Back To Search Results

Friedreich Ataxia

Editor: Orlando De Jesus Updated: 8/23/2023 12:39:10 PM

Introduction

Friedreich ataxia (FA) is the most common hereditary ataxia accounting for approximately 50% of all ataxia cases.[1][2][3][4][5] It was first reported in 1863 by the German physician Nikolaus Friedreich. The disease causes neurodegeneration and manifests as a combination of difficulty in ambulation, muscle weakness, loss of sensation and proprioception, and impaired speech.[6][7][8][9][10] It has an autosomal recessive inheritance pattern, and symptom onset is usually in childhood. Unfortunately, symptoms worsen as time progresses, so most people affected by this disease end up requiring mobility aids such as wheelchairs, lose their vision and hearing, and develop other medical complications such as diabetes mellitus and scoliosis.

The most common cause of death in patients with FA is hypertrophic cardiomyopathy.[11][12][13] Patients with FA have an abnormal amount of trinucleotide repeats on the frataxin (FXN) gene on chromosome 9.[2][3][4] The frataxin gene is responsible for producing frataxin, a protein that helps form enzymes needed for mitochondrial adenosine triphosphate (ATP) production and management of iron stores.[2] In FA, the pathological trinucleotide repeats result in gene silencing and a decrease in frataxin.[3][4][14] Highly active cells depending on ATP production, such as neurons, cardiomyocytes, and pancreatic beta cells, are adversely affected.[9][15]

Etiology

Register For Free And Read The Full Article
Get the answers you need instantly with the StatPearls Clinical Decision Support tool. StatPearls spent the last decade developing the largest and most updated Point-of Care resource ever developed. Earn CME/CE by searching and reading articles.
  • Dropdown arrow Search engine and full access to all medical articles
  • Dropdown arrow 10 free questions in your specialty
  • Dropdown arrow Free CME/CE Activities
  • Dropdown arrow Free daily question in your email
  • Dropdown arrow Save favorite articles to your dashboard
  • Dropdown arrow Emails offering discounts

Learn more about a Subscription to StatPearls Point-of-Care

Etiology

FA results from a loss of function mutation in the frataxin gene located in the centromeric region of chromosome 9q (9q13-21.1).[2][3][4][9][10][11][15][16][17] This gene codes the information for the protein frataxin. This protein is involved in mitochondrial regulation of iron homeostasis and ATP production.[2][4][7][15] It is found in all tissues but produced in higher concentrations in the nervous system, heart, and pancreatic beta cells. Studies have shown that frataxin is a mitochondrial protein essential for ATP production that also serves to regulate iron stores and prevent oxidative phosphorylation.[3][4][15] 

Without frataxin, iron accumulates within mitochondria, reacting with oxygen to generate free radicals while simultaneously reducing mitochondrial antioxidant capabilities. Cells that produce the most frataxin are most sensitive to FA. The deficiency of frataxin ultimately results in cell death, particularly of neurons, cardiomyocytes, and pancreatic beta cells.[9]

A repeat expansion of the trinucleotide GAA (guanine-adenine-adenine), typically in the gene's first intron, is the leading cause of this disease.[3][4][9][16][17][18] While a normal gene would have 7-34 repeats, there can be as many as 66-1700 trinucleotide repeats in FA. These repeats lead to reduced transcription of the frataxin gene, thereby silencing it and reducing frataxin production.[3]

Larger GAA expansions, particularly on the smaller allele, are associated with earlier onset of the disease, faster muscle weakness progression, higher frequency of cardiomyopathy, and areflexia in the upper extremities.[4][16] Repeats between 34 to 100 rarely cause disease, especially if they are interrupted by non-GAA repeats. Interruptions stabilize the repeat against expansion. However, uninterrupted repeats are considered pre-mutations and can expand to over 300 repeats in a single generation.

The vast majority of patients with FA are homozygous for the GAA expansion mutation.[2][5][9][17] Only 4% of patients with FA are compound heterozygotes. These patients have GAA repeat expansion on one allele and a point mutation (missense, nonsense, intronic, or exonic) on the other allele.[5][9][19] Patients with missense mutations display mild to moderate symptoms, whereas the remaining types all result in severe symptoms.[20] Point mutations involving the amino-terminal are more likely to result in a mild presentation than those affecting the frataxin gene's carboxy-terminal. There are 17 different point mutations described so far in the literature.[21]

The three most common include the II54F mutation in Southern Italians, the ATG>ATT mutation on the start codon, and the G130V mutation that is notable for slower disease progression, hyperreflexia, and minimal dysarthria. Compound heterozygotes may have atypical presentations such as the age of onset over 25, normoreflexia or hyperreflexia, and isolated spastic paraparesis without ataxia.[5][21] There are a few documented familial cases of genetic heterogeneity of FA; however, these are rare.[22][23][24]

Epidemiology

FA is the most common hereditary ataxia, accounting for approximately 50% of all ataxia cases and approximately 75% in patients less than 25 years of age.[8] In the United States, FA affects 1 in 50,000 people and is most common in people of Western European descent.[5] The prevalence of FA globally is 1 in 40,000. It frequently occurs in Europe, the Middle East, South Asia, and North Africa.[25][26]

FA is more prevalent in the White population than any other race, as the mutation is thought to originate from a common European ancestor. The carrier rate for FA is estimated to be 1 in 75. As an autosomal recessive disease, it affects males and females equally. The age of onset is usually in early adolescence, most commonly during the age of 8 to 15.

Pathophysiology

Frataxin is an integral part of many critical mitochondrial functions. It regulates iron homeostasis by chaperoning iron, detoxifying iron, and managing iron stores.[2][3][6][27] It works to create iron-sulfur clusters required for ATP production.[3][6][7][15][28] The mutation on the frataxin gene results in the gene's silencing; therefore, reducing the protein frataxin production.[3][6][7] The absence of frataxin impedes the activation of antioxidant defenses such as the enzyme aconitase, so the damage occurs unencumbered.[1][2][3][6][15][28][29] Iron accumulates within the mitochondria, generating free radicals.[9][15] The free radical damage and loss of ATP production result in cell death.

