“Acute necrotizing encephalopathy type 1 is likely a very rare condition, although its incidence is unknown. At least 59 cases of this condition have been reported in the scientific literature.”
OMIM: {Encephalopathy, acute, infection-induced, 3, susceptibility to}, AD
Clinical Validity Scoring Notes and points
Variant/Case Evidence:
RANBP2 c.1754C>T p.T585M
REVEL: 0.178
2 alleles in GnomAD v4.
PMID: 19118815: 35 unrelated families with clinical dx of ANE. This variant was identified in 9 of the families. Haplotype analysis was done and 7 families showed unique haplotypes, so only including those 7 families:
Descr. as c.1880C/T, p.Thr585Met.
Familial cases (total 3.5 points)
Family 586: 0.5 points
Family 102: 0.5 points
Family 112: 0.5 points
Family 105: 0.5 points
Family 670: 0.5 points
Family 690: 0.5 points
Family 119: 0.5 points
PMID: 19811512: 9 yo Caucasian female with rapid-onset severe encephalopathy triggered by viral infections. MRI characteristic of ANE during both episodes.
Mother had an episode of ‘encephalitis/polyneuritis’ after having a viral infection at the age of 19 years; she has had a foot drop since then.
Variant identified in proband and mother, de novo in mother.
Reported as c.1880C→T.
0.5 points (not counting mother since phenotype is unclear/unconfirmed)
PMID: 34377735: 9 month old female with seizure and 4 day hx of fever. EEG was consistent with encephalopathy. MRI suggestive of possible acute viral encephalitis.
Identified RANBP2 (c.1754C>T; p.Thr585Met) on an epilepsy panel. Parents not tested.
0.5 points
PMID: 37090838: Two Brazilian families with ANE and c.1754C > T (p.Thr585Met) (total 1 point)
Family 1 (0.5 points)
Family 2 (0.5 points)
PMID: 26923722
Patient P1, 10 month old boy with ANE confirmed on MRI.
p.Thr585Met identified, inherited from healthy father. (0.5 points)
Other reports of this variant were present but not reviewed. From HGMD, PMIDs: 21945312, 25128471, 24321870, 25522933, 27591117, 28336122, 29741717, 29687329, 31589614, 30796099, 32760653, 33879512, 34059398, 33777149, 33761695, 34400285, 33726816, 35870896.
RANBP2 c.1958C>T p.Thr653Ile
REVEL: 0.178
Absent from GnomAD.
PMID: 19118815:
Descr. as c.2085C/T, p.Thr653Ile.
Family 671: 0.5 points
PMID: 25170550
28 month old with ANE, confirmed on MRI.
Older sister died at 6 months within 12 hours of presenting with fever and seizures.
Father, paternal grandmother, and deceased sibling also had the same variant.
“DNA from the index case was sequenced” - not sure what method was used, it seems like the authors may have looked at RANBP2 specifically.
0.5 points.
RANBP2 c.1966A>G p.Ile656Val
REVEL: 0.306
1 allele in GnomAD v4
PMID: 19118815:
Descr. as c.2094A→G; p.Ile656Val
Family 613: 0.5 points
PMID: 36029610
Identified p.I656V in the homozygous state in a patient with ANE on WES. A sibling was also affected but DNA could not be tested. Both sibs died before reaching 1 yo.
Parents were heterozygous, unaffected.
Consanguineous family.
0.5 points
RANBP2 c.2043G>C p.Trp681Cys
REVEL: 0.460
Absent from GnomAD v4.
PMID: 26923722
Patient P2 with multiple episodes of ANE.
De novo missense mutation p.Trp681Cys in exon 14 of RANBP2. (1 point)
RANBP2 c.5249C>G Pro1750Arg
One case report where authors suspect digenic inheritance, not counted (PMID: 32102593)
RANBP2 c.1350A>T p.Leu450Phe
Seen in 6 individuals in GnomAD v4.
REVEL: 0.0570
PMID: 34377735: 6yo female with acute encephalopathy with seizures, MRI and EEG findings, and negative autoimmune, metabolic, infectious and toxic workup. Encephalopathy panel returned RANBP2 p.Leu450Phe, reported as a VUS.
Not counting due to higher AF and very low REVEL score.
Segregation Evidence:
RANBP2 c.1754C>T p.T585M
REVEL: 0.178
2 alleles in GnomAD v4.
PMID: 19118815: 35 unrelated families with clinical dx of ANE. 35 unrelated families with clinical dx of ANE. This variant was identified in 9 of the families. Haplotype analysis was done and 7 families showed unique haplotypes, so only including those 7 families:
PMID: 37090838: Two Brazilian families with ANE and c.1754C > T (p.Thr585Met)
Searched for variants in RANBP2 specifically and identified this. (total: 0 points)
Family 1 (0.5 points): 3 segregations (0 points)
Family 2 (0.5 points): 0 segregations (0 points)
Experimental Evidence
Category Totals
Variant/Case Evidence: 9 points (so far)
Segregation Evidence: 1 point (so far)
Case/Control Evidence: N/A
Experimental Evidence:
Clinical ValidityPoints Total
Source:
Clinical ValidityClassification
Definitive (12pts)
Strong (12pts)
Moderate (7-11pts)
Limited (0.1-6pts)
No genetic evidence
Refuted
Disputed
Source:
MolecularMechanism
Loss of function
Gain of function
Dominant negative
Unknown
Other
Loss of function / Gain of function / Dominant Negative
Penetrance
Complete (100%)
High (≥80%)
Moderate (<80% and >20%)
Low (≤20%)
(list source/PMID)
~40%
Source: PMID: 19811512
Age of Onset
Congenital
Pediatric
Adolescent
Adulthood
Late adulthood
(list source/PMID)
Most commonly in young children, but can also affect adults.
Severity
Clinical Features
Triggered by febrile viral illness, causing acute encephalopathy 1-3 days following the onset of the infection. This may include “deteriorating consciousness, with rapid progression to coma, and can be accompanied by seizures and focal neurologic deficits” (PMID: 32426208). Recurrent episodes are common. Outcomes span from recovery to death.