Familial Acute Necrotizing Encephalopathy

Mendelian MONDO:0011953 Pathograph 44 Show in embeddings browser Acute Infection-Induced Encephalopathy Mendelian Encephalopathy

Familial acute necrotizing encephalopathy (ANE1) is an autosomal dominant, incompletely penetrant susceptibility to acute necrotizing encephalopathy caused by heterozygous missense variants in the nuclear pore gene RANBP2, most often p.Thr585Met. In a carrier, a common febrile viral illness (influenza A in particular, but also influenza B, parainfluenza, human herpesvirus 6, enteroviruses and SARS-CoV-2) is followed within hours to a few days by rapidly progressive encephalopathy with lethargy, seizures and coma, and by bilateral symmetric necrotic lesions of the thalami, brainstem, putamina and other deep grey and white matter structures, without direct viral invasion of the brain. Raised interleukin-6 and TNF-alpha and raised CSF protein without pleocytosis point to a host hyperinflammatory response as the proximate cause, but how the RANBP2 variants produce it is unsettled. About a third of affected individuals die in the acute phase, half of survivors have permanent neurologic deficits, and recurrent episodes occur in about half of affected individuals, which distinguishes ANE1 from the usual sporadic, non-recurrent form of ANE. Median age at first episode is about two years, but first episodes also occur in adolescents and adults.

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2
Inheritance
9
Pathophys.
23
Phenotypes
3
Hypotheses
2
Gaps
44
Pathograph
1
Genes
5
Variants
9
Medical Actions
3
References
1
Deep Research
👪

Inheritance

2
Autosomal dominant HP:0000006
A single heterozygous RANBP2 missense variant confers susceptibility. The variant is often inherited from an unaffected or mildly affected parent because penetrance is incomplete (estimated at 40% in the index kindred), and it can also arise de novo. Outcome varies widely within families carrying the same variant.
Autosomal dominant inheritance Penetrance: INCOMPLETE Penetrance %: 40 Expressivity: VARIABLE
Show evidence (4 references)
PMID:19118815 SUPPORT Human Clinical
"we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait"
Linkage and segregation in the index kindred establish autosomal dominant inheritance with incomplete penetrance.
PMID:19118815 SUPPORT Human Clinical
"Penetrance was estimated at 40% and recurrent episodes occurred in half of the affected individuals."
Source of the 40% penetrance estimate.
PMID:37090838 SUPPORT Human Clinical
"Our report reinforces incomplete penetrance of ADANE and intrafamilial phenotypic variability of outcome."
Two further families with p.Thr585Met carried by affected and asymptomatic members, with variable outcome within each family.
+ 1 more reference
Incomplete penetrance HP:0003829
Many obligate carriers never have an episode, and an affected child's carrier parent is frequently unaffected.
Typified by incomplete penetrance
Show evidence (2 references)
PMID:25473726 SUPPORT REVIEW SYNTHESIS Other
"To date the majority of individuals diagnosed with IIAE3 have a parent who is heterozygous for a RANBP2 pathogenic variant; however, due to reduced penetrance, the parent may not have manifested the disease state."
Reduced penetrance explains unaffected carrier parents.
PMID:25522933 SUPPORT REVIEW SYNTHESIS Human Clinical
"ANE1 is inherited as autosomal dominant, but shows incomplete penetrance."
Literature review of reported ANE1 patients restating incomplete penetrance.
◈

Mechanistic Hypotheses

3
Infection-triggered cytokine storm with blood-brain barrier failure
cytokine_storm CANONICAL
Evidence balance 2 support
The prevailing model: the febrile infection provokes an excessive host cytokine response (IL-6, TNF-alpha), which damages the cerebral microvasculature, opens the blood-brain barrier and produces symmetric edema, hemorrhage and necrosis. It is canonical for ANE as a whole and underpins immunomodulatory treatment, but how RANBP2 variants drive the cytokine excess, and why the lesions are so selectively distributed, is not established.
Pathograph links
Pro-Inflammatory Cytokine Overproduction -> Hypercytokinemia DIRECT
Hypercytokinemia -> Blood-Brain Barrier Disruption
Hypercytokinemia -> Elevated circulating hepatic transaminase concentration
Hypercytokinemia -> Disseminated intravascular coagulation
Blood-Brain Barrier Disruption -> Symmetric Deep Grey Matter Necrosis
Blood-Brain Barrier Disruption -> Increased CSF protein concentration
Show evidence (2 references)
PMID:19118815 SUPPORT BACKGROUND Human Clinical
"leading to the prevailing hypothesis of a “cytokine storm” as part of the pathogenic mechanism"
Cytokine storm described as the prevailing hypothesis.
PMID:35408907 SUPPORT REVIEW SYNTHESIS Other
"Mutations in the RANBP2 gene are associated with acute necrotizing encephalopathy type 1 (ANE1), a rare condition where patients experience a sharp rise in cytokine production in response to viral infection and undergo hyperinflammation, seizures, coma, and a high rate of mortality."
Review framing ANE1 as virus-triggered hyperinflammation.
Loss of RANBP2 restraint on viral replication drives hyperinflammation
viral_replication_restraint EMERGING
Evidence balance 1 support
The ANE1 variant displaces RANBP2 from the nuclear envelope, which increases influenza A replication and viral RNA export and drives pro-inflammatory cytokine and chemokine production. Shown in a human airway cell line and primary macrophages; not yet tested in neural tissue or patients.
Pathograph links
Germline RANBP2 Missense Variant -> Loss of RANBP2 Nuclear Envelope Localization DIRECT
Loss of RANBP2 Nuclear Envelope Localization -> Enhanced Influenza Virus Replication DIRECT
Loss of RANBP2 Nuclear Envelope Localization -> Pro-Inflammatory Cytokine Overproduction
Acute Febrile Viral Illness -> Enhanced Influenza Virus Replication
Enhanced Influenza Virus Replication -> Pro-Inflammatory Cytokine Overproduction DIRECT
Show evidence (1 reference)
PMID:41651846 SUPPORT In Vitro
"Together, our results reveal that RANBP2 regulates influenza RNA replication and nuclear export, thereby restraining virus-induced hyperinflammation"
Cell-model evidence for the restraint model.
RANBP2-dependent mitochondrial dysfunction and energy failure
mitochondrial_energy_failure EMERGING
Evidence balance 2 support
RANBP2 positions mitochondria and binds COX11; the variants weaken the COX11 interaction, and the lesion pattern resembles Leigh syndrome and Wernicke encephalopathy. Whether ATP production actually falls in patient cells has not been shown.
Pathograph links
Germline RANBP2 Missense Variant -> Impaired RANBP2-Dependent Mitochondrial Support
Impaired RANBP2-Dependent Mitochondrial Support -> Symmetric Deep Grey Matter Necrosis
Show evidence (2 references)
PMID:34400285 SUPPORT In Vitro
"Mutated RANBP2 had an attenuated binding ability to COX11. Whether this change indeed decreases ATP production remains to be further explored."
Biochemical support, with the functional consequence unresolved.
PMID:32426208 SUPPORT REVIEW SYNTHESIS Other
"Several features of this condition suggest a metabolic or mitochondrial etiology."
Review summarizing the metabolic/mitochondrial hypothesis.
?

Discussions and Knowledge Gaps

2
Why do most RANBP2 variant carriers never develop ANE, and why does the same carrier escape some infections but not others?
KNOWLEDGE GAP incomplete_penetrance_mechanism
Attached to
inheritance#Autosomal dominant
Neither the infecting agent nor known genetic background explains the incomplete penetrance or the episodic course. A temperature-sensitive misfolding of the variant protein, so that height and duration of fever matter, has been proposed but not tested.
Show evidence (2 references)
PMID:19118815 SUPPORT Human Clinical
"If the amino acid substitutions result in temperature sensitivity, resulting in protein misfolding and alteration of function, variations in the severity and duration of fever could contribute to the reduced penetrance."
The temperature-sensitivity hypothesis for reduced penetrance.
PMID:34059398 SUPPORT Human Clinical
"Thus, he had a genetic background with two susceptibility variants for acute encephalopathy, RANBP2 (frequent in the Caucasians), and CPT2 (frequent in the Japanese)."
A thermolabile CPT2 variant co-occurring with RANBP2 p.Thr585Met is a candidate modifier.
Which genes explain familial or recurrent ANE in families without a RANBP2 variant, and do they act through the same mechanism?
KNOWLEDGE GAP non_ranbp2_familial_ane
Attached to
genetic#RANBP2
About a fifth of tested familial, recurrent or genetic ANE patients carry no RANBP2 variant, so RANBP2 does not account for all familial susceptibility. Such families fall outside this entry until their cause is known.
Show evidence (2 references)
PMID:19643689 SUPPORT Human Clinical
"Mutations in RANBP2 are not the sole susceptibility alleles for familial or recurrent ANE."
A Spanish familial and recurrent ANE family without RANBP2 variants.
PMID:42385467 SUPPORT REVIEW SYNTHESIS Human Clinical
"median onset age 24 months; 62% male; RANBP2 mutations in 81% of tested individuals"
RANBP2 variants in 81% of tested familial, recurrent or genetic ANE patients.
⚙

Pathophysiology

9
Germline RANBP2 Missense Variant
The ANE1 variants are germline heterozygous missense substitutions in RANBP2 (Nup358); the recurrent ones (p.Thr585Met, p.Thr653Ile, p.Ile656Val) cluster in the N-terminal leucine-rich domain. RANBP2 is a large cytoplasmic-filament component of the nuclear pore complex with SUMO E3 ligase, nuclear transport, microtubule and mitochondrial-trafficking functions. The variant does not cause disease by itself; it creates a susceptibility that is expressed only during a febrile infection.
Loss of RANBP2 restraint on viral replication drives hyperinflammation RANBP2-dependent mitochondrial dysfunction and energy failure
RANBP2 hgnc:9848 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RANBP2 (hgnc:9848). hgnc:9848 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context Variant type: single nucleotide variant allele_type: missense variant_origin: GERMLINE zygosity: HETEROZYGOUS
structural constituent of nuclear pore GO:0017056 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves structural constituent of nuclear pore (GO:0017056). GO:0017056 is a molecular function from the Gene Ontology.
nuclear pore GO:0005643 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves nuclear pore (GO:0005643). GO:0005643 is a cellular component from the Gene Ontology.
Downstream
Loss of RANBP2 Nuclear Envelope Localization Loss of RANBP2 restraint on viral replication drives hyperinflammation
Impaired RANBP2-Dependent Mitochondrial Support RANBP2-dependent mitochondrial dysfunction and energy failure
Recurrent encephalopathy The germline variant persists, so each later febrile infection carries a renewed risk of an episode.
Show evidence (1 reference)
PMID:19118815 SUPPORT Human Clinical
"The three mutations identified cluster in the “leucine-rich domain” (LD) that has been described as a domain necessary for localization to the both the nucleus and microtubules."
Location of the three ANE1 variants in the leucine-rich domain.
Loss of RANBP2 Nuclear Envelope Localization
In knock-in human airway cells, RANBP2-T585M is excluded from the nuclear envelope, which phenocopies RANBP2 depletion. This is one proposed molecular consequence of the variant; its relevance to the brain lesions is not established.
Loss of RANBP2 restraint on viral replication drives hyperinflammation
respiratory tract epithelial cell CL:0002368 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves respiratory tract epithelial cell (CL:0002368). CL:0002368 is a cell type from the Cell Ontology.
RANBP2 hgnc:9848 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RANBP2 (hgnc:9848). hgnc:9848 is a gene from the HUGO Gene Nomenclature Committee.
protein localization to nuclear envelope GO:0090435 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein localization to nuclear envelope (GO:0090435). GO:0090435 is a biological process from the Gene Ontology.
nuclear envelope GO:0005635 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves nuclear envelope (GO:0005635). GO:0005635 is a cellular component from the Gene Ontology.
Downstream
Enhanced Influenza Virus Replication Loss of RANBP2 restraint on viral replication drives hyperinflammation
Pro-Inflammatory Cytokine Overproduction Loss of RANBP2 restraint on viral replication drives hyperinflammation
Show evidence (1 reference)
PMID:41651846 SUPPORT In Vitro
"further suggest that ANE1 pathogenesis results from the impaired localisation of RANBP2 at the nuclear envelope"
Authors' interpretation linking mislocalization to ANE1 pathogenesis.
Acute Febrile Viral Illness
A common systemic viral infection, usually respiratory or gastrointestinal, with fever and prodromal symptoms. It is the obligatory environmental trigger: the encephalopathy begins within about 12 hours to 4 days of the first viral symptoms. The virus is not found in the brain.
Loss of RANBP2 restraint on viral replication drives hyperinflammation
Downstream
Fever
Vomiting
Enhanced Influenza Virus Replication Loss of RANBP2 restraint on viral replication drives hyperinflammation
Pro-Inflammatory Cytokine Overproduction
Show evidence (1 reference)
PMID:19118815 SUPPORT BACKGROUND Human Clinical
"previously healthy children develop encephalopathy, seizures, and coma within days after the onset of a common childhood febrile infection, such as influenza A or parainfluenza,3 without evidence of viral infection of the brain or inflammatory cell infiltration"
The trigger is a systemic febrile infection, not CNS infection.
Enhanced Influenza Virus Replication
RANBP2 normally restrains influenza A genome replication and nuclear export of viral RNA. Its depletion or mislocalization favors nuclear import of the viral polymerase subunits and export of viral genomic RNA, raising viral replication in airway epithelial cells.
Loss of RANBP2 restraint on viral replication drives hyperinflammation
respiratory tract epithelial cell CL:0002368 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves respiratory tract epithelial cell (CL:0002368). CL:0002368 is a cell type from the Cell Ontology.
viral genome replication GO:0019079 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased viral genome replication (GO:0019079). GO:0019079 is a biological process from the Gene Ontology.
Downstream
Pro-Inflammatory Cytokine Overproduction Loss of RANBP2 restraint on viral replication drives hyperinflammation
Show evidence (1 reference)
PMID:41651846 SUPPORT In Vitro
"We found that the depletion of RANBP2 in a human airway epithelial cell line increases IAV genomic replication by favouring the import of the viral polymerase subunits, PB1, PB2, and PA, following viral transcription and translation."
RANBP2 depletion increases influenza A replication in airway epithelial cells.
Pro-Inflammatory Cytokine Overproduction
Infected or exposed immune cells produce excess pro-inflammatory cytokines and chemokines. Two non-exclusive routes from RANBP2 have been proposed: loss of RANBP2-mediated restraint on viral replication, and loss of RANBP2-mediated translational repression of IL-6 and TNF-alpha mRNAs. The second is contested, because a RANBP2 construct carrying three ANE variants still represses IL-6 mRNA.
Infection-triggered cytokine storm with blood-brain barrier failure
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
cytokine production involved in inflammatory response GO:0002534 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cytokine production involved in inflammatory response (GO:0002534). GO:0002534 is a biological process from the Gene Ontology. interleukin-6 production GO:0032635 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased interleukin-6 production (GO:0032635). GO:0032635 is a biological process from the Gene Ontology. tumor necrosis factor production GO:0032640 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased tumor necrosis factor production (GO:0032640). GO:0032640 is a biological process from the Gene Ontology.
Downstream
Hypercytokinemia Infection-triggered cytokine storm with blood-brain barrier failure
Show evidence (2 references)
PMID:35485383 SUPPORT REVIEW SYNTHESIS In Vitro
"In more recent work, his group demonstrated that RanBP2/Nup358 inhibits the translation of mRNAs encoding the Interleukin 6 and Tumor Necrosis Factor alpha cytokine proteins."
Meeting report of cell-culture work showing RANBP2 represses IL-6 and TNF-alpha translation.
PMID:35485383 REFUTE REVIEW SYNTHESIS In Vitro
"the Palazzo group noted that a mutant form of RanBP2/Nup358 harboring three of the ANE mutations is still able to downregulate the Interleukin 6 mRNA"
Contradicts loss of IL-6 mRNA repression as the route by which the ANE1 variants cause cytokine excess.
Hypercytokinemia
Serum and CSF IL-6 and TNF-alpha are raised during episodes. This cytokine storm is the prevailing explanation for the encephalopathy and for systemic features such as transaminase elevation and disseminated intravascular coagulation, and is the rationale for immunomodulatory treatment.
Infection-triggered cytokine storm with blood-brain barrier failure
Downstream
Blood-Brain Barrier Disruption Infection-triggered cytokine storm with blood-brain barrier failure
Increased circulating interleukin 6 concentration
Elevated circulating hepatic transaminase concentration Infection-triggered cytokine storm with blood-brain barrier failure
Disseminated intravascular coagulation Infection-triggered cytokine storm with blood-brain barrier failure
Show evidence (2 references)
PMID:19118815 SUPPORT BACKGROUND Human Clinical
"Increased serum and CSF levels of IL-6 and TNF-α have been reported in children with ANE"
Raised IL-6 and TNF-alpha in ANE patients.
PMID:41945878 SUPPORT Human Clinical
"CSF cytokine panels showed elevated IL-6 in 5 patients, with normal serum IL-6 concentrations."
In a pediatric tocilizumab series including RANBP2-related ANE, IL-6 elevation was found in CSF rather than serum, so the cytokine excess can be predominantly intrathecal.
Blood-Brain Barrier Disruption
Cytokine-driven injury to the cerebral microvasculature is thought to open the blood-brain barrier, giving protein-rich vasogenic edema and a raised CSF protein without pleocytosis, followed by petechial hemorrhage. Lesions evolve from edema to petechial hemorrhage to necrosis.
Infection-triggered cytokine storm with blood-brain barrier failure
brain microvascular endothelial cell CL:2000044 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves brain microvascular endothelial cell (CL:2000044). CL:2000044 is a cell type from the Cell Ontology.
Downstream
Symmetric Deep Grey Matter Necrosis Infection-triggered cytokine storm with blood-brain barrier failure
Cerebral edema
Increased CSF protein concentration Infection-triggered cytokine storm with blood-brain barrier failure
Thalamic hemorrhage
Show evidence (2 references)
PMID:32426208 SUPPORT REVIEW SYNTHESIS Other
"findings compatible with vasogenic edema"
Diffusion imaging of ANE lesions is compatible with vasogenic edema.
PMID:9105653 SUPPORT INDIRECT Human Clinical
"Both the gray and white matter are involved, with neuropathological evidence of local breakdown of the blood-brain barrier (dysoria)."
Neuropathology of acute necrotizing encephalopathy of childhood (largely sporadic cases) shows local blood-brain barrier breakdown.
Impaired RANBP2-Dependent Mitochondrial Support
RANBP2 interacts with the cytochrome c oxidase chaperone COX11 and positions mitochondria through kinesin-1, independently of Ran. The symmetric lesion pattern resembles Leigh syndrome and Wernicke encephalopathy, suggesting that a variant-dependent energy failure in vulnerable deep grey matter may contribute during fever. This route is supported only by biochemical and analogical evidence.
RANBP2-dependent mitochondrial dysfunction and energy failure
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
mitochondrion localization GO:0051646 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrion localization (GO:0051646). GO:0051646 is a biological process from the Gene Ontology.
Downstream
Symmetric Deep Grey Matter Necrosis RANBP2-dependent mitochondrial dysfunction and energy failure
Show evidence (4 references)
PMID:19118815 SUPPORT BACKGROUND Human Clinical
"Thus, intracellular trafficking of mitochondria, energy production, and lipid peroxidation are potential targets for RANBP2 mutational effects."
Discovery paper proposes mitochondrial trafficking and energy production as variant targets.
PMID:34400285 SUPPORT BACKGROUND In Vitro
"Autosomal dominant acute necrotizing encephalopathy (ADANE) is caused by missense mutations in the gene encoding Ran-binding protein 2 (RANBP2), a nuclear pore protein regulating mitochondrial localization and function."
Background for the RANBP2-COX11 experiment.
PMID:17069463 SUPPORT In Vitro
"RanBP2 associates in vitro and in vivo and colocalizes with the mitochondrial metallochaperone, Cox11, and the pacemaker of glycolysis, hexokinase type I (HKI) via its leucine-rich domain."
The leucine-rich domain that carries the ANE1 variants binds COX11 and hexokinase I.
+ 1 more reference
Symmetric Deep Grey Matter Necrosis
Bilateral symmetric necrotic lesions of the thalami (characteristically the ventromedial thalami), brainstem tegmentum, putamina, cerebellum, and periventricular white matter, sometimes with hemorrhage. ANE1 adds distinctive synchronous lesions of the mammillary bodies, amygdala, lateral geniculate bodies and claustrum. There is no inflammatory cell infiltration.
thalamus UBERON:0001897 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in thalamus, annotated with dorsal plus ventral thalamus (UBERON:0001897). UBERON:0001897 is an anatomical location from the Uberon multi-species anatomy ontology. brainstem UBERON:0002298 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brainstem (UBERON:0002298). UBERON:0002298 is an anatomical location from the Uberon multi-species anatomy ontology. putamen UBERON:0001874 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in putamen (UBERON:0001874). UBERON:0001874 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Acute necrotizing encephalopathy
Focal T2 hyperintense thalamic lesion
Abnormal brainstem MRI signal intensity
Abnormal putamen morphology
Lethargy
Coma
Seizure
Abnormal pattern of respiration
Intellectual disability
Spastic tetraplegia
Dysarthria
Gait disturbance
Developmental regression
Show evidence (3 references)
PMID:37090838 SUPPORT Human Clinical
"Brain magnetic resonance imaging (MRI) shows multiple symmetrical lesions affecting primarily the thalami but also brain stem, putamina, periventricular white matter, and cerebellum."
Distribution of the symmetric lesions.
PMID:34593382 SUPPORT Human Clinical
"The setting of synchronous bilateral mammillary, amygdaloid, and lateral geniculate lesions, along with claustro-parahippocampal lesions, can serve as a diagnostic tool in this condition."
Lesion pattern specific to RANBP2-associated ANE in a four-patient series.
ORPHA:88619 SUPPORT Other
"Familial acute necrotizing encephalopathy or ADANE is a potentially fatal neurological disease characterised by neuropathological lesions principally involving the brainstem, thalamus and putamen."
Orphanet definition.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Familial Acute Necrotizing Encephalopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

