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Friedreich ataxia 1(FRDA1)

MedGen UID:
383962
Concept ID:
C1856689
Disease or Syndrome
Synonym: FRDA1
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): FXN (9q21.11)
 
Monarch Initiative: MONDO:0100340
OMIM®: 229300
Orphanet: ORPHA95

Definition

Friedreich ataxia (FRDA) is characterized by slowly progressive ataxia with onset usually before age 25 years (mean age at onset: 10-15 yrs). FRDA is typically associated with dysarthria, muscle weakness, spasticity particularly in the lower limbs, scoliosis, bladder dysfunction, absent lower-limb reflexes, and loss of position and vibration sense. Approximately two thirds of individuals with FRDA have cardiomyopathy, up to 30% have diabetes mellitus, and approximately 25% have an "atypical" presentation with later onset or retained tendon reflexes. [from GeneReviews]

Additional descriptions

From OMIM
Friedreich ataxia is an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia with associated limb muscle weakness, absent lower limb reflexes, extensor plantar responses, dysarthria, and decreased vibratory sense and proprioception. Onset is usually in the first or second decade, before the end of puberty. It is one of the most common forms of autosomal recessive ataxia, occurring in about 1 in 50,000 individuals. Other variable features include visual defects, scoliosis, pes cavus, and cardiomyopathy (review by Delatycki et al., 2000). Pandolfo (2008) provided an overview of Friedreich ataxia, including pathogenesis, mutation mechanisms, and genotype/phenotype correlation. Genetic Heterogeneity of Friedreich Ataxia Another locus for Friedreich ataxia has been mapped to chromosome 9p (FRDA2; 601992).  http://www.omim.org/entry/229300
From MedlinePlus Genetics
Friedreich ataxia is a genetic 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 of this condition include the gradual loss of strength and sensation in the arms and legs; muscle stiffness (spasticity); and impaired speech, hearing, and vision. Individuals with Friedreich ataxia often have a form of heart disease called hypertrophic cardiomyopathy, which enlarges and weakens the heart muscle and can be life-threatening. Some affected individuals develop diabetes or an abnormal curvature of the spine (scoliosis).

Most people with Friedreich ataxia begin to experience the signs and symptoms of the disorder between ages 5 and 15. Poor coordination and balance are often the first noticeable features. Affected individuals typically require the use of a wheelchair about 10 years after signs and symptoms appear.

About 25 percent of people with Friedreich ataxia have an atypical form in which signs and symptoms begin after age 25. Affected individuals who develop Friedreich ataxia between ages 26 and 39 are considered to have late-onset Friedreich ataxia (LOFA). When the signs and symptoms begin after age 40 the condition is called very late-onset Friedreich ataxia (VLOFA). LOFA and VLOFA usually progress more slowly than typical Friedreich ataxia.  https://medlineplus.gov/genetics/condition/friedreich-ataxia

