Details of Disease

General Information of Disease (ID: DIS5DV35)

• Disease Name: Friedreich's ataxia
• Synonyms: hereditary spinal ataxia; Friedreich ataxia with retained reflexes; spinocerebellar ataxia, Friedreich; hereditary spinal sclerosis; FRDA; Friedreich's Ataxia; FA; Friedreich's ataxia; Friedreich ataxia; Friedreich's tabes
• Disease Class: 8A03: Ataxic disorder
• Definition: An inherited condition that affects the nervous system and causes movement problems. People with this condition develop impaired muscle coordination (ataxia) that worsens over time. Other features include the gradual loss of strength and sensation in the arms and legs, muscle stiffness (spasticity), and impaired speech. Many individuals have a form of heart disease called hypertrophic cardiomyopathy. Some develop diabetes, impaired vision, hearing loss, or an abnormal curvature of the spine (scoliosis). Most people with Friedreich ataxia begin to experience the signs and symptoms around puberty.
• Disease Hierarchy:
  DISY8J7U: Autosomal recessive degenerative and progressive cerebellar ataxia
  DIS5DV35: Friedreich's ataxia
• ICD Code:
  ICD-11: ICD-11: 8A03.10
  ICD-9: ICD-9: 334
  Expand ICD-11: '8A03.10
  Expand ICD-9: 334
• Disease Identifiers:
  MONDO ID: MONDO_0100339
  MESH ID: D005621
  UMLS CUI: C0016719
  OMIM ID: 229300
  MedGen ID: 5276
  SNOMED CT ID: 10394003

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 3 Approved Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Actimmune	DM3APM9	Approved	NA	[1]
Idebenone	DMQFDRC	Approved	Small molecular drug	[2]
Omaveloxolone	DMLMNFX	Approved	Small molecular drug	[3]

This Disease is Treated as An Indication in 11 Clinical Trial Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
RT001	DM5XZJY	Phase 3	NA	[4]
A-0001	DMN6QRQ	Phase 2	NA	[5]
CTI-1601	DMM4JMB	Phase 2	Recombinant protein	[6]
EPI-A0001	DMQDJQS	Phase 2	NA	[5]
JOT101	DML4JSX	Phase 2	NA	[7]
RT-001	DM3FS1G	Phase 2	Small molecular drug	[7]
TAK-831	DMWPSJR	Phase 2	NA	[7]
Vatiquinone	DMKS0J0	Phase 2	NA	[1]
EPICATECHIN	DMN0EMP	Phase 1/2	Small molecular drug	[7]
RG-2833	DM7B650	Phase 1	Small molecular drug	[8]
VP20629	DM30L0U	Phase 1	NA	[9]

This Disease is Treated as An Indication in 1 Preclinical Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
CAT4001	DMDUKMR	Preclinical	Small molecular drug	[10]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 6 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
CRTC1	TT4GO0F	Strong	Biomarker	[11]
CTCFL	TTY0RZT	Strong	Altered Expression	[12]
GAA	TTLPC70	Strong	Genetic Variation	[13]
KCNC3	TTALSY9	Strong	Genetic Variation	[14]
KCNJ5	TTEO25X	Strong	Biomarker	[15]
TNNT2	TTWAS18	Strong	Genetic Variation	[16]

This Disease Is Related to 1 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC17A7	DTNK0FR	Strong	Biomarker	[17]

This Disease Is Related to 1 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
FXN	DEXVHDB	Definitive	Autosomal recessive	[18]