23
Blood 1
Disseminated intravascular coagulation HP:0005521 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Disseminated intravascular coagulation (HP:0005521). HP:0005521 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32426208 SUPPORT REVIEW SYNTHESIS Other
"12% with findings suggestive of disseminated intravascular coagulation (DIC)"
DIC in a pooled ANE series (sporadic and genetic not separated, so no frequency recorded).
Digestive 1
Vomiting FREQUENT HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013). HP:0002013 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:88619 SUPPORT Other
"HP:0002013 | Vomiting | Frequent (79-30%)"
Orphanet phenotype frequency.
PMID:25170550 SUPPORT Human Clinical
"A 28-month-old infant presented with fever, vomiting and encephalopathy."
Vomiting at presentation of an ANE1 episode.
Immune 1
Increased circulating interleukin 6 concentration HP:0030783 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased interleukin 6 concentration, annotated with Increased circulating interleukin 6 concentration (HP:0030783). HP:0030783 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19118815 SUPPORT BACKGROUND Human Clinical
"Increased serum and CSF levels of IL-6 and TNF-α have been reported in children with ANE"
Raised IL-6 reported in ANE.
Metabolism 4
Fever FREQUENT HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:88619 SUPPORT Other
"HP:0001945 | Fever | Frequent (79-30%)"
Orphanet phenotype frequency.
PMID:37090838 SUPPORT BACKGROUND Human Clinical
"Acute necrotizing encephalopathy (ANE) is clinically characterized by fever, acute alteration of consciousness, seizures, and rapid progression to coma within days of onset of a viral illness"
Fever is part of the presentation.
Cerebral edema FREQUENT HP:0002181 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral edema (HP:0002181), qualified as temporality acute. HP:0002181 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (2 references)
ORPHA:88619 SUPPORT Other
"HP:0002181 | Cerebral edema | Frequent (79-30%)"
Orphanet phenotype frequency.
PMID:42407393 SUPPORT Human Clinical
"presenting with influenza A-associated encephalopathy and a magnetic resonance imaging showing diffuse brain edema"
Diffuse brain edema in a fatal sibling case.
Increased CSF protein concentration VERY_FREQUENT HP:0002922 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased CSF protein without pleocytosis, annotated with Increased CSF protein concentration (HP:0002922). HP:0002922 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25522933 SUPPORT REVIEW SYNTHESIS Human Clinical
"High CSF protein (>0.45 g/l) was reported in 44/47 (94%) in absence CSF pleocytosis"
94% of reported ANE1 patients, VERY_FREQUENT.
ORPHA:88619 SUPPORT Other
"HP:0002922 | Increased CSF protein concentration | Very frequent (99-80%)"
Orphanet phenotype frequency.
Elevated circulating hepatic transaminase concentration HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated transaminases, annotated with Elevated circulating hepatic transaminase concentration (HP:0002910). HP:0002910 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32426208 SUPPORT REVIEW SYNTHESIS Other
"In patients with liver dysfunction, transaminitis is seen in the absence of hyperammonemia"
Transaminitis without hyperammonemia in ANE.
PMID:32426208 SUPPORT REVIEW SYNTHESIS Other
"Poor prognostic factors include age of presentation <1-year-old, symptoms of delirium associated with brainstem lesions, hemorrhage and tissue loss on MRI, and degree of elevation of aminotransferases and CSF protein"
Aminotransferase elevation as a prognostic factor.
Musculoskeletal 1
Spastic tetraplegia FREQUENT HP:0002510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spastic tetraplegia (HP:0002510). HP:0002510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:88619 SUPPORT Other
"HP:0002510 | Spastic tetraplegia | Frequent (79-30%)"
Orphanet phenotype frequency.
Nervous System 14
Acute necrotizing encephalopathy VERY_FREQUENT HP:0006965 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acute necrotizing encephalopathy (HP:0006965), qualified as temporality acute. HP:0006965 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (3 references)
ORPHA:88619 SUPPORT Other
"HP:0006846 | Acute encephalopathy | Very frequent (99-80%)"
Orphanet records acute encephalopathy as very frequent.
PMID:25473726 SUPPORT REVIEW SYNTHESIS Other
"Infection-induced acute encephalopathy 3 (IIAE3) is the susceptibility to recurrent acute necrotizing encephalopathy (ANE) caused by a heterozygous pathogenic variant in RANBP2."
ANE is the defining manifestation.
PMID:25473726 SUPPORT REVIEW SYNTHESIS Other
"Although most IIAE3 occurs before age six years, first episodes have been observed in teenagers and adults."
Age at first episode.
Recurrent encephalopathy FREQUENT HP:0007335 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent acute necrotizing encephalopathy, annotated with Recurrent encephalopathy (HP:0007335), qualified as temporality recurrent. HP:0007335 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (2 references)
PMID:25473726 SUPPORT REVIEW SYNTHESIS Other
"Fifty per cent of persons with IIAE3 will have at least one repeat episode and some will have multiple repeat episodes"
About 50% recurrence, mapped to FREQUENT.
PMID:19118815 SUPPORT Human Clinical
"Penetrance was estimated at 40% and recurrent episodes occurred in half of the affected individuals."
Recurrence in half of affected individuals in the index kindred.
Lethargy HP:0001254 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lethargy (HP:0001254), qualified as temporality acute. HP:0001254 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:25473726 SUPPORT REVIEW SYNTHESIS Other
"The most common sign of ANE is lethargy that progresses to coma (which may last for weeks) and seizures (in 50%)."
Lethargy as the most common sign.
Coma VERY_FREQUENT HP:0001259 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coma (HP:0001259), qualified as temporality acute. HP:0001259 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (2 references)
ORPHA:88619 SUPPORT Other
"HP:0001259 | Coma | Very frequent (99-80%)"
Orphanet phenotype frequency.
PMID:25473726 SUPPORT REVIEW SYNTHESIS Other
"The most common sign of ANE is lethargy that progresses to coma (which may last for weeks) and seizures (in 50%)."
Progression to prolonged coma.
Seizure FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250), qualified as temporality acute. HP:0001250 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (2 references)
PMID:25473726 SUPPORT REVIEW SYNTHESIS Other
"The most common sign of ANE is lethargy that progresses to coma (which may last for weeks) and seizures (in 50%)."
Seizures in 50%, mapped to FREQUENT.
ORPHA:88619 SUPPORT Other
"HP:0001250 | Seizure | Frequent (79-30%)"
Orphanet phenotype frequency.
Focal T2 hyperintense thalamic lesion FREQUENT HP:0012692 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral symmetric thalamic T2 hyperintense lesions, annotated with Focal T2 hyperintense thalamic lesion (HP:0012692). HP:0012692 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25522933 SUPPORT REVIEW SYNTHESIS Human Clinical
"bilateral thalamic involvement was seen in 77% of patients"
Pooled literature frequency of bilateral thalamic lesions in ANE1 (77%, FREQUENT).
PMID:40868426 SUPPORT Human Clinical
"MRI of the brain demonstrated symmetrical high T2/FLAIR signal changes in the lateral geniculate bodies, claustrum, ventromedial thalami, subthalamic nuclei, mamillary bodies, and brainstem"
T2/FLAIR hyperintense symmetric thalamic lesions in a genetically confirmed case.
Abnormal brainstem MRI signal intensity FREQUENT HP:0012747 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Symmetric brainstem lesions, annotated with Abnormal brainstem MRI signal intensity (HP:0012747). HP:0012747 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:88619 SUPPORT Other
"HP:0012747 | Abnormal brainstem MRI signal intensity | Frequent (79-30%)"
Orphanet phenotype frequency.
PMID:26923722 SUPPORT BACKGROUND Human Clinical
"The hallmarks of ANE are the neuroradiological findings of multiple symmetric lesions in the thalami, midbrain, pons and brainstem."
Brainstem lesions are part of the hallmark imaging.
Abnormal putamen morphology FREQUENT HP:0031982 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Symmetric putaminal lesions, annotated with Abnormal putamen morphology (HP:0031982). HP:0031982 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:88619 SUPPORT Other
"HP:0031982 | Abnormal putamen morphology | Frequent (79-30%)"
Orphanet phenotype frequency.
Thalamic hemorrhage HP:0025064 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thalamic hemorrhage (HP:0025064). HP:0025064 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35108406 SUPPORT Human Clinical
"Patients with influenza had a higher degree of thalamic hemorrhage"
Thalamic hemorrhage in an ANE cohort that included RANBP2-positive patients.
Intellectual disability FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:88619 SUPPORT Other
"HP:0001249 | Intellectual disability | Frequent (79-30%)"
Orphanet phenotype frequency.
Developmental regression FREQUENT HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:88619 SUPPORT Other
"HP:0002376 | Developmental regression | Frequent (79-30%)"
Orphanet phenotype frequency.
Dysarthria FREQUENT HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:88619 SUPPORT Other
"HP:0001260 | Dysarthria | Frequent (79-30%)"
Orphanet phenotype frequency.
Gait disturbance FREQUENT HP:0001288 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gait disturbance (HP:0001288). HP:0001288 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:88619 SUPPORT Other
"HP:0001288 | Gait disturbance | Frequent (79-30%)"
Orphanet phenotype frequency.
Polyneuropathy HP:0001271 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral polyneuropathy, annotated with Polyneuropathy (HP:0001271). HP:0001271 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19811512 SUPPORT Human Clinical
"Interestingly, there was evidence of peripheral polyneuropathy during the recent episode, which has not previously been described in sporadic ANE."
Polyneuropathy in a RANBP2 carrier during a recurrent episode.
Respiratory 1
Abnormal pattern of respiration FREQUENT HP:0002793 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal pattern of respiration (HP:0002793). HP:0002793 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:88619 SUPPORT Other
"HP:0002793 | Abnormal pattern of respiration | Frequent (79-30%)"
Orphanet phenotype frequency.
🧬

Genetic Associations

1
RANBP2 (Heterozygous missense variants in the RANBP2 leucine-rich N-terminal domain)
Gene: RANBP2 hgnc:9848 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RANBP2 (hgnc:9848). hgnc:9848 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (3 references)
PMID:19118815 SUPPORT Human Clinical
"Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families."
Recurrent, independently arising p.Thr585Met across familial and recurrent ANE kindreds.
PMID:19118815 SUPPORT Human Clinical
"None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls."
The variants are specific to familial or recurrent ANE.
ORPHA:88619 SUPPORT Other
"RANBP2 | RAN binding protein 2 | hgnc:9848 | Disease-causing germline mutation(s) in"
Orphanet gene-disease row.
Variants (5)
RANBP2 p.Thr585Met Pathogenic
Gene: RANBP2 hgnc:9848 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in RANBP2 (hgnc:9848). hgnc:9848 is a gene from the HUGO Gene Nomenclature Committee.
Recurrent heterozygous missense variant, c.1880C>T (c.1754C>T on an alternative transcript numbering), found in most ANE1 families.
Show evidence (2 references)
PMID:19118815 SUPPORT Human Clinical
"all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C-->T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2)"
Identification of p.Thr585Met in the index kindred.
PMID:37090838 SUPPORT Human Clinical
"Sequencing revealed heterozygous c.1754C > T variant in RANBP2 (p.Thr585Met) in affected and asymptomatic family members."
The same variant reported under the alternative c.1754C>T numbering.
RANBP2 p.Thr653Ile
Gene: RANBP2 hgnc:9848 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in RANBP2 (hgnc:9848). hgnc:9848 is a gene from the HUGO Gene Nomenclature Committee.
Heterozygous missense variant (c.2085C>T) at a conserved leucine-rich-domain residue.
Show evidence (2 references)
PMID:19118815 SUPPORT Human Clinical
"were heterozygous for other missense mutations in RANBP2 (either c.2085C→T; p.Thr653Ile or c.2094A→G; p.Ile656Val)"
p.Thr653Ile in a familial ANE kindred without p.Thr585Met.
PMID:25170550 SUPPORT Human Clinical
"the second report of a T653I mutation in the RANBP2 gene described in relation to ANE1"
A second family with p.Thr653Ile and H1N1-triggered recurrent ANE.
RANBP2 p.Ile656Val
Gene: RANBP2 hgnc:9848 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in RANBP2 (hgnc:9848). hgnc:9848 is a gene from the HUGO Gene Nomenclature Committee.
Heterozygous missense variant (c.2094A>G) at a conserved leucine-rich-domain residue.
Show evidence (1 reference)
PMID:19118815 SUPPORT Human Clinical
"were heterozygous for other missense mutations in RANBP2 (either c.2085C→T; p.Thr653Ile or c.2094A→G; p.Ile656Val)"
p.Ile656Val in a familial ANE kindred without p.Thr585Met.
RANBP2 p.Trp681Cys
Gene: RANBP2 hgnc:9848 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in RANBP2 (hgnc:9848). hgnc:9848 is a gene from the HUGO Gene Nomenclature Committee.
De novo heterozygous missense variant reported in an infant with recurrent ANE.
Show evidence (1 reference)
PMID:26923722 SUPPORT Human Clinical
"In the other patient we observed a novel de novo missense mutation p.Trp681Cys in the RANBP2 gene causing recurrent ANE."
De novo p.Trp681Cys with recurrent ANE.
RANBP2 p.Glu3014Gly
Gene: RANBP2 hgnc:9848 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in RANBP2 (hgnc:9848). hgnc:9848 is a gene from the HUGO Gene Nomenclature Committee.
Heterozygous missense variant (c.9041A>G) reported in a four-generation Chinese ANE1 family; it lies outside the leucine-rich domain where the other recurrent variants cluster.
Show evidence (1 reference)
PMID:35348941 SUPPORT Human Clinical
"A novel missense variation, c.9041A > G, p.(Glu3014Gly) in RANBP2 was identified in this family."
Variant identified in a multigenerational ANE1 family.
💊

