Friedreich ataxia

Summary

Friedreich ataxia (MONDO:0100339) is a disease caused by FXN (GenCC Strong), with 1 cohort gene and 100 clinical trials. Top therapeutic interventions include idebenone, omaveloxolone, and bupropion.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: FXN (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 8
• Phenotypes (HPO): 53
• Clinical trials: 100

Clinical features

Epidemiology

Prevalence records

17 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	2	Europe	Validated
Point prevalence	1-9 / 100 000	2.3	France	Validated
Point prevalence	1-9 / 100 000	1.1	Italy	Validated
Point prevalence	1-9 / 1 000 000	0.13	Finland	Validated
Point prevalence	1-9 / 1 000 000	0.9	Portugal	Validated
Point prevalence	1-9 / 100 000	1.8	United Kingdom	Validated
Point prevalence	1-9 / 1 000 000	0.9	Greece	Validated
Point prevalence	1-9 / 100 000	1	Norway	Validated
Point prevalence	1-9 / 100 000	2.1	Germany	Validated
Point prevalence	1-9 / 1 000 000	0.24	Sweden	Validated
Point prevalence	1-9 / 1 000 000	0.27	Czech Republic	Validated
Point prevalence	1-9 / 100 000	3.03	Russian Federation	Validated
Prevalence at birth	1-9 / 100 000	2.8	Italy	Validated
Prevalence at birth	1-9 / 100 000	6.2	Spain	Validated
Prevalence at birth	1-9 / 100 000	1	Finland	Validated
Point prevalence	1-9 / 100 000	4.3	Spain	Not yet validated
Point prevalence	1-9 / 1 000 000	0.7	Denmark	Not yet validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0002066	Gait ataxia	Obligate (100%)
HP:0001260	Dysarthria	Very frequent (80-99%)
HP:0002070	Limb ataxia	Very frequent (80-99%)
HP:0002141	Gait imbalance	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0009130	Hand muscle atrophy	Very frequent (80-99%)
HP:0010831	Impaired proprioception	Very frequent (80-99%)
HP:0002522	Areflexia of lower limbs	Frequent (30-79%)
HP:0002527	Falls	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002839	Urinary bladder sphincter dysfunction	Frequent (30-79%)
HP:0003115	Abnormal EKG	Frequent (30-79%)
HP:0003390	Sensory axonal neuropathy	Frequent (30-79%)
HP:0003394	Muscle spasm	Frequent (30-79%)
HP:0007010	Poor fine motor coordination	Frequent (30-79%)
HP:0010873	Cervical spinal cord atrophy	Frequent (30-79%)
HP:0012079	Abnormality of central motor conduction	Frequent (30-79%)
HP:0012452	Restless legs	Frequent (30-79%)
HP:0030183	Impaired visually enhanced vestibulo-ocular reflex	Frequent (30-79%)
HP:0000012	Urinary urgency	Frequent (30-79%)
HP:0000570	Abnormal saccadic eye movements	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0001063	Acrocyanosis	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001638	Cardiomyopathy	Frequent (30-79%)
HP:0001760	Abnormal foot morphology	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0002037	Inflammation of the large intestine	Frequent (30-79%)
HP:0002080	Intention tremor	Frequent (30-79%)
HP:0002270	Abnormality of the autonomic nervous system	Frequent (30-79%)
HP:0002312	Clumsiness	Frequent (30-79%)
HP:0002495	Impaired vibratory sensation	Frequent (30-79%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0000819	Diabetes mellitus	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001618	Dysphonia	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002075	Dysdiadochokinesis	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0002546	Incomprehensible speech	Occasional (5-29%)
HP:0003431	Decreased motor nerve conduction velocity	Occasional (5-29%)
HP:0004349	Reduced bone mineral density	Occasional (5-29%)
HP:0007663	Reduced visual acuity	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Friedreich ataxia
Mondo ID	MONDO:0100339
MeSH	D005621
Orphanet	95
DOID	DOID:12705
ICD-10-CM	G11.11
ICD-11	980686666
NCIT	C84718
SNOMED CT	10394003
UMLS	C0016719
MedGen	5276
GARD	0006468
MedDRA	10017374
NORD	818
Is cancer (heuristic)	no

