Familial acute necrotizing encephalopathy

Summary

Familial acute necrotizing encephalopathy (MONDO:0011953) is a disease caused by RANBP2 (GenCC Strong), with 7 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RANBP2 (GenCC Strong)
• Cohort genes: 7
• ClinVar variants: 849
• Phenotypes (HPO): 24

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		14	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0001259	Coma	Very frequent (80-99%)
HP:0002922	Increased CSF protein concentration	Very frequent (80-99%)
HP:0006846	Acute encephalopathy	Very frequent (80-99%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001945	Fever	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002063	Rigidity	Frequent (30-79%)
HP:0002171	Gliosis	Frequent (30-79%)
HP:0002181	Cerebral edema	Frequent (30-79%)
HP:0002363	Abnormal brainstem morphology	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002510	Spastic tetraplegia	Frequent (30-79%)
HP:0002793	Abnormal pattern of respiration	Frequent (30-79%)
HP:0003324	Generalized muscle weakness	Frequent (30-79%)
HP:0010663	Abnormality of thalamus morphology	Frequent (30-79%)
HP:0011887	Choroid hemorrhage	Frequent (30-79%)
HP:0012747	Abnormal brainstem MRI signal intensity	Frequent (30-79%)
HP:0025404	Abnormal visual fixation	Frequent (30-79%)
HP:0031982	Abnormal putamen morphology	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial acute necrotizing encephalopathy
Mondo ID	MONDO:0011953
OMIM	608033
Orphanet	88619
SNOMED CT	723359002
UMLS	C2675556
MedGen	382634
GARD	0013232
Is cancer (heuristic)	no

Also known as: acute necrotizing encephalopathy type 1 · ADANE · ANE1 · autosomal dominant acute necrotizing encephalopathy · encephalopathy, acute, infection-induced, 3, susceptibility to · encephalopathy, acute, infection-induced, susceptibility to, 3 · encephalopathy, acute, infection-induced, susceptibility to, type 3 · IIAE3 · infection-induced acute encephalopathy 3 · Postinfectious acute necrotizing hemorrhagic encephalopathy · recurrent acute necrotizing encephalopathy · susceptibility to acute infection-induced encephalopathy-3 · susceptibility to acute necrotizing encephalopathy · susceptibility to infection-induced acute encephalopathy 3

Data availability: 849 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › encephalopathy, acute, infection-induced › familial acute necrotizing encephalopathy