Clinical features

From HPO
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
An increase in height of the medial longitudinal arch of the foot that does not flatten on weight bearing (i.e., a distinctly hollow form of the sole of the foot when it is bearing weight).
Areflexia of lower limbs
MedGen UID:
347285
Concept ID:
C1856694
Finding
Inability to elicit tendon reflexes in the lower limbs.
Hypertrophic cardiomyopathy
MedGen UID:
2881
Concept ID:
C0007194
Disease or Syndrome
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.
Congestive heart failure
MedGen UID:
9169
Concept ID:
C0018802
Disease or Syndrome
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Abnormality of the cardiovascular system
MedGen UID:
116727
Concept ID:
C0243050
Congenital Abnormality
Any abnormality of the cardiovascular system.
Abnormal EKG
MedGen UID:
105507
Concept ID:
C0522055
Finding
Abnormal rhythm of the heart.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Sensory neuropathy
MedGen UID:
101791
Concept ID:
C0151313
Disease or Syndrome
Peripheral neuropathy affecting the sensory nerves.
Abnormality of visual evoked potentials
MedGen UID:
105509
Concept ID:
C0522214
Finding
An anomaly of visually evoked potentials (VEP), which are electrical potentials, initiated by brief visual stimuli, which are recorded from the scalp overlying the visual cortex.
Limb ataxia
MedGen UID:
196692
Concept ID:
C0750937
Finding
A kind of ataxia that affects movements of the extremities.
Gait ataxia
MedGen UID:
155642
Concept ID:
C0751837
Sign or Symptom
A type of ataxia characterized by the impairment of the ability to coordinate the movements required for normal walking. Gait ataxia is characteirzed by a wide-based staggering gait with a tendency to fall.
Impaired vibratory sensation
MedGen UID:
220959
Concept ID:
C1295585
Finding
A decrease in the ability to perceive vibration. Clinically, this is usually tested with a tuning fork which vibrates at 128 Hz and is applied to bony prominences such as the malleoli at the ankles or the metacarpal-phalangeal joints. There is a slow decay of vibration from the tuning fork. The degree of vibratory sense loss can be crudely estimated by counting the number of seconds that the examiner can perceive the vibration longer than the patient.
Decreased sensory nerve conduction velocity
MedGen UID:
336512
Concept ID:
C1849148
Finding
Reduced speed of conduction of the action potential along a sensory nerve.
Impaired proprioception
MedGen UID:
346424
Concept ID:
C1856691
Finding
A loss or impairment of the sensation of the relative position of parts of the body and joint position.
Decreased amplitude of sensory action potentials
MedGen UID:
870496
Concept ID:
C4024943
Finding
A reduction in the amplitude of sensory nerve action potential. This feature is measured by nerve conduction studies.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Diabetes mellitus
MedGen UID:
8350
Concept ID:
C0011849
Disease or Syndrome
A group of abnormalities characterized by hyperglycemia and glucose intolerance.
Decreased pyruvate carboxylase activity
MedGen UID:
871167
Concept ID:
C4025641
Finding
A decreased rate of pyruvate carboxylase activity.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Reduced visual acuity
MedGen UID:
65889
Concept ID:
C0234632
Finding
Diminished clarity of vision.
Visual impairment
MedGen UID:
777085
Concept ID:
C3665347
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.
Visual field defect
MedGen UID:
854603
Concept ID:
C3887875
Finding
An absolute or relative reduction in the extent of the normal field of vision.
Mitochondrial malic enzyme reduced
MedGen UID:
383965
Concept ID:
C1856697
Finding

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Professional guidelines

PubMed

Sommerville RB, Vincenti MG, Winborn K, Casey A, Stitziel NO, Connolly AM, Mann DL
Trends Cardiovasc Med 2017 Jan;27(1):51-58. Epub 2016 Jun 14 doi: 10.1016/j.tcm.2016.06.005. PMID: 27452966

Recent clinical studies

Etiology

Rafehi H, Read J, Szmulewicz DJ, Davies KC, Snell P, Fearnley LG, Scott L, Thomsen M, Gillies G, Pope K, Bennett MF, Munro JE, Ngo KJ, Chen L, Wallis MJ, Butler EG, Kumar KR, Wu KH, Tomlinson SE, Tisch S, Malhotra A, Lee-Archer M, Dolzhenko E, Eberle MA, Roberts LJ, Fogel BL, Brüggemann N, Lohmann K, Delatycki MB, Bahlo M, Lockhart PJ
Am J Hum Genet 2023 Jan 5;110(1):105-119. Epub 2022 Dec 8 doi: 10.1016/j.ajhg.2022.11.015. PMID: 36493768Free PMC Article
Lynch DR, Chin MP, Boesch S, Delatycki MB, Giunti P, Goldsberry A, Hoyle JC, Mariotti C, Mathews KD, Nachbauer W, O'Grady M, Perlman S, Subramony SH, Wilmot G, Zesiewicz T, Meyer CJ
Mov Disord 2023 Feb;38(2):313-320. Epub 2022 Nov 29 doi: 10.1002/mds.29286. PMID: 36444905
Groh WJ, Bhakta D, Tomaselli GF, Aleong RG, Teixeira RA, Amato A, Asirvatham SJ, Cha YM, Corrado D, Duboc D, Goldberger ZD, Horie M, Hornyak JE, Jefferies JL, Kääb S, Kalman JM, Kertesz NJ, Lakdawala NK, Lambiase PD, Lubitz SA, McMillan HJ, McNally EM, Milone M, Namboodiri N, Nazarian S, Patton KK, Russo V, Sacher F, Santangeli P, Shen WK, Sobral Filho DC, Stambler BS, Stöllberger C, Wahbi K, Wehrens XHT, Weiner MM, Wheeler MT, Zeppenfeld K
Heart Rhythm 2022 Oct;19(10):e61-e120. Epub 2022 Apr 29 doi: 10.1016/j.hrthm.2022.04.022. PMID: 35500790
Lynch DR, Chin MP, Delatycki MB, Subramony SH, Corti M, Hoyle JC, Boesch S, Nachbauer W, Mariotti C, Mathews KD, Giunti P, Wilmot G, Zesiewicz T, Perlman S, Goldsberry A, O'Grady M, Meyer CJ
Ann Neurol 2021 Feb;89(2):212-225. Epub 2020 Nov 5 doi: 10.1002/ana.25934. PMID: 33068037Free PMC Article
Ruano L, Melo C, Silva MC, Coutinho P
Neuroepidemiology 2014;42(3):174-83. Epub 2014 Mar 5 doi: 10.1159/000358801. PMID: 24603320