The cells most susceptible to damage are the ones that produce the most frataxin, which mainly includes the neurons and cardiomyocytes.[15] There is a “dying back phenomena” with the progressive axonal loss of myelinated peripheral neurons and secondary gliosis in the spinal cord and spinal roots in patients with FA.[9] The posterior columns, corticospinal tract, and ventral/dorsal spinocerebellar tracts display demyelination. This is due to the loss of large myelinated nerve fibers. The lost neurons are replaced by fibrosis, and the spinal cord becomes thin. This is evidenced by a reduction in the anteroposterior and transverse diameter of the thoracic spinal cord. The dorsal spinal ganglia are also affected.[30] 

Eventually, neurons in this area, particularly lumbosacral and nerve cells in the Clarke column, are lost and are replaced by capsular cells. Of note, corticospinal tracts are relatively spared down to the level of the cervicomedullary junction. Degeneration of the posterior column correlates with the loss of proprioception and sensory ataxia. Likewise, the loss of the sensory ganglia is responsible for the loss of tendon reflexes. The complication of kyphoscoliosis is a result of spinal muscular imbalance.

Other affected areas include the dentate nucleus, which typically has mild to moderate neuronal loss, and the middle and superior cerebellar peduncles, which show atrophy. There is a patchy loss of Purkinje cells in the superior vermis of the cerebellum, and neuronal loss in the inferior olivary, pontine and medullary nuclei, along with the optic tracts.[9] The cerebellar ataxia is caused by the loss of the lateral and ventral spinocerebellar tracts, Clarke column, dentate nucleus, superior vermis, and dentatorubral pathways. Cranial nerves VII, X, and XII are also commonly affected. Facial weakness, slurred speech, and dysphagia are also present due to the affected aforementioned cranial nerves.

Another major group of cells that have relatively high frataxin production are the cardiomyocytes.[11][13][14][15] In the heart, muscle fibers are replaced by macrophages and fibroblasts, causing inflammation and interstitial fibrosis.[9] Affected cardiomyocytes exhibit hyperchromatic nuclei, vacuolation, and cytoplasm appears granular with frequent lipofuscin depositions. These changes result in hypertrophic cardiomyopathy.

Histopathology

Many histopathological findings in FA have been confirmed and described since the original publication in 1863:[31][32][33][34][35][36]

  • Loss of myelinated fibers of the dorsal columns and corticospinal tracts on the spinal cord
  • Compact fibrillary gliosis without inflammatory cells within dorsal columns and corticospinal tracts
  • Degeneration and death of fibers of the dorsal columns and corticospinal tracts
  • Shrinkage of dorsal columns and corticospinal tracts with capsular cell proliferation
  • Absence of large myelinated fibers in posterior roots
  • A decrease in myelinated axons in peripheral nerves
  • Neuronal destruction with atrophy of dorsal root ganglion
  • Hypoplasia of dorsal root ganglion
  • Degeneration and loss of cells of the Clarke column in the thoracic spinal cord
  • Progressive atrophy of large neurons of the dentate nucleus
  • Patchy loss of Purkinje cells in the superior vermis of the cerebellum
  • Neuronal loss in the inferior olivary, pontine and medullary nuclei
  • Neuronal loss in the optic tracts
  • Lack of Betz cells in the motor cortex

History and Physical

Ataxia

Symmetric gait ataxia in a young patient is usually the presenting symptom.[1] The development of the ataxia is insidious and usually begins with difficulty standing and running. It occurs in a child/adolescent who had normal physical development. Some patients may experience hemiataxia, but this will eventually become generalized. A febrile illness may precipitate gait ataxia.[12] 

Patients adopt a wide-based gait with constant shifting to maintain balance. Attempts to correct imbalances usually result in wild or uncontrolled movements. Patients may have a steppage gait characterized by the uneven and irregular striking of the floor by the feet' soles due to the loss of sensation. As the disease progresses, the ataxia ascends to affect the trunk and arms. Titubation while sitting and standing is also noted and may also involve the trunk. As the ataxia progresses to involve the arms, the patients develop action and intention tremors and even display choreiform movements. They may also have facial and buccal tremors. Eventually, patients will lose mobility, requiring ambulatory aids such as a walker, then a wheelchair, before ultimately becoming bedridden.

Other Symptoms

Constitutional symptoms include easy fatiguability, weakness, and daytime sleepiness. Dysarthria occurs due to cerebellar involvement. Slurred, slow speech takes place that will eventually become incomprehensible. Dysphagia arises as the muscles responsible for swallowing weaken. Dysphagia, combined with incoordination of speech and swallowing, can lead to choking incidents. Vision loss is caused by the loss of the optic tract fibers. Neuropsychological testing reveals impairment in executive functioning and temporoparietal dysfunction. This is most likely a result of the interruption of cerebrocerebellar circuits. A family history of FA will also be pivotal in the diagnosis.

Musculoskeletal Exam

  • Progressive limb and gait ataxia develops typically in adolescence
  • Truncal ataxia
  • Motor weakness
  • Loss of muscle tone
  • Muscular atrophy
  • Foot deformities such as high plantar arch, foot inversion, hammertoes
  • Pes cavus
  • Kyphoscoliosis

Neurological Exam

  • Hyporeflexia or areflexia
  • Extensor plantar responses
  • Flexor spasms
  • Sensory neuropathy
  • Loss of two-point discrimination
  • Loss of proprioception and vibration
  • Loss of pain and temperature sensation
  • Dysarthria
  • Dysmetria
  • Urinary urgency or incontinence
  • Loss of visual acuity
  • Horizontal nystagmus, particularly with lateral gaze
  • Abnormal extraocular movements such as square-wave jerks, saccadic pursuit, and poor fixation
  • Abnormal visual evoked potentials with reduced amplitude and delayed latency
  • Impaired vestibulo-ocular reflexes
  • Deafness
  • Vertigo

Psychological Exam

  • Mild executive dysfunction
  • Emotional lability

Cardiovascular Exam

  • Peripheral cyanosis
  • Cardiomegaly
  • Tachycardia
  • Atrial fibrillation
  • Systolic ejection murmurs and additional heart sounds

Evaluation

The diagnosis of FA is heavily reliant on history and physical examination. The studies conducted serve to rule out alternative diagnoses and to evaluate for life-threatening complications of the disease. Evaluation to rule out other causes includes:

  • Glucose level
  • Vitamin E level
  • Electromyogram
  • Nerve conduction studies - notable for absent or reduced amplitude sensory nerve action potentials 

Once a diagnosis of FA is suspected, the following tests should be performed:

Genetic Testing

Genetic testing is the cornerstone of the evaluation of patients with FA. A trinucleotide repeat expansion assay is available, and FA is the only disease with pathological GAA repeats.[9] Prenatal testing is available via direct mutation testing.[9]

Imaging

Magnetic resonance imaging (MRI) is the preferred modality for evaluation of the extent of atrophic changes. Patients suspected of having FA should have an MRI of the brain and spinal cord, which will show atrophy of the cervical/thoracic spinal cord and cerebellum.

