vacuolization (the name proposed by Kurahashi et al. 2018); familial MERS; familial mild encephalopathy with a reversible splenial lesion and extensive white matter involvement.

Source of the data: Everything comes from individual pedigree and case reports. No registry or EHR cohort exists.

Name origin (verified, PMID:29265453): "We propose the term 'MYRF-related mild encephalopathy with reversible myelin vacuolization.'"

2. Etiology

Primary cause. A heterozygous germline missense variant in MYRF. The recurrent variant is c.1208A>G, p.Gln403Arg (Q403R), which sits in the conserved Ndt80-like DNA-binding domain.

"we identified a heterozygous c.1208A>G predicting p.Gln403Arg in the highly conserved DNA-binding domain in the myelin regulatory factor (MYRF) gene." (PMID:29265453, verified)

Triggers (environmental and infectious). Febrile infections trigger episodes. Reported triggers include unspecified febrile viral illnesses, SARS-CoV-2 (PMID:35990002), and influenza or COVID-like fever in the Chinese proband (PMID:38155716). One allelic case with a different variant was triggered by influenza A H1N1 (PMID:41190523). OMIM also lists stress as a trigger.

"Infectious diseases in children are a major triggering factor for MMERV" (PMID:38155716, verified)

Gene–environment interaction. The published working model is that mutant MYRF supports myelin adequately at baseline but becomes insufficient under the metabolic and inflammatory stress of infection. OMIM attributes this hypothesis to Kurahashi et al. It is plausible but has not been tested experimentally.

Genetic risk and modifiers. No modifier genes are known. Penetrance is incomplete (Section 9).

Protective factors. None are known. The 2023 review suggests reducing infections:

"Minimizing infections can help reduce disease recurrence." (PMID:38155716, verified) This is an expert suggestion without supporting data.

Sporadic MERS is genetically different. Kurahashi et al. sequenced MYRF in 33 sporadic MERS cases and found the variant only in the second family. MYRF therefore does not account for typical sporadic MERS.

3. Phenotypes

All phenotypes are episodic, start in childhood (as young as 2–3 years) through young adulthood, are mild, and reverse completely. Frequencies cannot be estimated reliably from roughly 9–15 patients; the qualitative estimates below are my own.

Phenotype	HPO (from current entry, or suggested)	Frequency / notes
Acute encephalopathy	HP:0001298 Encephalopathy	Defining (all affected)
Impaired consciousness / confusion	HP:0001289 Confusion; suggest looking up "Reduced consciousness/confusion"	Very frequent
Delirium / abnormal behavior	HP:0031258 Delirium	Frequent
Seizures, often febrile in early childhood, with lip smacking or eye deviation	HP:0001250 Seizure; consider HP:0002373 Febrile seizure (look up)	Frequent; often the first sign
Speech disturbance: dysarthria, non-fluency, aphasia-like "impaired verbal communication"	HP:0001260 Dysarthria	Frequent; recurrent episodes of non-fluency in the adult Chinese proband
Ataxia	HP:0001251 Ataxia	Occasional
Limb numbness / transient motor weakness	Suggest paresthesia or hemiparesis terms (look up)	Occasional (PMID:35990002)
Reversible white matter lesions (corpus callosum, centrum semiovale)	HP:0002352 Leukoencephalopathy; suggest a "splenium of corpus callosum" abnormality term; HP:0002181 Brain edema (intramyelinic)	Defining imaging finding
Restricted diffusion on DWI (low ADC)	Suggest a "restricted diffusion on MRI" term (look up)	Defining
Normal serum sodium	Laboratory finding	Differs from sporadic MERS, where hyponatremia is common (Imamura 2010)

Key clinical quotes (verified): - PMID:29265453: "recurrent encephalopathy with extensive but reversible cerebral myelin vacuolization and neurological symptoms similar to those of MERS spanning 3 generations." - PMID:35990002: "a 14-year-old girl with a heterozygous p. Gln403Arg variant in the MYRF gene, who had five episodes of encephalopathy. She experienced reduced consciousness, numbness in the arm, and impaired verbal communication from day 4 of SARS-CoV-2 infection." - PMID:38155716: "The clinical manifestations of MMERV include seizures, impaired speech (such as lack of fluency, dysarthria, and language difficulties), recurrent episodes of impaired consciousness (confusion or delirium), spontaneous motor difficulties, and limb numbness"

Quality of life. No quality-of-life instrument data exist. Between episodes patients function normally. The burden comes from recurrent acute hospitalizations and the anxiety that goes with them.

