Behavioral variant of frontotemporal dementia

Summary

Behavioral variant of frontotemporal dementia (MONDO:0017160) is a disease with 3 cohort genes and 4 clinical trials.

At a glance

• Prevalence: 1-9 / 100 000 (Netherlands) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 1
• Phenotypes (HPO): 40
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	4	Netherlands	Validated

Signs & symptoms

Clinical features (HPO)

40 HPO clinical features (Orphanet curated; top 40 by frequency):

HPO ID	Term	Frequency
HP:0000474	Thickened nuchal skin fold	Very frequent (80-99%)
HP:0000708	Atypical behavior	Very frequent (80-99%)
HP:0000710	Hyperorality	Very frequent (80-99%)
HP:0000711	Restlessness	Very frequent (80-99%)
HP:0000718	Aggressive behavior	Very frequent (80-99%)
HP:0000719	Inappropriate behavior	Very frequent (80-99%)
HP:0000723	Restrictive behavior	Very frequent (80-99%)
HP:0000733	Abnormal repetitive mannerisms	Very frequent (80-99%)
HP:0000734	Disinhibition	Very frequent (80-99%)
HP:0000737	Irritability	Very frequent (80-99%)
HP:0000751	Personality changes	Very frequent (80-99%)
HP:0000757	Lack of insight	Very frequent (80-99%)
HP:0001268	Mental deterioration	Very frequent (80-99%)
HP:0002145	Frontotemporal dementia	Very frequent (80-99%)
HP:0002354	Memory impairment	Very frequent (80-99%)
HP:0002371	Loss of speech	Very frequent (80-99%)
HP:0002381	Aphasia	Very frequent (80-99%)
HP:0002442	Dyscalculia	Very frequent (80-99%)
HP:0002465	Poor speech	Very frequent (80-99%)
HP:0006892	Frontotemporal cerebral atrophy	Very frequent (80-99%)
HP:0010522	Dyslexia	Very frequent (80-99%)
HP:0010526	Dysgraphia	Very frequent (80-99%)
HP:0010529	Echolalia	Very frequent (80-99%)
HP:0030213	Emotional blunting	Very frequent (80-99%)
HP:0030223	Perseveration	Very frequent (80-99%)
HP:0002500	Abnormal cerebral white matter morphology	Frequent (30-79%)
HP:0011204	EEG with continuous slow activity	Frequent (30-79%)
HP:0012658	Abnormal brain FDG positron emission tomography	Frequent (30-79%)
HP:0030212	Collectionism	Frequent (30-79%)
HP:0000709	Psychosis	Occasional (5-29%)
HP:0000741	Apathy	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002071	Abnormality of extrapyramidal motor function	Occasional (5-29%)
HP:0002300	Mutism	Occasional (5-29%)
HP:0002380	Fasciculations	Occasional (5-29%)
HP:0002446	Astrocytosis	Occasional (5-29%)
HP:0002493	Upper motor neuron dysfunction	Occasional (5-29%)
HP:0012671	Abulia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	behavioral variant of frontotemporal dementia
Mondo ID	MONDO:0017160
Orphanet	275864
SNOMED CT	716994006
UMLS	C4011788
MedGen	860225
GARD	0007392
Is cancer (heuristic)	no

Also known as: bv-FTD

Data availability: 1 ClinVar variant · 2 GenCC gene-disease records · 164 cell lines.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › behavioral variant of frontotemporal dementia

Related subtypes (53): cerebellar ataxia, chronic tic disorder, choreatic disease, extrapyramidal and movement disease, benign shuddering attacks, transient tic disorder, essential tremor, lingual-facial-buccal dyskinesia, kuru, inherited Creutzfeldt-Jakob disease, Tourette syndrome, clonic hemifacial spasm, Huntington disease, multiple system atrophy, spinal muscular atrophy-progressive myoclonic epilepsy syndrome, benign paroxysmal tonic upgaze of childhood with ataxia, hereditary geniospasm, tremor-nystagmus-duodenal ulcer syndrome, arthrogryposis, Lafora disease, Unverricht-Lundborg syndrome, neuronal intranuclear inclusion disease, Huntington disease-like 3, brain-lung-thyroid syndrome, myoclonus, familial, proximal myopathy with extrapyramidal signs, progressive myoclonic epilepsy type 7, progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome, progressive non-fluent aphasia, opsoclonus-myoclonus syndrome, isolated facial myokymia, primary orthostatic tremor, familial congenital mirror movements, neuroacanthocytosis, frontotemporal dementia with motor neuron disease, hyperekplexia, intellectual disability-hyperkinetic movement-truncal ataxia syndrome, neurodegeneration with brain iron accumulation, Huntington disease-like syndrome due to C9ORF72 expansions, variably protease-sensitive prionopathy, corticobasal syndrome, sensorineural hearing loss-early graying-essential tremor syndrome, progressive supranuclear palsy, Sandifer syndrome, psychogenic movement disorders, epilepsy with myoclonic absences, infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome, childhood-onset benign chorea with striatal involvement, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, PRRT2-associated paroxysmal movement disorder, SLC6A3-related dopamine transporter deficiency syndrome, dyskinesia with orofacial involvement, autosomal dominant, complex movement disorder with or without neurodevelopmental features