Evaluation of common manifestations includes the following studies:

  • An electrocardiogram can show tachycardia or atrial fibrillation.[37]
  • An echocardiogram typically shows symmetric concentric ventricular hypertrophy.[16] Some patients have shown asymmetric septal hypertrophy.[11][13][14][38]
  • Auditory testing shows absent waves III and IV, while wave I is preserved.
  • Vision testing shows abnormal visual evoked potentials with absent or delayed latency and reduced amplitude of the p100 wave.

Treatment / Management

Despite being first recognized more than 150 years ago, there is still no cure for FA.[1][2][8][18] Treatment involves the management of symptoms and complications such as diabetes mellitus and heart failure.[1](B3)

Physical and Occupational Therapy

Physical therapy (PT) is the main recommendation to delay the disease's progression and preserve function.[39][40][41] The goal of PT is to strengthen posture and encourage muscle use. PT regimens involve exercises such as low-intensity strength training to improve coordination, balance, strength, and stabilization. These exercises help patients to maintain functional use of extremities, improve ataxia, and manage scoliosis. Frenkel exercises and proprioceptive neuromuscular facilitation stretching are also done to try to improve proprioception. Stretching and muscle relaxation exercises improve muscle spasticity and prevent back and foot deformities. Breathing exercises are also crucial, as are techniques for reducing body energy expenditure. Occupational therapy focuses on maintaining independence such as transfers, locomotion, “safe fall” strategies, and mobility aids.(A1)

Devices

Orthopedic shoes, avoiding tight clothing, and using correctly adjusted ambulatory devices like canes, wheelchairs, and orthoses, have shown benefit in ambulation, muscle spasticity, and prevention of scoliosis and other deformities. Functional electrical stimulation and transcutaneous nerve stimulation may alleviate gait and spasticity symptoms. A standing frame can help reduce prolonged wheelchair usage. 

Medication

Medication treatment is focused primarily on pain management, heart failure, and prevention of infection.[11][12] (B3)

Surgery

Surgery can be performed when indicated for kyphoscoliosis and foot deformities. Automated implantable cardioverter-defibrillator placement is done when indicated.[11] Heart transplantation for FA has also been performed in patients with milder forms but significant cardiomyopathy.[42](B3)

Differential Diagnosis

  • Spinocerebellar ataxia types 1, 2, 3, or pure cerebellar ataxia – an autosomal dominant disease characterized by early-onset ataxia, ophthalmoplegia, hearing loss, sensory axonal neuropathy, epilepsy, oculomotor apraxia, choreoathetosis, facial and limb dystonias, sensorimotor polyneuropathy, cerebellar atrophy, and cognitive impairment. It is distinguished from FA by imaging revealing characteristic clinical features of cerebellar atrophy.[14][43]
  • Dentatorubro-pallidoluysian atrophy – characterized by myoclonus, epilepsy, choreoathetosis, behavioral changes, intellectual disability, and ataxia. It is distinguished from FA by behavioral, psychiatric, and intellectual symptoms.[43][44]
  • Demyelinating peripheral neuropathy or chronic inflammatory demyelinating polyneuropathy – an autoimmune disorder characterized by symmetric weakness of proximal and distal muscles and sensorimotor peripheral neuropathy. It is distinguished from FA by evidence of inflammation on lumbar puncture.[45][46][47]
  • Roussy-Levy variant of Charcot-Marie-Tooth disease – an autosomal dominant disease characterized by areflexia and ataxia. It is distinguished from FA by dysmyelination (instead of axonal neuropathy) and inheritance pattern.[48][49]
  • Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss syndrome – a disorder caused by single mutation E818K of the ATP1A3 gene on chromosome 19q13.[50] It is distinguished from FA by genetic testing. 
  • Episodic ataxia – distinguished from FA by history.[51][52][53]
  • Autosomal recessive spastic ataxia of Charlevoix-Saguenay – an autosomal recessive disease caused by a mutation on the SACS gene characterized by a triad of early spasticity, cerebellar ataxia, and sensorimotor peripheral neuropathy. It is distinguished from FA by the brain MRI, showing the involvement of the pons.[54][55]
  • Abetalipoproteinemia (Bassen-Kornzweig disease) – an autosomal recessive disease caused by mutation of microsomal triglyceride transfer protein gene characterized by impaired fat absorption, low cholesterol/triglyceride levels, absent serum beta lipoprotein, retinal degeneration, peripheral neuropathy, and ataxia. It is distinguished from FA by abnormal lipid levels and neurologic improvement with fat-soluble vitamin supplementation.[56]
  • Drug-induced ataxia - distinguished from FA by history and resolution of symptoms with removal of the offending agent.[57]
  • Ataxia with vitamin E deficiency – an autosomal recessive disease caused by mutation of the alpha-tocopherol transfer protein gene, characterized by slowly progressive gait ataxia with neuropathy and retinitis pigmentosa. It is distinguished from FA by low vitamin E levels and neurologic improvement with vitamin E supplementation.[58]
  • Ataxia-telangiectasia – an autosomal recessive disease caused by a mutation on the ATM gene characterized by progressive cerebellar ataxia, abnormal eye movements, other neurologic abnormalities, immune deficiency, and oculocutaneous telangiectasias. Complications include pulmonary disease, increased risk of malignancy, radiation sensitivity, and diabetes mellitus. It is distinguished from FA by elevated alpha-fetoprotein.[59]
  • Refsum disease – an autosomal recessive disease caused by a mutation on the PHYH gene characterized by elevated phytanic acid levels, retinitis pigmentosa, ichthyosis, sensorimotor polyneuropathy, cerebellar ataxia, and sensorineural hearing loss. It is distinguished from FA by elevated phytanic acid levels and improvement with dietary restriction.[60][61]

Pertinent Studies and Ongoing Trials

While no effective treatment for FA exists, multiple therapies are being developed to increase frataxin levels, such as protein and gene replacement therapies, antioxidants, iron chelators, and inflammation modulators.[1][2][7][62][63][64][65][66][67]

Gene Therapy

There is ongoing research into the mechanism of gene silencing of the expanded frataxin gene to develop a treatment for FA. While medications involved in iron chelation and antioxidants are being studied, gene therapy is considered the best chance of altering the disease course.[18][68][69] Histone deacetylase inhibitors are being investigated.[6][7] Modulation of transcription factor Nrf2, found to be decreased in cells affected in FA, is also being tested. Present studies suggest that Nrf2 induction may prevent oxidative damage.[6][70]

Iron Chelation

  • Deferiprone - An iron chelator, deferiprone, is used to reduce iron accumulation in mitochondria.[7][71] This drug is often used in conjunction with idebenone and vitamin B2.[7][71][72]

Antioxidants

  • Idebenone - A synthetic form of coenzyme Q10, idebenone is a free radical scavenger used in FA to combat free radical damage.[7][15][71][72] The effect of this medication on cardiomyopathy is also a major focus of research.[15][73]
  • Coenzyme Q10[7][15][74]
  • Vitamin E[15][72][74]
  • Vitamin B2 (riboflavin)[72]
  • Vitamin B1 (thiamine)[7]

Inflammatory Modulators

  • INF-gamma[7]
  • Phosphodiesterase inhibitors[75]
  • Steroids[7]

Staging

There are three different scales to measure the severity and progression of FA.