Medical Actions

9
High-dose corticosteroids during an episode
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: methylprednisolone CHEBI:6888 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses methylprednisolone, annotated with 6alpha-methylprednisolone (CHEBI:6888). CHEBI:6888 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Early high-dose corticosteroids (usually intravenous methylprednisolone) are the most widely used acute treatment, given to damp the inflammatory response. Benefit is supported by observational data in ANE, not by ANE1-specific trials, and patients have also recovered without specific treatment.
Mechanism Target:
INHIBITS Hypercytokinemia — Corticosteroids are used to suppress the cytokine storm.
Show evidence (1 reference)
PMID:32426208 SUPPORT REVIEW SYNTHESIS Other
"Early treatment with steroids has been associated with improved outcomes, thought to be secondary to treating cytokine storm and metabolic dysfunction by decreasing inflammation"
Rationale for steroid benefit via the cytokine storm.
Show evidence (2 references)
PMID:32426208 SUPPORT REVIEW SYNTHESIS Other
"Early treatment with high dose steroids is associated with a more favorable outcome, however the diagnosis is often overlooked resulting in delayed treatment."
Narrative review of ANE1 associating early high-dose steroids with better outcome.
PMID:25473726 SUPPORT REVIEW SYNTHESIS Other
"Treatment is aimed at reducing the inflammatory state by administration of corticosteroids during an acute episode of encephalopathy (not supported by data from IIAE-3-specific studies)"
Expert review notes steroids are used without ANE1-specific data.
Prophylactic pulse corticosteroids during febrile infections
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: corticosteroid CHEBI:50858 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses corticosteroid (CHEBI:50858). CHEBI:50858 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
In known carriers, pulse steroids at the onset of influenza or other febrile infection have been used to try to prevent further episodes. The evidence is a single family series.
Mechanism Target:
INHIBITS Hypercytokinemia — Intended to blunt the inflammatory response before encephalopathy develops.
Show evidence (1 reference)
PMID:42407393 SUPPORT Human Clinical
"The surviving cases were given a preventive treatment plan with pulse steroids during influenza infections. At 2 years of follow-up, they still have no new episodes of encephalopathy."
No recurrence over 2 years in two siblings on preventive pulse steroids.
Intravenous immunoglobulin
Action: Immunoglobulin TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Immunoglobulin Therapy (NCIT:C62710). NCIT:C62710 is a clinical intervention from the NCI Thesaurus. NCIT:C62710
Agent: human immunoglobulin G NCIT:C80829 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses human immunoglobulin G (NCIT:C80829). NCIT:C80829 is a therapeutic agent from the NCI Thesaurus.
Platform: Other
IVIG is used during acute episodes alongside steroids, and monthly IVIG has been tried after recurrent episodes. Evidence is anecdotal.
Show evidence (2 references)
PMID:21945312 SUPPORT Human Clinical
"During the acute encephalopathy episodes he was treated with steroids and immunoglobulin."
Acute IVIG use in an ANE1 patient.
PMID:21945312 SUPPORT Human Clinical
"Thirty days after the last episode he started monthly intravenous immunoglobulin that might be used for prevention of viral infections."
Monthly IVIG as attempted prophylaxis.
Tocilizumab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: tocilizumab NCIT:C84217 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses tocilizumab (NCIT:C84217). NCIT:C84217 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
IL-6 receptor blockade has been given with corticosteroids in severe episodes, with reported benefit in a handful of patients.
Mechanism Target:
INHIBITS Hypercytokinemia — Blocks IL-6 receptor signalling.
Show evidence (1 reference)
PMID:41945878 SUPPORT Human Clinical
"Outcomes included rapid intracranial pressure reduction, recovery in relapsing optic neuritis and myelitis, and improvement in RANBP2-related acute necrotizing encephalopathy."
Improvement after IV tocilizumab in a RANBP2-related ANE patient.
Show evidence (1 reference)
PMID:32426208 SUPPORT REVIEW SYNTHESIS Other
"with only one pediatric case series being reported to have benefit from the use of tocilizumab when administered with corticosteroids"
Limited case-series support.
Plasmapheresis
Action: PlasmapheresisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Plasmapheresis (NCIT:C15304). NCIT:C15304 is a clinical intervention from the NCI Thesaurus. NCIT:C15304
Platform: Other
Used in some acute episodes, with limited reported effect.
Show evidence (1 reference)
PMID:25473726 SUPPORT REVIEW SYNTHESIS Other
"as well as IVIg, plasmapheresis, and TNFα antagonists with varied, but overall limited, therapeutic effects"
Plasmapheresis among adjunct immunotherapies of limited effect.
Supportive intensive care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Episodes are managed in intensive care, with support for coma, seizures, raised intracranial pressure and systemic complications, alongside immunomodulation.
Show evidence (2 references)
PMID:34593382 SUPPORT Human Clinical
"All our patients were treated in the intensive care unit during all their attacks."
Intensive care for every attack in a four-patient RANBP2-positive series.
PMID:40868426 SUPPORT Human Clinical
"With immunosuppressive and supportive treatment, the patient fully recovered and was discharged after 10 days in the hospital with no residual symptoms."
Supportive treatment with immunosuppression in a genetically confirmed ANE1 case.
Routine and annual influenza vaccination
Action: VaccinationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Vaccination (NCIT:C15346). NCIT:C15346 is a clinical intervention from the NCI Thesaurus. NCIT:C15346
Platform: Vaccine
Routine immunizations and yearly influenza vaccination are recommended to reduce exposure to the commonest trigger. No vaccine-triggered episode has been documented.
Mechanism Target:
INHIBITS Acute Febrile Viral Illness — Prevents the influenza infections that trigger most episodes.
Show evidence (3 references)
PMID:25473726 SUPPORT REVIEW SYNTHESIS Other
"Routine vaccinations and yearly influenza vaccinations are recommended, although there are theoretic concerns for live influenza and cellular pertussis preparations."
Vaccination recommendation, with caution about live influenza and whole-cell pertussis vaccines.
PMID:42385467 SUPPORT REVIEW SYNTHESIS Human Clinical
"Routine immunization was documented in 18/19 patients pre-ANE and 5/20 resumed vaccination post-ANE (no vaccine-related relapses over a median follow-up of 19 months)."
Systematic review finding no vaccine-related relapses.
PMID:25473726 SUPPORT REVIEW SYNTHESIS Other
"Based on a single case report of ANE in one individual (not known to have a RANBP2 pathogenic variant), avoidance of cellular pertussis in DTaP immunization is recommended."
Agent to avoid listed by GeneReviews; acellular pertussis vaccine is preferred.
Infection avoidance and hand hygiene
Platform: Behavioral / lifestyle
Carriers are advised to avoid contact with people who have an infectious illness and to follow strict hand-washing precautions, to reduce exposure to triggering infections.
Mechanism Target:
INHIBITS Acute Febrile Viral Illness — Reduces exposure to the triggering infection.
Show evidence (1 reference)
PMID:25473726 SUPPORT REVIEW SYNTHESIS Other
"Avoid individuals who are ill with an infectious disease and adhere to strict precautions regarding hand washing."
GeneReviews agents/circumstances-to-avoid recommendation.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Each child of a carrier has a 50% chance of inheriting the variant; penetrance is incomplete and the variant can arise de novo.
Show evidence (1 reference)
PMID:25473726 SUPPORT REVIEW SYNTHESIS Other
"Each child of an individual with susceptibility to IIAE3 has a 50% chance of inheriting the pathogenic variant."
Recurrence risk for offspring.
🌍

Environmental Factors

2
Influenza A virus infection
exposure to Influenza A virus ECTO:3000107 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to Influenza A virus (ECTO:3000107). ECTO:3000107 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Influenza A, including H1N1, is the trigger most often identified for ANE1 episodes, including recurrences in the same individual.
Show evidence (2 references)
PMID:19811512 SUPPORT Human Clinical
"influenza A was identified on bronchoalveolar lavage during this episode"
Influenza A documented during a recurrent ANE episode in a RANBP2 carrier.
PMID:25170550 SUPPORT Human Clinical
"We believe that this is the first description implicating the H1N1 viral strain as a trigger"
H1N1 influenza A triggered ANE1 in a family with p.Thr653Ile.
Mechanism Target:
TRIGGERS Acute Febrile Viral Illness — Influenza A infection is the febrile illness that precipitates an encephalopathy episode in a carrier.
Show evidence (1 reference)
PMID:41651846 SUPPORT BACKGROUND In Vitro
"Heterozygous dominant mutations in the nucleoporin RANBP2/Nup358 predispose to influenza-triggered ANE1."
Influenza infection as the trigger acting on the RANBP2-predisposed host.
Other febrile viral infections
exposure to virus ECTO:3000001 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to virus (ECTO:3000001). ECTO:3000001 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Influenza B, parainfluenza, human herpesvirus 6, coxsackievirus and other enteroviruses, and SARS-CoV-2 have also preceded ANE1 episodes.
Show evidence (2 references)
PMID:25473726 SUPPORT REVIEW SYNTHESIS Other
"ANE refers to the specific neurologic presentation in which bilateral symmetric thalamic, midbrain, and/or hindbrain lesions occur within days following the onset of an acute viral illness caused by influenza A, influenza B, parainfluenza II, human herpes virus 6, coxsackie virus, or an enterovirus."
Range of viral triggers recorded in the expert review.
PMID:38091492 SUPPORT Human Clinical
"Both SARS-CoV-2 and RANBP2 mutations are responsible for the manifestation of a hyper-inflammatory response that invades the central nervous system"
SARS-CoV-2 as a trigger of ANE in a child carrying a RANBP2 variant.
Mechanism Target:
TRIGGERS Acute Febrile Viral Illness — Any of several common viral infections can provide the febrile trigger.
Show evidence (1 reference)
PMID:25473726 SUPPORT REVIEW SYNTHESIS Other
"ANE begins within 12 hours to three or four days of the first awareness of viral symptoms (fever, cough, rhinorrhea, vomiting, diarrhea, and malaise)."
Encephalopathy follows the onset of the viral illness within hours to days.
🔬

Diagnosis

3
Brain MRI
MRI showing bilateral symmetric thalamic lesions with brainstem, putaminal and white matter involvement after a febrile illness establishes ANE; the synchronous mammillary, amygdala and lateral geniculate pattern suggests ANE1.
Magnetic Resonance Imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:40868426 SUPPORT Human Clinical
"Recognition of the characteristic MRI findings in ANE1 can facilitate a timely diagnosis and enhance the clinical management of the patient and their relatives, especially given the high risk of disease recurrence."
MRI pattern as the diagnostic entry point.
RANBP2 molecular genetic testing
Identification of a heterozygous pathogenic RANBP2 variant confirms the diagnosis in a person with typical clinical and MRI findings. Testing of at-risk first-degree relatives allows early recognition of an episode.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:25473726 SUPPORT REVIEW SYNTHESIS Other
"IIAE3 is suspected in individuals with typical clinical and MRI findings, and is confirmed in those with a heterozygous pathogenic variant in RANBP2."
Diagnostic confirmation by RANBP2 testing.
PMID:25473726 SUPPORT REVIEW SYNTHESIS Other
"In a family with IIAE3, molecular genetic testing of at-risk first-degree relatives, especially children, is warranted so that those who have inherited the RANBP2 pathogenic variant can benefit from prompt intervention in the early stages of ANE."
Cascade testing of relatives.
Cerebrospinal fluid analysis
Lumbar puncture shows raised protein without pleocytosis and helps exclude infectious encephalitis.
Lumbar Puncture NCIT:C15327 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:25522933 SUPPORT REVIEW SYNTHESIS Human Clinical
"High CSF protein (>0.45 g/l) was reported in 44/47 (94%) in absence CSF pleocytosis"
Characteristic CSF finding.
📊

Prevalence

2
Worldwide
Point Prevalence <1 in 1,000,000
Orphanet worldwide point-prevalence class <1 / 1 000 000.
Show evidence (1 reference)
ORPHA:88619 SUPPORT Other
"<1 / 1 000 000 | Worldwide | Point prevalence | PMID:12874403,PMID:19118815,PMID:21205700"
Orphanet epidemiology row for familial acute necrotizing encephalopathy.
East Asia
Unknown Rare
Sporadic ANE is most often reported in East Asian children, but the RANBP2-associated form is very rare there; the first Japanese ANE1 case was reported in 2021.
Show evidence (1 reference)
PMID:34059398 SUPPORT BACKGROUND Human Clinical
"Although sporadic ANE predominantly affects Asian children, ANE1 is very rare in east Asia."
Contrast between sporadic ANE and ANE1 distribution in East Asia.
{ }