Subtypes (3): semantic dementia, frontotemporal dementia and/or amyotrophic lateral sclerosis 7, frontotemporal dementia and/or amyotrophic lateral sclerosis 3

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

1 retrieved; paginated sample, class counts are floors:

1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1319877	NM_005236.3(ERCC4):c.37G>A (p.Ala13Thr)	ERCC4	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 25 · Orphanet: 13 · 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
PSEN1	Strong	Autosomal dominant	semantic dementia	12
SQSTM1	Strong	Autosomal dominant	frontotemporal dementia and/or amyotrophic lateral sclerosis 3	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SQSTM1	Orphanet:275864	Behavioral variant of frontotemporal dementia
SQSTM1	Orphanet:275872	Frontotemporal dementia with motor neuron disease
SQSTM1	Orphanet:603	Distal myopathy, Welander type
SQSTM1	Orphanet:803	Amyotrophic lateral sclerosis
PSEN1	Orphanet:100069	Semantic dementia
PSEN1	Orphanet:100070	Progressive non-fluent aphasia
PSEN1	Orphanet:1020	Early-onset autosomal dominant Alzheimer disease
PSEN1	Orphanet:154	Familial isolated dilated cardiomyopathy
PSEN1	Orphanet:275864	Behavioral variant of frontotemporal dementia
ERCC4	Orphanet:220295	Xeroderma pigmentosum-Cockayne syndrome complex
ERCC4	Orphanet:84	Fanconi anemia
ERCC4	Orphanet:90321	Cockayne syndrome type 1
ERCC4	Orphanet:910	Xeroderma pigmentosum

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SQSTM1	HGNC:11280	ENSG00000161011	Q13501	Sequestosome-1	gencc
PSEN1	HGNC:9508	ENSG00000080815	P49768	Presenilin-1	gencc
ERCC4	HGNC:3436	ENSG00000175595	Q92889	DNA repair endonuclease XPF	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SQSTM1	Sequestosome-1	Molecular adapter required for selective macroautophagy (aggrephagy) by acting as a bridge between polyubiquitinated proteins and autophagosomes.
PSEN1	Presenilin-1	Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein).
ERCC4	DNA repair endonuclease XPF	Catalytic component of a structure-specific DNA repair endonuclease responsible for the 5-prime incision during DNA repair, and which is essential for nucleotide excision repair (NER) and interstrand cross-link (ICL) repair.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Protease	1	12.2×	0.239
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SQSTM1	Transcription factor	no		PB1_dom, Znf_ZZ, UBA-like_sf
PSEN1	Protease	yes		Peptidase_A22A, Pept_A22A_PS1, Preselin/SPP
ERCC4	Other/Unknown	no		ERCC4_domain, XPF, RuvA_2-like

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1
C1 segment of cervical spinal cord	1
corpus callosum	1
middle frontal gyrus	1
adrenal tissue	1
male germ line stem cell (sensu Vertebrata) in testis	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SQSTM1	241	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
PSEN1	287	ubiquitous	marker	middle frontal gyrus, corpus callosum, C1 segment of cervical spinal cord
ERCC4	242	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SQSTM1	7,269
PSEN1	3,732
ERCC4	2,102