Also known as: FA · FRDA · Friedreich ataxia · Friedreich’s Ataxia · Friedreich’s ataxia · hereditary spinal ataxia · hereditary spinal sclerosis · spinocerebellar ataxia, Friedreich

Data availability: 8 ClinVar variants · 1 GenCC gene-disease record · 85 cell lines.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive cerebellar ataxia › autosomal recessive degenerative and progressive cerebellar ataxia › Friedreich ataxia

Related subtypes (6): early-onset cerebellar ataxia with retained tendon reflexes, Marinesco-Sjogren syndrome, mitochondrial DNA depletion syndrome 7 (hepatocerebral type), congenital cataracts-facial dysmorphism-neuropathy syndrome, early-onset progressive encephalopathy-spastic ataxia-distal spinal muscular atrophy syndrome, FLVCR1-related retinopathy with or without ataxia

Subtypes (3): Friedreich ataxia 2, Friedreich ataxia 1, Friedreich ataxia with retained reflexes

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

8 retrieved; paginated sample, class counts are floors:

6 pathogenic, 1 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3979	NM_000144.5(FXN):c.317T>G (p.Leu106Ter)	FXN	Pathogenic	no assertion criteria provided
3980	NM_000144.5(FXN):c.385-2A>G	FXN	Pathogenic	no assertion criteria provided
3981	NM_000144.5(FXN):c.460A>T (p.Ile154Phe)	FXN	Pathogenic	criteria provided, single submitter
3983	NM_000144.5(FXN):c.3G>T (p.Met1Ile)	FXN	Pathogenic	criteria provided, multiple submitters, no conflicts
3985	NM_000144.5(FXN):c.157del (p.Arg53fs)	FXN	Pathogenic	criteria provided, single submitter
561195	NG_008845.2:g.6725GAA[(200_900)]	FXN	Pathogenic	no assertion criteria provided
3984	NM_000144.5(FXN):c.517T>G (p.Trp173Gly)	FXN	Likely pathogenic	no assertion criteria provided
3982	NM_000144.5(FXN):c.389G>T (p.Gly130Val)	FXN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
FXN	Definitive	Autosomal recessive	Friedreich ataxia 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FXN	Orphanet:95	Friedreich ataxia

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
FXN	HGNC:3951	ENSG00000165060	Q16595	Frataxin, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FXN	Frataxin, mitochondrial	Functions as an activator of persulfide transfer to the scaffoding protein ISCU as component of the core iron-sulfur cluster (ISC) assembly complex and participates to the [2Fe-2S] cluster assembly.

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)
FXN	Other/Unknown	no		Frataxin/CyaY, Frataxin, Frataxin_CS

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
heart left ventricle	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FXN	251	ubiquitous	marker	right lobe of liver, apex of heart, heart left ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FXN	2,291

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FXN	Q16595	19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Mitochondrial iron-sulfur cluster biogenesis	1	815.7×	0.003	FXN
Maturation of TCA enzymes and regulation of TCA cycle	1	571.0×	0.003	FXN
Complex III assembly	1	439.2×	0.003	FXN
Mitochondrial protein import	1	167.9×	0.006	FXN

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
positive regulation of lyase activity	1	16852.0×	0.001	FXN
proprioception	1	4213.0×	0.002	FXN
[4Fe-4S] cluster assembly	1	3370.4×	0.002	FXN
oxidative phosphorylation	1	1404.3×	0.002	FXN
[2Fe-2S] cluster assembly	1	1404.3×	0.002	FXN
negative regulation of organ growth	1	1404.3×	0.002	FXN
mitochondrial respiratory chain complex III assembly	1	1203.7×	0.002	FXN
negative regulation of multicellular organism growth	1	1123.5×	0.002	FXN
response to iron ion	1	936.2×	0.002	FXN
iron ion transport	1	887.0×	0.002	FXN
negative regulation of release of cytochrome c from mitochondria	1	802.5×	0.002	FXN
embryo development ending in birth or egg hatching	1	732.7×	0.002	FXN
organ growth	1	732.7×	0.002	FXN
protein autoprocessing	1	648.1×	0.002	FXN
muscle cell cellular homeostasis	1	648.1×	0.002	FXN
heme biosynthetic process	1	601.9×	0.002	FXN
iron-sulfur cluster assembly	1	601.9×	0.002	FXN
adult walking behavior	1	495.6×	0.002	FXN
intracellular iron ion homeostasis	1	244.2×	0.005	FXN
cellular response to hydrogen peroxide	1	234.1×	0.005	FXN
protein maturation	1	163.6×	0.006	FXN
negative regulation of apoptotic process	1	34.8×	0.029	FXN