4. Genetic and Molecular Information

Gene: MYRF (myelin regulatory factor; formerly C11orf9). Location 11q12.2. hgnc:1181 (in the local HGNC cache).
Variant: NM_001127392 c.1208A>G, p.Gln403Arg. It is in the N-terminal Ndt80/PhoG-like DNA-binding domain and was found in both Japanese families. OMIM reports that haplotype analysis suggested a founder effect. The Chinese family (PMID:38155716) carries a heterozygous MYRF variant described as related. Check the exact variant in that paper's full text before recording it.
Classification: OMIM lists it as allelic variant .0001. I did not check its ClinVar classification in this session.
Origin: Germline, segregating with disease.
Population frequency: Not established here. Kurahashi et al. filtered for rare variants. Check gnomAD.
Functional effect: Partial loss of function, a hypomorphic reduction in transactivation:

"Luciferase assay revealed that transcriptional activity of the N-terminal region of MYRF was significantly diminished by introducing the c.1208A>G variant." (PMID:29265453, verified)

Whether Q403R acts dominant-negatively on the MYRF trimer has not been tested. The trimerization requirement (PMID:23966832) makes this a reasonable open question. - Allelic MYRF disorders (spectrum context). These are the reason to keep MMERV as its own entry: - Cardiac-urogenital syndrome: de novo, mostly loss-of-function variants; congenital heart disease, diaphragmatic hernia, and genital anomalies. Key paper: Pinz et al. 2018 (unverified PMID). - Nanophthalmos / high hyperopia: Garnai et al. 2019 and others (unverified PMIDs). - Persistent (non-reversible) leukoencephalopathy after H1N1 infection, caused by the C-terminal variant p.Gly735Asp: > "establishes persistent leukoencephalopathy as a novel clinical phenotype within the MYRF disease spectrum." (PMID:41190523, verified) - Epigenetic or chromosomal changes: None reported.

5. Environmental Information

Infectious triggers: non-specific febrile viral infections; SARS-CoV-2 (NCBITaxon:2697049, look up); influenza A virus (NCBITaxon:11320, look up) in the allelic persistent-leukoencephalopathy case.
Lifestyle factors: none known.
Toxins: none implicated.
Suggested exposure term: an ECTO "exposure to virus" class. Search ECTO before binding one; the repository forbids writing CURIEs from memory.

6. Mechanism and Pathophysiology

Causal chain

Heterozygous MYRF c.1208A>G (p.Gln403Arg) changes a conserved residue in the N-terminal DNA-binding domain (PMID:29265453).
This reduces the transcriptional activation activity of the cleaved N-terminal MYRF fragment. This was shown in luciferase assays (in vitro).
MYRF is normally a membrane-anchored ER protein. It trimerizes and cleaves itself through an intramolecular chaperone domain related to bacteriophage tailspike proteins, which releases the N-terminal transcription factor into the nucleus (PMID:23966832, PMID:23966833). The variant therefore weakens a normally constitutive myelin-gene transcription program after release; the cleavage step itself is unaffected.
Less direct activation of myelin and oligodendrocyte gene enhancers. The link to specific genes is inferred. ChIP-seq in the normal state shows that the N-terminal fragment "directly binds the enhancer regions of oligodendrocyte-specific and myelin genes" (PMID:23966833, verified). Target genes include MBP, PLP1, MOG, and MAG.
Mature oligodendrocytes have a reduced reserve for maintaining myelin. This is inferred from mouse models: adult deletion of Myrf causes loss of oligodendrocyte identity and myelin integrity (Koenning et al. 2012, J Neurosci, PMID:22956843, unverified).
Febrile or systemic infection acts as a second hit, through fever, cytokines, and possibly metabolic stress. The mechanism is hypothesized, not demonstrated.
Intramyelinic edema and myelin vacuolization follow, through splitting of myelin lamellae at the intraperiod line. The authors infer this from imaging; there is no human histopathology.
Branch, imaging: restricted diffusion (low ADC) and T2/FLAIR hyperintensity in the corpus callosum (splenium first) and the centrum semiovale.
Transiently impaired axonal conduction in the affected white matter tracts (inferred) causes encephalopathy, confusion or delirium, seizures, dysarthria, and ataxia.
The vacuolization resolves once the trigger clears, so imaging and symptoms normalize within about 1–2 weeks. Steroids may speed recovery, but there are no controlled data.