This Disease Is Related to 24 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
PIP5K1B	OT8JQ1F7	Limited	Posttranslational Modification	[19]
APTX	OTPAS5G8	Strong	Genetic Variation	[20]
ATXN1	OTQF0HNR	Strong	Genetic Variation	[21]
ATXN10	OTKRDUNN	Strong	Biomarker	[22]
C16orf82	OT77Z5Y5	Strong	Biomarker	[23]
CHMP1B	OTP715L8	Strong	Biomarker	[24]
CIR1	OTKP5JKH	Strong	Biomarker	[15]
COG5	OTZEG7K0	Strong	Biomarker	[25]
CTCF	OT8ZB70U	Strong	Biomarker	[26]
DLD	OT378CU9	Strong	Altered Expression	[27]
FTMT	OTIUX6XG	Strong	Altered Expression	[28]
GLRX5	OTE3L48D	Strong	Biomarker	[29]
GPAA1	OTWVRR35	Strong	Genetic Variation	[30]
ISCU	OTSW6DQP	Strong	Genetic Variation	[31]
JPH3	OTHTJO2I	Strong	Genetic Variation	[32]
MLH3	OT91PPBI	Strong	Altered Expression	[33]
NCF2	OTAUW7L2	Strong	Biomarker	[34]
PDLIM1	OT4EGCPG	Strong	Biomarker	[34]
PPP2R2B	OTSFVC82	Strong	Genetic Variation	[22]
RNF126	OTTECSYY	Strong	Biomarker	[35]
SETX	OTG3JNOQ	Strong	Biomarker	[36]
TJP2	OTQUY6BV	Strong	Genetic Variation	[37]
TNNT1	OT8PBOAR	Strong	Biomarker	[23]
FXN	OTE9U09A	Definitive	Autosomal recessive	[18]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] FDA Approved Drug Products from FDA Official Website. 2023. Application Number: 216718.
• [4] ClinicalTrials.gov (NCT04102501) A Study to Assess Efficacy, Long Term Safety and Tolerability of RT001 in Subjects With Friedreich's Ataxia. U.S. National Institutes of Health.
• [5] ClinicalTrials.gov (NCT01035671) Safety and Efficacy Study of A0001 in Subjects With Friedreich's Ataxia. U.S. National Institutes of Health.
• [6] ClinicalTrials.gov (NCT05579691) A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose Exploration Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Subcutaneous CTI-1601 in Adult Subjects With Friedreich's Ataxia. U.S.National Institutes of Health.
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7501).
• [9] ClinicalTrials.gov (NCT01898884) Safety and Pharmacology Study of VP 20629 in Adults With Friedreich's Ataxia. U.S. National Institutes of Health.
• [10] Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov. 2019 Apr;18(4):295-317.
• [11] TORC1 Inhibition by Rapamycin Promotes Antioxidant Defences in a Drosophila Model of Friedreich's Ataxia.PLoS One. 2015 Jul 9;10(7):e0132376. doi: 10.1371/journal.pone.0132376. eCollection 2015.
• [12] Epigenetic silencing in Friedreich ataxia is associated with depletion of CTCF (CCCTC-binding factor) and antisense transcription.PLoS One. 2009 Nov 19;4(11):e7914. doi: 10.1371/journal.pone.0007914.
• [13] Altered nucleosome positioning at the transcription start site and deficient transcriptional initiation in Friedreich ataxia.J Biol Chem. 2014 May 30;289(22):15194-202. doi: 10.1074/jbc.M114.566414. Epub 2014 Apr 15.
• [14] Frequency of KCNC3 DNA variants as causes of spinocerebellar ataxia 13 (SCA13).PLoS One. 2011 Mar 29;6(3):e17811. doi: 10.1371/journal.pone.0017811.
• [15] Glucose intolerance in first-degree relatives of patients with Friedreich's ataxia is associated with insulin resistance: evidence for a closely linked inherited trait.Metabolism. 1991 Aug;40(8):788-93. doi: 10.1016/0026-0495(91)90004-g.
• [16] Co-existence of frataxin and cardiac troponin T gene mutations in a child with Friedreich Ataxia and familial hypertrophic cardiomyopathy.Hum Mutat. 2002 Mar;19(3):309-10. doi: 10.1002/humu.9019.
• [17] Early VGLUT1-specific parallel fiber synaptic deficits and dysregulated cerebellar circuit in the KIKO mouse model of Friedreich ataxia.Dis Model Mech. 2017 Dec 19;10(12):1529-1538. doi: 10.1242/dmm.030049.