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

300 uncertain significance, 202 likely benign, 48 benign, 27 benign/likely benign, 20 conflicting classifications of pathogenicity, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3065283	NM_006267.5(RANBP2):c.5822_5823insTG (p.Ser1942fs)	RANBP2	Likely pathogenic	criteria provided, single submitter
3065984	NM_006267.5(RANBP2):c.2070G>T (p.Lys690Asn)	RANBP2	Likely pathogenic	no assertion criteria provided
393529	NM_006267.5(RANBP2):c.5249C>G (p.Pro1750Arg)	RANBP2	Likely pathogenic	no assertion criteria provided
2426740	NC_000002.11:g.(?108604612)(109579739_?)del	CCDC138	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1055692	NM_006267.5(RANBP2):c.3419C>T (p.Ser1140Leu)	RANBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1083464	NM_006267.5(RANBP2):c.5801G>A (p.Arg1934His)	RANBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1116450	NM_006267.5(RANBP2):c.2954C>T (p.Pro985Leu)	RANBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1161033	NM_006267.5(RANBP2):c.9346G>A (p.Val3116Ile)	RANBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1494520	NM_006267.5(RANBP2):c.4549A>G (p.Thr1517Ala)	RANBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
382598	NM_006267.5(RANBP2):c.560A>G (p.His187Arg)	RANBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
383037	NM_006267.5(RANBP2):c.783-6T>C	RANBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
383048	NM_006267.5(RANBP2):c.3934G>A (p.Val1312Ile)	RANBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
417861	NM_006267.5(RANBP2):c.3226T>G (p.Leu1076Val)	RANBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
426227	NM_006267.5(RANBP2):c.7966A>G (p.Thr2656Ala)	RANBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
432054	NM_006267.5(RANBP2):c.2502C>G (p.Asn834Lys)	RANBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
445641	NM_006267.5(RANBP2):c.7751A>G (p.Asp2584Gly)	RANBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
469435	NM_006267.5(RANBP2):c.2084A>C (p.Glu695Ala)	RANBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
469452	NM_006267.5(RANBP2):c.3363G>T (p.Lys1121Asn)	RANBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
469478	NM_006267.5(RANBP2):c.6461C>G (p.Pro2154Arg)	RANBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
469479	NM_006267.5(RANBP2):c.6613G>C (p.Gly2205Arg)	RANBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
469484	NM_006267.5(RANBP2):c.7340C>T (p.Ser2447Phe)	RANBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
469495	NM_006267.5(RANBP2):c.8461A>C (p.Thr2821Pro)	RANBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
517033	NM_006267.5(RANBP2):c.7463T>C (p.Val2488Ala)	RANBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1047235	NC_000002.11:g.(?109336063)(109579739_?)dup	CCDC138	Uncertain significance	criteria provided, single submitter
2425552	NC_000002.11:g.(?108604612)(109579739_?)dup	CCDC138	Uncertain significance	criteria provided, single submitter
2425553	NC_000002.11:g.(?109368307)(109579739_?)dup	CCDC138	Uncertain significance	criteria provided, single submitter
3247345	NC_000002.11:g.(?109368307)(109579739_?)del	CCDC138	Uncertain significance	criteria provided, single submitter
1444169	NC_000002.11:g.(?108604612)(109378671_?)dup	GCC2	Uncertain significance	criteria provided, single submitter
1000143	NM_006267.5(RANBP2):c.5786G>A (p.Gly1929Asp)	RANBP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1000431	NM_006267.5(RANBP2):c.374T>G (p.Phe125Cys)	RANBP2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RANBP2	Strong	Autosomal dominant	familial acute necrotizing encephalopathy	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RANBP2	Orphanet:178342	Inflammatory myofibroblastic tumor
RANBP2	Orphanet:263524	Acute necrotizing encephalopathy of childhood
RANBP2	Orphanet:88619	Familial acute necrotizing encephalopathy
RSPH9	Orphanet:244	Primary ciliary dyskinesia
EDAR	Orphanet:1810	Autosomal dominant hypohidrotic ectodermal dysplasia
EDAR	Orphanet:248	Autosomal recessive hypohidrotic ectodermal dysplasia

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RANBP2	HGNC:9848	ENSG00000153201	P49792	E3 SUMO-protein ligase RanBP2	gencc,clinvar
SULT1C4	HGNC:11457	ENSG00000198075	O75897	Sulfotransferase 1C4	clinvar
RSPH9	HGNC:21057	ENSG00000172426	Q9H1X1	Radial spoke head protein 9 homolog	clinvar
GCC2	HGNC:23218	ENSG00000135968	Q8IWJ2	GRIP and coiled-coil domain-containing protein 2	clinvar
BEND4	HGNC:23815	ENSG00000188848	Q6ZU67	BEN domain-containing protein 4	clinvar
CCDC138	HGNC:26531	ENSG00000163006	Q96M89	Coiled-coil domain-containing protein 138	clinvar
EDAR	HGNC:2895	ENSG00000135960	Q9UNE0	Tumor necrosis factor receptor superfamily member EDAR	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RANBP2	E3 SUMO-protein ligase RanBP2	E3 SUMO-protein ligase which facilitates SUMO1 and SUMO2 conjugation by UBE2I.
SULT1C4	Sulfotransferase 1C4	Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of phenolic compounds.
RSPH9	Radial spoke head protein 9 homolog	Functions as part of axonemal radial spoke complexes that play an important part in the motility of sperm and cilia.
GCC2	GRIP and coiled-coil domain-containing protein 2	Golgin which probably tethers transport vesicles to the trans-Golgi network (TGN) and regulates vesicular transport between the endosomes and the Golgi.
EDAR	Tumor necrosis factor receptor superfamily member EDAR	Receptor for EDA isoform A1, but not for EDA isoform A2.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 5 · Druggable fraction: 0.14