Contrast with sporadic MERS / cytotoxic lesions of the corpus callosum (CLOCCs). In sporadic MERS, cytokine-mediated cytotoxic edema and hyponatremia have been proposed. MMERV adds a constitutional myelin-maintenance defect, which probably explains why its lesions are more extensive and why episodes recur.

Annotations (from the current entry unless marked)

Molecular function: GO:0000981, DNA-binding transcription factor activity, RNA polymerase II-specific.
Biological processes: GO:0045944 positive regulation of transcription by RNA polymerase II; GO:0043217 myelin maintenance; GO:0022010 central nervous system myelination; GO:0019227 neuronal action potential propagation. Suggested additions, to look up: protein autoprocessing and protein homotrimerization.
Cell types: CL:0000128 oligodendrocyte; CL:0002453 mature oligodendrocyte.
Cellular component, suggested: endoplasmic reticulum membrane (full-length MYRF) and nucleus (cleaved N-terminal fragment).
Biological scale tags: the variant node is MOLECULAR; oligodendrocyte myelin maintenance is CELLULAR; vacuolization and edema are TISSUE; encephalopathy is ORGANISM.

Molecular profiling: No transcriptomic, proteomic, metabolomic, or single-cell data exist for MMERV patients. No GEO datasets were found.

7. Anatomical Structures Affected

Organ and system: brain, central nervous system (UBERON:0001017). No other organs are involved, unlike the syndromic MYRF disorders.
Specific sites: corpus callosum (UBERON:0002336), splenium of the corpus callosum (UBERON:0013750), cerebral hemisphere white matter (UBERON:0002437; centrum semiovale), white matter (UBERON:0002316).
Cells: oligodendrocytes, mature oligodendrocytes, and the myelin sheath (GO cellular component "myelin sheath"; look up).
Lateralization: bilateral and symmetric.

8. Temporal Development

Onset: early childhood (seizures from about 32 months in Family A; ages 2–9 in Family B, with the mother affected at age 6). The Chinese proband had adult episodes from age 19, after febrile seizures in childhood.
Pattern: acute, starting within days of a febrile illness (day 4 of SARS-CoV-2 infection in PMID:35990002).
Course: episodic, relapsing and remitting. The disease does not progress between episodes. Up to five episodes have been reported in one patient.
Duration of an episode: a few days to about 1 week clinically. MRI normalized within days to 13 days (PMID:38155716).
Critical window: the febrile phase of infection.
Remission: spontaneous, or after steroid treatment.

9. Inheritance and Population

Inheritance: autosomal dominant (HP:0000006). Three-generation transmission is documented.
Penetrance: incomplete. Verified quote from PMID:38155716: "His father, aunt, and grandmother all carry the same variant in the MYRF gene, despite having no history of recursive neurological symptoms or cognitive deterioration." (Note: the cached sentence says "His", although the proband is described elsewhere in the paper as female. Check this against the full text before quoting.)
Expressivity: variable. It ranges from a single childhood febrile seizure, to adult speech dysfluency, to five or more full encephalopathy episodes.
Founder effect: suggested in the two Japanese families (OMIM, from Kurahashi et al.).
Epidemiology: ultra-rare. About 9 individuals in the two Japanese families (4 definite, 5 suspected affected according to OMIM), plus the Saito 2022 patient (one of the original family members followed up) and the Chinese family (2023). There is no prevalence figure.
Populations: Japanese and Chinese so far. This probably reflects ascertainment bias, since MERS is recognized most often in East Asia.
Sex ratio: both sexes affected.
Anticipation, consanguinity: not reported.