  1. International cooperative ataxia rating scale[76]
  2. Friedreich ataxia rating scale[77][78]
  3. Scale for the assessment and rating of ataxia[79]

Prognosis

Overall, the prognosis of FA is poor. The vast majority of patients are wheelchair-bound by the age of 45, and the mean duration of the disease is 15 to 20 years. The primary cause of death is cardiac dysfunction, specifically congestive heart failure or arrhythmia. The average age at death was 36.5 years with a range from 12 to 87.[80]

Cardiac dysfunction is the most frequent cause of death.[11][12][13][14][16] Two-third of patients will die from congestive heart failure or arrhythmia.

Complications

Cardiac

  • Myocarditis
  • Myocardial fibrosis
  • Cardiomegaly
  • Symmetrical hypertrophy
  • Congestive heart failure caused by dilated or hypertrophic cardiomyopathy [11][12][13]
  • Tachycardia
  • Atrial fibrillation
  • Heart block

Musculoskeletal

  • Kyphoscoliosis - can produce significant cardiopulmonary morbidity due to restricted respiratory function
  • Pes cavus

Endocrine

  • Diabetes mellitus

Consultations

  • Neurologist
  • Cardiologist
  • Ophthalmologist
  • Otolaryngologist
  • Physiatrist
  • Physical therapy
  • Occupational therapy
  • Orthopedic surgeon
  • Speech and language therapist
  • Psychologist
  • Psychiatrist
  • Social worker

Deterrence and Patient Education

FA cannot be prevented as the condition is inherited with an autosomal recessive inheritance pattern. The age of onset is usually in childhood or early adolescence, most commonly in children 8 to 15 years old. Those families with an affected child have a 25% chance of having another child with the disease. In cases of a consanguineous union, the risk of having a child with FA is higher.

Genetic screening and counseling are essential before pregnancy to determine the carrier status and risk for FA offspring. The defective gene can be passed from one parent, and the child will be a carrier.

As the disease has no cure, symptoms worsen as time progresses, and most patients end up requiring mobility aids such as wheelchairs, lose their vision and hearing, and develop other medical complications such as diabetes mellitus and scoliosis. Those patients with less severe symptoms can live longer and, in some cases, beyond their sixties. The most common cause of death in patients with FA is hypertrophic cardiomyopathy.[11] Close cardiologist monitoring is vital throughout a patient's life.

Pearls and Other Issues

  • FA is the most common hereditary ataxia accounting for roughly 50% of all ataxia cases.
  • The disease causes neurodegeneration that manifests as a combination of difficulty ambulating, muscle weakness, impaired speech, and loss of sensation and proprioception.
  • FA has an autosomal recessive inheritance pattern, and symptom onset is usually in childhood or early adolescence, most commonly in children 8 to 15 years old.
  • The global prevalence is 1 in 40,000.
  • In the United States, FA affects 1 in 50,000 people and is most common in people of Western European descent.
  • Symptoms worsen as time progresses, so most people affected by this disease end up requiring mobility aids such as wheelchairs, lose their vision and hearing, and develop other medical complications such as diabetes mellitus and scoliosis.
  • Patients with FA have an abnormal amount of trinucleotide repeats on the frataxin gene on chromosome 9.
  • Frataxin is a mitochondrial protein essential for ATP production, regulating iron stores, and preventing oxidative phosphorylation.
  • Genetic testing is the cornerstone of the evaluation of patients with FA.
  • A repeat expansion of the trinucleotide GAA (guanine-adenine-adenine), typically in the gene's first intron, is the leading cause of this disease.
  • There is still no cure for FA. Treatment is centered around the management of symptoms and complications such as diabetes mellitus and heart failure.
  • Overall, the prognosis of FA is poor.
  • The mean duration of the disease is 15 to 20 years. Since the disease presents in childhood or adolescence, most patients live to 25 to 30 years of age.
  • Cardiac dysfunction with hypertrophic cardiomyopathy is the most frequent cause of death. Two-third of patients will die from congestive heart failure or arrhythmia.
  • Close cardiologist monitoring is vital throughout a patient's life.
  • Gene therapy is considered the best chance of altering the disease course.

Enhancing Healthcare Team Outcomes

While the neurologist is always involved in patient care, it is essential to consult with an interprofessional team of specialists, including a cardiologist, orthopedic surgeon, speech pathologist, and physiatrist. Patients eventually lose the ability to ambulate and require prostheses, walking aids, wheelchairs, and physical therapy to maintain an active lifestyle. Physical and occupational therapy improves patients' physical function and helps with the working environment and at home. Physiatrists or movement specialists can provide pharmacological drugs to improve spasticity.

Urologists can provide evaluation and treatment for bladder dysfunction. Patients may require non-operative and operative interventions by the orthopedic surgeon for foot deformities and scoliosis. A speech pathologist is essential in those patients with dysphagia and communication skills; however, some may require gastronomy feedings. Strict cardiologic monitoring is necessary for the treatment of arrhythmias and cardiac failure to improve morbidity and mortality.[11][81]

Psychological evaluation and counseling are of utmost importance to help those affected patients and families. Patients need close monitoring of dietary intake, and modifications can improve dysphagia and diabetes mellitus complications. An endocrinologist evaluation may be required for complex cases.

The Friedreich’s Ataxia Research Alliance is an organization that helps patients and families with information, resources, and research.

