Friedreich's ataxia | |
---|---|
Other names | Spinocerebellar ataxia, FRDA, FA |
![]() | |
Frataxin | |
Specialty | Neurology |
Symptoms | Lack of coordination, balance issues, gait abnormality |
Complications | Cardiomyopathy, scoliosis, diabetes |
Usual onset | 5–20 years |
Duration | Long-term |
Causes | Genetic |
Diagnostic method | Medical history and physical examination |
Treatment | None |
Prognosis | Shortened life expectancy |
Frequency | 1 in 50,000 (United States) |
Friedreich's ataxia (FRDA or FA) is an autosomal-recessive genetic disease that causes difficulty walking, a loss of coordination in the arms and legs, and impaired speech that worsens over time. Symptoms generally start between 5 and 20 years of age. Many develop hypertrophic cardiomyopathy and require a mobility aid such as a cane, walker, or wheelchair in their teens. As the disease progresses, some affected people lose their sight and hearing. Other complications may include scoliosis and diabetes.
The condition is caused by mutations in the FXN gene on chromosome 9, which makes a protein called frataxin. In FRDA, cells produce less frataxin. Degeneration of nerve tissue in the spinal cord causes the ataxia; particularly affected are the sensory neurons essential for directing muscle movement of the arms and legs through connections with the cerebellum. The spinal cord becomes thinner, and nerve cells lose some myelin sheath.
In February 2023, the first approval of a treatment for FRDA, omaveloxolone, was granted by the US Food and Drug Administration (FDA). Approval in the European Union was granted in February 2024.
FRDA affects one in 50,000 people in the United States and is the most common inherited ataxia.[ not verified in body ] Rates are highest in people of Western European descent.[ not verified in body ] The condition is named after German physician Nikolaus Friedreich, who first described it in the 1860s.
Symptoms typically start between the ages of 5 and 15, but in late-onset FRDA, they may occur after age 25 years. [1] The symptoms are broad, but consistently involve gait and limb ataxia, dysarthria and loss of lower limb reflexes. [1]
There is some variability in symptom frequency, onset and progression. All individuals with FRDA develop neurological symptoms, including dysarthria and loss of lower limb reflexes, and more than 90% present with ataxia. [1] Cardiac issues are very common with early onset FRDA . [1] Most individuals develop heart problems such as enlargement of the heart, symmetrical hypertrophy, heart murmurs, atrial fibrillation, tachycardia, hypertrophic cardiomyopathy, and conduction defects. Scoliosis is present in about 60%. 7% of people with FRDA also have diabetes and having diabetes has an adverse impact on people with FA, especially those that show symptoms when young. [2] [3]
People who have been living with FRDA for a long time may develop other complications. 36.8% experience decreased visual acuity, which may be progressive and could lead to functional blindness. [3] Hearing loss is present in about 10.9% of cases. [3] Some patients report bladder and bowel symptoms. [4] Advanced stages of disease are associated with supraventricular tachyarrhythmias, most commonly atrial fibrillation. [1]
Other later stage symptoms can include, cerebellar effects such as nystagmus, fast saccadic eye movements, dysmetria and loss of coordination (truncal ataxia, and stomping gait). [1] Symptoms can involve the dorsal column such as the loss of vibratory sensation and proprioceptive sensation. [1]
The progressive loss of coordination and muscle strength leads to the full-time use of a wheelchair. Most young people diagnosed with FRDA require mobility aids such as a cane, walker, or wheelchair by early 20s. [5] The disease is progressive, with increasing staggering or stumbling gait and frequent falling. By the third decade, affected people lose the ability to stand or walk without assistance and require a wheelchair for mobility. [6]
Non-neurological symptoms such as scoliosis, pes cavus, cardiomyopathy and diabetes are more frequent amongst the early-onset cases. [1]
FRDA is an autosomal-recessive disorder that affects a gene (FXN) on chromosome 9, which produces an important protein called frataxin. [7]
In 96% of cases, the mutant FXN gene has 90–1,300 GAA trinucleotide repeat expansions in intron 1 of both alleles. [8] This expansion causes epigenetic changes and formation of heterochromatin near the repeat. [7] The length of the shorter GAA repeat is correlated with the age of onset and disease severity. [9] The formation of heterochromatin results in reduced transcription of the gene and low levels of frataxin. [10] People with FDRA might have 5-35% of the frataxin protein compared to healthy individuals. Heterozygous carriers of the mutant FXN gene have 50% lower frataxin levels, but this decrease is not enough to cause symptoms. [11]