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	1.7×	0.595
Other/Unknown	5	1.3×	0.595
Transcription factor	1	1.2×	0.595

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RANBP2	Transcription factor	no		Ran_bind_dom, Znf_RanBP2, Cyclophilin-type_PPIase_dom
SULT1C4	Enzyme (other)	yes	2.8.2.1	Sulfotransferase_dom, P-loop_NTPase
RSPH9	Other/Unknown	no		RSP9
GCC2	Other/Unknown	no		GRIP_dom, GCC2_Rab_bind, MT-Golgi_org_protein
BEND4	Other/Unknown	no		BEN_domain, BEND4
CCDC138	Other/Unknown	no		CCDC138, CCDC138_C, CCDC138_CC
EDAR	Other/Unknown	no		DEATH-like_dom_sf, EDAR_N, TNR19/27/EDAR

Expression context

Cohort genes with no expression data: 0.

5 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	3
male germ line stem cell (sensu Vertebrata) in testis	3
mucosa of paranasal sinus	2
sperm	2
endothelial cell	1
gall bladder	1
left ovary	1
bronchial epithelial cell	1
bronchus	1
calcaneal tendon	1
corpus epididymis	1
primordial germ cell in gonad	1
oocyte	1
pancreatic ductal cell	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RANBP2	294	ubiquitous	marker	endothelial cell, sperm, mucosa of paranasal sinus
SULT1C4	164	broad	marker	ventricular zone, gall bladder, left ovary
RSPH9	167	broad	marker	bronchial epithelial cell, bronchus, mucosa of paranasal sinus
GCC2	285	ubiquitous	marker	calcaneal tendon, corpus epididymis, male germ line stem cell (sensu Vertebrata) in testis
BEND4	87	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, ventricular zone
CCDC138	178	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, sperm, ventricular zone
EDAR	100	tissue_specific	yes	secondary oocyte, oocyte, pancreatic ductal cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RANBP2	7,348
GCC2	2,441
EDAR	1,307
RSPH9	1,230
SULT1C4	884
CCDC138	829
BEND4	546

