Friedreich's ataxia - Wikipedia, the free encyclopedia

7/17/15, 15:15

Friedreich's ataxia
From Wikipedia, the free encyclopedia

Friedreich's ataxia is an autosomal

recessive inherited disease that
causes progressive damage to the
nervous system. It manifests in
initial symptoms of poor
coordination such as gait
disturbance; it can also lead to
scoliosis, heart disease and diabetes,
but does not affect cognitive
function. The disease progresses
until a wheelchair is required for
mobility. Its incidence in the general
population is roughly 1 in 50,000.
The particular genetic mutation
(expansion of an intronic GAA
triplet repeat in the FXN gene) leads
to reduced expression of the
mitochondrial protein frataxin. Over
time this deficiency causes the
aforementioned damage, as well as
frequent fatigue due to effects on
cellular metabolism.

Friedreich's ataxia

Frataxin
Classification and external resources
ICD-10

G11.1
(http://apps.who.int/classifications/icd10/browse/2015/en#/G11.1)

ICD-9-CM

334.0 (http://www.icd9data.com/getICD9Code.ashx?icd9=334.0)

OMIM

229300 (http://omim.org/entry/229300)

DiseasesDB

4980 (http://www.diseasesdatabase.com/ddb4980.htm)

MedlinePlus 001411
(http://www.nlm.nih.gov/medlineplus/ency/article/001411.htm)
eMedicine

article/1150420 (http://emedicine.medscape.com/article/1150420overview)

The ataxia of Friedreich's ataxia

Patient UK Friedreich's ataxia (http://patient.info/doctor/friedreichs-ataxia)
results from the degeneration of
MeSH
D005621 (https://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?
nervous tissue in the spinal cord, in
particular sensory neurons essential
field=uid&term=D005621)
(through connections with the
GeneReviews
Friedreich Ataxia
cerebellum) for directing muscle
(http://www.ncbi.nlm.nih.gov/books/NBK1281/)
movement of the arms and legs. The
spinal cord becomes thinner and
nerve cells lose some of their myelin sheath (the insulating covering on some nerve cells that helps conduct
nerve impulses).

The condition is named after the German physician Nikolaus Friedreich, who first described it in the 1860s.[1]

Contents
1 History
2 Signs and symptoms
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3 Genetics
4 Pathology
4.1 Pathogenesis
5 Treatment
5.1 Idebenone
5.2 RG2833
5.3 Nicotinamide
5.4 In Research
6 Epidemiology
7 In popular culture
8 References
9 External links

History
Friedreich, working as a professor of pathology at the University of Heidelberg, reported five patients with the
condition in a series of three papers in 1863.[2][3][4] Further observations appeared in a subsequent paper in
1876.[5]

Signs and symptoms

Symptoms typically begin sometime between the ages of 5 to 15 years, but in Late Onset FA may occur in the
20s or 30s. Symptoms include any combination, but not necessarily all, of the following:
Muscle weakness in the arms and legs
Loss of coordination
Vision impairment
Hearing impairment
Slurred speech
Curvature of the spine (scoliosis)
High plantar arches (pes cavus deformity of the foot)
Diabetes (about 20% of people with Friedreich's ataxia develop carbohydrate intolerance and 10%
develop diabetes mellitus)[6]
Heart disorders (e.g., atrial fibrillation, and resultant tachycardia (fast heart rate) and hypertrophic
cardiomyopathy)
It presents before 25 years of age with progressive staggering or stumbling gait and frequent falling. Lower
extremities are more severely involved. The symptoms are slow and progressive. Long-term observation shows
that many patients reach a plateau in symptoms in the patient's early adulthood. On average, after 1015 years
with the disease, patients are usually wheelchair bound and require assistance with all activities of daily
living.[7]
The following physical signs may be detected on physical examination:
Cerebellar: Nystagmus, fast saccadic eye movements, truncal ataxia, dysarthria, dysmetria.
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Lower motor neuron lesion: absent deep tendon reflexes.

