Multiple system atrophy, cerebellar type

Summary

Multiple system atrophy, cerebellar type (MONDO:0016418) is a disease with 1 cohort gene and 3 clinical trials. Top therapeutic interventions include troriluzole hydrochloride.

At a glance

• Prevalence: 1-9 / 100 000 (Europe)
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 35
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

35 HPO clinical features (Orphanet curated; top 35 by frequency):

HPO ID	Term	Frequency
HP:0000640	Gaze-evoked nystagmus	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001618	Dysphonia	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002068	Neuromuscular dysphagia	Frequent (30-79%)
HP:0002070	Limb ataxia	Frequent (30-79%)
HP:0002073	Progressive cerebellar ataxia	Frequent (30-79%)
HP:0002136	Broad-based gait	Frequent (30-79%)
HP:0002172	Postural instability	Frequent (30-79%)
HP:0002174	Postural tremor	Frequent (30-79%)
HP:0002310	Orofacial dyskinesia	Frequent (30-79%)
HP:0002359	Frequent falls	Frequent (30-79%)
HP:0002494	Abnormal rapid eye movement sleep	Frequent (30-79%)
HP:0002530	Axial dystonia	Frequent (30-79%)
HP:0004926	Orthostatic hypotension due to autonomic dysfunction	Frequent (30-79%)
HP:0005341	Autonomic bladder dysfunction	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0008652	Autonomic erectile dysfunction	Frequent (30-79%)
HP:0010307	Stridor	Frequent (30-79%)
HP:0010536	Central sleep apnea	Frequent (30-79%)
HP:0010545	Downbeat nystagmus	Frequent (30-79%)
HP:0012332	Abnormal autonomic nervous system physiology	Frequent (30-79%)
HP:0012658	Abnormal brain FDG positron emission tomography	Frequent (30-79%)
HP:0012670	Orthostatic syncope	Frequent (30-79%)
HP:0030015	Female anorgasmia	Frequent (30-79%)
HP:0030880	Raynaud phenomenon	Frequent (30-79%)
HP:0000741	Apathy	Occasional (5-29%)
HP:0001300	Parkinsonism	Occasional (5-29%)
HP:0002063	Rigidity	Occasional (5-29%)
HP:0002067	Bradykinesia	Occasional (5-29%)
HP:0002322	Resting tremor	Occasional (5-29%)
HP:0100595	Camptocormia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple system atrophy, cerebellar type
Mondo ID	MONDO:0016418
Orphanet	227510
ICD-11	1585600114
UMLS	C5554234
MedGen	1843304
GARD	0020565
Is cancer (heuristic)	no

Also known as: MSA, cerebellar type · MSA-c · sporadic olivopontocerebellar atrophy type 1 · sporadic OPCA type 1

Data availability: 1 ClinVar variant.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › synucleinopathy › multiple system atrophy › multiple system atrophy, cerebellar type

Related subtypes (3): striatonigral degeneration, pure autonomic failure, multiple system atrophy, parkinsonian type

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 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
245809	NM_014874.4(MFN2):c.838C>T (p.Arg280Cys)	MFN2	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MFN2	Orphanet:2398	Multiple symmetric lipomatosis
MFN2	Orphanet:64751	Hereditary motor and sensory neuropathy type 5
MFN2	Orphanet:90118	Severe early-onset axonal neuropathy due to MFN2 deficiency
MFN2	Orphanet:90120	Hereditary motor and sensory neuropathy type 6
MFN2	Orphanet:99947	Autosomal dominant Charcot-Marie-Tooth disease type 2A2

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
MFN2	HGNC:16877	ENSG00000116688	O95140	Mitofusin-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MFN2	Mitofusin-2	Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion.

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)
MFN2	Other/Unknown	no		Fzo/mitofusin_HR2, Mitofusin_fam, P-loop_NTPase

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
apex of heart	1
cardiac ventricle	1
heart left ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MFN2	297	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MFN2	3,853

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MFN2	O95140	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Miro GTPase Cycle	1	2284.0×	0.003	MFN2
RHOT2 GTPase cycle	1	1631.4×	0.003	MFN2
Mitophagy	1	1038.2×	0.004	MFN2
PINK1-PRKN Mediated Mitophagy	1	356.9×	0.008	MFN2
Selective autophagy	1	278.5×	0.008	MFN2
Autophagy	1	148.3×	0.012	MFN2
Macroautophagy	1	115.3×	0.014	MFN2
Factors involved in megakaryocyte development and platelet production	1	66.4×	0.021	MFN2
Hemostasis	1	36.0×	0.033	MFN2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.033	MFN2
Signal Transduction	1	10.2×	0.098	MFN2

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
type 2 mitophagy	1	3370.4×	0.002	MFN2
mitochondrial membrane organization	1	2407.4×	0.002	MFN2
positive regulation of vascular associated smooth muscle cell apoptotic process	1	2106.5×	0.002	MFN2
mitochondrion localization	1	1685.2×	0.002	MFN2
protein localization to phagophore assembly site	1	991.3×	0.003	MFN2
mitochondrial fusion	1	842.6×	0.003	MFN2
blastocyst formation	1	766.0×	0.003	MFN2
camera-type eye morphogenesis	1	766.0×	0.003	MFN2
negative regulation of Ras protein signal transduction	1	674.1×	0.003	MFN2
negative regulation of smooth muscle cell proliferation	1	624.1×	0.003	MFN2
obsolete protein targeting to mitochondrion	1	581.1×	0.003	MFN2
positive regulation of vascular associated smooth muscle cell proliferation	1	432.1×	0.003	MFN2
response to unfolded protein	1	300.9×	0.004	MFN2
aerobic respiration	1	247.8×	0.005	MFN2
positive regulation of cold-induced thermogenesis	1	163.6×	0.007	MFN2
apoptotic process	1	28.7×	0.035	MFN2

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
MFN2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MFN2	3	Binding:3

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	MFN2

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)
MFN2	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT06647641	Not specified	RECRUITING	The CurePSP Genetics Program

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TRORILUZOLE HYDROCHLORIDE	3	1