In about 4% of cases, the disease is caused by a (missense, nonsense, or intronic) point mutation, with an expansion in one allele and a point mutation in the other. [12] A missense point mutation can have milder symptoms. [12] Depending on the point mutation, cells can produce no frataxin, nonfunctional frataxin, or frataxin that is not properly localized to the mitochondria. [13] [14]
FRDA affects the nervous system, heart, pancreas, and other systems. [15] [16]
Degeneration of nerve tissue in the spinal cord causes ataxia. [15] The sensory neurons essential for directing muscle movement of the arms and legs through connections with the cerebellum are particularly affected. [15] The disease primarily affects the spinal cord and peripheral nerves.[ medical citation needed ]
The spinal cord becomes thinner and nerve cells lose some myelin sheath. [15] The diameter of the spinal cord is smaller than that of unaffected individuals mainly due to smaller dorsal root ganglia. [16] The motor neurons of the spinal cord are affected to a lesser extent than sensory neurons. [15] In peripheral nerves, a loss of large myelinated sensory fibers occurs. [15]
Structures in the brain are also affected by FRDA, notably the dentate nucleus of the cerebellum. [16] The heart often develops some fibrosis, and over time, develops left-ventricle hypertrophy and dilatation of the left ventricle. [16]
The exact role of frataxin remains unclear. [17] Frataxin assists iron-sulfur protein synthesis in the electron transport chain to generate adenosine triphosphate, the energy molecule necessary to carry out metabolic functions in cells. It also regulates iron transfer in the mitochondria by providing a proper amount of reactive oxygen species (ROS) to maintain normal processes. [18] One result of frataxin deficiency is mitochondrial iron overload, which damages many proteins due to effects on cellular metabolism. [19]
Without frataxin, the energy in the mitochondria falls, and excess iron creates extra ROS, leading to further cell damage. [18] 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. [19]
Balance difficulty, loss of proprioception, an absence of reflexes, and signs of other neurological problems are common signs from a physical examination. [6] [20] Diagnostic tests are made to confirm a physical examination such as electromyogram, nerve conduction studies, electrocardiogram, echocardiogram, blood tests for elevated glucose levels and vitamin E levels, and scans such as X-ray radiograph for scoliosis. [21] MRI and CT scans of brain and spinal cord are done to rule out other neurological conditions. [22] Finally, a genetic test is conducted to confirm. [22]
Other diagnoses might include Charcot-Marie-Tooth types 1 and 2, ataxia with vitamin E deficiency, ataxia-oculomotor apraxia types 1 and 2, and other early-onset ataxias. [23]
Physicians and patients can reference the clinical management guidelines for Friedreich ataxia. [24] These Guidelines are intended to assist qualified healthcare professionals in making informed treatment decisions about the care of individuals with Friedreich ataxia. [25]
Omaveloxolone, sold under the brand name Skyclarys, is a medication used for the treatment of Friedreich's ataxia. [26] [27] It is taken by mouth. [26]
The most common side effects include an increase in alanine transaminase and an increase of aspartate aminotransferase, which can be signs of liver damage, headache, nausea, abdominal pain, fatigue, diarrhea and musculoskeletal pain. [27]
Omaveloxolone was approved for medical use in the United States in February 2023, [26] [27] [28] [29] [30] and in the European Union in February 2024. [31] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication. [32]Physical therapists play a critical role in educating on correct posture, muscle use, and the identification and avoidance of features that aggravate spasticities such as tight clothing, poorly adjusted wheelchairs, pain, and infection. [33]
Physical therapy typically includes intensive motor coordination, balance, and stabilization training to preserve gains. [34] Low-intensity strengthening exercises are incorporated to maintain functional use of the upper and lower extremities. [34] Stretching and muscle relaxation exercises can be prescribed to help manage spasticity and prevent deformities. [34] Other physical therapy goals include increased transfer and locomotion independence, muscle strengthening, increased physical resilience, "safe fall" strategy, learning to use mobility aids, learning how to reduce the body's energy expenditure, and developing specific breathing patterns. [34] Speech therapy can improve voice quality. [35]
Well-fitted orthoses can promote correct posture, support normal joint alignment, stabilize joints during walking, improve range of motion and gait, reduce spasticity, and prevent foot deformities and scoliosis. [5]
Functional electrical stimulation or transcutaneous nerve stimulation devices may alleviate symptoms. [5]