Diagnosis

Costa I, Barbosa DJ, Benfeito S, Silva V, Chavarria D, Borges F, Remião F, Silva R
Pharmacol Ther 2023 Apr;244:108373. Epub 2023 Mar 8 doi: 10.1016/j.pharmthera.2023.108373. PMID: 36894028
Radmard S, Zesiewicz TA, Kuo SH
Neurol Clin 2023 Feb;41(1):21-44. Epub 2022 Aug 31 doi: 10.1016/j.ncl.2022.05.002. PMID: 36400556Free PMC Article
Coarelli G, Wirth T, Tranchant C, Koenig M, Durr A, Anheim M
J Neurol 2023 Jan;270(1):208-222. Epub 2022 Sep 24 doi: 10.1007/s00415-022-11383-6. PMID: 36152050Free PMC Article
Keita M, McIntyre K, Rodden LN, Schadt K, Lynch DR
Neurodegener Dis Manag 2022 Oct;12(5):267-283. Epub 2022 Jun 29 doi: 10.2217/nmt-2022-0011. PMID: 35766110Free PMC Article
Ruano L, Melo C, Silva MC, Coutinho P
Neuroepidemiology 2014;42(3):174-83. Epub 2014 Mar 5 doi: 10.1159/000358801. PMID: 24603320

Therapy

Lynch DR, Chin MP, Boesch S, Delatycki MB, Giunti P, Goldsberry A, Hoyle JC, Mariotti C, Mathews KD, Nachbauer W, O'Grady M, Perlman S, Subramony SH, Wilmot G, Zesiewicz T, Meyer CJ
Mov Disord 2023 Feb;38(2):313-320. Epub 2022 Nov 29 doi: 10.1002/mds.29286. PMID: 36444905
Keita M, McIntyre K, Rodden LN, Schadt K, Lynch DR
Neurodegener Dis Manag 2022 Oct;12(5):267-283. Epub 2022 Jun 29 doi: 10.2217/nmt-2022-0011. PMID: 35766110Free PMC Article
Lynch DR, Chin MP, Delatycki MB, Subramony SH, Corti M, Hoyle JC, Boesch S, Nachbauer W, Mariotti C, Mathews KD, Giunti P, Wilmot G, Zesiewicz T, Perlman S, Goldsberry A, O'Grady M, Meyer CJ
Ann Neurol 2021 Feb;89(2):212-225. Epub 2020 Nov 5 doi: 10.1002/ana.25934. PMID: 33068037Free PMC Article
Lynch DR, Farmer J, Hauser L, Blair IA, Wang QQ, Mesaros C, Snyder N, Boesch S, Chin M, Delatycki MB, Giunti P, Goldsberry A, Hoyle C, McBride MG, Nachbauer W, O'Grady M, Perlman S, Subramony SH, Wilmot GR, Zesiewicz T, Meyer C
Ann Clin Transl Neurol 2019 Jan;6(1):15-26. Epub 2018 Nov 10 doi: 10.1002/acn3.660. PMID: 30656180Free PMC Article
Cook A, Giunti P
Br Med Bull 2017 Dec 1;124(1):19-30. doi: 10.1093/bmb/ldx034. PMID: 29053830Free PMC Article

Prognosis

Lynch DR, Chin MP, Boesch S, Delatycki MB, Giunti P, Goldsberry A, Hoyle JC, Mariotti C, Mathews KD, Nachbauer W, O'Grady M, Perlman S, Subramony SH, Wilmot G, Zesiewicz T, Meyer CJ
Mov Disord 2023 Feb;38(2):313-320. Epub 2022 Nov 29 doi: 10.1002/mds.29286. PMID: 36444905
Coarelli G, Wirth T, Tranchant C, Koenig M, Durr A, Anheim M
J Neurol 2023 Jan;270(1):208-222. Epub 2022 Sep 24 doi: 10.1007/s00415-022-11383-6. PMID: 36152050Free PMC Article
Keita M, McIntyre K, Rodden LN, Schadt K, Lynch DR
Neurodegener Dis Manag 2022 Oct;12(5):267-283. Epub 2022 Jun 29 doi: 10.2217/nmt-2022-0011. PMID: 35766110Free PMC Article
Plantone D, Pardini M, Rinaldi G
Clin Drug Investig 2021 Jun;41(6):513-527. Epub 2021 Apr 22 doi: 10.1007/s40261-021-01038-1. PMID: 33886098
Schirinzi T, Sancesario A, Bertini E, Castelli E, Vasco G
Cerebellum 2020 Feb;19(1):126-130. doi: 10.1007/s12311-019-01084-8. PMID: 31701351