Therapeutics

Drugs indicated for this disease

1 approved, 3 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Omaveloxolone	Approved (phase 4)
Idebenone	Phase 3 (in late-stage trials)
Pioglitazone	Phase 3 (in late-stage trials)
Vatiquinone	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Deferiprone, Epoetin Alfa, Etravirine, Ginkgo, INTERFERON GAMMA-1B, Leriglitazone, Niacinamide, Resveratrol, Varenicline, Vitamin E.

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
FXN	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
FXN	7	Binding:7

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	FXN

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)
FXN	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 100.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	39
PHASE2	23
PHASE1	13
PHASE3	11
PHASE1/PHASE2	8
PHASE4	2
PHASE2/PHASE3	2
EARLY_PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01716221	PHASE4	COMPLETED	An Objective Double-blind Evaluation of Bupropion and Citalopram in an Individual With Friedreich Ataxia
NCT04801303	PHASE4	COMPLETED	Evaluation of the Effects of Calcitriol’s in the Neurological Symptoms of Friedreich’s Ataxia Patients
NCT05515536	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Assess the Safety and Efficacy of Vatiquinone in Participants With Friedreich Ataxia
NCT06953583	PHASE3	RECRUITING	A Study to Learn More About the Effects and Long-Term Safety of BIIB141 (Omaveloxolone) in Participants With Friedreich’s Ataxia Aged 2 to 15 Years Old (BRAVE)
NCT00537680	PHASE3	COMPLETED	Study to Assess the Efficacy, Safety and Tolerability of Idebenone in the Treatment of Friedreich’s Ataxia
NCT00697073	PHASE3	COMPLETED	Study to Assess the Safety and Tolerability of Idebenone in the Treatment of Friedreich’s Ataxia Patients
NCT00803868	PHASE2/PHASE3	TERMINATED	Pilot Study of Varenicline (Chantix®) in the Treatment of Friedreich’s Ataxia
NCT00811681	PHASE3	COMPLETED	Effect of Pioglitazone Administered to Patients With Friedreich’s Ataxia: Proof of Concept
NCT00905268	PHASE3	COMPLETED	A Study of Efficacy, Safety and Tolerability of Idebenone in the Treatment of Friedreich’s Ataxia (FRDA) Patients
NCT01303406	PHASE3	COMPLETED	Patient Reported Outcomes in Friedreich’s Ataxia Patients After Withdrawal From Treatment With Idebenone (PROTI)
NCT02415127	PHASE3	COMPLETED	Safety, Tolerability and Efficacy of ACTIMMUNE® Dose Escalation in Friedreich’s Ataxia
NCT02593773	PHASE3	COMPLETED	Safety, Tolerability and Efficacy of ACTIMMUNE® Dose Escalation in Friedreich’s Ataxia Study
NCT02797080	PHASE3	COMPLETED	Long-Term Safety Extension Study of ACTIMMUNE® (Interferon γ-1b) in Children and Young Adults With Friedreich’s Ataxia
NCT04102501	PHASE3	COMPLETED	A Study to Assess Efficacy, Long Term Safety and Tolerability of RT001 in Subjects With Friedreich’s Ataxia
NCT04577352	PHASE2/PHASE3	COMPLETED	A Study to Assess the Efficacy and Safety of Vatiquinone for the Treatment of Participants With Friedreich Ataxia