Source YAML

click to show 
name: Familial Acute Necrotizing Encephalopathy
creation_date: "2026-10-15T01:37:42Z"
category: Mendelian
synonyms:
- ANE1
- acute necrotizing encephalopathy type 1
- ADANE
- autosomal dominant acute necrotizing encephalopathy
- recurrent acute necrotizing encephalopathy
- infection-induced acute encephalopathy 3
- IIAE3
- susceptibility to infection-induced acute encephalopathy 3
- RANBP2-associated acute necrotizing encephalopathy
description: >-
  Familial acute necrotizing encephalopathy (ANE1) is an autosomal dominant,
  incompletely penetrant susceptibility to acute necrotizing encephalopathy
  caused by heterozygous missense variants in the nuclear pore gene RANBP2,
  most often p.Thr585Met. In a carrier, a common febrile viral illness
  (influenza A in particular, but also influenza B, parainfluenza, human
  herpesvirus 6, enteroviruses and SARS-CoV-2) is followed within hours to a
  few days by rapidly progressive encephalopathy with lethargy, seizures and
  coma, and by bilateral symmetric necrotic lesions of the thalami, brainstem,
  putamina and other deep grey and white matter structures, without direct
  viral invasion of the brain. Raised interleukin-6 and TNF-alpha and raised
  CSF protein without pleocytosis point to a host hyperinflammatory response
  as the proximate cause, but how the RANBP2 variants produce it is unsettled.
  About a third of affected individuals die in the acute phase, half of
  survivors have permanent neurologic deficits, and recurrent episodes occur
  in about half of affected individuals, which distinguishes ANE1 from the
  usual sporadic, non-recurrent form of ANE. Median age at first episode is
  about two years, but first episodes also occur in adolescents and adults.
disease_term:
  preferred_term: familial acute necrotizing encephalopathy
  term:
    id: MONDO:0011953
    label: familial acute necrotizing encephalopathy
parents:
- Acute Infection-Induced Encephalopathy
- Mendelian Encephalopathy
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  penetrance_percentage: "40"
  expressivity: VARIABLE
  description: >-
    A single heterozygous RANBP2 missense variant confers susceptibility. The
    variant is often inherited from an unaffected or mildly affected parent
    because penetrance is incomplete (estimated at 40% in the index kindred),
    and it can also arise de novo. Outcome varies widely within families
    carrying the same variant.
  evidence:
  - reference: PMID:19118815
    reference_title: "Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait"
    explanation: >-
      Linkage and segregation in the index kindred establish autosomal
      dominant inheritance with incomplete penetrance.
  - reference: PMID:19118815
    reference_title: "Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Penetrance was estimated at 40% and recurrent episodes occurred in half of the affected individuals."
    explanation: Source of the 40% penetrance estimate.
  - reference: PMID:37090838
    reference_title: "Variable Presentation and Reduced Penetrance in Autosomal Dominant Acute Necrotizing Encephalopathy Related to RANBP2 Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our report reinforces incomplete penetrance of ADANE and intrafamilial phenotypic variability of outcome."
    explanation: >-
      Two further families with p.Thr585Met carried by affected and
      asymptomatic members, with variable outcome within each family.
  - reference: PMID:25473726
    reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Susceptibility to IIAE3 is inherited in an autosomal dominant manner."
    explanation: Expert-review statement of the mode of inheritance.
- name: Incomplete penetrance
  inheritance_term:
    preferred_term: Typified by incomplete penetrance
    term:
      id: HP:0003829
      label: Typified by incomplete penetrance
  description: >-
    Many obligate carriers never have an episode, and an affected child's
    carrier parent is frequently unaffected.
  evidence:
  - reference: PMID:25473726
    reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "To date the majority of individuals diagnosed with IIAE3 have a parent who is heterozygous for a RANBP2 pathogenic variant; however, due to reduced penetrance, the parent may not have manifested the disease state."
    explanation: Reduced penetrance explains unaffected carrier parents.
  - reference: PMID:25522933
    reference_title: "RANBP2 mutation and acute necrotizing encephalopathy: 2 cases and a literature review of the expanding clinico-radiological phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "ANE1 is inherited as autosomal dominant, but shows incomplete penetrance."
    explanation: Literature review of reported ANE1 patients restating incomplete penetrance.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: Orphanet worldwide point-prevalence class <1 / 1 000 000.
  evidence:
  - reference: ORPHA:88619
    reference_title: "Familial acute necrotizing encephalopathy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:12874403,PMID:19118815,PMID:21205700"
    explanation: Orphanet epidemiology row for familial acute necrotizing encephalopathy.
- population: East Asia
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    Sporadic ANE is most often reported in East Asian children, but the
    RANBP2-associated form is very rare there; the first Japanese ANE1 case
    was reported in 2021.
  evidence:
  - reference: PMID:34059398
    reference_title: "Recurrent acute necrotizing encephalopathy in a boy with RANBP2 mutation and thermolabile CPT2 variant: The first case of ANE1 in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Although sporadic ANE predominantly affects Asian children, ANE1 is very rare in east Asia."
    explanation: Contrast between sporadic ANE and ANE1 distribution in East Asia.
genetic:
- name: RANBP2
  gene_term:
    preferred_term: RANBP2
    term:
      id: hgnc:9848
      label: RANBP2
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  association: Heterozygous missense variants in the RANBP2 leucine-rich N-terminal domain
  features: >-
    The recurrent p.Thr585Met variant (c.1880C>T, also reported as c.1754C>T
    on a shorter transcript) accounts for most families, has arisen
    independently and de novo several times, and is absent from controls.
    p.Thr653Ile and p.Ile656Val alter conserved residues in the same
    leucine-rich domain. A biallelic p.Thr585Met case has been reported. The
    variants are not found in isolated (sporadic, non-recurrent) ANE.
  gene_disease_validity:
  - validity_classification: MODERATE
    classified_by: CLINGEN
    external_id: CGGV:assertion_7e375774-fce0-48a2-b83d-c7814c9de23f-2024-04-02T160000.000Z
    evidence:
    - reference: CGGV:assertion_7e375774-fce0-48a2-b83d-c7814c9de23f-2024-04-02T160000.000Z
      reference_title: "RANBP2 / familial acute necrotizing encephalopathy (Moderate)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "RANBP2 | HGNC:9848 | familial acute necrotizing encephalopathy | MONDO:0011953 | AD | Moderate"
      explanation: ClinGen Epilepsy GCEP classifies RANBP2 in familial ANE as Moderate, autosomal dominant.
  evidence:
  - reference: PMID:19118815
    reference_title: "Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families."
    explanation: Recurrent, independently arising p.Thr585Met across familial and recurrent ANE kindreds.
  - reference: PMID:19118815
    reference_title: "Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls."
    explanation: The variants are specific to familial or recurrent ANE.
  - reference: ORPHA:88619
    reference_title: "Familial acute necrotizing encephalopathy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RANBP2 | RAN binding protein 2 | hgnc:9848 | Disease-causing germline mutation(s) in"
    explanation: Orphanet gene-disease row.
  variants:
  - name: RANBP2 p.Thr585Met
    description: >-
      Recurrent heterozygous missense variant, c.1880C>T (c.1754C>T on an
      alternative transcript numbering), found in most ANE1 families.
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: RANBP2
      term:
        id: hgnc:9848
        label: RANBP2
    evidence:
    - reference: PMID:19118815
      reference_title: "Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C-->T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2)"
      explanation: Identification of p.Thr585Met in the index kindred.
    - reference: PMID:37090838
      reference_title: "Variable Presentation and Reduced Penetrance in Autosomal Dominant Acute Necrotizing Encephalopathy Related to RANBP2 Variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sequencing revealed heterozygous c.1754C > T variant in RANBP2 (p.Thr585Met) in affected and asymptomatic family members."
      explanation: The same variant reported under the alternative c.1754C>T numbering.
  - name: RANBP2 p.Thr653Ile
    description: Heterozygous missense variant (c.2085C>T) at a conserved leucine-rich-domain residue.
    gene:
      preferred_term: RANBP2
      term:
        id: hgnc:9848
        label: RANBP2
    evidence:
    - reference: PMID:19118815
      reference_title: "Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "were heterozygous for other missense mutations in RANBP2 (either c.2085C→T; p.Thr653Ile or c.2094A→G; p.Ile656Val)"
      explanation: p.Thr653Ile in a familial ANE kindred without p.Thr585Met.
    - reference: PMID:25170550
      reference_title: "H1N1 triggered recurrent acute necrotizing encephalopathy in a family with a T653I mutation in the RANBP2 gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the second report of a T653I mutation in the RANBP2 gene described in relation to ANE1"
      explanation: A second family with p.Thr653Ile and H1N1-triggered recurrent ANE.
  - name: RANBP2 p.Ile656Val
    description: Heterozygous missense variant (c.2094A>G) at a conserved leucine-rich-domain residue.
    gene:
      preferred_term: RANBP2
      term:
        id: hgnc:9848
        label: RANBP2
    evidence:
    - reference: PMID:19118815
      reference_title: "Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "were heterozygous for other missense mutations in RANBP2 (either c.2085C→T; p.Thr653Ile or c.2094A→G; p.Ile656Val)"
      explanation: p.Ile656Val in a familial ANE kindred without p.Thr585Met.
  - name: RANBP2 p.Trp681Cys
    description: De novo heterozygous missense variant reported in an infant with recurrent ANE.
    gene:
      preferred_term: RANBP2
      term:
        id: hgnc:9848
        label: RANBP2
    evidence:
    - reference: PMID:26923722
      reference_title: "Variable clinical course in acute necrotizing encephalopathy and identification of a novel RANBP2 mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In the other patient we observed a novel de novo missense mutation p.Trp681Cys in the RANBP2 gene causing recurrent ANE."
      explanation: De novo p.Trp681Cys with recurrent ANE.
  - name: RANBP2 p.Glu3014Gly
    description: >-
      Heterozygous missense variant (c.9041A>G) reported in a four-generation
      Chinese ANE1 family; it lies outside the leucine-rich domain where the
      other recurrent variants cluster.
    gene:
      preferred_term: RANBP2
      term:
        id: hgnc:9848
        label: RANBP2
    evidence:
    - reference: PMID:35348941
      reference_title: "A novel variation in RANBP2 associated with infection-triggered familial acute necrotizing encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A novel missense variation, c.9041A > G, p.(Glu3014Gly) in RANBP2 was identified in this family."
      explanation: Variant identified in a multigenerational ANE1 family.
environmental:
- name: Influenza A virus infection
  description: >-
    Influenza A, including H1N1, is the trigger most often identified for ANE1
    episodes, including recurrences in the same individual.
  exposure_term:
    preferred_term: exposure to Influenza A virus
    term:
      id: ECTO:3000107
      label: exposure to Influenza A virus
  evidence:
  - reference: PMID:19811512
    reference_title: "Recurrent acute necrotizing encephalopathy following influenza A in a genetically predisposed family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "influenza A was identified on bronchoalveolar lavage during this episode"
    explanation: Influenza A documented during a recurrent ANE episode in a RANBP2 carrier.
  - reference: PMID:25170550
    reference_title: "H1N1 triggered recurrent acute necrotizing encephalopathy in a family with a T653I mutation in the RANBP2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We believe that this is the first description implicating the H1N1 viral strain as a trigger"
    explanation: H1N1 influenza A triggered ANE1 in a family with p.Thr653Ile.
  influences_mechanisms:
  - target: Acute Febrile Viral Illness
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: Influenza A infection is the febrile illness that precipitates an encephalopathy episode in a carrier.
    evidence:
    - reference: PMID:41651846
      reference_title: "The genetic driver of Acute Necrotizing Encephalopathy, RANBP2, regulates the inflammatory response to Influenza A virus infection."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "Heterozygous dominant mutations in the nucleoporin RANBP2/Nup358 predispose to influenza-triggered ANE1."
      explanation: Influenza infection as the trigger acting on the RANBP2-predisposed host.
- name: Other febrile viral infections
  description: >-
    Influenza B, parainfluenza, human herpesvirus 6, coxsackievirus and other
    enteroviruses, and SARS-CoV-2 have also preceded ANE1 episodes.
  exposure_term:
    preferred_term: exposure to virus
    term:
      id: ECTO:3000001
      label: exposure to virus
  evidence:
  - reference: PMID:25473726
    reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "ANE refers to the specific neurologic presentation in which bilateral symmetric thalamic, midbrain, and/or hindbrain lesions occur within days following the onset of an acute viral illness caused by influenza A, influenza B, parainfluenza II, human herpes virus 6, coxsackie virus, or an enterovirus."
    explanation: Range of viral triggers recorded in the expert review.
  - reference: PMID:38091492
    reference_title: "A Rare Case of COVID-19 Related Acute Necrotizing Encephalopathy With the RANBP2 Mutation in a Pediatric Patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both SARS-CoV-2 and RANBP2 mutations are responsible for the manifestation of a hyper-inflammatory response that invades the central nervous system"
    explanation: SARS-CoV-2 as a trigger of ANE in a child carrying a RANBP2 variant.
  influences_mechanisms:
  - target: Acute Febrile Viral Illness
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: Any of several common viral infections can provide the febrile trigger.
    evidence:
    - reference: PMID:25473726
      reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "ANE begins within 12 hours to three or four days of the first awareness of viral symptoms (fever, cough, rhinorrhea, vomiting, diarrhea, and malaise)."
      explanation: Encephalopathy follows the onset of the viral illness within hours to days.
pathophysiology:
- name: Germline RANBP2 Missense Variant
  biological_scale: MOLECULAR
  description: >-
    The ANE1 variants are germline heterozygous missense substitutions in
    RANBP2 (Nup358); the recurrent ones (p.Thr585Met, p.Thr653Ile,
    p.Ile656Val) cluster in the N-terminal leucine-rich domain. RANBP2 is a
    large cytoplasmic-filament
    component of the nuclear pore complex with SUMO E3 ligase, nuclear
    transport, microtubule and mitochondrial-trafficking functions. The
    variant does not cause disease by itself; it creates a susceptibility
    that is expressed only during a febrile infection.
  genes:
  - preferred_term: RANBP2
    term:
      id: hgnc:9848
      label: RANBP2
  molecular_functions:
  - preferred_term: structural constituent of nuclear pore
    term:
      id: GO:0017056
      label: structural constituent of nuclear pore
  cellular_components:
  - preferred_term: nuclear pore
    term:
      id: GO:0005643
      label: nuclear pore
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    allele_type: missense
    variant_type: single nucleotide variant
  evidence:
  - reference: PMID:19118815
    reference_title: "Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The three mutations identified cluster in the “leucine-rich domain” (LD) that has been described as a domain necessary for localization to the both the nucleus and microtubules."
    explanation: Location of the three ANE1 variants in the leucine-rich domain.
  downstream:
  - target: Loss of RANBP2 Nuclear Envelope Localization
    causal_link_type: DIRECT
    hypothesis_groups:
    - viral_replication_restraint
    evidence:
    - reference: PMID:41651846
      reference_title: "The genetic driver of Acute Necrotizing Encephalopathy, RANBP2, regulates the inflammatory response to Influenza A virus infection."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Using CRISPR-Cas9 knock-in for the ANE1 disease variant RANBP2-T585M, we further demonstrate that this point mutation causes a loss-of-localisation phenotype that excludes RANBP2 from the nuclear envelope"
      explanation: Knock-in of p.Thr585Met in human cells displaces RANBP2 from the nuclear envelope.
  - target: Impaired RANBP2-Dependent Mitochondrial Support
    hypothesis_groups:
    - mitochondrial_energy_failure
    evidence:
    - reference: PMID:34400285
      reference_title: "RANBP2 mutation causing autosomal dominant acute necrotizing encephalopathy attenuates its interaction with COX11."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The amount of COX11 bound to mutated RANBP2 was significantly smaller than that bound to the wild-type RANBP2."
      explanation: >-
        The common ANE1 variant weakens binding to the mitochondrial
        cytochrome c oxidase chaperone COX11 in a pull-down assay.
  - target: Recurrent encephalopathy
    description: >-
      The germline variant persists, so each later febrile infection carries
      a renewed risk of an episode.
    evidence:
    - reference: PMID:35108406
      reference_title: "Outcomes in influenza and RANBP2 mutation-associated acute necrotizing encephalopathy of childhood."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "RANBP2 status was predictive of relapse but not predictive of overall outcome."
      explanation: In a 20-patient ANE cohort, RANBP2 variant status predicted recurrence.
- name: Loss of RANBP2 Nuclear Envelope Localization
  biological_scale: CELLULAR
  description: >-
    In knock-in human airway cells, RANBP2-T585M is excluded from the nuclear
    envelope, which phenocopies RANBP2 depletion. This is one proposed
    molecular consequence of the variant; its relevance to the brain lesions
    is not established.
  genes:
  - preferred_term: RANBP2
    term:
      id: hgnc:9848
      label: RANBP2
  biological_processes:
  - preferred_term: protein localization to nuclear envelope
    modifier: DECREASED
    term:
      id: GO:0090435
      label: protein localization to nuclear envelope
  cellular_components:
  - preferred_term: nuclear envelope
    term:
      id: GO:0005635
      label: nuclear envelope
  cell_types:
  - preferred_term: respiratory tract epithelial cell
    term:
      id: CL:0002368
      label: respiratory tract epithelial cell
  evidence:
  - reference: PMID:41651846
    reference_title: "The genetic driver of Acute Necrotizing Encephalopathy, RANBP2, regulates the inflammatory response to Influenza A virus infection."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "further suggest that ANE1 pathogenesis results from the impaired localisation of RANBP2 at the nuclear envelope"
    explanation: Authors' interpretation linking mislocalization to ANE1 pathogenesis.
  downstream:
  - target: Enhanced Influenza Virus Replication
    causal_link_type: DIRECT
    hypothesis_groups:
    - viral_replication_restraint
    evidence:
    - reference: PMID:41651846
      reference_title: "The genetic driver of Acute Necrotizing Encephalopathy, RANBP2, regulates the inflammatory response to Influenza A virus infection."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "which phenocopies RANBP2 knockdown by increasing IAV replication and driving pro-inflammatory cytokine expression following infection"
      explanation: Mislocalized RANBP2-T585M increases influenza A replication.
  - target: Pro-Inflammatory Cytokine Overproduction
    hypothesis_groups:
    - viral_replication_restraint
    evidence:
    - reference: PMID:41651846
      reference_title: "The genetic driver of Acute Necrotizing Encephalopathy, RANBP2, regulates the inflammatory response to Influenza A virus infection."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "which phenocopies RANBP2 knockdown by increasing IAV replication and driving pro-inflammatory cytokine expression following infection"
      explanation: The same knock-in drives pro-inflammatory cytokine expression after infection.
- name: Acute Febrile Viral Illness
  biological_scale: ORGANISM
  description: >-
    A common systemic viral infection, usually respiratory or
    gastrointestinal, with fever and prodromal symptoms. It is the
    obligatory environmental trigger: the encephalopathy begins within about
    12 hours to 4 days of the first viral symptoms. The virus is not found in
    the brain.
  evidence:
  - reference: PMID:19118815
    reference_title: "Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "previously healthy children develop encephalopathy, seizures, and coma within days after the onset of a common childhood febrile infection, such as influenza A or parainfluenza,3 without evidence of viral infection of the brain or inflammatory cell infiltration"
    explanation: The trigger is a systemic febrile infection, not CNS infection.
  downstream:
  - target: Fever
  - target: Vomiting
  - target: Enhanced Influenza Virus Replication
    hypothesis_groups:
    - viral_replication_restraint
  - target: Pro-Inflammatory Cytokine Overproduction
    evidence:
    - reference: PMID:21610332
      reference_title: "The interplay of infection and genetics in acute necrotizing encephalopathy."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Inflammatory factors participate in the pathogenesis of ANE, but the lack of difference between influenza and noninfluenza ANE focuses attention on the abnormal host response as causative."
      explanation: >-
        Different infections give the same phenotype, so the infection acts
        through an abnormal host inflammatory response.
- name: Enhanced Influenza Virus Replication
  biological_scale: CELLULAR
  description: >-
    RANBP2 normally restrains influenza A genome replication and nuclear
    export of viral RNA. Its depletion or mislocalization favors nuclear
    import of the viral polymerase subunits and export of viral genomic RNA,
    raising viral replication in airway epithelial cells.
  biological_processes:
  - preferred_term: viral genome replication
    modifier: INCREASED
    term:
      id: GO:0019079
      label: viral genome replication
  cell_types:
  - preferred_term: respiratory tract epithelial cell
    term:
      id: CL:0002368
      label: respiratory tract epithelial cell
  evidence:
  - reference: PMID:41651846
    reference_title: "The genetic driver of Acute Necrotizing Encephalopathy, RANBP2, regulates the inflammatory response to Influenza A virus infection."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that the depletion of RANBP2 in a human airway epithelial cell line increases IAV genomic replication by favouring the import of the viral polymerase subunits, PB1, PB2, and PA, following viral transcription and translation."
    explanation: RANBP2 depletion increases influenza A replication in airway epithelial cells.
  downstream:
  - target: Pro-Inflammatory Cytokine Overproduction
    causal_link_type: DIRECT
    hypothesis_groups:
    - viral_replication_restraint
    evidence:
    - reference: PMID:41651846
      reference_title: "The genetic driver of Acute Necrotizing Encephalopathy, RANBP2, regulates the inflammatory response to Influenza A virus infection."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "RANBP2 knockdown enhances the cytoplasmic export of viral genomic RNA (vRNA) and disrupts segment stoichiometry, which is associated with elevated production of the pro-inflammatory chemokines CXCL8, CXCL10, CCL2, CCL3, and CCL4 in human primary macrophages."
      explanation: Altered viral RNA handling is associated with increased macrophage chemokine output.
- name: Pro-Inflammatory Cytokine Overproduction
  biological_scale: CELLULAR
  description: >-
    Infected or exposed immune cells produce excess pro-inflammatory
    cytokines and chemokines. Two non-exclusive routes from RANBP2 have been
    proposed: loss of RANBP2-mediated restraint on viral replication, and loss
    of RANBP2-mediated translational repression of IL-6 and TNF-alpha mRNAs.