10. Diagnostics

Neuroimaging (the key test): brain MRI during an episode shows symmetric diffusion-weighted hyperintensity with low ADC in the corpus callosum and centrum semiovale, and follow-up imaging shows it resolving. Suggested NCIT term: NCIT:C16809 Magnetic Resonance Imaging (already in the entry). Repeat MRI to document reversal is required for the diagnosis.
EEG: may show slowing during an episode (Kurahashi et al. used EEG; the details are in the full text).
Laboratory: cerebrospinal fluid is generally unremarkable. Serum sodium is normal, unlike in many sporadic MERS cases. Infectious workup identifies the trigger. Mitochondrial DNA testing was negative in the Chinese proband.
Genetic testing: exome sequencing found the gene. Targeted MYRF sequencing, or a leukoencephalopathy or epilepsy panel that includes MYRF, is appropriate for familial or recurrent MERS. Testing of relatives (cascade testing) is reasonable. Suggested NCIT term: NCIT:C15709 Genetic Testing (already in the entry).

"The definitive diagnosis of MMERV can be confirmed through genetic analysis." (PMID:38155716, verified)
Diagnostic criteria: none formal. In practice: familial or recurrent MERS-like episodes, plus extensive reversible white matter diffusion restriction, plus a heterozygous MYRF variant.
Differential diagnosis:
Sporadic MERS / CLOCCs (single episode, mostly splenial lesion, often hyponatremia)
X-linked Charcot-Marie-Tooth disease type 1 (CMTX1, GJB1), which causes transient stroke-like white matter lesions
Acute disseminated encephalomyelitis (ADEM)
Acute necrotizing encephalopathy (RANBP2)
Mitochondrial disease
Toxic or metabolic leukoencephalopathy (for example, metronidazole)
Persistent MYRF leukoencephalopathy (PMID:41190523)
Screening: none at the population level.

11. Outcome and Prognosis

Mortality: none reported.
Recovery: complete after each episode. OMIM states there are no permanent neurologic sequelae. The Saito patient recovered "completely within a week" (PMID:35990002, verified).
Morbidity: recurrent acute admissions. No cognitive decline was seen in follow-up up to adulthood.
Prognostic factors: unknown. Allelic variants outside the DNA-binding domain (G735D) can leave persistent lesions, which suggests that genotype affects reversibility.

12. Treatment

No disease-specific therapy exists, and there are no trials. - Corticosteroids (empirical): intravenous methylprednisolone pulse, 1 g/day for 3 days (PMID:35990002), or a methylprednisolone 500 mg taper followed by oral prednisone (PMID:38155716). Suggested annotation: NCIT:C15986 Pharmacotherapy as treatment_term, with methylprednisolone (CHEBI term, look up) as therapeutic_agent and modality SMALL_MOLECULE. Recovery also happens spontaneously, so the benefit of steroids is unproven.

"She was treated with a single course of intravenous methylprednisolone pulse therapy (1 g/day for 3 days), which resulted in an immediate improvement in her symptoms." (PMID:35990002, verified) - Supportive care: antiseizure medication for acute seizures, fever control, and treatment of the infection. Suggested NCIT term: NCIT:C15747 Supportive Care. - Gene, cell, or RNA therapies; clinical trials: none. No NCT or ICTRP records were found.

13. Prevention

Primary prevention: not applicable beyond genetic counseling. Each child of a carrier has a 50% chance of inheriting the variant, and penetrance is incomplete. Suggested NCIT term: NCIT:C15240 Genetic Counseling.
Secondary and tertiary prevention: avoid infections and keep vaccinations up to date, including influenza and COVID-19 (expert suggestion, PMID:38155716). Prompt MRI and supportive care during febrile illness in known carriers.
Prenatal or preimplantation testing: technically possible once the familial variant is known. Its use for a mild, reversible disorder would need careful counseling.