Pyramidal: extensor plantar responses, and distal weakness are commonly found.
Dorsal column: Loss of vibratory and proprioceptive sensation occurs.
Cardiac involvement occurs in 91% of patients, including cardiomegaly (up to dilated cardiomyopathy),
symmetrical hypertrophy, heart murmurs, and conduction defects. Median age of death is 35 years, while
females have better prognosis with a 20-year survival of 100% as compared to 63% in men.
20% of cases are found in association with diabetes mellitus.[6]

Genetics
Friedreich's ataxia is an autosomal recessive disorder that occurs when
the FXN gene contains amplified intronic GAA repeats (an example of
Trinucleotide repeat expansion). The FXN gene encodes the protein
frataxin.[8] GAA repeat expansion causes frataxin levels to be reduced.
Frataxin is an iron-binding protein responsible for forming ironsulphur
clusters. One result of frataxin deficiency is mitochondrial iron overload
which can cause damage to many proteins.[8] The exact role of frataxin
in normal physiology remains unclear.[9] The gene is located on
chromosome 9.
The mutant gene contains expanded GAA triplet repeats in the first
intron;[10] in a few pedigrees, point mutations have been detected.
Because the defect is located in an intron (which is removed from the
mRNA transcript between transcription and translation), this mutation
does not result in the production of abnormal frataxin proteins. Instead,
the mutation causes gene silencing (i.e., the mutation decreases the
transcription of the gene) through induction of a heterochromatin

Friedreich's ataxia has an autosomal

recessive pattern of inheritance.

structure in a manner similar to position-effect variegation.[11]

Besides reducing expression of frataxin, long tracts of GAA repeats induce chromosome breaks in in vivo yeast
studies.

Pathology
The primary site of pathology is spinal cord and peripheral nerves. Sclerosis and degeneration of dorsal root
ganglion, spinocerebellar tracts, Lateral corticospinal tracts, and posterior columns.[12] The motor neurons of
the spinal cord are spared. In peripheral nerves there is a loss of large myelinated fibres.
Progressive destruction of dorsal root ganglia accounts for thinning of dorsal roots, degeneration of dorsal
columns, transsynaptic atrophy of nerve cells in Clarke's column and dorsal spinocerebellar fibers, atrophy of
gracile and cuneate nuclei and neuropathy of sensory nerves. The lesion of the dentate nucleus consists of
progressive and selective atrophy of large glutamatergic neurons and grumose degeneration of corticonuclear

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synaptic terminals that contain gamma-aminobutyric acid (GABA). Small GABA-ergic neurons and their
projection fibers in the dentato-olivary tract survive. Atrophy of Betz cells and corticospinal tracts constitute a
second lesion.

Pathogenesis
Low frataxin levels lead to insufficient biosynthesis of iron-sulfur clusters that are required for mitochondrial
electron transport and assembly of functional aconitase and iron dysmetabolism of the entire cell. In normal
individuals, the FXN gene encodes frataxin, a mitochondrial matrix protein. This globular protein consists of
two helices and seven strands and is highly conserved, occurring in all eukaryotes and some
prokaryotes.[13] Frataxin has a variety of known functions. Frataxin assists iron-sulfur protein synthesis in the
electron transport chain to ultimately generate adenosine triphosphate (ATP), the energy currency necessary to
carry out metabolic functions in cells. Frataxin also regulates iron transfer in the mitochondria in order provide
a proper amount of reactive oxygen species (ROS) to maintain normal processes.[14] Without frataxin, the
energy in the mitochondria fails, and excess iron causes extra ROS to be created, leading to further cell
damage.[13][14]

Treatment
A person suffering from Friedreich's Ataxia may require some surgical interventions (mainly for the spine and
heart). Often, titanium screws and rods are inserted in the spine to help prevent or slow the progression of
scoliosis. As progression of ataxia occurs, assistive devices such as a cane, walker, or wheelchair are required
for mobility and independence. Other assistive technology, such as a standing frame, can help reduce the
secondary complications of prolonged use of a wheelchair. The goal of surgery is to keep the patient ambulatory
as long as possible.
In many cases, patients experience significant heart conditions as well. These conditions are much more
treatable, and are often countered with ACE inhibitors such as enalapril or lisinopril and other heart medications
such as digoxin.
Persons with Friedreichs ataxia may also benefit from a conservative treatment approach for the management
of symptoms. Health professionals educated in neurological conditions, such as physical therapists and
occupational therapists, can prescribe an exercise program tailored to maximize function and independence. To
address the ataxic gait pattern and loss of proprioception typically seen in persons with Friedreichs ataxia,
physical therapists can use visual cueing during gait training to help facilitate a more efficient gait pattern.[15]
The prescription of an assistive device along with gait training can also prolong independent ambulation.[15]
Low intensity strengthening exercises should also be incorporated to maintain functional use of the upper and
lower extremities.[16] Fatigability should be monitored closely. Stabilization exercises of the trunk and low back
can help with postural control and the management of scoliosis.[15] This is especially indicative if the person is
non-ambulatory and requires the use of a wheelchair. Balance and coordination training using visual feedback