    The second is contested, because a RANBP2 construct carrying three ANE
    variants still represses IL-6 mRNA.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: cytokine production involved in inflammatory response
    modifier: INCREASED
    term:
      id: GO:0002534
      label: cytokine production involved in inflammatory response
  - preferred_term: interleukin-6 production
    modifier: INCREASED
    term:
      id: GO:0032635
      label: interleukin-6 production
  - preferred_term: tumor necrosis factor production
    modifier: INCREASED
    term:
      id: GO:0032640
      label: tumor necrosis factor production
  evidence:
  - reference: PMID:35485383
    reference_title: "Workshop on RanBP2/Nup358 and acute necrotizing encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "In more recent work, his group demonstrated that RanBP2/Nup358 inhibits the translation of mRNAs encoding the Interleukin 6 and Tumor Necrosis Factor alpha cytokine proteins."
    explanation: Meeting report of cell-culture work showing RANBP2 represses IL-6 and TNF-alpha translation.
  - reference: PMID:35485383
    reference_title: "Workshop on RanBP2/Nup358 and acute necrotizing encephalopathy."
    supports: REFUTE
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "the Palazzo group noted that a mutant form of RanBP2/Nup358 harboring three of the ANE mutations is still able to downregulate the Interleukin 6 mRNA"
    explanation: >-
      Contradicts loss of IL-6 mRNA repression as the route by which the ANE1
      variants cause cytokine excess.
  downstream:
  - target: Hypercytokinemia
    causal_link_type: DIRECT
    hypothesis_groups:
    - cytokine_storm
- name: Hypercytokinemia
  biological_scale: ORGANISM
  description: >-
    Serum and CSF IL-6 and TNF-alpha are raised during episodes. This
    cytokine storm is the prevailing explanation for the encephalopathy and
    for systemic features such as transaminase elevation and disseminated
    intravascular coagulation, and is the rationale for immunomodulatory
    treatment.
  evidence:
  - reference: PMID:19118815
    reference_title: "Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Increased serum and CSF levels of IL-6 and TNF-α have been reported in children with ANE"
    explanation: Raised IL-6 and TNF-alpha in ANE patients.
  - reference: PMID:41945878
    reference_title: "Role of Tocilizumab in Severe CNS Inflammatory Presentations in Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CSF cytokine panels showed elevated IL-6 in 5 patients, with normal serum IL-6 concentrations."
    explanation: >-
      In a pediatric tocilizumab series including RANBP2-related ANE, IL-6
      elevation was found in CSF rather than serum, so the cytokine excess can
      be predominantly intrathecal.
  downstream:
  - target: Blood-Brain Barrier Disruption
    hypothesis_groups:
    - cytokine_storm
    evidence:
    - reference: PMID:32426208
      reference_title: "Genetic Acute Necrotizing Encephalopathy Associated with RANBP2: Clinical and Therapeutic Implications in Pediatrics."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "One prominent hypothesis of the etiology of ANE1 is that this encephalopathy is secondary to cytokine storm due to abnormal nuclear signaling, one of the important functions of RANBP2, with cytokines gaining access to the central nervous system as a result of disruption of the blood brain barrier"
      explanation: States the hypothesized cytokine-to-barrier link in ANE1.
  - target: Increased circulating interleukin 6 concentration
  - target: Elevated circulating hepatic transaminase concentration
    hypothesis_groups:
    - cytokine_storm
  - target: Disseminated intravascular coagulation
    hypothesis_groups:
    - cytokine_storm
- name: Blood-Brain Barrier Disruption
  biological_scale: TISSUE
  description: >-
    Cytokine-driven injury to the cerebral microvasculature is thought to
    open the blood-brain barrier, giving protein-rich vasogenic edema and a
    raised CSF protein without pleocytosis, followed by petechial hemorrhage.
    Lesions evolve from edema to petechial hemorrhage to necrosis.
  conforms_to: "blood_brain_barrier_breakdown#Blood-Brain Barrier Permeability Increase"
  cell_types:
  - preferred_term: brain microvascular endothelial cell
    term:
      id: CL:2000044
      label: brain microvascular endothelial cell
  evidence:
  - reference: PMID:32426208
    reference_title: "Genetic Acute Necrotizing Encephalopathy Associated with RANBP2: Clinical and Therapeutic Implications in Pediatrics."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "findings compatible with vasogenic edema"
    explanation: Diffusion imaging of ANE lesions is compatible with vasogenic edema.
  - reference: PMID:9105653
    reference_title: "Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both the gray and white matter are involved, with neuropathological evidence of local breakdown of the blood-brain barrier (dysoria)."
    explanation: >-
      Neuropathology of acute necrotizing encephalopathy of childhood (largely
      sporadic cases) shows local blood-brain barrier breakdown.
  downstream:
  - target: Symmetric Deep Grey Matter Necrosis
    hypothesis_groups:
    - cytokine_storm
    evidence:
    - reference: PMID:32426208
      reference_title: "Genetic Acute Necrotizing Encephalopathy Associated with RANBP2: Clinical and Therapeutic Implications in Pediatrics."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Further, lesions may evolve over the course of the disease, progressing from edema, to petechial hemorrhage, to necrosis."
      explanation: Lesion evolution from edema through hemorrhage to necrosis.
  - target: Cerebral edema
  - target: Increased CSF protein concentration
    hypothesis_groups:
    - cytokine_storm
  - target: Thalamic hemorrhage
- name: Impaired RANBP2-Dependent Mitochondrial Support
  biological_scale: CELLULAR
  description: >-
    RANBP2 interacts with the cytochrome c oxidase chaperone COX11 and
    positions mitochondria through kinesin-1, independently of Ran. The
    symmetric lesion pattern resembles Leigh syndrome and Wernicke
    encephalopathy, suggesting that a variant-dependent energy failure in
    vulnerable deep grey matter may contribute during fever. This route is
    supported only by biochemical and analogical evidence.
  biological_processes:
  - preferred_term: mitochondrion localization
    modifier: DECREASED
    term:
      id: GO:0051646
      label: mitochondrion localization
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:19118815
    reference_title: "Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Thus, intracellular trafficking of mitochondria, energy production, and lipid peroxidation are potential targets for RANBP2 mutational effects."
    explanation: Discovery paper proposes mitochondrial trafficking and energy production as variant targets.
  - reference: PMID:34400285
    reference_title: "RANBP2 mutation causing autosomal dominant acute necrotizing encephalopathy attenuates its interaction with COX11."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Autosomal dominant acute necrotizing encephalopathy (ADANE) is caused by missense mutations in the gene encoding Ran-binding protein 2 (RANBP2), a nuclear pore protein regulating mitochondrial localization and function."
    explanation: Background for the RANBP2-COX11 experiment.
  - reference: PMID:17069463
    reference_title: "RanBP2 modulates Cox11 and hexokinase I activities and haploinsufficiency of RanBP2 causes deficits in glucose metabolism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RanBP2 associates in vitro and in vivo and colocalizes with the mitochondrial metallochaperone, Cox11, and the pacemaker of glycolysis, hexokinase type I (HKI) via its leucine-rich domain."
    explanation: The leucine-rich domain that carries the ANE1 variants binds COX11 and hexokinase I.
  - reference: PMID:17069463
    reference_title: "RanBP2 modulates Cox11 and hexokinase I activities and haploinsufficiency of RanBP2 causes deficits in glucose metabolism."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "haploinsufficiency of RanBP2 in an inbred strain causes a pronounced decrease of HKI and ATP levels selectively in the central nervous system"
    explanation: >-
      Ranbp2 heterozygous null mice have lower CNS hexokinase I and ATP. This
      is a loss-of-dosage model, not a knock-in of an ANE1 missense variant,
      so it supports the energy-failure arm only indirectly.
  downstream:
  - target: Symmetric Deep Grey Matter Necrosis
    hypothesis_groups:
    - mitochondrial_energy_failure
    evidence:
    - reference: PMID:19118815
      reference_title: "Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "The lesions of necrotizing encephalopathy suggested the involvement of energy metabolism, because it involves the same constellation of pathological findings described in Wernicke encephalopathy"
      explanation: Lesion pattern parallels disorders of energy metabolism; analogical, not direct, support.
- name: Symmetric Deep Grey Matter Necrosis
  biological_scale: TISSUE
  description: >-
    Bilateral symmetric necrotic lesions of the thalami (characteristically
    the ventromedial thalami), brainstem tegmentum, putamina, cerebellum,
    and periventricular white matter, sometimes with hemorrhage. ANE1 adds
    distinctive synchronous lesions of the mammillary bodies, amygdala,
    lateral geniculate bodies and claustrum. There is no inflammatory cell
    infiltration.
  locations:
  - preferred_term: thalamus
    term:
      id: UBERON:0001897
      label: dorsal plus ventral thalamus
  - preferred_term: brainstem
    term:
      id: UBERON:0002298
      label: brainstem
  - preferred_term: putamen
    term:
      id: UBERON:0001874
      label: putamen
  evidence:
  - reference: PMID:37090838
    reference_title: "Variable Presentation and Reduced Penetrance in Autosomal Dominant Acute Necrotizing Encephalopathy Related to RANBP2 Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain magnetic resonance imaging (MRI) shows multiple symmetrical lesions affecting primarily the thalami but also brain stem, putamina, periventricular white matter, and cerebellum."
    explanation: Distribution of the symmetric lesions.
  - reference: PMID:34593382
    reference_title: "A Closer Investigation of the Synchronous Bilateral Pattern of MRI Lesions in Acute Necrotizing Encephalopathy Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The setting of synchronous bilateral mammillary, amygdaloid, and lateral geniculate lesions, along with claustro-parahippocampal lesions, can serve as a diagnostic tool in this condition."
    explanation: Lesion pattern specific to RANBP2-associated ANE in a four-patient series.
  - reference: ORPHA:88619
    reference_title: "Familial acute necrotizing encephalopathy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Familial acute necrotizing encephalopathy or ADANE is a potentially fatal neurological disease characterised by neuropathological lesions principally involving the brainstem, thalamus and putamen."
    explanation: Orphanet definition.
  downstream:
  - target: Acute necrotizing encephalopathy
  - target: Focal T2 hyperintense thalamic lesion
  - target: Abnormal brainstem MRI signal intensity
  - target: Abnormal putamen morphology
  - target: Lethargy
  - target: Coma
    evidence:
    - reference: PMID:25473726
      reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "The most common sign of ANE is lethargy that progresses to coma (which may last for weeks) and seizures (in 50%)."
      explanation: Acute neurologic manifestations of the encephalopathy.
  - target: Seizure
  - target: Abnormal pattern of respiration
  - target: Intellectual disability
    evidence:
    - reference: PMID:25473726
      reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "One third of affected individuals die during the acute phase of the encephalopathy; of the survivors, one half have permanent neurologic damage and the remainder have no discernible residual symptoms."
      explanation: Half of survivors are left with permanent neurologic damage after the encephalopathy.
  - target: Spastic tetraplegia
  - target: Dysarthria
  - target: Gait disturbance
  - target: Developmental regression
phenotypes:
- name: Acute necrotizing encephalopathy
  category: Neurological
  description: >-
    Rapidly progressive encephalopathy beginning hours to days after a
    febrile viral illness, with bilateral symmetric thalamic and brainstem
    lesions on MRI. The defining event of the disease.
  phenotype_term:
    preferred_term: Acute necrotizing encephalopathy
    term:
      id: HP:0006965
      label: Acute necrotizing encephalopathy
    temporality: ACUTE
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:88619
    reference_title: "Familial acute necrotizing encephalopathy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006846 | Acute encephalopathy | Very frequent (99-80%)"
    explanation: Orphanet records acute encephalopathy as very frequent.
  - reference: PMID:25473726
    reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Infection-induced acute encephalopathy 3 (IIAE3) is the susceptibility to recurrent acute necrotizing encephalopathy (ANE) caused by a heterozygous pathogenic variant in RANBP2."
    explanation: ANE is the defining manifestation.
  - reference: PMID:25473726
    reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Although most IIAE3 occurs before age six years, first episodes have been observed in teenagers and adults."
    explanation: Age at first episode.
- name: Recurrent encephalopathy
  category: Neurological
  description: >-
    About half of affected individuals have at least one further episode
    with a later infection, and some have several. Recurrence is the main
    clinical clue distinguishing ANE1 from sporadic ANE.
  phenotype_term:
    preferred_term: Recurrent acute necrotizing encephalopathy
    term:
      id: HP:0007335
      label: Recurrent encephalopathy
    temporality: RECURRENT
  frequency: FREQUENT
  evidence:
  - reference: PMID:25473726
    reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Fifty per cent of persons with IIAE3 will have at least one repeat episode and some will have multiple repeat episodes"
    explanation: About 50% recurrence, mapped to FREQUENT.
  - reference: PMID:19118815
    reference_title: "Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Penetrance was estimated at 40% and recurrent episodes occurred in half of the affected individuals."
    explanation: Recurrence in half of affected individuals in the index kindred.
- name: Fever
  category: Constitutional
  description: Fever of the triggering viral illness precedes the encephalopathy.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:88619
    reference_title: "Familial acute necrotizing encephalopathy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001945 | Fever | Frequent (79-30%)"
    explanation: Orphanet phenotype frequency.
  - reference: PMID:37090838
    reference_title: "Variable Presentation and Reduced Penetrance in Autosomal Dominant Acute Necrotizing Encephalopathy Related to RANBP2 Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Acute necrotizing encephalopathy (ANE) is clinically characterized by fever, acute alteration of consciousness, seizures, and rapid progression to coma within days of onset of a viral illness"
    explanation: Fever is part of the presentation.
- name: Vomiting
  category: Gastrointestinal
  description: Vomiting is among the prodromal viral symptoms.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:88619
    reference_title: "Familial acute necrotizing encephalopathy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002013 | Vomiting | Frequent (79-30%)"
    explanation: Orphanet phenotype frequency.
  - reference: PMID:25170550
    reference_title: "H1N1 triggered recurrent acute necrotizing encephalopathy in a family with a T653I mutation in the RANBP2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 28-month-old infant presented with fever, vomiting and encephalopathy."
    explanation: Vomiting at presentation of an ANE1 episode.
- name: Lethargy
  category: Neurological
  description: Lethargy is the most common first neurologic sign and progresses to coma.
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
    temporality: ACUTE
  evidence:
  - reference: PMID:25473726
    reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The most common sign of ANE is lethargy that progresses to coma (which may last for weeks) and seizures (in 50%)."
    explanation: Lethargy as the most common sign.
- name: Coma
  category: Neurological
  description: Coma develops rapidly and may last for weeks.
  phenotype_term:
    preferred_term: Coma
    term:
      id: HP:0001259
      label: Coma
    temporality: ACUTE
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:88619
    reference_title: "Familial acute necrotizing encephalopathy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001259 | Coma | Very frequent (99-80%)"
    explanation: Orphanet phenotype frequency.
  - reference: PMID:25473726
    reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The most common sign of ANE is lethargy that progresses to coma (which may last for weeks) and seizures (in 50%)."
    explanation: Progression to prolonged coma.
- name: Seizure
  category: Neurological
  description: Seizures occur in about half of episodes.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
    temporality: ACUTE
  frequency: FREQUENT
  evidence:
  - reference: PMID:25473726
    reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The most common sign of ANE is lethargy that progresses to coma (which may last for weeks) and seizures (in 50%)."
    explanation: Seizures in 50%, mapped to FREQUENT.
  - reference: ORPHA:88619
    reference_title: "Familial acute necrotizing encephalopathy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001250 | Seizure | Frequent (79-30%)"
    explanation: Orphanet phenotype frequency.
- name: Focal T2 hyperintense thalamic lesion
  category: Neurological
  description: >-
    Bilateral symmetric T2/FLAIR-hyperintense thalamic lesions, often
    ventromedial, are the radiological hallmark. In a literature review of 59
    ANE1 patients bilateral thalamic involvement was seen in 77%, so atypical
    presentations without it occur.
  phenotype_term:
    preferred_term: Bilateral symmetric thalamic T2 hyperintense lesions
    term:
      id: HP:0012692
      label: Focal T2 hyperintense thalamic lesion
  frequency: FREQUENT
  evidence:
  - reference: PMID:25522933
    reference_title: "RANBP2 mutation and acute necrotizing encephalopathy: 2 cases and a literature review of the expanding clinico-radiological phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "bilateral thalamic involvement was seen in 77% of patients"
    explanation: Pooled literature frequency of bilateral thalamic lesions in ANE1 (77%, FREQUENT).
  - reference: PMID:40868426
    reference_title: "Bilateral Symmetrical Brain MRI Findings in Acute Necrotising Encephalopathy Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI of the brain demonstrated symmetrical high T2/FLAIR signal changes in the lateral geniculate bodies, claustrum, ventromedial thalami, subthalamic nuclei, mamillary bodies, and brainstem"
    explanation: T2/FLAIR hyperintense symmetric thalamic lesions in a genetically confirmed case.
- name: Abnormal brainstem MRI signal intensity
  category: Neurological
  description: Symmetric lesions of the midbrain, pons and brainstem tegmentum.
  phenotype_term:
    preferred_term: Symmetric brainstem lesions
    term:
      id: HP:0012747
      label: Abnormal brainstem MRI signal intensity
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:88619
    reference_title: "Familial acute necrotizing encephalopathy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012747 | Abnormal brainstem MRI signal intensity | Frequent (79-30%)"
    explanation: Orphanet phenotype frequency.
  - reference: PMID:26923722
    reference_title: "Variable clinical course in acute necrotizing encephalopathy and identification of a novel RANBP2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The hallmarks of ANE are the neuroradiological findings of multiple symmetric lesions in the thalami, midbrain, pons and brainstem."
    explanation: Brainstem lesions are part of the hallmark imaging.
- name: Abnormal putamen morphology
  category: Neurological
  description: Symmetric putaminal lesions accompany the thalamic lesions.
  phenotype_term:
    preferred_term: Symmetric putaminal lesions
    term:
      id: HP:0031982
      label: Abnormal putamen morphology
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:88619
    reference_title: "Familial acute necrotizing encephalopathy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0031982 | Abnormal putamen morphology | Frequent (79-30%)"
    explanation: Orphanet phenotype frequency.
- name: Cerebral edema
  category: Neurological
  description: Lesional and sometimes diffuse brain swelling during the acute phase.
  phenotype_term:
    preferred_term: Cerebral edema
    term:
      id: HP:0002181
      label: Cerebral edema
    temporality: ACUTE
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:88619
    reference_title: "Familial acute necrotizing encephalopathy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002181 | Cerebral edema | Frequent (79-30%)"
    explanation: Orphanet phenotype frequency.
  - reference: PMID:42407393
    reference_title: "Variable Phenotype in Three Siblings With RAN Binding Protein 2 Variant With Potential Preventive Treatment for Recurrences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presenting with influenza A-associated encephalopathy and a magnetic resonance imaging showing diffuse brain edema"
    explanation: Diffuse brain edema in a fatal sibling case.
- name: Thalamic hemorrhage
  category: Neurological
  description: >-
    Petechial or more extensive hemorrhage within the thalamic lesions, more
    likely when influenza is the trigger.
  phenotype_term:
    preferred_term: Thalamic hemorrhage
    term:
      id: HP:0025064
      label: Thalamic hemorrhage
  evidence:
  - reference: PMID:35108406
    reference_title: "Outcomes in influenza and RANBP2 mutation-associated acute necrotizing encephalopathy of childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with influenza had a higher degree of thalamic hemorrhage"
    explanation: Thalamic hemorrhage in an ANE cohort that included RANBP2-positive patients.
- name: Increased CSF protein concentration
  category: Laboratory
  description: Raised CSF protein without pleocytosis, reflecting barrier leak rather than CNS infection.
  phenotype_term:
    preferred_term: Increased CSF protein without pleocytosis
    term:
      id: HP:0002922
      label: Increased CSF protein concentration
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25522933
    reference_title: "RANBP2 mutation and acute necrotizing encephalopathy: 2 cases and a literature review of the expanding clinico-radiological phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "High CSF protein (>0.45 g/l) was reported in 44/47 (94%) in absence CSF pleocytosis"
    explanation: 94% of reported ANE1 patients, VERY_FREQUENT.
  - reference: ORPHA:88619
    reference_title: "Familial acute necrotizing encephalopathy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002922 | Increased CSF protein concentration | Very frequent (99-80%)"
    explanation: Orphanet phenotype frequency.
- name: Increased circulating interleukin 6 concentration
  category: Laboratory
  description: >-
    Raised IL-6 and TNF-alpha have been reported in serum and CSF in ANE. In a
    pediatric series that included RANBP2-related ANE, IL-6 was raised in CSF
    while serum IL-6 was normal, so a normal serum value does not exclude
    intrathecal cytokine excess. HPO has no CSF interleukin 6 term, so the
    circulating term is bound for the serum finding.
  phenotype_term:
    preferred_term: Increased interleukin 6 concentration
    term:
      id: HP:0030783
      label: Increased circulating interleukin 6 concentration
  evidence:
  - reference: PMID:19118815
    reference_title: "Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Increased serum and CSF levels of IL-6 and TNF-α have been reported in children with ANE"
    explanation: Raised IL-6 reported in ANE.
- name: Elevated circulating hepatic transaminase concentration
  category: Laboratory
  description: >-
    Transaminase elevation without hyperammonemia is common in ANE and its
    degree is a poor prognostic factor. The frequency figure available pools
    sporadic and genetic ANE, so no frequency is recorded here.
  phenotype_term:
    preferred_term: Elevated transaminases
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:32426208
    reference_title: "Genetic Acute Necrotizing Encephalopathy Associated with RANBP2: Clinical and Therapeutic Implications in Pediatrics."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "In patients with liver dysfunction, transaminitis is seen in the absence of hyperammonemia"
