Gerstmann-Straussler-Scheinker syndrome

Summary

Gerstmann-Straussler-Scheinker syndrome (MONDO:0007656) is a disease caused by PRNP (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PRNP (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 29
• Phenotypes (HPO): 18

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000	0.0055	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0002066	Gait ataxia	Very frequent (80-99%)
HP:0007340	Lower limb muscle weakness	Very frequent (80-99%)
HP:0012534	Dysesthesia	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)
HP:0000726	Dementia	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001268	Mental deterioration	Frequent (30-79%)
HP:0001284	Areflexia	Frequent (30-79%)
HP:0001315	Reduced tendon reflexes	Frequent (30-79%)
HP:0001317	Abnormal cerebellum morphology	Frequent (30-79%)
HP:0002062	Morphological abnormality of the pyramidal tract	Frequent (30-79%)
HP:0002071	Abnormality of extrapyramidal motor function	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0003401	Paresthesia	Frequent (30-79%)
HP:0011730	Abnormality of central sensory function	Frequent (30-79%)
HP:0031006	Acroparesthesia	Frequent (30-79%)
HP:0410263	Brain imaging abnormality	Frequent (30-79%)
HP:0045084	Limb myoclonus	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Gerstmann-Straussler-Scheinker syndrome
Mondo ID	MONDO:0007656
MeSH	C535800
OMIM	137440
Orphanet	356
DOID	DOID:4249
ICD-10-CM	A81.82
ICD-11	406818835
NCIT	C84727
SNOMED CT	67155006
UMLS	C0017495
MedGen	4886
GARD	0007690
MedDRA	10072075
Is cancer (heuristic)	no

Also known as: amyloidosis cerebral with spongiform encephalopathy · cerebellar ataxia, progressive dementia, and amyloid deposits in the central nervous system · encephalopathy subacute spongiform Gerstmann-Straussler type · Gerstmann Straussler Scheinker syndrome · Gerstmann-Straussler disease · Gerstmann-Straussler-Scheinker disease · GSD · prion dementia · subacute spongiform encephalopathy, Gerstmann-Straussler type

Data availability: 29 ClinVar variants · 3 GenCC gene-disease records · 2 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 › Gerstmann-Straussler-Scheinker syndrome

Related subtypes (9): Creutzfeldt Jacob disease, kuru, scrapie, fatal familial insomnia, Huntington disease-like 1, spongiform encephalopathy with neuropsychiatric features, familial Alzheimer-like prion disease, PrP systemic amyloidosis, sporadic fatal insomnia

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

29 retrieved; paginated sample, class counts are floors:

9 pathogenic, 6 uncertain significance, 4 likely pathogenic, 4 benign/likely benign, 2 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 1 pathogenic/likely pathogenic/pathogenic, low penetrance, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
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
13396	NM_000311.5(PRNP):c.350C>T (p.Ala117Val)	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
13401	NM_000311.5(PRNP):c.593T>C (p.Phe198Ser)	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
13404	NM_000311.5(PRNP):c.314C>T (p.Pro105Leu)	PRNP	Pathogenic	criteria provided, single submitter
13410	NM_000311.5(PRNP):c.392G>T (p.Gly131Val)	PRNP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13412	NM_000311.5(PRNP):c.560A>G (p.His187Arg)	PRNP	Pathogenic	no assertion criteria provided
13414	NM_000311.5(PRNP):c.398C>T (p.Ala133Val)	PRNP	Pathogenic	no assertion criteria provided
39359	NM_000311.5(PRNP):c.532G>A (p.Asp178Asn)	PRNP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
88927	NM_000311.5(PRNP):c.679C>T (p.Gln227Ter)	PRNP	Pathogenic	no assertion criteria provided
1334094	NM_000311.5(PRNP):c.392G>A (p.Gly131Glu)	PRNP	Likely pathogenic	criteria provided, single submitter
13402	NM_000311.5(PRNP):c.650A>G (p.Gln217Arg)	PRNP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3366860	NM_000311.5(PRNP):c.304C>T (p.Pro102Ser)	PRNP	Likely pathogenic	no assertion criteria provided
4819098	NM_000311.5(PRNP):c.353C>T (p.Ala118Val)	PRNP	Likely pathogenic	criteria provided, single submitter
1326274	NM_000311.5(PRNP):c.635A>C (p.Gln212Pro)	PRNP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
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
13415	NM_000311.5(PRNP):c.313C>T (p.Pro105Ser)	PRNP	Uncertain significance	criteria provided, single submitter
1468083	NM_000311.5(PRNP):c.498G>A (p.Met166Ile)	PRNP	Uncertain significance	criteria provided, multiple submitters, no conflicts
1705547	NM_000311.5(PRNP):c.206A>T (p.His69Leu)	PRNP	Uncertain significance	criteria provided, single submitter
338656	NM_000311.5(PRNP):c.*115G>A	PRNP	Uncertain significance	criteria provided, multiple submitters, no conflicts
88922	NM_000311.5(PRNP):c.633G>C (p.Glu211Asp)	PRNP	Uncertain significance	criteria provided, single submitter
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 dominant	Gerstmann-Straussler-Scheinker syndrome	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: 0.