Clinical prediction guides

Rafehi H, Read J, Szmulewicz DJ, Davies KC, Snell P, Fearnley LG, Scott L, Thomsen M, Gillies G, Pope K, Bennett MF, Munro JE, Ngo KJ, Chen L, Wallis MJ, Butler EG, Kumar KR, Wu KH, Tomlinson SE, Tisch S, Malhotra A, Lee-Archer M, Dolzhenko E, Eberle MA, Roberts LJ, Fogel BL, Brüggemann N, Lohmann K, Delatycki MB, Bahlo M, Lockhart PJ
Am J Hum Genet 2023 Jan 5;110(1):105-119. Epub 2022 Dec 8 doi: 10.1016/j.ajhg.2022.11.015. PMID: 36493768Free PMC Article
Lynch DR, Chin MP, Boesch S, Delatycki MB, Giunti P, Goldsberry A, Hoyle JC, Mariotti C, Mathews KD, Nachbauer W, O'Grady M, Perlman S, Subramony SH, Wilmot G, Zesiewicz T, Meyer CJ
Mov Disord 2023 Feb;38(2):313-320. Epub 2022 Nov 29 doi: 10.1002/mds.29286. PMID: 36444905
Coarelli G, Wirth T, Tranchant C, Koenig M, Durr A, Anheim M
J Neurol 2023 Jan;270(1):208-222. Epub 2022 Sep 24 doi: 10.1007/s00415-022-11383-6. PMID: 36152050Free PMC Article
Lynch DR, Chin MP, Delatycki MB, Subramony SH, Corti M, Hoyle JC, Boesch S, Nachbauer W, Mariotti C, Mathews KD, Giunti P, Wilmot G, Zesiewicz T, Perlman S, Goldsberry A, O'Grady M, Meyer CJ
Ann Neurol 2021 Feb;89(2):212-225. Epub 2020 Nov 5 doi: 10.1002/ana.25934. PMID: 33068037Free PMC Article
Lynch DR, Farmer J, Hauser L, Blair IA, Wang QQ, Mesaros C, Snyder N, Boesch S, Chin M, Delatycki MB, Giunti P, Goldsberry A, Hoyle C, McBride MG, Nachbauer W, O'Grady M, Perlman S, Subramony SH, Wilmot GR, Zesiewicz T, Meyer C
Ann Clin Transl Neurol 2019 Jan;6(1):15-26. Epub 2018 Nov 10 doi: 10.1002/acn3.660. PMID: 30656180Free PMC Article

Recent systematic reviews

Naeije G, Schulz JB, Corben LA
BMC Neurol 2022 Mar 17;22(1):97. doi: 10.1186/s12883-022-02615-3. PMID: 35300598Free PMC Article
Chaudhry D, Chaudhry A, Muzaffar J, Monksfield P, Bance M
J Int Adv Otol 2020 Dec;16(3):411-431. doi: 10.5152/iao.2020.9035. PMID: 33136025Free PMC Article
Zesiewicz TA, Wilmot G, Kuo SH, Perlman S, Greenstein PE, Ying SH, Ashizawa T, Subramony SH, Schmahmann JD, Figueroa KP, Mizusawa H, Schöls L, Shaw JD, Dubinsky RM, Armstrong MJ, Gronseth GS, Sullivan KL
Neurology 2018 Mar 6;90(10):464-471. Epub 2018 Feb 9 doi: 10.1212/WNL.0000000000005055. PMID: 29440566Free PMC Article
Kearney M, Orrell RW, Fahey M, Brassington R, Pandolfo M
Cochrane Database Syst Rev 2016 Aug 30;2016(8):CD007791. doi: 10.1002/14651858.CD007791.pub4. PMID: 27572719Free PMC Article
Ruano L, Melo C, Silva MC, Coutinho P
Neuroepidemiology 2014;42(3):174-83. Epub 2014 Mar 5 doi: 10.1159/000358801. PMID: 24603320

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