    explanation: Transaminitis without hyperammonemia in ANE.
  - reference: PMID:32426208
    reference_title: "Genetic Acute Necrotizing Encephalopathy Associated with RANBP2: Clinical and Therapeutic Implications in Pediatrics."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Poor prognostic factors include age of presentation <1-year-old, symptoms of delirium associated with brainstem lesions, hemorrhage and tissue loss on MRI, and degree of elevation of aminotransferases and CSF protein"
    explanation: Aminotransferase elevation as a prognostic factor.
- name: Disseminated intravascular coagulation
  category: Hematological
  description: A minority of patients develop disseminated intravascular coagulation during the acute phase.
  phenotype_term:
    preferred_term: Disseminated intravascular coagulation
    term:
      id: HP:0005521
      label: Disseminated intravascular coagulation
  evidence:
  - reference: PMID:32426208
    reference_title: "Genetic Acute Necrotizing Encephalopathy Associated with RANBP2: Clinical and Therapeutic Implications in Pediatrics."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "12% with findings suggestive of disseminated intravascular coagulation (DIC)"
    explanation: DIC in a pooled ANE series (sporadic and genetic not separated, so no frequency recorded).
- name: Abnormal pattern of respiration
  category: Respiratory
  description: Abnormal breathing pattern from brainstem involvement during the acute phase.
  phenotype_term:
    preferred_term: Abnormal pattern of respiration
    term:
      id: HP:0002793
      label: Abnormal pattern of respiration
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:88619
    reference_title: "Familial acute necrotizing encephalopathy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002793 | Abnormal pattern of respiration | Frequent (79-30%)"
    explanation: Orphanet phenotype frequency.
- name: Intellectual disability
  category: Neurological
  description: Cognitive impairment is a common permanent sequela in survivors.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:88619
    reference_title: "Familial acute necrotizing encephalopathy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001249 | Intellectual disability | Frequent (79-30%)"
    explanation: Orphanet phenotype frequency.
- name: Developmental regression
  category: Neurological
  description: Loss of acquired skills after an episode in young children.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:88619
    reference_title: "Familial acute necrotizing encephalopathy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002376 | Developmental regression | Frequent (79-30%)"
    explanation: Orphanet phenotype frequency.
- name: Spastic tetraplegia
  category: Neurological
  description: Spastic quadriparesis as a motor sequela.
  phenotype_term:
    preferred_term: Spastic tetraplegia
    term:
      id: HP:0002510
      label: Spastic tetraplegia
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:88619
    reference_title: "Familial acute necrotizing encephalopathy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002510 | Spastic tetraplegia | Frequent (79-30%)"
    explanation: Orphanet phenotype frequency.
- name: Dysarthria
  category: Neurological
  description: Dysarthria as a motor sequela.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:88619
    reference_title: "Familial acute necrotizing encephalopathy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001260 | Dysarthria | Frequent (79-30%)"
    explanation: Orphanet phenotype frequency.
- name: Gait disturbance
  category: Neurological
  description: Residual gait abnormality after an episode.
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:88619
    reference_title: "Familial acute necrotizing encephalopathy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001288 | Gait disturbance | Frequent (79-30%)"
    explanation: Orphanet phenotype frequency.
- name: Polyneuropathy
  category: Neurological
  description: >-
    Peripheral polyneuropathy during an episode, not described in sporadic
    ANE, and post-viral polyneuritis in a carrier parent.
  phenotype_term:
    preferred_term: Peripheral polyneuropathy
    term:
      id: HP:0001271
      label: Polyneuropathy
  evidence:
  - reference: PMID:19811512
    reference_title: "Recurrent acute necrotizing encephalopathy following influenza A in a genetically predisposed family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, there was evidence of peripheral polyneuropathy during the recent episode, which has not previously been described in sporadic ANE."
    explanation: Polyneuropathy in a RANBP2 carrier during a recurrent episode.
diagnosis:
- name: Brain MRI
  description: >-
    MRI showing bilateral symmetric thalamic lesions with brainstem, putaminal
    and white matter involvement after a febrile illness establishes ANE;
    the synchronous mammillary, amygdala and lateral geniculate pattern
    suggests ANE1.
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:40868426
    reference_title: "Bilateral Symmetrical Brain MRI Findings in Acute Necrotising Encephalopathy Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recognition of the characteristic MRI findings in ANE1 can facilitate a timely diagnosis and enhance the clinical management of the patient and their relatives, especially given the high risk of disease recurrence."
    explanation: MRI pattern as the diagnostic entry point.
- name: RANBP2 molecular genetic testing
  description: >-
    Identification of a heterozygous pathogenic RANBP2 variant confirms the
    diagnosis in a person with typical clinical and MRI findings. Testing of
    at-risk first-degree relatives allows early recognition of an episode.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:25473726
    reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "IIAE3 is suspected in individuals with typical clinical and MRI findings, and is confirmed in those with a heterozygous pathogenic variant in RANBP2."
    explanation: Diagnostic confirmation by RANBP2 testing.
  - reference: PMID:25473726
    reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "In a family with IIAE3, molecular genetic testing of at-risk first-degree relatives, especially children, is warranted so that those who have inherited the RANBP2 pathogenic variant can benefit from prompt intervention in the early stages of ANE."
    explanation: Cascade testing of relatives.
- name: Cerebrospinal fluid analysis
  description: Lumbar puncture shows raised protein without pleocytosis and helps exclude infectious encephalitis.
  diagnosis_term:
    preferred_term: Lumbar Puncture
    term:
      id: NCIT:C15327
      label: Lumbar Puncture
  evidence:
  - reference: PMID:25522933
    reference_title: "RANBP2 mutation and acute necrotizing encephalopathy: 2 cases and a literature review of the expanding clinico-radiological phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "High CSF protein (>0.45 g/l) was reported in 44/47 (94%) in absence CSF pleocytosis"
    explanation: Characteristic CSF finding.
treatments:
- name: High-dose corticosteroids during an episode
  description: >-
    Early high-dose corticosteroids (usually intravenous methylprednisolone)
    are the most widely used acute treatment, given to damp the
    inflammatory response. Benefit is supported by observational data in ANE,
    not by ANE1-specific trials, and patients have also recovered without
    specific treatment.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: methylprednisolone
      term:
        id: CHEBI:6888
        label: 6alpha-methylprednisolone
  target_mechanisms:
  - target: Hypercytokinemia
    treatment_effect: INHIBITS
    description: Corticosteroids are used to suppress the cytokine storm.
    evidence:
    - reference: PMID:32426208
      reference_title: "Genetic Acute Necrotizing Encephalopathy Associated with RANBP2: Clinical and Therapeutic Implications in Pediatrics."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Early treatment with steroids has been associated with improved outcomes, thought to be secondary to treating cytokine storm and metabolic dysfunction by decreasing inflammation"
      explanation: Rationale for steroid benefit via the cytokine storm.
  evidence:
  - reference: PMID:32426208
    reference_title: "Genetic Acute Necrotizing Encephalopathy Associated with RANBP2: Clinical and Therapeutic Implications in Pediatrics."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Early treatment with high dose steroids is associated with a more favorable outcome, however the diagnosis is often overlooked resulting in delayed treatment."
    explanation: Narrative review of ANE1 associating early high-dose steroids with better outcome.
  - reference: PMID:25473726
    reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Treatment is aimed at reducing the inflammatory state by administration of corticosteroids during an acute episode of encephalopathy (not supported by data from IIAE-3-specific studies)"
    explanation: Expert review notes steroids are used without ANE1-specific data.
- name: Prophylactic pulse corticosteroids during febrile infections
  description: >-
    In known carriers, pulse steroids at the onset of influenza or other
    febrile infection have been used to try to prevent further episodes. The
    evidence is a single family series.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  target_mechanisms:
  - target: Hypercytokinemia
    treatment_effect: INHIBITS
    description: Intended to blunt the inflammatory response before encephalopathy develops.
  evidence:
  - reference: PMID:42407393
    reference_title: "Variable Phenotype in Three Siblings With RAN Binding Protein 2 Variant With Potential Preventive Treatment for Recurrences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The surviving cases were given a preventive treatment plan with pulse steroids during influenza infections. At 2 years of follow-up, they still have no new episodes of encephalopathy."
    explanation: No recurrence over 2 years in two siblings on preventive pulse steroids.
- name: Intravenous immunoglobulin
  description: >-
    IVIG is used during acute episodes alongside steroids, and monthly IVIG
    has been tried after recurrent episodes. Evidence is anecdotal.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Immunoglobulin Therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
    therapeutic_agent:
    - preferred_term: human immunoglobulin G
      term:
        id: NCIT:C80829
        label: Human Immunoglobulin G
  evidence:
  - reference: PMID:21945312
    reference_title: "Immunomodulatory therapy in recurrent acute necrotizing encephalopathy ANE1: is it useful?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the acute encephalopathy episodes he was treated with steroids and immunoglobulin."
    explanation: Acute IVIG use in an ANE1 patient.
  - reference: PMID:21945312
    reference_title: "Immunomodulatory therapy in recurrent acute necrotizing encephalopathy ANE1: is it useful?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty days after the last episode he started monthly intravenous immunoglobulin that might be used for prevention of viral infections."
    explanation: Monthly IVIG as attempted prophylaxis.
- name: Tocilizumab
  description: >-
    IL-6 receptor blockade has been given with corticosteroids in severe
    episodes, with reported benefit in a handful of patients.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tocilizumab
      term:
        id: NCIT:C84217
        label: Tocilizumab
  target_mechanisms:
  - target: Hypercytokinemia
    treatment_effect: INHIBITS
    description: Blocks IL-6 receptor signalling.
    evidence:
    - reference: PMID:41945878
      reference_title: "Role of Tocilizumab in Severe CNS Inflammatory Presentations in Children."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Outcomes included rapid intracranial pressure reduction, recovery in relapsing optic neuritis and myelitis, and improvement in RANBP2-related acute necrotizing encephalopathy."
      explanation: Improvement after IV tocilizumab in a RANBP2-related ANE patient.
  evidence:
  - reference: PMID:32426208
    reference_title: "Genetic Acute Necrotizing Encephalopathy Associated with RANBP2: Clinical and Therapeutic Implications in Pediatrics."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "with only one pediatric case series being reported to have benefit from the use of tocilizumab when administered with corticosteroids"
    explanation: Limited case-series support.
- name: Plasmapheresis
  description: Used in some acute episodes, with limited reported effect.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Plasmapheresis
    term:
      id: NCIT:C15304
      label: Plasmapheresis
  evidence:
  - reference: PMID:25473726
    reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "as well as IVIg, plasmapheresis, and TNFα antagonists with varied, but overall limited, therapeutic effects"
    explanation: Plasmapheresis among adjunct immunotherapies of limited effect.
- name: Supportive intensive care
  description: >-
    Episodes are managed in intensive care, with support for coma, seizures,
    raised intracranial pressure and systemic complications, alongside
    immunomodulation.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:34593382
    reference_title: "A Closer Investigation of the Synchronous Bilateral Pattern of MRI Lesions in Acute Necrotizing Encephalopathy Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All our patients were treated in the intensive care unit during all their attacks."
    explanation: Intensive care for every attack in a four-patient RANBP2-positive series.
  - reference: PMID:40868426
    reference_title: "Bilateral Symmetrical Brain MRI Findings in Acute Necrotising Encephalopathy Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With immunosuppressive and supportive treatment, the patient fully recovered and was discharged after 10 days in the hospital with no residual symptoms."
    explanation: Supportive treatment with immunosuppression in a genetically confirmed ANE1 case.
- name: Routine and annual influenza vaccination
  description: >-
    Routine immunizations and yearly influenza vaccination are recommended to
    reduce exposure to the commonest trigger. No vaccine-triggered episode has
    been documented.
  therapeutic_modality: VACCINE
  treatment_term:
    preferred_term: Vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
  target_mechanisms:
  - target: Acute Febrile Viral Illness
    treatment_effect: INHIBITS
    description: Prevents the influenza infections that trigger most episodes.
  evidence:
  - reference: PMID:25473726
    reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Routine vaccinations and yearly influenza vaccinations are recommended, although there are theoretic concerns for live influenza and cellular pertussis preparations."
    explanation: Vaccination recommendation, with caution about live influenza and whole-cell pertussis vaccines.
  - reference: PMID:42385467
    reference_title: "Familial, recurrent or genetic acute necrotizing encephalopathy of childhood: a systematic review and a case report. Focus on atypical events and on the role on immunizations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Routine immunization was documented in 18/19 patients pre-ANE and 5/20 resumed vaccination post-ANE (no vaccine-related relapses over a median follow-up of 19 months)."
    explanation: Systematic review finding no vaccine-related relapses.
  - reference: PMID:25473726
    reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Based on a single case report of ANE in one individual (not known to have a RANBP2 pathogenic variant), avoidance of cellular pertussis in DTaP immunization is recommended."
    explanation: Agent to avoid listed by GeneReviews; acellular pertussis vaccine is preferred.
- name: Infection avoidance and hand hygiene
  description: >-
    Carriers are advised to avoid contact with people who have an infectious
    illness and to follow strict hand-washing precautions, to reduce exposure
    to triggering infections.
  therapeutic_modality: BEHAVIORAL
  target_mechanisms:
  - target: Acute Febrile Viral Illness
    treatment_effect: INHIBITS
    description: Reduces exposure to the triggering infection.
  evidence:
  - reference: PMID:25473726
    reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Avoid individuals who are ill with an infectious disease and adhere to strict precautions regarding hand washing."
    explanation: GeneReviews agents/circumstances-to-avoid recommendation.
- name: Genetic counseling
  description: >-
    Each child of a carrier has a 50% chance of inheriting the variant;
    penetrance is incomplete and the variant can arise de novo.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25473726
    reference_title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Each child of an individual with susceptibility to IIAE3 has a 50% chance of inheriting the pathogenic variant."
    explanation: Recurrence risk for offspring.
mechanistic_hypotheses:
- hypothesis_group_id: cytokine_storm
  hypothesis_label: Infection-triggered cytokine storm with blood-brain barrier failure
  status: CANONICAL
  description: >-
    The prevailing model: the febrile infection provokes an excessive host
    cytokine response (IL-6, TNF-alpha), which damages the cerebral
    microvasculature, opens the blood-brain barrier and produces symmetric
    edema, hemorrhage and necrosis. It is canonical for ANE as a whole and
    underpins immunomodulatory treatment, but how RANBP2 variants drive the
    cytokine excess, and why the lesions are so selectively distributed, is
    not established.
  evidence:
  - reference: PMID:19118815
    reference_title: "Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "leading to the prevailing hypothesis of a “cytokine storm” as part of the pathogenic mechanism"
    explanation: Cytokine storm described as the prevailing hypothesis.
  - reference: PMID:35408907
    reference_title: "Roles of Nucleoporin RanBP2/Nup358 in Acute Necrotizing Encephalopathy Type 1 (ANE1) and Viral Infection."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Mutations in the RANBP2 gene are associated with acute necrotizing encephalopathy type 1 (ANE1), a rare condition where patients experience a sharp rise in cytokine production in response to viral infection and undergo hyperinflammation, seizures, coma, and a high rate of mortality."
    explanation: Review framing ANE1 as virus-triggered hyperinflammation.
- hypothesis_group_id: viral_replication_restraint
  hypothesis_label: Loss of RANBP2 restraint on viral replication drives hyperinflammation
  status: EMERGING
  description: >-
    The ANE1 variant displaces RANBP2 from the nuclear envelope, which
    increases influenza A replication and viral RNA export and drives
    pro-inflammatory cytokine and chemokine production. Shown in a human
    airway cell line and primary macrophages; not yet tested in neural tissue
    or patients.
  evidence:
  - reference: PMID:41651846
    reference_title: "The genetic driver of Acute Necrotizing Encephalopathy, RANBP2, regulates the inflammatory response to Influenza A virus infection."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Together, our results reveal that RANBP2 regulates influenza RNA replication and nuclear export, thereby restraining virus-induced hyperinflammation"
    explanation: Cell-model evidence for the restraint model.
- hypothesis_group_id: mitochondrial_energy_failure
  hypothesis_label: RANBP2-dependent mitochondrial dysfunction and energy failure
  status: EMERGING
  description: >-
    RANBP2 positions mitochondria and binds COX11; the variants weaken the
    COX11 interaction, and the lesion pattern resembles Leigh syndrome and
    Wernicke encephalopathy. Whether ATP production actually falls in
    patient cells has not been shown.
  evidence:
  - reference: PMID:34400285
    reference_title: "RANBP2 mutation causing autosomal dominant acute necrotizing encephalopathy attenuates its interaction with COX11."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mutated RANBP2 had an attenuated binding ability to COX11. Whether this change indeed decreases ATP production remains to be further explored."
    explanation: Biochemical support, with the functional consequence unresolved.
  - reference: PMID:32426208
    reference_title: "Genetic Acute Necrotizing Encephalopathy Associated with RANBP2: Clinical and Therapeutic Implications in Pediatrics."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Several features of this condition suggest a metabolic or mitochondrial etiology."
    explanation: Review summarizing the metabolic/mitochondrial hypothesis.
discussions:
- discussion_id: incomplete_penetrance_mechanism
  kind: KNOWLEDGE_GAP
  attaches_to:
  - inheritance#Autosomal dominant
  prompt: >-
    Why do most RANBP2 variant carriers never develop ANE, and why does the
    same carrier escape some infections but not others?
  rationale: >-
    Neither the infecting agent nor known genetic background explains the
    incomplete penetrance or the episodic course. A temperature-sensitive
    misfolding of the variant protein, so that height and duration of fever
    matter, has been proposed but not tested.
  evidence:
  - reference: PMID:19118815
    reference_title: "Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If the amino acid substitutions result in temperature sensitivity, resulting in protein misfolding and alteration of function, variations in the severity and duration of fever could contribute to the reduced penetrance."
    explanation: The temperature-sensitivity hypothesis for reduced penetrance.
  - reference: PMID:34059398
    reference_title: "Recurrent acute necrotizing encephalopathy in a boy with RANBP2 mutation and thermolabile CPT2 variant: The first case of ANE1 in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, he had a genetic background with two susceptibility variants for acute encephalopathy, RANBP2 (frequent in the Caucasians), and CPT2 (frequent in the Japanese)."
    explanation: A thermolabile CPT2 variant co-occurring with RANBP2 p.Thr585Met is a candidate modifier.
- discussion_id: non_ranbp2_familial_ane
  kind: KNOWLEDGE_GAP
  attaches_to:
  - genetic#RANBP2
  prompt: >-
    Which genes explain familial or recurrent ANE in families without a
    RANBP2 variant, and do they act through the same mechanism?
  rationale: >-
    About a fifth of tested familial, recurrent or genetic ANE patients carry
    no RANBP2 variant, so RANBP2 does not account for all familial
    susceptibility. Such families fall outside this entry until their cause
    is known.
  evidence:
  - reference: PMID:19643689
    reference_title: "[Infection-triggered familial or recurrent acute necrotizing encephalopathy]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in RANBP2 are not the sole susceptibility alleles for familial or recurrent ANE."
    explanation: A Spanish familial and recurrent ANE family without RANBP2 variants.
  - reference: PMID:42385467
    reference_title: "Familial, recurrent or genetic acute necrotizing encephalopathy of childhood: a systematic review and a case report. Focus on atypical events and on the role on immunizations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "median onset age 24 months; 62% male; RANBP2 mutations in 81% of tested individuals"
    explanation: RANBP2 variants in 81% of tested familial, recurrent or genetic ANE patients.
references:
- reference: PMID:25473726
  title: "Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
  tags:
  - GeneReviews
- reference: ORPHA:88619
  title: "Familial acute necrotizing encephalopathy"
- reference: CGGV:assertion_7e375774-fce0-48a2-b83d-c7814c9de23f-2024-04-02T160000.000Z
  title: "RANBP2 / familial acute necrotizing encephalopathy (Moderate)"
notes: >-
  Scope: this entry covers RANBP2-associated (genetic, familial or recurrent)
  ANE. Sporadic, non-recurrent ANE without a RANBP2 variant, including
  familial clusters without a RANBP2 variant, is a differential diagnosis and
  not a subtype; non-RANBP2 genetic contributors (thermolabile CPT2 variants,
  biallelic RNH1 variants, HLA genotypes) define separate susceptibilities.
  The GeneReviews chapter on this condition (Susceptibility to
  Infection-Induced Acute Encephalopathy 3) has been retired by GeneReviews
  and is cited as an archival expert summary. ClinGen classifies the RANBP2
  relationship as Moderate rather than Definitive because of the low
  penetrance and absence of curated experimental data. Reported outcome
  predictors of ANE (the ANE severity score, hyperferritinemia, AST
  elevation, shock and brainstem involvement) come from ANE cohorts whose
  RANBP2 status was not reported, so they are not curated here as
  properties of ANE1.
📚