References


[1]

Cook A, Giunti P. Friedreich's ataxia: clinical features, pathogenesis and management. British medical bulletin. 2017 Dec 1:124(1):19-30. doi: 10.1093/bmb/ldx034. Epub     [PubMed PMID: 29053830]


[2]

Delatycki MB, Bidichandani SI. Friedreich ataxia- pathogenesis and implications for therapies. Neurobiology of disease. 2019 Dec:132():104606. doi: 10.1016/j.nbd.2019.104606. Epub 2019 Sep 5     [PubMed PMID: 31494282]


[3]

Lodi R, Tonon C, Calabrese V, Schapira AH. Friedreich's ataxia: from disease mechanisms to therapeutic interventions. Antioxidants & redox signaling. 2006 Mar-Apr:8(3-4):438-43     [PubMed PMID: 16677089]

Level 3 (low-level) evidence

[4]

Alper G, Narayanan V. Friedreich's ataxia. Pediatric neurology. 2003 May:28(5):335-41     [PubMed PMID: 12878293]


[5]

Zhu D, Burke C, Leslie A, Nicholson GA. Friedreich's ataxia with chorea and myoclonus caused by a compound heterozygosity for a novel deletion and the trinucleotide GAA expansion. Movement disorders : official journal of the Movement Disorder Society. 2002 May:17(3):585-9     [PubMed PMID: 12112211]

Level 3 (low-level) evidence

[6]

Strawser CJ, Schadt KA, Lynch DR. Therapeutic approaches for the treatment of Friedreich's ataxia. Expert review of neurotherapeutics. 2014 Aug:14(8):949-57. doi: 10.1586/14737175.2014.939173. Epub 2014 Jul 18     [PubMed PMID: 25034024]


[7]

Strawser C, Schadt K, Hauser L, McCormick A, Wells M, Larkindale J, Lin H, Lynch DR. Pharmacological therapeutics in Friedreich ataxia: the present state. Expert review of neurotherapeutics. 2017 Sep:17(9):895-907. doi: 10.1080/14737175.2017.1356721. Epub 2017 Jul 26     [PubMed PMID: 28724340]


[8]

Aranca TV, Jones TM, Shaw JD, Staffetti JS, Ashizawa T, Kuo SH, Fogel BL, Wilmot GR, Perlman SL, Onyike CU, Ying SH, Zesiewicz TA. Emerging therapies in Friedreich's ataxia. Neurodegenerative disease management. 2016:6(1):49-65. doi: 10.2217/nmt.15.73. Epub     [PubMed PMID: 26782317]


[9]

Palau F. Friedreich's ataxia and frataxin: molecular genetics, evolution and pathogenesis (Review). International journal of molecular medicine. 2001 Jun:7(6):581-9     [PubMed PMID: 11351269]

Level 3 (low-level) evidence

[10]

Tanaka H. [Friedreich ataxia with GAA repeat expansion: molecular mechanism and clinical feature]. Nihon rinsho. Japanese journal of clinical medicine. 1999 Apr:57(4):960-6     [PubMed PMID: 10222797]


[11]

Lynch DR, Regner SR, Schadt KA, Friedman LS, Lin KY, St John Sutton MG. Management and therapy for cardiomyopathy in Friedreich's ataxia. Expert review of cardiovascular therapy. 2012 Jun:10(6):767-77. doi: 10.1586/erc.12.57. Epub     [PubMed PMID: 22894632]

Level 3 (low-level) evidence

[12]

Hanley A, Corrigan R, Mohammad S, MacMahon B. Friedreich's ataxia cardiomyopathy: case based discussion and management issues. Irish medical journal. 2010 Apr:103(4):117-8     [PubMed PMID: 20486316]

Level 3 (low-level) evidence

[13]

Bertoni PD, Canziani R, Cozzi G, Arancio F, Marforio S. [Cardiac involvement in Friedreich's heredo-ataxia]. Giornale italiano di cardiologia. 1986 Jan:16(1):22-9     [PubMed PMID: 2940141]


[14]

Weidemann F, Scholz F, Florescu C, Liu D, Hu K, Herrmann S, Ertl G, Störk S. [Heart involvement in Friedreich's ataxia]. Herz. 2015 Mar:40 Suppl 1():85-90. doi: 10.1007/s00059-014-4097-y. Epub 2014 May 23     [PubMed PMID: 24848865]


[15]

Lodi R, Rajagopalan B, Bradley JL, Taylor DJ, Crilley JG, Hart PE, Blamire AM, Manners D, Styles P, Schapira AH, Cooper JM. Mitochondrial dysfunction in Friedreich's ataxia: from pathogenesis to treatment perspectives. Free radical research. 2002 Apr:36(4):461-6     [PubMed PMID: 12069111]

Level 3 (low-level) evidence

[16]

Bit-Avragim N, Perrot A, Schöls L, Hardt C, Kreuz FR, Zühlke C, Bubel S, Laccone F, Vogel HP, Dietz R, Osterziel KJ. The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity of cardiac manifestation in patients with Friedreich's ataxia. Journal of molecular medicine (Berlin, Germany). 2001:78(11):626-32     [PubMed PMID: 11269509]

Level 2 (mid-level) evidence

[17]

Campuzano V, Montermini L, Moltò MD, Pianese L, Cossée M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Cañizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, De Michele G, Filla A, De Frutos R, Palau F, Patel PI, Di Donato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science (New York, N.Y.). 1996 Mar 8:271(5254):1423-7     [PubMed PMID: 8596916]


[18]

Hebert MD, Whittom AA. Gene-based approaches toward Friedreich ataxia therapeutics. Cellular and molecular life sciences : CMLS. 2007 Dec:64(23):3034-43     [PubMed PMID: 17828464]

Level 3 (low-level) evidence

[19]

Zühlke CH, Dalski A, Habeck M, Straube K, Hedrich K, Hoeltzenbein M, Konstanzer A, Hellenbroich Y, Schwinger E. Extension of the mutation spectrum in Friedreich's ataxia: detection of an exon deletion and novel missense mutations. European journal of human genetics : EJHG. 2004 Nov:12(11):979-82     [PubMed PMID: 15340363]


[20]

Bartolo C, Mendell JR, Prior TW. Identification of a missense mutation in a Friedreich's ataxia patient: implications for diagnosis and carrier studies. American journal of medical genetics. 1998 Oct 12:79(5):396-9     [PubMed PMID: 9779809]

Level 3 (low-level) evidence

[21]

Cossée M,Dürr A,Schmitt M,Dahl N,Trouillas P,Allinson P,Kostrzewa M,Nivelon-Chevallier A,Gustavson KH,Kohlschütter A,Müller U,Mandel JL,Brice A,Koenig M,Cavalcanti F,Tammaro A,De Michele G,Filla A,Cocozza S,Labuda M,Montermini L,Poirier J,Pandolfo M, Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes. Annals of neurology. 1999 Feb;     [PubMed PMID: 9989622]


[22]

Kellett MW, Fletcher NA, Wood N, Enevoldson TP. Trinucleotide (GAA)n repeat expansion in two families with Friedreich's ataxia with retained reflexes. Journal of neurology, neurosurgery, and psychiatry. 1997 Dec:63(6):780-3     [PubMed PMID: 9416816]

Level 3 (low-level) evidence

[23]