• [18] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [19] Cis-silencing of PIP5K1B evidenced in Friedreich's ataxia patient cells results in cytoskeleton anomalies.Hum Mol Genet. 2013 Jul 15;22(14):2894-904. doi: 10.1093/hmg/ddt144. Epub 2013 Apr 2.
• [20] Absence of aprataxin gene mutations in a Greek cohort with sporadic early onset ataxia and normal GAA triplets in frataxin gene.Neurol Sci. 2010 Jun;31(3):393-7. doi: 10.1007/s10072-009-0201-0. Epub 2009 Dec 2.
• [21] Gait pattern in inherited cerebellar ataxias.Cerebellum. 2012 Mar;11(1):194-211. doi: 10.1007/s12311-011-0296-8.
• [22] Detection of large pathogenic expansions in FRDA1, SCA10, and SCA12 genes using a simple fluorescent repeat-primed PCR assay.J Mol Diagn. 2004 May;6(2):96-100. doi: 10.1016/S1525-1578(10)60496-5.
• [23] Value of cardiac biomarker measurement in the differential diagnosis of infiltrative cardiomyopathy patients with preserved left ventricular systolic function.J Thorac Dis. 2018 Aug;10(8):4966-4975. doi: 10.21037/jtd.2018.07.56.
• [24] A mitochondrial implication in a Tunisian patient with Friedreich's ataxia-like.Pathol Biol (Paris). 2014 Feb;62(1):41-8. doi: 10.1016/j.patbio.2013.07.013. Epub 2013 Sep 4.
• [25] A Mild Form of COG5 Defect Showing Early-Childhood-Onset Friedreich's-Ataxia-Like Phenotypes with Isolated Cerebellar Atrophy.J Korean Med Sci. 2017 Nov;32(11):1885-1890. doi: 10.3346/jkms.2017.32.11.1885.
• [26] Friedreich ataxia patient tissues exhibit increased 5-hydroxymethylcytosine modification and decreased CTCF binding at the FXN locus.PLoS One. 2013 Sep 4;8(9):e74956. doi: 10.1371/journal.pone.0074956. eCollection 2013.
• [27] Lipoamide dehydrogenase: rapid heat inactivation in platelets of patients with recessively inherited ataxia.Neurology. 1981 Feb;31(2):199-202. doi: 10.1212/wnl.31.2.199.
• [28] Characterization of human mitochondrial ferritin promoter: identification of transcription factors and evidences of epigenetic control.Sci Rep. 2016 Sep 14;6:33432. doi: 10.1038/srep33432.
• [29] Iron-sulfur cluster biogenesis and human disease.Trends Genet. 2008 Aug;24(8):398-407. doi: 10.1016/j.tig.2008.05.008. Epub 2008 Jul 5.
• [30] Very late-onset Friedreich's ataxia with minimal GAA1 expansion mimicking multiple system atrophy of cerebellar type.Mov Disord. 2005 Dec;20(12):1643-5. doi: 10.1002/mds.20644.
• [31] Biogenesis of iron-sulfur clusters in mammalian cells: new insights and relevance to human disease.Dis Model Mech. 2012 Mar;5(2):155-64. doi: 10.1242/dmm.009019.
• [32] Huntington's disease phenocopies are clinically and genetically heterogeneous.Mov Disord. 2008 Apr 15;23(5):716-20. doi: 10.1002/mds.21915.
• [33] GAATTC repeat expansion in human cells is mediated by mismatch repair complex MutL and depends upon the endonuclease domain in MLH3 isoform one.Nucleic Acids Res. 2018 May 4;46(8):4022-4032. doi: 10.1093/nar/gky143.
• [34] Lymphoblast Oxidative Stress Genes as Potential Biomarkers of Disease Severity and Drug Effect in Friedreich's Ataxia.PLoS One. 2016 Apr 14;11(4):e0153574. doi: 10.1371/journal.pone.0153574. eCollection 2016.
• [35] E3 Ligase RNF126 Directly Ubiquitinates Frataxin, Promoting Its Degradation: Identification of a Potential Therapeutic Target for Friedreich Ataxia.Cell Rep. 2017 Feb 21;18(8):2007-2017. doi: 10.1016/j.celrep.2017.01.079.
• [36] Autosomal recessive cerebellar ataxias.Orphanet J Rare Dis. 2006 Nov 17;1:47. doi: 10.1186/1750-1172-1-47.
• [37] The Friedreich ataxia critical region spans a 150-kb interval on chromosome 9q13.Am J Hum Genet. 1995 Nov;57(5):1061-7.