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can also be incorporated into activities of daily living.[15] Exercises should reflect functional tasks such as
cooking, transfers and self-care. Along with gait training, balance and coordination training should be
developed to help minimize the risk of falls.[15]
Stretching exercises can be prescribed to help relieve tight musculature due to scoliosis and pes cavus
deformities.[16]

Idebenone
Idebenone, an antioxidant, was recently removed from the Canadian market in 2013 due to lack of
effectiveness. [17]
There is a Cochrane review on Antioxidants and other Pharmacological treatment in Friedreich Ataxia which
was published in 2012 and is due to be updated before the end of 2015.[18]

RG2833
RG2833 is a histone deacetylase inhibitor originally developed by Repligen but later acquired by BioMarin
Pharmaceutical in January 2014.[19] The first human trials with this compound began in 2012.[20]

Nicotinamide
Nicotinamide administration on patients was associated with a sustained improvement in frataxin concentrations
towards those seen in asymptomatic carriers during 8 weeks of daily dosing. The daily oral administration of
nicotinamide at the doage of 38 g would result in a 15-times increase and 75 g in a doubling of frataxin
protein concentration.[21]
Speech Therapy
Patients also often undertake speech therapy since dysarthria (a motor speech disorder) occurs in almost 100%
of Friedreich's ataxia patients. Speech therapy seeks to improve speech outcomes and/or compensate for
communication deficits.[22]

In Research
Studies by Horizon Pharma on the use of interferon gamma-1B for treatment was recently given fast track
designation by the Food and Drug Administration. [23]

Epidemiology
Friedreich's ataxia is the most prevalent inherited ataxia,[24] affecting about 1 in 50,000 people in the United
States. Males and females are affected equally. The estimated carrier prevalence is 1:110.

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A 1984 Canadian study was able to trace 40 cases of classical Friedreich's disease from 14 French-Canadian
kindreds previously thought to be unrelated to one common ancestral couple arriving in New France in 1634:
Jean Guyon and Mathurine Robin.[25]

In popular culture
The 2007 film The Cake Eaters stars Kristen Stewart as Georgia Kaminski, a teenager living with the condition.
The 2003 book "The Great Fire (novel)" by Shirley Hazzard has Benedict, a teenager living with the condition.