Lucotte G, Berriche S, David F, Bathelier C, Turpin JC. Trinucleotide GAA repeat expansions in seven French Friedreich ataxia families. Genetic counseling (Geneva, Switzerland). 1997:8(3):189-94     [PubMed PMID: 9327260]


[24]

Rao VK, DiDonato CJ, Larsen PD. Friedreich's Ataxia: Clinical Presentation of a Compound Heterozygote Child with a Rare Nonsense Mutation and Comparison with Previously Published Cases. Case reports in neurological medicine. 2018:2018():8587203. doi: 10.1155/2018/8587203. Epub 2018 Aug 9     [PubMed PMID: 30159187]

Level 3 (low-level) evidence

[25]

Yilmaz MB, Koç AF, Kasap H, Güzel AI, Sarica Y, Süleymanova D. GAA repeat polymorphism in Turkish Friedreich's ataxia patients. The International journal of neuroscience. 2006 May:116(5):565-74     [PubMed PMID: 16644517]


[26]

Houshmand M, Panahi MS, Nafisi S, Soltanzadeh A, Alkandari FM. Identification and sizing of GAA trinucleotide repeat expansion, investigation for D-loop variations and mitochondrial deletions in Iranian patients with Friedreich's ataxia. Mitochondrion. 2006 Apr:6(2):82-8     [PubMed PMID: 16581313]

Level 2 (mid-level) evidence

[27]

Martelli A, Puccio H. Dysregulation of cellular iron metabolism in Friedreich ataxia: from primary iron-sulfur cluster deficit to mitochondrial iron accumulation. Frontiers in pharmacology. 2014:5():130. doi: 10.3389/fphar.2014.00130. Epub 2014 Jun 3     [PubMed PMID: 24917819]


[28]

Rötig A, Sidi D, Munnich A, Rustin P. Molecular insights into Friedreich's ataxia and antioxidant-based therapies. Trends in molecular medicine. 2002 May:8(5):221-4     [PubMed PMID: 12067631]

Level 3 (low-level) evidence

[29]

Rötig A, de Lonlay P, Chretien D, Foury F, Koenig M, Sidi D, Munnich A, Rustin P. Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nature genetics. 1997 Oct:17(2):215-7     [PubMed PMID: 9326946]


[30]

Koeppen AH, Becker AB, Qian J, Feustel PJ. Friedreich Ataxia: Hypoplasia of Spinal Cord and Dorsal Root Ganglia. Journal of neuropathology and experimental neurology. 2017 Feb 1:76(2):101-108. doi: 10.1093/jnen/nlw111. Epub     [PubMed PMID: 28082326]

Level 2 (mid-level) evidence

[31]

Morral JA, Davis AN, Qian J, Gelman BB, Koeppen AH. Pathology and pathogenesis of sensory neuropathy in Friedreich's ataxia. Acta neuropathologica. 2010 Jul:120(1):97-108. doi: 10.1007/s00401-010-0675-0. Epub 2010 Mar 26     [PubMed PMID: 20339857]

Level 2 (mid-level) evidence

[32]

Koeppen AH, Morral JA, Davis AN, Qian J, Petrocine SV, Knutson MD, Gibson WM, Cusack MJ, Li D. The dorsal root ganglion in Friedreich's ataxia. Acta neuropathologica. 2009 Dec:118(6):763-76. doi: 10.1007/s00401-009-0589-x. Epub 2009 Aug 30     [PubMed PMID: 19727777]

Level 2 (mid-level) evidence

[33]

Koeppen AH, Mazurkiewicz JE. Friedreich ataxia: neuropathology revised. Journal of neuropathology and experimental neurology. 2013 Feb:72(2):78-90. doi: 10.1097/NEN.0b013e31827e5762. Epub     [PubMed PMID: 23334592]


[34]

Koeppen AH. Nikolaus Friedreich and degenerative atrophy of the dorsal columns of the spinal cord. Journal of neurochemistry. 2013 Aug:126 Suppl 1(0 1):4-10. doi: 10.1111/jnc.12218. Epub     [PubMed PMID: 23859337]


[35]

Koeppen AH. Friedreich's ataxia: pathology, pathogenesis, and molecular genetics. Journal of the neurological sciences. 2011 Apr 15:303(1-2):1-12. doi: 10.1016/j.jns.2011.01.010. Epub     [PubMed PMID: 21315377]

Level 3 (low-level) evidence

[36]

Koeppen AH, Morral JA, McComb RD, Feustel PJ. The neuropathology of late-onset Friedreich's ataxia. Cerebellum (London, England). 2011 Mar:10(1):96-103. doi: 10.1007/s12311-010-0235-0. Epub     [PubMed PMID: 21128039]

Level 2 (mid-level) evidence

[37]

Wood AH, Dubrey SW. Cardiomyopathy and the electrocardiogram in Friedreich's ataxia. British journal of hospital medicine (London, England : 2005). 2013 Apr:74(4):232-3     [PubMed PMID: 23571398]

Level 3 (low-level) evidence

[38]

Dutka DP, Donnelly JE, Nihoyannopoulos P, Oakley CM, Nunez DJ. Marked variation in the cardiomyopathy associated with Friedreich's ataxia. Heart (British Cardiac Society). 1999 Feb:81(2):141-7     [PubMed PMID: 9922348]


[39]

Milne SC, Corben LA, Roberts M, Murphy A, Tai G, Georgiou-Karistianis N, Yiu EM, Delatycki MB. Can rehabilitation improve the health and well-being in Friedreich's ataxia: a randomized controlled trial? Clinical rehabilitation. 2018 May:32(5):630-643. doi: 10.1177/0269215517736903. Epub 2017 Oct 26     [PubMed PMID: 29072092]

Level 1 (high-level) evidence

[40]

Bonnechère B, Jansen B, Haack I, Omelina L, Feipel V, Van Sint Jan S, Pandolfo M. Automated functional upper limb evaluation of patients with Friedreich ataxia using serious games rehabilitation exercises. Journal of neuroengineering and rehabilitation. 2018 Oct 4:15(1):87. doi: 10.1186/s12984-018-0430-7. Epub 2018 Oct 4     [PubMed PMID: 30286776]


[41]

Maring JR, Croarkin E. Presentation and progression of Friedreich ataxia and implications for physical therapist examination. Physical therapy. 2007 Dec:87(12):1687-96     [PubMed PMID: 17911272]


[42]

Sedlak TL, Chandavimol M, Straatman L. Cardiac transplantation: a temporary solution for Friedreich's ataxia-induced dilated cardiomyopathy. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2004 Nov:23(11):1304-6     [PubMed PMID: 15539131]