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSEN1	P49768	27
SQSTM1	Q13501	26
ERCC4	Q92889	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 49. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
NRIF signals cell death from the nucleus	2	475.8×	3e-04	SQSTM1, PSEN1
p75NTR signals via NF-kB	1	634.4×	0.017	SQSTM1
Noncanonical activation of NOTCH3	1	475.8×	0.017	PSEN1
Regulated proteolysis of p75NTR	1	346.1×	0.017	PSEN1
Mitophagy	1	346.1×	0.017	SQSTM1
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	346.1×	0.017	PSEN1
Pexophagy	1	317.2×	0.017	SQSTM1
TGFBR3 PTM regulation	1	317.2×	0.017	PSEN1
p75NTR recruits signalling complexes	1	292.8×	0.017	SQSTM1
NF-kB is activated and signals survival	1	292.8×	0.017	SQSTM1
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	158.6×	0.025	PSEN1
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	146.4×	0.025	PSEN1
Activated NOTCH1 Transmits Signal to the Nucleus	1	119.0×	0.025	PSEN1
PINK1-PRKN Mediated Mitophagy	1	119.0×	0.025	SQSTM1
Nuclear signaling by ERBB4	1	115.3×	0.025	PSEN1
Nuclear events mediated by NFE2L2	1	112.0×	0.025	SQSTM1
HDR through Single Strand Annealing (SSA)	1	97.6×	0.025	ERCC4
Fanconi Anemia Pathway	1	92.8×	0.025	ERCC4
Selective autophagy	1	92.8×	0.025	SQSTM1
Interleukin-1 family signaling	1	90.6×	0.025	SQSTM1
Signaling by ALK in cancer	1	90.6×	0.025	SQSTM1
Dual Incision in GG-NER	1	86.5×	0.025	ERCC4
Formation of Incision Complex in GG-NER	1	84.6×	0.025	ERCC4
Cell death signalling via NRAGE, NRIF and NADE	1	73.2×	0.027	SQSTM1
EPH-ephrin mediated repulsion of cells	1	73.2×	0.027	PSEN1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	65.6×	0.028	PSEN1
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	65.6×	0.028	PSEN1
p75 NTR receptor-mediated signalling	1	62.4×	0.028	SQSTM1
Dual incision in TC-NER	1	57.7×	0.029	ERCC4
Signaling by ALK fusions and activated point mutants	1	50.1×	0.032	SQSTM1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of L-glutamate import across plasma membrane	1	2808.7×	0.008	PSEN1
Cajal-Retzius cell differentiation	1	2808.7×	0.008	PSEN1
smooth endoplasmic reticulum calcium ion homeostasis	1	2808.7×	0.008	PSEN1
brown fat cell proliferation	1	1872.4×	0.008	SQSTM1
protein targeting to vacuole involved in autophagy	1	1872.4×	0.008	SQSTM1
protein catabolic process at postsynapse	1	1872.4×	0.008	PSEN1
nucleotide-excision repair involved in interstrand cross-link repair	1	1872.4×	0.008	ERCC4
astrocyte activation involved in immune response	1	1404.3×	0.008	PSEN1
obsolete synaptic vesicle targeting	1	1404.3×	0.008	PSEN1
telomeric DNA-containing double minutes formation	1	1404.3×	0.008	ERCC4
negative regulation of protection from non-homologous end joining at telomere	1	1404.3×	0.008	ERCC4
obsolete sequestering of calcium ion	1	1123.5×	0.008	PSEN1
positive regulation of amyloid fibril formation	1	1123.5×	0.008	PSEN1
negative regulation of telomere maintenance	1	936.2×	0.008	ERCC4
positive regulation of coagulation	1	936.2×	0.008	PSEN1
response to mitochondrial depolarisation	1	936.2×	0.008	SQSTM1
positive regulation of apoptotic process	2	37.8×	0.008	SQSTM1, PSEN1
Notch receptor processing	1	624.1×	0.009	PSEN1
amyloid-beta formation	1	624.1×	0.009	PSEN1
regulation of Ras protein signal transduction	1	624.1×	0.009	SQSTM1
L-glutamate import across plasma membrane	1	624.1×	0.009	PSEN1
aggrephagy	1	561.7×	0.009	SQSTM1
choline transport	1	510.7×	0.009	PSEN1
cerebral cortex cell migration	1	510.7×	0.009	PSEN1
locomotion	1	510.7×	0.009	PSEN1
skin morphogenesis	1	468.1×	0.009	PSEN1
negative regulation of telomere maintenance via telomere lengthening	1	468.1×	0.009	ERCC4
protein localization to perinuclear region of cytoplasm	1	468.1×	0.009	SQSTM1
amyloid precursor protein metabolic process	1	432.1×	0.009	PSEN1
negative regulation of axonogenesis	1	432.1×	0.009	PSEN1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 3 of 3 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PSEN1	NIROGACESTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSEN1	8	4
SQSTM1	0	0
ERCC4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIROGACESTAT	4	PSEN1
TARENFLURBIL	3	PSEN1
SEMAGACESTAT	3	PSEN1
AVAGACESTAT	2	PSEN1
RG-4733	2	PSEN1
BEGACESTAT	2	PSEN1
E-2212	1	PSEN1
MK-0752	1	PSEN1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PSEN1	557	Binding:538, Functional:12, ADMET:6, Unclassified:1
ERCC4	28	Binding:28
SQSTM1	20	Binding:20

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PSEN1	557

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

8 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.

Compound	Max phase	Cohort target (bioactivity)
NIROGACESTAT	4	PSEN1
TARENFLURBIL	3	PSEN1
SEMAGACESTAT	3	PSEN1
AVAGACESTAT	2	PSEN1
RG-4733	2	PSEN1
BEGACESTAT	2	PSEN1
E-2212	1	PSEN1
MK-0752	1	PSEN1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PSEN1
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	2	SQSTM1, ERCC4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SQSTM1	20	—
ERCC4	28	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02736695	PHASE1	COMPLETED	Assessment of Hyperphosphorylated Tau PET Binding in Primary Progressive Aphasia and Frontotemporal Dementia
NCT04680130	Not specified	ENROLLING_BY_INVITATION	Clinico-Pathologic-Genetic-Imaging Study of Neurodegenerative and Related Disorders
NCT04686266	Not specified	COMPLETED	Improving Self-Care of Behavioral Variant Frontotemporal Dementia Caregivers
NCT04883229	Not specified	WITHDRAWN	tDCS and Speech Therapy for Motor Speech Disorders Caused by FTLD Syndromes: a Feasibility Study