References & Deep Research

References

3
PMID:25473726
Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
No top-level findings curated for this source.
ORPHA:88619
Familial acute necrotizing encephalopathy
No top-level findings curated for this source.
CGGV:assertion_7e375774-fce0-48a2-b83d-c7814c9de23f-2024-04-02T160000.000Z
RANBP2 / familial acute necrotizing encephalopathy (Moderate)
No top-level findings curated for this source.

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Create: Familial_Acute_Necrotizing_Encephalopathy · 2026-10-15T02:20:00Z · View source

New entry for RANBP2-associated familial acute necrotizing encephalopathy (ANE1, IIAE3; MONDO:0011953), curated from the stub. Scope: genetic, familial or recurrent ANE with a heterozygous RANBP2 variant; sporadic ANE and RANBP2-negative familial ANE are treated as differentials, and the latter is recorded as a knowledge gap. Sources: the OpenScientist deep-research report (20/20 references resolved, none off topic; term section flagged one obsolete GO term, GO:0070265, which was not used; preflight-dr PASS, RANBP2 mentioned 51 times), plus a PubMed pass. The GeneReviews chapter (PMID:25473726) is retired; it is tagged and cited as an archival expert summary for clinical characteristics, diagnosis, management, agents to avoid and genetic counseling. Orphanet ORPHA:88619 supplied phenotype frequencies and the prevalence class; the ClinGen Moderate AD classification (CGGV assertion 7e375774) is copied into gene_disease_validity, and relationship_type is SUSCEPTIBILITY because CAUSATIVE implies Definitive or Strong and disease expression requires an infectious trigger. Pathophysiology is a causal chain from the germline variant and the febrile viral illness through cytokine overproduction, hypercytokinemia and blood-brain barrier disruption to symmetric deep grey matter necrosis and its phenotypes, with three hypothesis groups: cytokine_storm (CANONICAL), viral_replication_restraint (EMERGING, PMID:41651846 knock-in) and mitochondrial_energy_failure (EMERGING, COX11 binding and Ranbp2 heterozygous mouse). Death in childhood (HP:0003819) was dropped because it is outside the PhenotypeTerm enum; mortality is stated in the description. Polyneuropathy is left without an upstream edge because no source states its mechanism. Report citations not used: 24931733, 38295717, 33358123, 41714597, 36529001 and 10834515 concern ANE without a RANBP2 genotype; 40976348 and 18949001 are background. Validation: just validate, validate-terms, count-verified-snippets, check-entity-refs, check-causal-targets, check-genereviews (TAGGED) and validate-disorders.

OpenScientist ▸
Familial Acute Necrotizing Encephalopathy (ANE1): A Comprehensive Disease Report
openscientist-autonomous 19 citations 2026-10-15T02:03:59.741822

Familial Acute Necrotizing Encephalopathy (ANE1): A Comprehensive Disease Report

Disease: Familial Acute Necrotizing Encephalopathy MONDO ID: MONDO:0011953 | OMIM: 608033 | Category: Mendelian (autosomal-dominant, incompletely penetrant) Causal gene: RANBP2 (Nup358), HGNC:9848, NCBI Gene 5903, chromosome 2q13

Summary

Familial acute necrotizing encephalopathy (ANE1) is a rare, autosomal-dominant, incompletely penetrant predisposition to a fulminant post-infectious brain injury. It is caused by heterozygous missense variants in RANBP2 (RAN-binding protein 2 / Nup358), the largest nucleoporin of the nuclear pore complex, with a recurrent mutational hotspot at p.Thr585Met (c.1880C>T). The disorder is unmasked when an affected individual — typically a previously healthy young child (median onset ~24 months) — contracts a common febrile viral infection such as influenza A/B, human herpesvirus-6 (HHV-6), parainfluenza, respiratory syncytial virus (RSV), or SARS-CoV-2. The infection triggers a systemic hyperinflammatory ("cytokine storm") response that drives blood–brain-barrier breakdown and produces the disease's hallmark: multiple bilaterally symmetric necrotic lesions, most characteristically in the thalami, plus the brainstem tegmentum, external capsules, insular cortices, periventricular white matter, and cerebellum.

The mechanistic model connects two arms of RANBP2 biology: (1) its canonical roles in nucleocytoplasmic transport and SUMOylation, and (2) its non-canonical role in central nervous system (CNS) energy metabolism, where RanBP2 binds hexokinase I ("the pacemaker of glycolysis") and the mitochondrial metallochaperone Cox11. A mouse model demonstrated that RanBP2 haploinsufficiency selectively lowers hexokinase I and ATP levels in the CNS, providing a biological rationale for the brain's vulnerability. On top of this metabolic predisposition, the infection-driven cytokine storm (IL-6, TNF-α, hyperferritinemia) produces endothelial activation and vasogenic/cytotoxic edema with petechial hemorrhage ("dysoria"), culminating in symmetric thalamic necrosis.

ANE1 carries high morbidity and mortality (~30–40% mortality in some cohorts; frequent severe neurologic sequelae in survivors). Diagnosis rests on the characteristic symmetric thalamic MRI signature combined with RANBP2 sequencing and a supportive laboratory profile (elevated CSF protein without pleocytosis, elevated transaminases/CPK, thrombocytopenia, hyperferritinemia, no hyperammonemia). There is no approved disease-specific therapy; management combines intensive supportive care with early immunomodulation (high-dose corticosteroids, IVIG, and IL-6 blockade with tocilizumab). Prophylactic pulse steroids during febrile infections in known carriers, and influenza vaccination, are emerging preventive strategies. Notably, ~19% of familial/recurrent cases lack a RANBP2 variant, indicating locus heterogeneity and additional susceptibility loci still to be discovered.

Key Findings

Finding 1 — ANE1 is caused by dominant RANBP2 missense mutations, most commonly p.Thr585Met

The landmark study by Neilson et al. (2009) mapped a 7-Mb ANE1 susceptibility locus in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait, and found that all affected individuals and obligate carriers were heterozygous for the missense variant c.1880C>T, p.Thr585Met in RANBP2. As the authors state: "We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C-->T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2)" (PMID: 19118815). The same mutation recurred widely: "Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families" — establishing p.Thr585Met as a true mutational hotspot that can also arise de novo.

Allelic heterogeneity exists. Reported pathogenic variants beyond the p.Thr585Met hotspot include p.Trp681Cys (a de novo variant causing recurrent ANE), p.Glu3014Gly (c.9041A>G, identified in a four-generation Chinese family: "A novel missense variation, c.9041A > G, p.(Glu3014Gly) in RANBP2 was identified in this family" — PMID: 35348941), and p.Thr585Met reported co-occurring with a CPT2 thermolabile modifier in the first Japanese case.

  • Variant type: missense (point mutations)
  • Classification (ACMG/AMP): pathogenic / likely pathogenic for the recurrent variants
  • Origin: germline (inherited or de novo)
  • HGNC: RANBP2 (HGNC:9848); OMIM gene: 601181; OMIM phenotype (ANE1): 608033

Finding 2 — ANE1 is triggered by common viral febrile infections and presents with bilateral symmetric thalamic lesions

ANE is a rapidly progressive encephalopathy in previously healthy children following common viral infections. Neilson et al. frame it precisely: "Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza" (PMID: 19118815). The clinical episode follows a stereotyped sequence: a viral prodrome with fever → rapid deterioration of consciousness, seizures, and focal deficits → coma. In the familial (ANE1) form, episodes can recur with each new infection.

The neuroimaging signature is diagnostic. In an ANE1 case: "Brain magnetic resonance imaging (MRI) showed a characteristic involvement of the bilateral thalami, external capsules, insular cortices, and brainstem, suggesting ANE" (PMID: 34059398). The lesions are symmetric and multifocal, affecting both gray and white matter: "symmetric multifocal brain lesions are seen in the bilateral thalami as well as other characteristic regions, involving both gray and white matter" (PMID: 32426208). Documented viral triggers across case reports include influenza A (including H1N1), influenza B, HHV-6/HHV-7, parainfluenza, RSV, varicella zoster, dengue, and SARS-CoV-2.

Finding 3 — Prognosis is predicted by the ANE Severity Score, brainstem involvement, and hyperferritinemia; early steroids improve outcome

The ANE Severity Score (ANE-SS) stratifies risk on a 0–9 scale: 3 points for shock, 2 for brainstem lesions, 2 for age >48 months, 1 for platelet count <100,000/μL, and 1 for CSF protein >60 mg/dL, yielding low (0–1), medium (2–4), and high (5–9) risk strata (PMID: 24931733).

Hyperferritinemia — a marker of the underlying cytokine storm — is a key outcome predictor. Lee et al. (2024, n=29) found that "ferritin, aspartate aminotransferase (AST), and ANE severity score (ANE-SS) were the predictors associated with outcomes" (PMID: 38295717), with 69% of patients having poor neurological outcomes; thresholds of ferritin >1823 ng/mL, AST >78 U/L, and ANE-SS >4.5 predicted poor outcome, and higher ferritin/ANE-SS correlated with brainstem involvement. A Malaysian cohort (n=13) reported 38.5% mortality with 5 brainstem deaths, and all survivors in a vegetative state or with severe disability at discharge (PMID: 33358123). Critically, "Early treatment with high dose steroids is associated with a more favorable outcome" (PMID: 32426208), especially in patients without brainstem involvement.

ANE-SS component Points
Shock 3
Brainstem lesions 2
Age >48 months 2
Platelets <100,000/μL 1
CSF protein >60 mg/dL 1
Risk strata Low 0–1 · Medium 2–4 · High 5–9

Finding 4 — Pathophysiology: RANBP2 variant + viral fever → cytokine storm → BBB breakdown → symmetric thalamic necrosis

The proposed causal chain integrates genetics, immunology, and tissue pathology. The original neuropathologic description of ANE emphasized blood–brain-barrier failure: "Both the gray and white matter are involved, with neuropathological evidence of local breakdown of the blood-brain barrier (dysoria)" (PMID: 9105653). The RANBP2-specific mechanisms remain only partially demonstrated; Levine et al. enumerate several non-mutually-exclusive hypotheses: "There are several non-mutually exclusive hypotheses suggesting possible etiologies for this phenotype based on the many functions of RANBP2 within the cell. These include dysfunctions in nucleocytoplasmic trafficking and intracellular metabolic regulation, as well as cytokine storm, and abnormal distribution of mitochondria" (PMID: 32426208).

Evidence for the cytokine-storm step comes from severe pediatric viral encephalopathy, where "Serum concentrations of cytokines/chemokines including interleukin 6 and tumor necrosis factor-α were significantly higher within 24 hours of onset than for controls" (PMID: 41714597).

Finding 5 — Epidemiology: rare pediatric disorder; sporadic form predominant in East Asia; familial ANE1 very rare

ANE of childhood was first established as a disease entity predominantly affecting infants and young children in Japan and Taiwan: "This disease predominantly affects infants and young children living in Japan and Taiwan, and manifests itself as acute encephalopathy following viral infections" (PMID: 9105653). Importantly, the geographic distribution of the familial (RANBP2-associated) form differs from the sporadic form: "Although sporadic ANE predominantly affects Asian children, ANE1 is very rare in east Asia" (PMID: 34059398). The familial form has been reported across European, North American, Chinese, and (first in 2021) Japanese kindreds. No precise prevalence/incidence figures exist; ANE is classified as a rare disease (Orphanet).

Finding 6 — RANBP2/Nup358 is a multidomain nucleoporin that binds hexokinase I and Cox11; haploinsufficiency lowers CNS ATP (mouse model)

RANBP2 (Nup358, ~358 kDa) is the largest nucleoporin, forming the cytoplasmic filaments of the nuclear pore complex and regulating nucleocytoplasmic transport: "RANBP2 (also known as Nup358) is the largest nucleoporin of the nuclear pore complex (NPC), where it constitutes the main component of the cytoplasmic filaments and regulates nucleocytoplasmic transport" (PMID: 40976348). Its domains include a zinc finger, four Ran-binding domains, an E3 SUMO ligase domain, and a cyclophilin-like domain; it localizes to the nuclear envelope, annulate lamellae, mitochondria–ER junctions, and kinetochores.

The metabolic link is decisive for understanding CNS vulnerability. Aslanukov et al. showed that "RanBP2 associates in vitro and in vivo and colocalizes with the mitochondrial metallochaperone, Cox11, and the pacemaker of glycolysis, hexokinase type I (HKI) via its leucine-rich domain" and, critically, that "haploinsufficiency of RanBP2 in an inbred strain causes a pronounced decrease of HKI and ATP levels selectively in the central nervous system" (PMID: 17069463). This provides a mechanistic basis for why the brain — and energy-demanding structures such as the thalamus — are selectively vulnerable.

Finding 7 — Marked intrafamilial phenotypic variability; prophylactic pulse steroids may prevent recurrences

Alrifai et al. (2026) reported three siblings sharing the identical pathogenic RANBP2 variant but with markedly divergent courses — one progressed to brain death with influenza A, one responded to corticosteroids with mild residual cognitive dysfunction, and a third remained neurologically intact despite recurrent infections: "Despite sharing the same genotype, the clinical spectrum was markedly variable" (PMID: 42407393). This illustrates variable expressivity and incomplete penetrance. Importantly, the surviving siblings received a preventive strategy: "The surviving cases were given a preventive treatment plan with pulse steroids during influenza infections. At 2 years of follow-up, they still have no new episodes of encephalopathy" (PMID: 42407393) — proof-of-concept for anti-inflammatory prophylaxis during febrile illness.

Finding 8 — Systematic review (n=92): demographics and vaccine safety

Cavaliere et al. (2026) conducted a PRISMA systematic review of familial/recurrent/genetic ANE: "Ninety-two patients were analysed (91 literature cases and 1 novel case) (median onset age 24 months; 62% male; RANBP2 mutations in 81% of tested individuals)" (PMID: 42385467). Of 142 clinical events, 108 were definite/probable ANE and 34 were atypical (25 infection-triggered encephalopathy without bithalamic involvement; 9 other acute neurological events); in 13% of patients, atypical episodes preceded a subsequent ANE event. Regarding vaccination safety: "5/20 resumed vaccination post-ANE (no vaccine-related relapses over a median follow-up of 19 months)" (PMID: 42385467).

Finding 9 — Diagnosis rests on characteristic MRI plus RANBP2 sequencing; key labs distinguish from Reye syndrome

The diagnosis is clinical-radiological, supported by a characteristic laboratory profile. A classic case description notes: "His serum CPK was markedly elevated, but there was no hyperammonaemia or hypoglycaemia. His CSF showed an increased protein level, but the cell count and glucose level were normal" (PMID: 10834515) — the elevated CSF protein without pleocytosis and the absence of hyperammonemia/hypoglycemia distinguish ANE from Reye syndrome. The para-infectious (non-neuroinvasive) nature is supported by PCR-negative CSF: "Antibody production without detectable levels of influenza virus in cerebrospinal fluid suggests that virus infection occurred, but the virus did not replicate in sufficient numbers in his central nervous system" (PMID: 10834515). Molecular confirmation of ANE1 is by RANBP2 single-gene sequencing or multigene panel/WES. A rapid bedside functional assay for RANBP2-ANE1 has been proposed (PMID: 38046586).

Finding 10 — ANE1 is a gene–environment disorder with modifiers and locus heterogeneity

ANE1 is a paradigmatic gene–environment interaction: it requires both a genetic predisposition (RANBP2 variant) and an environmental trigger (febrile viral infection), with incomplete penetrance. Ohashi et al. reported a modifier: a patient carrying both RANBP2 p.Thr585Met and a thermolabile CPT2 polymorphism — "The patient also harbored a CPT2 polymorphism that is linked to acute encephalopathy in Japanese patients. Thus, he had a genetic background with two susceptibility variants for acute encephalopathy, RANBP2 (frequent in the Caucasians), and CPT2 (frequent in the Japa[nese])" (PMID: 34059398). Locus heterogeneity is established by López-Laso et al., who described a familial/recurrent ANE family without RANBP2 mutations: "Mutations in RANBP2 are not the sole susceptibility alleles for familial or recurrent ANE" (PMID: 19643689) — consistent with the systematic review's finding of RANBP2 variants in only 81% of tested cases.

Finding 11 — Management is supportive plus early immunomodulation; prophylactic steroids in carriers are emerging prevention

No RANBP2-targeted or disease-specific approved therapy exists. Acute management combines ICU-level supportive care with immunomodulation. For SARS-CoV-2-related ANE: "Treatment with a combination of early steroid therapy, intravenous immunoglobulin therapy, and targeted interleukin 6 (IL-6) blockade yielded good neurological improvements" (PMID: 36529001). Preventive strategies include prophylactic pulse steroids during infections in carriers (PMID: 42407393) and influenza vaccination, which did not provoke relapses (PMID: 42385467).

Report by Template Section

1. Disease Information

ANE1 is a rare, autosomal-dominant, incompletely penetrant Mendelian predisposition to infection-triggered acute necrotizing encephalopathy. Identifiers: MONDO:0011953; OMIM 608033 (phenotype); RANBP2 gene OMIM 601181; Orphanet (rare disease). Synonyms: acute necrotizing encephalopathy type 1; familial/recurrent/genetic acute necrotizing encephalopathy; RANBP2-associated ANE; infection-induced acute encephalopathy 3 (IIAE3). Information is derived from aggregated disease-level resources (case reports, kindred studies, and systematic reviews) rather than EHR.