14. Other Species and Natural Disease

No naturally occurring MYRF-related reversible myelin vacuolization has been reported in animals. No OMIA entry was found.
Orthologs: mouse Myrf (MGI), zebrafish myrf, and C. elegans myrf-1 (which acts in synaptic rewiring). The Ndt80-like DNA-binding domain is conserved down to yeast Ndt80 and Dictyostelium.
Comparative note: some veterinary toxic and inherited spongiform leukoencephalopathies show intramyelinic vacuolization, but none has been linked to MYRF.

15. Model Organisms

Model	Phenotype	Relevance and limits
Myrf oligodendrocyte-specific conditional knockout, developmental (Emery et al. 2009, Cell; PMID:19596243, unverified)	Severe CNS hypomyelination; oligodendrocytes fail to mature	Shows MYRF is needed for myelination. It is a null allele, not a hypomorph, and does not model episodic disease.
Inducible adult Myrf deletion in mature oligodendrocytes (Koenning et al. 2012, J Neurosci; PMID:22956843, unverified)	Progressive demyelination; loss of myelin gene expression	Shows MYRF is needed to maintain myelin. This is the closest mechanistic support for the model above, but it is progressive and irreversible, not episodic.
Cell lines / HEK293 luciferase assays (PMID:29265453)	Reduced transactivation by Q403R	The only functional test of the variant itself (in vitro).
Heterologous reconstitution in E. coli and yeast (PMID:23966832)	Constitutive trimerization-dependent self-cleavage	Mechanism of MYRF activation.
Gap	No Q403R knock-in mouse; no fever or infection challenge model; no patient iPSC-derived oligodendrocytes	Whether infection causes reversible vacuolization in a hypomorphic Myrf background has not been tested. In the repository's scheme this is a `KNOWLEDGE_GAP` (evidence absent), not a `HUMAN_MODEL_MISMATCH`.

Key References

PMID	Citation	Use	Status
29265453	Kurahashi H et al. MYRF is associated with encephalopathy with reversible myelin vacuolization. Ann Neurol 2018;83:98–106	Gene discovery, phenotype, functional assay	Cached, verified
35990002	Saito M et al. Mild encephalitis with a reversible splenial lesion associated with SARS-CoV-2 infection in a patient with MYRF variant. Front Pediatr 2022	Trigger, recurrence, steroids	Cached, verified
38155716	Yao S et al. MYRF-related MMERV: a case report and literature review. Front Genet 2023	Chinese family, penetrance, review	Cached, verified
41190523	Hu J et al. Persistent leukoencephalopathy following H1N1 infection associated with a novel MYRF variant (p.Gly735Asp). Ann Clin Transl Neurol 2026	Allelic, non-reversible phenotype	Cached, verified
23966833	Bujalka H et al. MYRF is a membrane-associated transcription factor that autoproteolytically cleaves… PLoS Biol 2013	Mechanism, ChIP-seq	Cached, verified
23966832	Li Z et al. A bacteriophage tailspike domain promotes self-cleavage of… MYRF. PLoS Biol 2013	Trimerization and self-cleavage	Cached, verified
20042198	Imamura T et al. Sisters with clinically mild encephalopathy with a reversible splenial lesion (MERS)-like features; familial MERS? J Neurol Sci 2010;290:153–156	First clinical description of Family B	PMID taken from OMIM; not cached
22956843	Koenning M et al. J Neurosci 2012 (adult Myrf deletion)	Model organism	Unverified
19596243	Emery B et al. Cell 2009 (Myrf discovery)	Model organism	Unverified

Web sources consulted: - OMIM #618113 (mirror) - OMIM *608329 MYRF (mirror) - MedGen C4722446 - KEGG H02489 - Frontiers in Genetics 2023 (PMID:38155716) - Saito et al. 2022, PMC9386134 - Imamura et al. 2010 bibliographic record - Recurrent MERS case series, PMC8722321

Encephalitis/Encephalopathy, Mild, with Reversible Myelin Vacuolization

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Encephalitis/Encephalopathy, Mild, with Reversible Myelin Vacuolization (MMERV): Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic and Molecular Information

5. Environmental Information

6. Mechanism and Pathophysiology

Causal chain

Annotations (from the current entry unless marked)

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome and Prognosis

12. Treatment

13. Prevention

14. Other Species and Natural Disease

15. Model Organisms

Key References