inherited Creutzfeldt-Jakob disease

Summary

inherited Creutzfeldt-Jakob disease (MONDO:0007403) is a disease caused by PRNP (GenCC Strong), with 1 cohort gene and 4 clinical trials. Top therapeutic interventions include quinacrine.

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Causal gene: PRNP (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 17
• Phenotypes (HPO): 50
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

50 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000504	Abnormality of vision	Frequent (30-79%)
HP:0000605	Supranuclear gaze palsy	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000712	Emotional lability	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0000726	Dementia	Frequent (30-79%)
HP:0000736	Short attention span	Frequent (30-79%)
HP:0000737	Irritability	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0000741	Apathy	Frequent (30-79%)
HP:0000751	Personality changes	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001289	Confusion	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0001350	Slurred speech	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002067	Bradykinesia	Frequent (30-79%)
HP:0002073	Progressive cerebellar ataxia	Frequent (30-79%)
HP:0002283	Global brain atrophy	Frequent (30-79%)
HP:0002312	Clumsiness	Frequent (30-79%)
HP:0002401	Stroke-like episode	Frequent (30-79%)
HP:0002446	Astrocytosis	Frequent (30-79%)
HP:0002464	Spastic dysarthria	Frequent (30-79%)
HP:0002529	Neuronal loss in central nervous system	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0005327	Loss of facial expression	Frequent (30-79%)
HP:0006943	Diffuse spongiform leukoencephalopathy	Frequent (30-79%)
HP:0007009	Central nervous system degeneration	Frequent (30-79%)
HP:0007017	Progressive forgetfulness	Frequent (30-79%)
HP:0007158	Progressive extrapyramidal muscular rigidity	Frequent (30-79%)
HP:0007183	Focal T2 hyperintense basal ganglia lesion	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0010846	EEG with persistent abnormal rhythmic activity	Frequent (30-79%)
HP:0011099	Spastic hemiparesis	Frequent (30-79%)
HP:0012332	Abnormal autonomic nervous system physiology	Frequent (30-79%)
HP:0012672	Akinetic mutism	Frequent (30-79%)
HP:0025152	Poor visual behavior for age	Frequent (30-79%)
HP:0100256	Senile plaques	Frequent (30-79%)
HP:0100785	Insomnia	Frequent (30-79%)
HP:0100786	Hypersomnia	Frequent (30-79%)
HP:0000738	Hallucinations	Occasional (5-29%)
HP:0000746	Delusion	Occasional (5-29%)
HP:0002072	Chorea	Occasional (5-29%)
HP:0002922	Increased CSF protein concentration	Occasional (5-29%)
HP:0007686	Abnormal pupillary function	Occasional (5-29%)
HP:0010542	Vestibular nystagmus	Occasional (5-29%)
HP:0100292	Amyloidosis of peripheral nerves	Occasional (5-29%)
HP:0100661	Trigeminal neuralgia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	inherited Creutzfeldt-Jakob disease
Mondo ID	MONDO:0007403
OMIM	123400
Orphanet	282166
ICD-11	607607042
SNOMED CT	715807002
UMLS	C0751254
MedGen	155837
GARD	0017307
Is cancer (heuristic)	no

Also known as: CJD · Creutzfeldt-Jakob disease · Creutzfeldt-Jakob disease, variant, resistance to · hereditary Creutzfeldt Jacob disease · inherited CJD

Data availability: 17 ClinVar variants · 3 GenCC gene-disease records · 10 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › prion disease › Creutzfeldt Jacob disease › inherited Creutzfeldt-Jakob disease

Related subtypes (2): sporadic Creutzfeldt-Jakob disease, acquired Creutzfeldt-Jakob disease

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

17 retrieved; paginated sample, class counts are floors:

5 pathogenic, 4 benign/likely benign, 3 uncertain significance, 1 pathogenic/likely pathogenic/pathogenic, low penetrance, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
13399	NM_000311.3(PRNP):c.[385A>G;532G>A]		Pathogenic	no assertion criteria provided
13394	NM_000311.5(PRNP):c.154_177[6_13]	PRNP	Pathogenic	no assertion criteria provided
13395	NM_000311.5(PRNP):c.305C>T (p.Pro102Leu)	PRNP	Pathogenic	criteria provided, multiple submitters, no conflicts
13398	NM_000311.5(PRNP):c.598G>A (p.Glu200Lys)	PRNP	Pathogenic	criteria provided, multiple submitters, no conflicts
13403	NM_000311.5(PRNP):c.628G>A (p.Val210Ile)	PRNP	Pathogenic/Likely pathogenic/Pathogenic, low penetrance	criteria provided, multiple submitters, no conflicts
13411	NM_000311.5(PRNP):c.623G>A (p.Arg208His)	PRNP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
88923	NM_000311.5(PRNP):c.631G>C (p.Glu211Gln)	PRNP	Pathogenic	no assertion criteria provided
1507942	NM_000311.5(PRNP):c.443G>A (p.Arg148His)	PRNP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
13405	NM_000311.5(PRNP):c.538G>A (p.Val180Ile)	PRNP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13406	NM_000311.5(PRNP):c.695T>G (p.Met232Arg)	PRNP	Uncertain significance	criteria provided, multiple submitters, no conflicts
1468083	NM_000311.5(PRNP):c.498G>A (p.Met166Ile)	PRNP	Uncertain significance	criteria provided, multiple submitters, no conflicts
338656	NM_000311.5(PRNP):c.*115G>A	PRNP	Uncertain significance	criteria provided, multiple submitters, no conflicts
13397	NM_000311.5(PRNP):c.385A>G (p.Met129Val)	PRNP	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1576397	NM_000311.5(PRNP):c.636G>A (p.Gln212=)	PRNP	Likely benign	criteria provided, multiple submitters, no conflicts
338645	NM_000311.5(PRNP):c.159C>T (p.Gly53=)	PRNP	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
65494	NM_000311.3(PRNP):c.204_227del24 (p.Pro84_Gln91del)	PRNP	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
766882	NM_000311.5(PRNP):c.306G>A (p.Pro102=)	PRNP	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 7 · 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
PRNP	Definitive	Autosomal recessive	inherited glutathione synthetase deficiency	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRNP	Orphanet:157941	Huntington disease-like 1
PRNP	Orphanet:280397	Familial Alzheimer-like prion disease
PRNP	Orphanet:282166	Inherited Creutzfeldt-Jakob disease
PRNP	Orphanet:356	Gerstmann-Straussler-Scheinker syndrome
PRNP	Orphanet:397606	PrP systemic amyloidosis
PRNP	Orphanet:454745	Kuru
PRNP	Orphanet:466	Fatal familial insomnia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRNP	HGNC:9449	ENSG00000171867	F7VJQ1	Alternative prion protein	gencc,clinvar

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRNP	Other/Unknown	no		Prion, Prion_copper_b_octapeptide, Prion/Doppel_prot_b-ribbon_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
CA1 field of hippocampus	1
pigmented layer of retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRNP	294	ubiquitous	marker	CA1 field of hippocampus, Brodmann (1909) area 23, pigmented layer of retina

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRNP	2,594

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRNP	F7VJQ1	70

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	1	475.8×	0.004	PRNP
NCAM1 interactions	1	248.3×	0.004	PRNP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 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 glutamate receptor signaling pathway	1	3370.4×	0.003	PRNP
negative regulation of amyloid precursor protein catabolic process	1	3370.4×	0.003	PRNP
negative regulation of dendritic spine maintenance	1	2808.7×	0.003	PRNP
regulation of calcium ion import across plasma membrane	1	2808.7×	0.003	PRNP
positive regulation of glutamate receptor signaling pathway	1	1532.0×	0.003	PRNP
dendritic spine maintenance	1	1296.3×	0.003	PRNP
negative regulation of long-term synaptic potentiation	1	1296.3×	0.003	PRNP
negative regulation of protein processing	1	1123.5×	0.003	PRNP
neuron projection maintenance	1	1123.5×	0.003	PRNP
negative regulation of interleukin-17 production	1	1053.2×	0.003	PRNP
negative regulation of activated T cell proliferation	1	1053.2×	0.003	PRNP
response to amyloid-beta	1	991.3×	0.003	PRNP
intracellular copper ion homeostasis	1	936.2×	0.003	PRNP
negative regulation of calcineurin-NFAT signaling cascade	1	936.2×	0.003	PRNP
negative regulation of amyloid-beta formation	1	887.0×	0.003	PRNP
response to cadmium ion	1	732.7×	0.003	PRNP
cellular response to copper ion	1	624.1×	0.003	PRNP
regulation of potassium ion transmembrane transport	1	624.1×	0.003	PRNP
negative regulation of interleukin-2 production	1	581.1×	0.003	PRNP
positive regulation of protein targeting to membrane	1	561.7×	0.003	PRNP
long-term memory	1	421.3×	0.004	PRNP
positive regulation of calcium-mediated signaling	1	421.3×	0.004	PRNP
cellular response to amyloid-beta	1	391.9×	0.004	PRNP
negative regulation of type II interferon production	1	383.0×	0.004	PRNP
negative regulation of T cell receptor signaling pathway	1	366.4×	0.004	PRNP
protein destabilization	1	290.6×	0.005	PRNP
positive regulation of neuron apoptotic process	1	271.8×	0.005	PRNP
positive regulation of protein localization to plasma membrane	1	271.8×	0.005	PRNP
learning or memory	1	240.7×	0.005	PRNP
cellular response to xenobiotic stimulus	1	240.7×	0.005	PRNP

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRNP	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PRNP

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PRNP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE3	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07482085	PHASE3	NOT_YET_RECRUITING	Efavirenz for the Treatment of Creutzfeldt-Jakob Disease
NCT00183092	PHASE2	COMPLETED	CJD (Creutzfeldt-Jakob Disease) Quinacrine Study
NCT05746715	Not specified	RECRUITING	A Natural History Study of Preclinical Genetic Creutzfeldt-Jakob Disease (CJD)
NCT04944732	Not specified	COMPLETED	Evaluation of Diagnostic Criteria for Creutzfeldt Jakob Disease

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
QUINACRINE	4	1
CHEMBL207216	0	1