References
1. synd/1406 (http://www.whonamedit.com/synd.cfm/1406.html) at Who Named It?
2. Friedreich N (1863). "Ueber degenerative Atrophie der spinalen Hinterstrnge" [About degenerative atrophy of the
spinal posterior column]. Arch Pathol Anat Phys Klin Med (in German) 26 (34): 391419. doi:10.1007/BF01930976
(https://dx.doi.org/10.1007%2FBF01930976).
3. Friedreich N (1863). "Ueber degenerative Atrophie der spinalen Hinterstrnge" [About degenerative atrophy of the
spinal posterior column]. Arch Pathol Anat Phys Klin Med (in German) 26 (56): 433459. doi:10.1007/BF01878006
(https://dx.doi.org/10.1007%2FBF01878006).
4. Friedreich N (1863). "Ueber degenerative Atrophie der spinalen Hinterstrnge" [About degenerative atrophy of the
spinal posterior column]. Arch Pathol Anat Phys Klin Med (in German) 27 (12): 126. doi:10.1007/BF01938516
(https://dx.doi.org/10.1007%2FBF01938516).
5. Friedreich N (1876). "Ueber Ataxie mit besonderer Bercksichtigung der hereditren Formen" [About ataxia with
special reference to hereditary forms]. Arch Pathol Anat Phys Klin Med (in German) 68 (2): 145245.
doi:10.1007/BF01879049 (https://dx.doi.org/10.1007%2FBF01879049).
6. Thoren, Claes (June 1962). "Diabetes Mellitus in Friedreich's Ataxia". Acta Paediatrica 51: 239247.
doi:10.1111/j.1651-2227.1962.tb08680.x (https://dx.doi.org/10.1111%2Fj.1651-2227.1962.tb08680.x). PMID 13921008
(https://www.ncbi.nlm.nih.gov/pubmed/13921008).
7. Pandolfo M (2009). "Friedreich ataxia: The clinical picture". Journal of Neurology, 256: (1 Suppl), 3-8, doi:
10.1007/s00415-009-1002-3
8. Klockgether T (August 2011). "Update on degenerative ataxias". Curr. Opin. Neurol. 24 (4): 33945.
doi:10.1097/WCO.0b013e32834875ba (https://dx.doi.org/10.1097%2FWCO.0b013e32834875ba). PMID 21734495
(https://www.ncbi.nlm.nih.gov/pubmed/21734495).
9. Marmolino, D. (2011). "Friedreich's ataxia: Past, present and future". Brain Research Reviews 67 (12): 311330.
doi:10.1016/j.brainresrev.2011.04.001 (https://dx.doi.org/10.1016%2Fj.brainresrev.2011.04.001). PMID 21550666
(https://www.ncbi.nlm.nih.gov/pubmed/21550666).
10. Montermini L, Andermann E, Labuda M et al. (August 1997). "The Friedreich ataxia GAA triplet repeat: premutation
and normal alleles". Hum. Mol. Genet. 6 (8): 12616. doi:10.1093/hmg/6.8.1261
(https://dx.doi.org/10.1093%2Fhmg%2F6.8.1261). PMID 9259271 (https://www.ncbi.nlm.nih.gov/pubmed/9259271).
11. Friedreich Ataxia (http://emedicine.medscape.com/article/1150420-overview) at eMedicine
12. Delatycki M, Williamson R, Forrest S (2000). "Friedreich ataxia: an overview"
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1734457). J Med Genet 37 (1): 18 As. doi:10.1136/jmg.37.1.1
(https://dx.doi.org/10.1136%2Fjmg.37.1.1). PMC 1734457 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1734457).
PMID 10633128 (https://www.ncbi.nlm.nih.gov/pubmed/10633128).
13. Pandolfo, M (October 2008). "Friedreich ataxia.". Archives of neurology 65 (10): 1296303.
doi:10.1001/archneur.65.10.1296 (https://dx.doi.org/10.1001%2Farchneur.65.10.1296). PMID 18852343
(https://www.ncbi.nlm.nih.gov/pubmed/18852343).