Level 3 (low-level) evidence

[43]

Musova Z, Sedlacek Z, Mazanec R, Klempir J, Roth J, Plevova P, Vyhnalek M, Kopeckova M, Apltova L, Krepelova A, Zumrova A. Spinocerebellar ataxias type 8, 12, and 17 and dentatorubro-pallidoluysian atrophy in Czech ataxic patients. Cerebellum (London, England). 2013 Apr:12(2):155-61. doi: 10.1007/s12311-012-0403-5. Epub     [PubMed PMID: 22872568]


[44]

Li H, Hu X, Fei L, Zhang P, Chen X, Ouyang M, Zhang W, Liu X. [Clinical and genetic characteristics of patients with dentatorubro-pallidoluysian atrophy]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics. 2016 Oct:33(5):610-4. doi: 10.3760/cma.j.issn.1003-9406.2016.05.006. Epub     [PubMed PMID: 27577205]


[45]

Lewis RA. Chronic inflammatory demyelinating polyneuropathy. Current opinion in neurology. 2017 Oct:30(5):508-512. doi: 10.1097/WCO.0000000000000481. Epub     [PubMed PMID: 28763304]

Level 3 (low-level) evidence

[46]

Kuwabara S, Misawa S. Chronic Inflammatory Demyelinating Polyneuropathy. Advances in experimental medicine and biology. 2019:1190():333-343. doi: 10.1007/978-981-32-9636-7_21. Epub     [PubMed PMID: 31760654]

Level 3 (low-level) evidence

[47]

Lehmann HC, Burke D, Kuwabara S. Chronic inflammatory demyelinating polyneuropathy: update on diagnosis, immunopathogenesis and treatment. Journal of neurology, neurosurgery, and psychiatry. 2019 Sep:90(9):981-987. doi: 10.1136/jnnp-2019-320314. Epub 2019 Apr 16     [PubMed PMID: 30992333]


[48]

Koehler PJ. Gabrielle Lévy and the Roussy-Lévy syndrome. Journal of the history of the neurosciences. 2018 Apr-Jun:27(2):117-144. doi: 10.1080/0964704X.2018.1423848. Epub 2018 Feb 22     [PubMed PMID: 29469679]


[49]

Bartosik-Psujek H, Stelmasiak Z. A case of the Roussy-Levy syndrome family. Annales Universitatis Mariae Curie-Sklodowska. Sectio D: Medicina. 2001:56():393-5     [PubMed PMID: 11977346]

Level 3 (low-level) evidence

[50]

Roenn CP, Li M, Schack VR, Forster IC, Holm R, Toustrup-Jensen MS, Andersen JP, Petrou S, Vilsen B. Functional consequences of the CAPOS mutation E818K of Na(+),K(+)-ATPase. The Journal of biological chemistry. 2019 Jan 4:294(1):269-280. doi: 10.1074/jbc.RA118.004591. Epub 2018 Nov 8     [PubMed PMID: 30409907]


[51]

Jen JC, Wan J. Episodic ataxias. Handbook of clinical neurology. 2018:155():205-215. doi: 10.1016/B978-0-444-64189-2.00013-5. Epub     [PubMed PMID: 29891059]


[52]

Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, Hasan SM, D'Adamo MC. Episodic Ataxia Type 1. GeneReviews(®). 1993:():     [PubMed PMID: 20301785]


[53]

Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, Spacey S. Episodic Ataxia Type 2 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. GeneReviews(®). 1993:():     [PubMed PMID: 20301674]


[54]

Synofzik M, Németh AH. Recessive ataxias. Handbook of clinical neurology. 2018:155():73-89. doi: 10.1016/B978-0-444-64189-2.00005-6. Epub     [PubMed PMID: 29891078]


[55]

Briand MM, Rodrigue X, Lessard I, Mathieu J, Brais B, Côté I, Gagnon C. Expanding the clinical description of autosomal recessive spastic ataxia of Charlevoix-Saguenay. Journal of the neurological sciences. 2019 May 15:400():39-41. doi: 10.1016/j.jns.2019.03.008. Epub 2019 Mar 12     [PubMed PMID: 30901567]


[56]

Hernandez-Diaz S, Soukup SF. The role of lipids in autophagy and its implication in neurodegeneration. Cell stress. 2020 May 19:4(7):167-186. doi: 10.15698/cst2020.07.225. Epub 2020 May 19     [PubMed PMID: 32656499]


[57]

van Gaalen J, Kerstens FG, Maas RP, Härmark L, van de Warrenburg BP. Drug-induced cerebellar ataxia: a systematic review. CNS drugs. 2014 Dec:28(12):1139-53. doi: 10.1007/s40263-014-0200-4. Epub     [PubMed PMID: 25391707]

Level 1 (high-level) evidence

[58]

Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, Schuelke M. Ataxia with Vitamin E Deficiency. GeneReviews(®). 1993:():     [PubMed PMID: 20301419]


[59]

Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM. Ataxia telangiectasia: a review. Orphanet journal of rare diseases. 2016 Nov 25:11(1):159     [PubMed PMID: 27884168]


[60]

Hochner I, Blickle JF, Brogard JM. [Refsum disease]. La Revue de medecine interne. 1996:17(5):391-8     [PubMed PMID: 8763099]


[61]

Wanders RJ, Jansen GA, Skjeldal OH. Refsum disease, peroxisomes and phytanic acid oxidation: a review. Journal of neuropathology and experimental neurology. 2001 Nov:60(11):1021-31     [PubMed PMID: 11706932]


[62]

Pallardó FV, Pagano G, Rodríguez LR, Gonzalez-Cabo P, Lyakhovich A, Trifuoggi M. Friedreich Ataxia: current state-of-the-art, and future prospects for mitochondrial-focused therapies. Translational research : the journal of laboratory and clinical medicine. 2021 Mar:229():135-141. doi: 10.1016/j.trsl.2020.08.009. Epub 2020 Aug 22     [PubMed PMID: 32841735]


[63]

Clay A, Hearle P, Schadt K, Lynch DR. New developments in pharmacotherapy for Friedreich ataxia. Expert opinion on pharmacotherapy. 2019 Oct:20(15):1855-1867. doi: 10.1080/14656566.2019.1639671. Epub 2019 Jul 16     [PubMed PMID: 31311349]

Level 3 (low-level) evidence

[64]

Lynch DR, Hauser L, McCormick A, Wells M, Dong YN, McCormack S, Schadt K, Perlman S, Subramony SH, Mathews KD, Brocht A, Ball J, Perdok R, Grahn A, Vescio T, Sherman JW, Farmer JM. Randomized, double-blind, placebo-controlled study of interferon-γ 1b in Friedreich Ataxia. Annals of clinical and translational neurology. 2019 Mar:6(3):546-553. doi: 10.1002/acn3.731. Epub 2019 Feb 27     [PubMed PMID: 30911578]