NCT05445323	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Gene Therapy for Cardiomyopathy Associated With Friedreich’s Ataxia
NCT06447025	PHASE2	RECRUITING	An Open-Label Study of CTI-1601 in Subjects With Friedreich’s Ataxia
NCT06874010	PHASE1/PHASE2	RECRUITING	A Multiple Ascending Dose Study of DT-216P2 in Patients With Friedreich’s Ataxia
NCT00224640	PHASE1/PHASE2	COMPLETED	Iron-Chelating Therapy and Friedreich Ataxia
NCT00229632	PHASE2	COMPLETED	Idebenone to Treat Friedreich’s Ataxia
NCT00530127	PHASE1/PHASE2	COMPLETED	A Study Investigating the Safety and Tolerability of Deferiprone in Patients With Friedreich’s Ataxia
NCT00631202	PHASE2	COMPLETED	Efficacy of Epoetin Alfa in Patients With Friedreich’s Ataxia
NCT00824512	PHASE2	COMPLETED	Efficacy of EGb761 in Patients Suffering From Friedreich Ataxia
NCT00897221	PHASE2	COMPLETED	A Study Investigating the Long-term Safety and Efficacy of Deferiprone in Patients With Friedreich’s Ataxia
NCT01016366	PHASE2	COMPLETED	Safety Study of Carbamylated Erythropoietin to Treat Patients With the Neurodegenerative Disorder Friedreich’s Ataxia
NCT01035671	PHASE2	COMPLETED	Safety and Efficacy Study of A0001 in Subjects With Friedreich’s Ataxia
NCT01339884	PHASE1/PHASE2	COMPLETED	A Study of Resveratrol as Treatment for Friedreich Ataxia
NCT01493973	PHASE2	COMPLETED	Efficacy Study of Epoetin Alfa in Friedreich Ataxia
NCT01728064	PHASE2	COMPLETED	Safety and Efficacy of EPI-743 in Patients With Friedreich’s Ataxia
NCT01962363	PHASE2	COMPLETED	EPI-743 in Friedreich’s Ataxia Point Mutations
NCT01965327	PHASE2	COMPLETED	Interferon Gamma-1b in Friedreich Ataxia (FRDA)
NCT02035020	PHASE2	COMPLETED	A Phase IIa Trial to Test Safety and Efficacy Interferon Gamma Treatment in Elevating Frataxin Levels in FRDA Patients
NCT02255435	PHASE2	COMPLETED	A Study to Learn About the Effects and Safety of RTA 408 (Omaveloxolone) in People Aged 16 to 40 With Friedreich’s Ataxia
NCT02445794	PHASE1/PHASE2	COMPLETED	A First in Human Study of RT001 in Patients With Friedreich’s Ataxia
NCT02660112	PHASE2	COMPLETED	(+) Epicatechin to Treat Friedreich’s Ataxia
NCT03214588	PHASE2	COMPLETED	Efficacy, Tolerability, and Pharmacokinetics of Multiple Doses of Oral TAK-831 in Adults With Friedreich Ataxia
NCT03761511	PHASE2	WITHDRAWN	Study of the Efficacy and Safety of Nicotinamide in Patients With Friedreich Ataxia
NCT03888664	PHASE2	COMPLETED	Open Trail of γIFN for Friedreich Ataxia
NCT03917225	PHASE2	COMPLETED	A Clinical Study to Evaluate the Effect of MIN-102 on the Progression of Friedreich’s Ataxia in Male and Female Patients
NCT03933163	PHASE2	COMPLETED	Micronised Resveratrol as a Treatment for Friedreich Ataxia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
IDEBENONE	4	7
OMAVELOXOLONE	4	6
BUPROPION	4	3
CITALOPRAM	4	3
DEFERIPRONE	4	2
VARENICLINE	4	2
ARTESUNATE	4	1
CALCITRIOL	4	1
ETRAVIRINE	4	1
INTERFERON GAMMA-1B	4	1
NIACINAMIDE	4	1
INTERFERON	3	5
VATIQUINONE	3	5
RESVERATROL	3	2
ACETYLCARNITINE	3	1
ELAMIPRETIDE	3	1
LERIGLITAZONE	3	1
NOMLABOFUSP	2	5
(+)-EPICATECHIN	2	1
LUVADAXISTAT	2	1
CHEMBL498563	0	1