Intra-cohort edges

A	B	Sources
GCC2	RANBP2	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RANBP2	P49792	33
SULT1C4	O75897	2
RSPH9	Q9H1X1	1
GCC2	Q8IWJ2	1
EDAR	Q9UNE0	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CCDC138	Q96M89	73.25
BEND4	Q6ZU67	60.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 45. Enrichment computed across 7 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by ALK fusions and activated point mutants	2	75.1×	0.012	RANBP2, GCC2
Cytosolic sulfonation of small molecules	1	129.8×	0.030	SULT1C4
Paracetamol ADME	1	105.7×	0.030	SULT1C4
TNFs bind their physiological receptors	1	98.5×	0.030	EDAR
IPs transport between nucleus and cytosol	1	95.2×	0.030	RANBP2
IP3 and IP4 transport between cytosol and nucleus	1	95.2×	0.030	RANBP2
IP6 and IP7 transport between cytosol and nucleus	1	95.2×	0.030	RANBP2
Transport of Ribonucleoproteins into the Host Nucleus	1	89.2×	0.030	RANBP2
Regulation of Glucokinase by Glucokinase Regulatory Protein	1	89.2×	0.030	RANBP2
Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)	1	89.2×	0.030	RANBP2
NEP/NS2 Interacts with the Cellular Export Machinery	1	86.5×	0.030	RANBP2
Nuclear import of Rev protein	1	84.0×	0.030	RANBP2
Vpr-mediated nuclear import of PICs	1	84.0×	0.030	RANBP2
Transport of the SLBP independent Mature mRNA	1	81.6×	0.030	RANBP2
SUMOylation of SUMOylation proteins	1	81.6×	0.030	RANBP2
Transport of the SLBP Dependant Mature mRNA	1	79.3×	0.030	RANBP2
Rev-mediated nuclear export of HIV RNA	1	79.3×	0.030	RANBP2
Nuclear Pore Complex (NPC) Disassembly	1	77.2×	0.030	RANBP2
SUMOylation of ubiquitinylation proteins	1	73.2×	0.030	RANBP2
NS1 Mediated Effects on Host Pathways	1	71.4×	0.030	RANBP2
Phase II - Conjugation of compounds	1	69.6×	0.030	SULT1C4
Transport of Mature mRNA Derived from an Intronless Transcript	1	68.0×	0.030	RANBP2
Viral Messenger RNA Synthesis	1	64.9×	0.030	RANBP2
SUMOylation of DNA replication proteins	1	62.1×	0.030	RANBP2
SUMOylation of RNA binding proteins	1	59.5×	0.030	RANBP2
Drug ADME	1	57.1×	0.030	SULT1C4
Retrograde transport at the Trans-Golgi-Network	1	54.9×	0.030	GCC2
snRNP Assembly	1	52.9×	0.030	RANBP2
tRNA processing in the nucleus	1	49.2×	0.031	RANBP2
SUMOylation of chromatin organization proteins	1	39.6×	0.037	RANBP2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of protein exit from endoplasmic reticulum	1	3370.4×	0.013	GCC2
recycling endosome to Golgi transport	1	1685.2×	0.013	GCC2
radial spoke assembly	1	1123.5×	0.013	RSPH9
salivary gland cavitation	1	674.1×	0.013	EDAR
late endosome to Golgi transport	1	561.7×	0.013	GCC2
axonemal central apparatus assembly	1	561.7×	0.013	RSPH9
flavonoid metabolic process	1	421.3×	0.013	SULT1C4
nuclear export	1	306.4×	0.013	RANBP2
Golgi ribbon formation	1	306.4×	0.013	GCC2
microtubule organizing center organization	1	280.9×	0.013	GCC2
microtubule anchoring	1	259.3×	0.013	GCC2
doxorubicin metabolic process	1	259.3×	0.013	SULT1C4
ethanol catabolic process	1	240.7×	0.013	SULT1C4
regulation of gluconeogenesis	1	224.7×	0.013	RANBP2
3’-phosphoadenosine 5’-phosphosulfate metabolic process	1	224.7×	0.013	SULT1C4
sulfation	1	210.7×	0.013	SULT1C4
centrosome localization	1	177.4×	0.014	RANBP2
NLS-bearing protein import into nucleus	1	160.5×	0.014	RANBP2
protein localization to Golgi apparatus	1	160.5×	0.014	GCC2
pigmentation	1	140.4×	0.015	EDAR
cilium movement involved in cell motility	1	134.8×	0.015	RSPH9
protein targeting to lysosome	1	124.8×	0.016	GCC2
intracellular glucose homeostasis	1	116.2×	0.016	RANBP2
motile cilium assembly	1	116.2×	0.016	RSPH9
axoneme assembly	1	108.7×	0.016	RSPH9
response to amphetamine	1	99.1×	0.017	RANBP2
cilium movement	1	78.4×	0.020	RSPH9
nucleocytoplasmic transport	1	78.4×	0.020	RANBP2
hair follicle development	1	76.6×	0.020	EDAR
protein sumoylation	1	64.8×	0.022	RANBP2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 7

Druggability breadth: 3 of 7 evidence-associated genes (43%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RANBP2	0	0
SULT1C4	0	0
RSPH9	0	0
GCC2	0	0
BEND4	0	0
CCDC138	0	0
EDAR	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RANBP2	1	Binding:1
SULT1C4	1	ADMET:1
EDAR	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SULT1C4	2.8.2.1	aryl sulfotransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	SULT1C4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	RANBP2, RSPH9, GCC2, BEND4, CCDC138, EDAR

Undrugged target profiles

7 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RANBP2	1	—
SULT1C4	1	—
RSPH9	0	—
GCC2	0	—
BEND4	0	—
CCDC138	0	—
EDAR	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.