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14. Sahdeo, S.; Scott, B. D.; McMackin, M. Z.; Jasoliya, M.; Brown, B.; Wulff, H.; Perlman, S. L.; Pook, M. A.; Cortopassi,
G. A. (11 August 2014). "Dyclonine rescues frataxin deficiency in animal models and buccal cells of patients with
Friedreich's ataxia". Human Molecular Genetics 23: 684862. doi:10.1093/hmg/ddu408
(https://dx.doi.org/10.1093%2Fhmg%2Fddu408). PMID 25113747 (https://www.ncbi.nlm.nih.gov/pubmed/25113747).
15. Powers, Wendy (2007-01-01). "Holding Steady: How physical therapy can help patients with Friedreich's Ataxia"
(http://www.fortnet.org/fapg/PTarticleFA.htm). Advance 18 (1): 26. Retrieved 2011-05-16.
16. "Facts About Friedreich's Ataxia (FA)" (http://www.mdausa.org/publications/fa-fried-qa.html). Muscular Dystrophy
Association. 2011. Retrieved 2011-05-16.
17. "CATENA (idebenone) - Voluntary withdrawal of CATENA from the Canadian market - For the Public - Recalls & alerts
- Healthy Canadians Website" (http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/23519a-eng.php).
Healthycanadians.gc.ca. Retrieved 2015-07-04.
18. Kearney, Mary; Orrell, Richard W; Fahey, Michael; Pandolfo, Massimo; Kearney, Mary (2012). "Antioxidants and other
pharmacological treatments for Friedreich ataxia". The Cochrane Database of Systematic Reviews 4: CD007791.
doi:10.1002/14651858.CD007791.pub3 (https://dx.doi.org/10.1002%2F14651858.CD007791.pub3). PMID 22513953
(https://www.ncbi.nlm.nih.gov/pubmed/22513953).
19. "BioMarin Announces Agreement With Repligen for Pre-clinical Compounds (NASDAQ:BMRN)"
(http://investors.bmrn.com/releasedetail.cfm?ReleaseID=820213). Investors.bmrn.com. 2014-01-21. Retrieved
2015-07-04.
20. "FARA Human Trials" (http://www.curefa.org/_pdf/PressRelease03-15-12.pdf) (PDF). Friedreich's Ataxia Research
Alliance. 2012. Retrieved 2012-03-15.
21. Libri, Vincenzo; Yandim, Cihangir; Athanasopoulos, Stavros; Loyse, Naomi; Natisvili, Theona; Law, Pui Pik; Chan,
Ping Kei; Mohammad, Tariq; Mauri, Marta; Tam, Kin Tung; Leiper, James; Piper, Sophie; Ramesh, Aravind; Parkinson,
Michael H; Huson, Les; Giunti, Paola; Festenstein, Richard (2014). "Epigenetic and neurological effects and safety of
high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study". The
Lancet 384 (9942): 50413. doi:10.1016/S0140-6736(14)60382-2 (https://dx.doi.org/10.1016%2FS01406736%2814%2960382-2). PMID 24794816 (https://www.ncbi.nlm.nih.gov/pubmed/24794816).
22. Vogel, Adam P; Folker, Joanne; Poole, Matthew L; Vogel, Adam P (2014). "Treatment for speech disorder in Friedreich
ataxia and other hereditary ataxia syndromes". The Cochrane Database of Systematic Reviews 10: CD008953.
doi:10.1002/14651858.CD008953.pub2 (https://dx.doi.org/10.1002%2F14651858.CD008953.pub2). PMID 25348587
(https://www.ncbi.nlm.nih.gov/pubmed/25348587).
23. Dulaney, Chelsey (2015-04-10). "Horizon Pharmas Friedreichs Ataxia Drug Gets Fast-Track Designation"
(http://www.wsj.com/articles/horizon-pharmas-friedreichs-ataxia-drug-gets-fast-track-designation-1428665791). WSJ.
Retrieved 2015-07-04.
24. Lodi R, Tonon C, Calabrese V, Schapira AH (2006). "Friedreich's ataxia: from disease mechanisms to therapeutic
interventions". Antioxid. Redox Signal. 8 (34): 43843. doi:10.1089/ars.2006.8.438
(https://dx.doi.org/10.1089%2Fars.2006.8.438). PMID 16677089 (https://www.ncbi.nlm.nih.gov/pubmed/16677089).
25. Barbeau A, Sadibelouiz M, Roy M, Lemieux B, Bouchard JP, Geoffroy G (1984). "Origin of Friedreich's disease in
Quebec". The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 11 (4 Suppl):
5069. PMID 6391645 (https://www.ncbi.nlm.nih.gov/pubmed/6391645).

External links
European Friedreich's Ataxia Consortium for Translational Studies (http://www.e-facts.eu/)
friedreichs_ataxia (http://www.ninds.nih.gov/disorders/friedreichs_ataxia) at NINDS
friedreich (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=friedreich) at NIH/UW
GeneTests
FARA The Friedreich's Ataxia Research Alliance (http://curefa.org/index.html) at www.cureFA.org
Asks the Experts - Responses: Friedreich's Ataxia (http://www.mdausa.org/experts/responses.cfm?id=92)
at Muscular Dystrophy Association
NCBI Genes and Disease: Friedreich's ataxia (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?
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rid=gnd.section.205) at National Center for Biotechnology Information

Canadian Association for Familial Ataxias - Claude St-Jean Foundation (http://www.lacaf.org/index.php?
option=com_frontpage&Itemid=1&lang=english)
British Columbia (BC) Ataxia Society (http://www.bcataxia.org/)
Retrieved from "https://en.wikipedia.org/w/index.php?title=Friedreich%27s_ataxia&oldid=669957367"
Categories: Systemic atrophies primarily affecting the central nervous system Autosomal recessive disorders
Mitochondrial diseases Trinucleotide repeat disorders
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