Level 1 (high-level) evidence

[65]

Nuñez MT, Chana-Cuevas P. New Perspectives in Iron Chelation Therapy for the Treatment of Neurodegenerative Diseases. Pharmaceuticals (Basel, Switzerland). 2018 Oct 19:11(4):. doi: 10.3390/ph11040109. Epub 2018 Oct 19     [PubMed PMID: 30347635]

Level 3 (low-level) evidence

[66]

Zesiewicz T, Salemi JL, Perlman S, Sullivan KL, Shaw JD, Huang Y, Isaacs C, Gooch C, Lynch DR, Klein MB. Double-blind, randomized and controlled trial of EPI-743 in Friedreich's ataxia. Neurodegenerative disease management. 2018 Aug:8(4):233-242. doi: 10.2217/nmt-2018-0013. Epub 2018 Jul 27     [PubMed PMID: 30051753]

Level 1 (high-level) evidence

[67]

Zesiewicz T, Heerinckx F, De Jager R, Omidvar O, Kilpatrick M, Shaw J, Shchepinov MS. Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's ataxia. Movement disorders : official journal of the Movement Disorder Society. 2018 Jul:33(6):1000-1005. doi: 10.1002/mds.27353. Epub 2018 Apr 6     [PubMed PMID: 29624723]

Level 1 (high-level) evidence

[68]

Carletti B, Piemonte F. Friedreich's Ataxia: A Neuronal Point of View on the Oxidative Stress Hypothesis. Antioxidants (Basel, Switzerland). 2014 Sep 10:3(3):592-603. doi: 10.3390/antiox3030592. Epub 2014 Sep 10     [PubMed PMID: 26785073]


[69]

Polak U, Li Y, Butler JS, Napierala M. Alleviating GAA Repeat Induced Transcriptional Silencing of the Friedreich's Ataxia Gene During Somatic Cell Reprogramming. Stem cells and development. 2016 Dec 1:25(23):1788-1800     [PubMed PMID: 27615158]


[70]

Abeti R, Baccaro A, Esteras N, Giunti P. Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich's Ataxia Models. Frontiers in cellular neuroscience. 2018:12():188. doi: 10.3389/fncel.2018.00188. Epub 2018 Jul 17     [PubMed PMID: 30065630]


[71]

Soriano S, Llorens JV, Blanco-Sobero L, Gutiérrez L, Calap-Quintana P, Morales MP, Moltó MD, Martínez-Sebastián MJ. Deferiprone and idebenone rescue frataxin depletion phenotypes in a Drosophila model of Friedreich's ataxia. Gene. 2013 Jun 1:521(2):274-81. doi: 10.1016/j.gene.2013.02.049. Epub 2013 Mar 28     [PubMed PMID: 23542074]

Level 3 (low-level) evidence

[72]

Arpa J, Sanz-Gallego I, Rodríguez-de-Rivera FJ, Domínguez-Melcón FJ, Prefasi D, Oliva-Navarro J, Moreno-Yangüela M. Triple therapy with deferiprone, idebenone and riboflavin in Friedreich's ataxia - open-label trial. Acta neurologica Scandinavica. 2014 Jan:129(1):32-40. doi: 10.1111/ane.12141. Epub 2013 May 14     [PubMed PMID: 23668357]

Level 3 (low-level) evidence

[73]

Cooper JM, Schapira AH. Friedreich's Ataxia: disease mechanisms, antioxidant and Coenzyme Q10 therapy. BioFactors (Oxford, England). 2003:18(1-4):163-71     [PubMed PMID: 14695932]


[74]

Cooper JM, Schapira AH. Friedreich's ataxia: coenzyme Q10 and vitamin E therapy. Mitochondrion. 2007 Jun:7 Suppl():S127-35     [PubMed PMID: 17485244]

Level 3 (low-level) evidence

[75]

Mollá B,Muñoz-Lasso DC,Calap P,Fernandez-Vilata A,de la Iglesia-Vaya M,Pallardó FV,Moltó MD,Palau F,Gonzalez-Cabo P, Phosphodiesterase Inhibitors Revert Axonal Dystrophy in Friedreich's Ataxia Mouse Model. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2019 Apr;     [PubMed PMID: 30761510]


[76]

Trouillas P, Takayanagi T, Hallett M, Currier RD, Subramony SH, Wessel K, Bryer A, Diener HC, Massaquoi S, Gomez CM, Coutinho P, Ben Hamida M, Campanella G, Filla A, Schut L, Timann D, Honnorat J, Nighoghossian N, Manyam B. International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. Journal of the neurological sciences. 1997 Feb 12:145(2):205-11     [PubMed PMID: 9094050]


[77]

Subramony SH, May W, Lynch D, Gomez C, Fischbeck K, Hallett M, Taylor P, Wilson R, Ashizawa T, Cooperative Ataxia Group. Measuring Friedreich ataxia: Interrater reliability of a neurologic rating scale. Neurology. 2005 Apr 12:64(7):1261-2     [PubMed PMID: 15824358]


[78]

Fahey MC, Corben L, Collins V, Churchyard AJ, Delatycki MB. How is disease progress in Friedreich's ataxia best measured? A study of four rating scales. Journal of neurology, neurosurgery, and psychiatry. 2007 Apr:78(4):411-3     [PubMed PMID: 17056635]


[79]

Schwabova J, Maly T, Laczo J, Zumrova A, Komarek V, Musova Z, Zahalka F. Application of a Scale for the Assessment and Rating of Ataxia (SARA) in Friedreich's ataxia patients according to posturography is limited. Journal of the neurological sciences. 2014 Jun 15:341(1-2):64-7. doi: 10.1016/j.jns.2014.04.001. Epub 2014 Apr 12     [PubMed PMID: 24768059]


[80]

Tsou AY, Paulsen EK, Lagedrost SJ, Perlman SL, Mathews KD, Wilmot GR, Ravina B, Koeppen AH, Lynch DR. Mortality in Friedreich ataxia. Journal of the neurological sciences. 2011 Aug 15:307(1-2):46-9. doi: 10.1016/j.jns.2011.05.023. Epub 2011 Jun 8     [PubMed PMID: 21652007]

Level 2 (mid-level) evidence

[81]

Hawley RJ, Gottdiener JS. Five-year follow-up of Friedreich's ataxia cardiomyopathy. Archives of internal medicine. 1986 Mar:146(3):483-8     [PubMed PMID: 3954519]