Huntington disease-like syndrome

Summary

Huntington disease-like syndrome (MONDO:0015548) is a disease (an umbrella term covering 10 Mondo subtypes) with 1 cohort gene.

At a glance

• Prevalence: 1-9 / 100 000 (Brazil) [Orphanet-validated]
• Umbrella term: 10 Mondo subtypes
• Cohort genes: 1
• ClinVar variants: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1.85	Brazil	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Huntington disease-like syndrome
Mondo ID	MONDO:0015548
MeSH	C580174
Orphanet	158266
SNOMED CT	702376003
UMLS	C3711380
MedGen	777988
GARD	0020029
Is cancer (heuristic)	no

Also known as: Huntington disease phenocopy syndrome

Data availability: 1 ClinVar variant.

Disease family

An umbrella term covering 10 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › Huntington disease and related disorders › Huntington disease-like syndrome

Related subtypes (1): Huntington disease

Subtypes (10): Machado-Joseph disease, dentatorubral-pallidoluysian atrophy, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, Huntington disease-like 3, neuroferritinopathy, spinocerebellar ataxia type 17, neuroacanthocytosis, Huntington disease-like syndrome due to C9ORF72 expansions, childhood-onset benign chorea with striatal involvement

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 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
424013	NM_000447.3(PSEN2):c.448G>A (p.Val150Met)	PSEN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PSEN2	Orphanet:1020	Early-onset autosomal dominant Alzheimer disease
PSEN2	Orphanet:154	Familial isolated dilated cardiomyopathy

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
PSEN2	HGNC:9509	ENSG00000143801	P49810	Presenilin-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PSEN2	Presenilin-2	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).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PSEN2	Protease	yes		Peptidase_A22A, Pept_A22A_PS2, Preselin/SPP

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
body of pancreas	1
male germ line stem cell (sensu Vertebrata) in testis	1
pancreas	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PSEN2	134	ubiquitous	marker	body of pancreas, male germ line stem cell (sensu Vertebrata) in testis, pancreas

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PSEN2	2,338

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSEN2	P49810	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
Noncanonical activation of NOTCH3	1	1427.5×	0.003	PSEN2
Regulated proteolysis of p75NTR	1	1038.2×	0.003	PSEN2
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	1038.2×	0.003	PSEN2
TGFBR3 PTM regulation	1	951.7×	0.003	PSEN2
NRIF signals cell death from the nucleus	1	713.8×	0.003	PSEN2
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	475.8×	0.004	PSEN2
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	439.2×	0.004	PSEN2
Activated NOTCH1 Transmits Signal to the Nucleus	1	356.9×	0.004	PSEN2
Nuclear signaling by ERBB4	1	346.1×	0.004	PSEN2
EPH-ephrin mediated repulsion of cells	1	219.6×	0.005	PSEN2
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	196.9×	0.005	PSEN2
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	196.9×	0.005	PSEN2

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 calcium import into the mitochondrion	1	5617.3×	0.001	PSEN2
obsolete mitochondrion-endoplasmic reticulum membrane tethering	1	2106.5×	0.001	PSEN2
Notch receptor processing	1	1872.4×	0.001	PSEN2
amyloid-beta formation	1	1872.4×	0.001	PSEN2
amyloid precursor protein catabolic process	1	1203.7×	0.002	PSEN2
membrane protein ectodomain proteolysis	1	648.1×	0.003	PSEN2
calcium ion homeostasis	1	443.5×	0.004	PSEN2
protein processing	1	170.2×	0.008	PSEN2
Notch signaling pathway	1	141.6×	0.009	PSEN2
response to hypoxia	1	95.8×	0.011	PSEN2
intracellular signal transduction	1	38.1×	0.026	PSEN2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
PSEN2	NIROGACESTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSEN2	8	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIROGACESTAT	4	PSEN2
TARENFLURBIL	3	PSEN2
SEMAGACESTAT	3	PSEN2
AVAGACESTAT	2	PSEN2
RG-4733	2	PSEN2
BEGACESTAT	2	PSEN2
E-2212	1	PSEN2
MK-0752	1	PSEN2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PSEN2	479	Binding:460, Functional:12, ADMET:6, Unclassified:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PSEN2	479

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

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	PSEN2
TARENFLURBIL	3	PSEN2
SEMAGACESTAT	3	PSEN2
AVAGACESTAT	2	PSEN2
RG-4733	2	PSEN2
BEGACESTAT	2	PSEN2
E-2212	1	PSEN2
MK-0752	1	PSEN2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PSEN2
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.