Continuing Education Activity

Friedreich ataxia is an inherited disease affecting the nervous system, which produces progressive ataxia, weakness, and sensory deficits. It is inherited as an autosomal recessive disease. This activity reviews the evaluation and management of Friedreich ataxia and highlights the role of the interprofessional team in the care of patients with this condition.

Objectives:

• Identify the etiology of Friedreich ataxia.
• Review the appropriate evaluation of Friedreich ataxia.
• Outline the management options available for Friedreich ataxia.
• Summarize interprofessional team strategies for improving care coordination and communication for patients with Friedreich ataxia and improve outcomes.

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

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]

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.

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] 

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]

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.