2. Etiology

Primary cause: heterozygous germline missense variants in RANBP2 (recurrent p.Thr585Met). Genetic risk factors: the causal RANBP2 variants; modifier/co-susceptibility alleles such as the thermolabile CPT2 p.Phe352Cys polymorphism (PMID: 34059398). Environmental risk factors: common febrile viral infections (influenza A/B, HHV-6/7, parainfluenza, RSV, varicella zoster, dengue, SARS-CoV-2); fever/hyperthermia is a key trigger. Protective factors: avoidance/mitigation of febrile viral illness (vaccination, antipyresis, antivirals) reduces trigger exposure; no genetic protective alleles are established. Gene–environment interaction: disease requires BOTH the genetic predisposition AND an infectious trigger — a canonical GxE disorder with incomplete penetrance (PMID: 19643689).

3. Phenotypes

Core phenotypes and suggested HPO terms: - Acute/recurrent encephalopathy (HP:0006846 Acute encephalopathy) — rapid deterioration of consciousness; severe; episodic/recurrent with infections. - Seizures (HP:0001250) — common in acute episodes. - Fever (HP:0001945) — prodromal trigger. - Coma / reduced consciousness (HP:0001259) — severe episodes. - Ataxia (HP:0001251), dysarthria (HP:0001260), developmental regression/delay (HP:0002376) — sequelae. - Elevated CSF protein (HP:0002922), elevated hepatic transaminases (HP:0002910), hyperferritinemia (HP:0003281), thrombocytopenia (HP:0001873), elevated CPK (HP:0003236) — laboratory abnormalities. - Age of onset: infancy–early childhood (median 24 months). Severity: severe/variable. Progression: episodic/relapsing with infections, often with cumulative deficits. Frequency: RANBP2 variant in ~81% of tested familial cases. QoL impact: survivors frequently have severe disability or vegetative state.

4. Genetic/Molecular Information

Causal gene: RANBP2 (HGNC:9848; OMIM 601181; NCBI Gene 5903). Pathogenic variants: p.Thr585Met (c.1880C>T, recurrent hotspot, pathogenic); p.Trp681Cys (de novo); p.Glu3014Gly (c.9041A>G). Variant type: missense. Classification: pathogenic/likely pathogenic (ACMG/AMP). Allele frequency: extremely rare in gnomAD (private/ultra-rare). Origin: germline (inherited or de novo). Functional consequence: altered function of a multidomain nucleoporin affecting nucleocytoplasmic transport, SUMOylation, and CNS energy metabolism (HKI/ATP). Modifier genes: CPT2 thermolabile polymorphism. Chromosomal abnormalities: none characteristic; the 2q12-13 region harboring RANBP2 is structurally dynamic with RGPD paralogs (PMID: 37795679).

5. Environmental Information

Environmental/infectious factors: viral febrile infections are the essential trigger — influenza A/B (including H1N1), HHV-6/HHV-7, parainfluenza, RSV, varicella zoster, dengue, and SARS-CoV-2. Lifestyle factors: not established; fever itself is the operative exposure. The para-infectious nature (PCR-negative CSF) indicates the brain injury is immune/inflammatory rather than directly virus-invasive.

6. Mechanism / Pathophysiology — Ordered Causal Chain

1. Germline heterozygous RANBP2 missense variant (e.g., p.Thr585Met)
      → creates an incompletely penetrant predisposition [demonstrated: genetics]
2. Baseline reduced RANBP2 function
      → lowers hexokinase I and ATP selectively in the CNS
[demonstrated in RanBP2+/- mouse; inferred for human variants]
3. A common febrile viral infection (influenza, HHV-6, SARS-CoV-2)
      → triggers a systemic hyperinflammatory response [demonstrated: clinical]
4. Excessive pro-inflammatory cytokines (IL-6, TNF-α; hyperferritinemia)
      → "cytokine storm" [demonstrated: serum cytokines elevated <24h]
5. Cytokines cause endothelial activation + local BBB breakdown ("dysoria")
      → vasogenic/cytotoxic edema + petechial hemorrhage [demonstrated: neuropathology]
         │
         ├─(branch A: metabolic) energy failure in
         │   high-demand gray matter (thalamus, brainstem)
         │
         └─(branch B: inflammatory) direct cytokine-mediated
             endothelial/parenchymal injury
6. Multifocal SYMMETRIC necrosis → bilateral thalami, brainstem tegmentum,
   external capsules, insular cortex, periventricular white matter, cerebellum
      → coma, seizures, focal deficits; recurrence with each infection
  • Molecular pathways: cytokine signaling (IL-6/JAK-STAT, TNF-α); nucleocytoplasmic transport; SUMOylation (RANBP2 E3 SUMO ligase); glycolysis (hexokinase I).
  • Cellular processes: inflammation (GO:0006954), necrosis (GO:0070265), blood–brain-barrier disruption, apoptosis (GO:0006915).
  • Protein dysfunction: altered function of the Nup358 cytoplasmic-filament nucleoporin.
  • Metabolic changes: reduced CNS hexokinase I and ATP (GO:0006006 glucose metabolic process; GO:0006754 ATP biosynthetic process).
  • Immune involvement: hyperinflammatory cytokine storm (not autoimmune, not immunodeficiency).
  • Tissue damage: BBB breakdown (dysoria), vasogenic/cytotoxic edema, petechial hemorrhage, necrosis.
  • Cell types (CL): vascular endothelial cells (CL:0000115), neurons (CL:0000540), astrocytes (CL:0000127), microglia (CL:0000129).
  • Subcellular (GO CC): nuclear pore (GO:0005643), cytoplasmic filaments, mitochondrion (GO:0005739), mitochondria–ER junction.

7. Anatomical Structures Affected

  • Primary organ: brain (UBERON:0000955); body system: central nervous system.
  • Specific sites (UBERON): thalamus (UBERON:0001897) — bilateral and symmetric; brainstem/midbrain tegmentum (UBERON:0002298 brainstem); external capsule; insular cortex (UBERON:0002022); periventricular white matter; cerebellum (UBERON:0002037); mammillary bodies, periaqueductal gray, hippocampus (reported in some cases).
  • Lateralization: bilateral, symmetric — a diagnostic hallmark.
  • Secondary involvement: rare multiorgan involvement (e.g., acute fulminant myocarditis reported concomitantly).
  • Tissue level: both gray and white matter; nervous tissue and cerebral vasculature.

8. Temporal Development

  • Onset: pediatric, typically infancy–early childhood (median ~24 months); pattern: acute/fulminant, following a viral prodrome by days.
  • Progression: episodic/relapsing — acute episodes recur with each new febrile infection; within an episode, rapid (hours–days) deterioration to coma.
  • Disease course: lifelong predisposition; between episodes patients may be stable, but cumulative deficits can accrue.
  • Remission: acute episodes may partially resolve (imaging shows resolution of swelling with residual cytotoxic edema); prophylactic steroids during infections may prevent new episodes.
  • Critical period: the first 24–72 hours of a febrile illness is the window for intervention (early steroids/immunomodulation).

9. Inheritance and Population

  • Inheritance: autosomal dominant, incomplete penetrance, variable expressivity (PMID: 19118815; PMID: 42407393).
  • Penetrance: incomplete; some carriers never develop ANE despite recurrent infections.
  • De novo / mosaicism: de novo occurrence documented in ≥2 families; germline mosaicism not specifically reported.
  • Epidemiology: no precise prevalence/incidence; ultra-rare. Sporadic ANE predominates in East Asian children; familial ANE1 is rare worldwide and very rare in East Asia.
  • Demographics (systematic review, n=92): median onset 24 months; 62% male; RANBP2 variant in 81% of tested.
  • Founder effect/consanguinity: no founder effect established; reported in non-consanguineous families.

10. Diagnostics

  • Imaging (definitive): brain MRI showing bilateral symmetric lesions of thalami, brainstem tegmentum, external capsules, insular cortex, periventricular white matter, cerebellum; thalamic "tricolour"/laminar/concentric pattern on ADC maps.
  • Laboratory: CSF elevated protein without pleocytosis; elevated serum transaminases (AST/ALT) and CPK; thrombocytopenia; hyperferritinemia; no hyperammonemia or hypoglycemia (distinguishes from Reye syndrome); CSF typically virus-PCR-negative.
  • Genetic testing: RANBP2 single-gene sequencing, multigene encephalopathy panels, or WES/WGS; a rapid bedside functional assay has been proposed (PMID: 38046586).
  • Differential diagnosis: sporadic ANE; acute disseminated encephalomyelitis (ADEM); Leigh/MELAS mitochondrial disease; Wernicke encephalopathy; acute bilateral striatal necrosis; Reye syndrome; acute encephalopathy with biphasic seizures and late reduced diffusion (AESD); dengue necrotizing encephalopathy-like encephalitis.
  • Screening: cascade genetic testing of at-risk relatives in known kindreds; prenatal/pre-symptomatic testing feasible once a familial variant is identified.

11. Outcome / Prognosis

  • Mortality: high — ~38.5% in the Malaysian cohort (5 brainstem deaths); ~30–40% range reported; 69% poor neurological outcome in a 29-patient series.
  • Morbidity: survivors frequently have severe disability or vegetative state at discharge, with variable later recovery.
  • Prognostic factors: ANE-SS (>4.5), brainstem involvement, shock, hyperferritinemia (>1823 ng/mL), AST (>78 U/L), low GCS at presentation, higher MRI scores.
  • Recovery: partial recovery possible with early immunomodulation, particularly when the brainstem is spared; ≥12-month follow-up recommended for accurate prognostication.

12. Treatment

No disease-specific approved therapy. Acute: intensive supportive/ICU care + immunomodulation: - High-dose IV corticosteroids (earliest treatment associated with better outcome) — NCIT: Corticosteroid Therapy. - IVIG (intravenous immunoglobulin). - IL-6 blockade (tocilizumab) — effective in SARS-CoV-2-related ANE (PMID: 36529001). - Trigger-directed therapy: oseltamivir + antipyresis for influenza. - Severe multiorgan cases: ECMO support reported. Prevention in carriers: prophylactic pulse steroids during febrile infections (PMID: 42407393); influenza vaccination. Pharmacogenomics / targeted / gene / cell / RNA therapies: none established.

13. Prevention

  • Primary: influenza vaccination (safe with respect to ANE relapse — PMID: 42385467); avoidance/early treatment of febrile viral illness.
  • Secondary: early recognition and prompt immunomodulation during febrile illness in known carriers; prophylactic pulse steroids.
  • Tertiary: rehabilitation; management of neurologic sequelae.
  • Genetic counseling: autosomal-dominant transmission with incomplete penetrance and variable expressivity must be conveyed; cascade testing in kindreds.

14. Other Species / Natural Disease

  • Taxonomy / orthologs: Ranbp2 mouse ortholog (Mus musculus, NCBI:txid10090). No naturally occurring companion-animal/wildlife equivalent of ANE1 is established (not reported in OMIA).
  • Comparative biology: RANBP2 is conserved across metazoans; the primate-specific RGPD paralog family arose via duplication during ape evolution (PMID: 37795679).
  • Zoonotic potential: not applicable (the human disorder is a host genetic predisposition, not a transmissible disease).

15. Model Organisms

  • Mouse (Mus musculus): RanBP2-null mice are embryonic lethal; inbred RanBP2(+/-) haploinsufficient mice show selectively decreased CNS hexokinase I and ATP, growth deficits, and impaired glucose catabolism (PMID: 17069463) — recapitulating the metabolic arm of ANE1.
  • Additional mouse phenotype: RanBP2 haploinsufficiency is neuroprotective against light-elicited, age-dependent photoreceptor degeneration and alters retinal free-fatty-acid metabolism (PMID: 18949001).
  • Model types available: knockout (lethal), haploinsufficient/heterozygous. Limitation: no mouse model fully reproduces the infection-triggered symmetric thalamic necrosis of human ANE1; the gene–environment (viral-trigger) dimension is not captured.
  • Resources: MGI (mouse), Alliance of Genome Resources.

Mechanistic Model / Interpretation

ANE1 is best understood as a two-hit, gene–environment disorder superimposed on an underlying metabolic vulnerability:

Layer Element Evidence strength
Predisposition Germline RANBP2 variant (p.Thr585Met) Demonstrated (genetics, PMID: 19118815)
Baseline vulnerability Reduced CNS hexokinase I / ATP Demonstrated in mouse (PMID: 17069463); inferred in humans
Trigger Febrile viral infection Demonstrated (clinical, PMID: 19118815)
Amplifier Cytokine storm (IL-6, TNF-α, ferritin) Demonstrated (serum cytokines, PMID: 41714597)
Effector BBB breakdown ("dysoria") Demonstrated (neuropathology, PMID: 9105653)
Lesion Symmetric thalamic/brainstem necrosis Demonstrated (MRI/pathology)

The convergence of a metabolic predisposition (why the brain, and specifically energy-hungry deep gray structures) with an inflammatory trigger (why infections, why symmetric and fulminant) explains both the anatomical selectivity and the episodic, infection-linked course. The therapeutic implication follows directly: interrupting the cytokine-storm amplifier early (steroids, IVIG, tocilizumab) and pre-empting it in carriers (prophylactic steroids during fevers) are the rational interventions, and both have preliminary clinical support.

The ~19% of familial cases without a RANBP2 variant (PMID: 42385467; PMID: 19643689) indicate genetic locus heterogeneity — additional susceptibility genes in the same mechanistic pathway remain to be identified.

Evidence Base

PMID Role Key contribution
19118815 Landmark Identifies RANBP2 p.Thr585Met as causal; AD, incomplete penetrance; viral trigger
35348941 Support Novel p.Glu3014Gly variant — allelic heterogeneity
34059398 Support First Japanese ANE1; CPT2 modifier; MRI signature; geographic contrast
32426208 Review Mechanistic hypotheses; symmetric lesions; early steroids beneficial
24931733 Tool Defines ANE Severity Score
38295717 Support Ferritin/AST/ANE-SS as outcome predictors
9105653 Foundational Defines ANE entity; BBB breakdown (dysoria); East Asian predominance
41714597 Support IL-6/TNF-α elevated <24h — cytokine storm evidence
17069463 Mechanism RanBP2–HKI–Cox11; haploinsufficiency lowers CNS ATP (mouse)
40976348 Background RANBP2 identity, domains, localization
42407393 Support Variable expressivity in 3 siblings; prophylactic steroids
42385467 Review n=92 demographics; RANBP2 in 81%; vaccine safety
10834515 Support Lab profile; para-infectious (PCR-negative CSF)
38046586 Support Proposed rapid bedside RANBP2-ANE1 diagnostic
19643689 Support Locus heterogeneity — RANBP2 not the sole susceptibility allele
36529001 Support Steroids + IVIG + tocilizumab effective (SARS-CoV-2 ANE)
33358123 Support Malaysian cohort: 38.5% mortality; severe sequelae
37795679 Background RANBP2 evolution, RGPD paralogs, disease associations
18949001 Model RanBP2 haploinsufficiency effects in mouse retina/metabolism
26923722 Support Variable course; novel p.Trp681Cys de novo variant

Limitations and Knowledge Gaps

  1. No precise epidemiology. Prevalence and incidence of ANE1 are unknown; evidence is from case reports, kindreds, and a single systematic review (n=92).
  2. Mechanism partly inferred. The link from human RANBP2 variants to the metabolic (HKI/ATP) deficit is demonstrated only in mice; direct human tissue evidence is lacking. The exact molecular pathway from variant to cytokine storm remains "elusive."
  3. Locus heterogeneity unresolved. ~19% of familial/recurrent cases lack a RANBP2 variant; the additional gene(s) are unidentified.
  4. Treatment evidence is low-grade. Steroids, IVIG, and tocilizumab are supported by case reports/small series, not randomized trials; one cohort found early immunomodulation did not change outcome, highlighting inconsistency.
  5. Penetrance/expressivity modifiers poorly characterized. Beyond CPT2, genetic and environmental modifiers that determine whether a carrier develops ANE are largely unknown.
  6. No faithful animal model reproduces the infection-triggered symmetric thalamic necrosis.
  7. Some citation snippets were normalized/approximate (e.g., PMID 24931733, 35348941, 38046586 flagged during verification), so exact wording should be re-verified against source abstracts.

Proposed Follow-up Experiments / Actions

  1. Establish an infection-challenge model in RanBP2 mutant (knock-in p.Thr585Met) mice, challenged with influenza/poly(I:C), to test whether the symmetric thalamic lesion and cytokine storm can be recapitulated and pharmacologically prevented.
  2. Identify the non-RANBP2 loci in the ~19% of familial cases via WGS/trio sequencing and GeneMatcher collaboration.
  3. Prospective registry + natural history study to generate true prevalence/incidence, penetrance estimates, and standardized outcomes.
  4. Biomarker study correlating serial serum IL-6, TNF-α, and ferritin trajectories with ANE-SS and MRI severity to define treatment-response thresholds.
  5. Randomized/adaptive trial (or structured prospective cohort) of early high-dose steroids ± tocilizumab ± IVIG, stratified by brainstem involvement.
  6. Carrier prophylaxis protocol formally evaluating prophylactic pulse steroids and influenza vaccination during febrile illness in genotyped carriers.
  7. Functional validation of the proposed rapid bedside RANBP2-ANE1 assay against genetic gold standard across multiple variants.

Report compiled from 11 confirmed findings and 42 reviewed papers across 5 investigation iterations. Evidence source types span human clinical case reports/cohorts, systematic review, mouse model organism, and in vitro biochemistry.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 20
Resolved 20
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 20
On topic 12
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 30
Resolved 28
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 1
Terms whose name was checked 13
Terms named correctly 5
Terms named as a different term 1
Terms whose name is worth a second look 7

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • UBERON:0000955 (1 mention) - the report calls it "Primary organ: brain"; UBERON calls it brain**

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0070265 (obsolete necrotic cell death) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0001259 (1 mention) - the report calls it "Coma / reduced consciousness"; HP calls it Coma, and lists "Unconsciousness" among its other names
  • HP:0002376 (1 mention) - the report calls it "developmental regression/delay"; HP calls it Developmental regression
  • HP:0002922 (1 mention) - the report calls it "Elevated CSF protein"; HP calls it Increased CSF protein concentration, and lists "Elevated csf protein" among its other names
  • HP:0002910 (1 mention) - the report calls it "elevated hepatic transaminases"; HP calls it Elevated circulating hepatic transaminase concentration, and lists "Elevated transaminases" among its other names
  • HP:0003281 (1 mention) - the report calls it "hyperferritinemia"; HP calls it Increased circulating ferritin concentration, and lists "Hyperferritinemia" among its other names
  • HP:0003236 (1 mention) - the report calls it "elevated CPK"; HP calls it Elevated circulating creatine kinase activity, and lists "Elevated serum CPK" among its other names
  • GO:0006954 (1 mention) - the report calls it "Cellular processes: inflammation"; GO calls it inflammatory response**, and lists "inflammation" among its other names