As progression of ataxia continues, assistive devices such as a cane, walker, or wheelchair may be required for mobility and independence. A standing frame can help reduce the secondary complications of prolonged use of a wheelchair. [36] [37]
Cardiac abnormalities can be controlled with ACE inhibitors such as enalapril, ramipril, lisinopril, or trandolapril, sometimes used in conjunction with beta blockers. Affected people who also have symptomatic congestive heart failure may be prescribed eplerenone or digoxin to keep cardiac abnormalities under control. [5]
Surgery may correct deformities caused by abnormal muscle tone. Titanium screws and rods inserted in the spine help prevent or slow the progression of scoliosis. Surgery to lengthen the Achilles tendon can improve independence and mobility to alleviate equinus deformity. [5] An automated implantable cardioverter-defibrillator can be implanted after a severe heart failure. [5]
The disease evolves differently in different people. [36] In general, those diagnosed at a younger age or with longer GAA triplet expansions tend to have more severe symptoms. [5]
Congestive heart failure and abnormal heart rhythms are the leading causes of death, [38] but people with fewer symptoms can live into their 60s or older. [22]
FRDA affects Indo-European populations. It is rare in East Asians, sub-Saharan Africans, and Native Americans. FRDA is the most prevalent inherited ataxia, affecting approximately 1 in 40,000 with European descent. [15] Males and females are affected equally. The estimated carrier prevalence is 1:100. [5] A 1990–1996 study of Europeans calculated the incidence rate was 2.8:100,000. [39] The prevalence rate of FRDA in Japan is 1:1,000,000. [40]
FRDA follows the same pattern as haplogroup R1b. Haplogroup R1b is the most frequently occurring paternal lineage in Western Europe. FRDA and Haplogroup R1b are more common in northern Spain, Ireland, and France, rare in Russia and Scandinavia, and follow a gradient through central and eastern Europe. A population carrying the disease went through a population bottleneck in the Franco-Cantabrian region during the last ice age. [41]
The condition is named after the nineteenth century German pathologist and neurologist, Nikolaus Friedreich. [42] Friedreich reported the disease in 1863 at the University of Heidelberg. [43] [44] [45] Further observations appeared in a paper in 1876. [46]
Frantz Fanon wrote his medical thesis on FRDA, in 1951. [47]
A 1984 Canadian study traced 40 cases to one common ancestral couple arriving in New France in 1634. [48]
FRDA was first linked to a GAA repeat expansion on chromosome 9 in 1996. [49]
The Cake Eaters is a 2007 independent drama film that stars Kristen Stewart as a young woman with FRDA. [50]
The Ataxian is a documentary that tells the story of Kyle Bryant, an athlete with FRDA who completes a long-distance bike race in an adaptive "trike" to raise money for research. [51]
Dynah Haubert spoke at the 2016 Democratic National Convention about supporting Americans with disabilities. [52]
Geraint Williams in an athlete affected by FRDA who is known for scaling Mount Kilimanjaro in an adaptive wheelchair. [53]
Shobhika Kalra is an activist with FRDA who helped build over 1000 wheelchair ramps across the United Arab Emirates in 2018 to try to make Dubai fully wheelchair-friendly by 2020. [54]
Butterflies Still Fly is a 2023 film, based on a true story, directed by Joseph Nenci. Italo is a light-hearted journalist, darkened by a personal drama that distracts him from work. He encounters with Giorgia, a young girl suffering from Friedreich's Ataxia, who will change his life.
There is no cure for Friedreich's ataxia, and treatment development is directed toward slowing, stopping, or reversing disease progression. In 2019, Reata Pharmaceuticals reported positive results in a phase 2 trial of RTA 408 (Omaveloxolone or Omav) to target activation of a transcriptional factor, Nrf2. [55] Nrf2 is decreased in FRDA cells. [56] [57] [58] [59]
There are several additional therapies in trial. Patients can enroll in a registry to make clinical trial recruiting easier. The Friedreich's Ataxia Global Patient Registry is the only worldwide registry of Friedreich's ataxia patients to characterize the symptoms and establish the rate of disease progression. [60] The Friedreich's Ataxia App is the only global community app which enables novel forms of research. [61]
As of May 2021, research continues along the following paths.
Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements, that indicates dysfunction of parts of the nervous system that coordinate movement, such as the cerebellum.
Abetalipoproteinemia is a disorder characterized by abnormal absorption of fat and fat-soluble vitamins from food. It is caused by a mutation in microsomal triglyceride transfer protein resulting in deficiencies in the apolipoproteins B-48 and B-100, which are used in the synthesis and exportation of chylomicrons and VLDL respectively. It is not to be confused with familial dysbetalipoproteinemia.
Scoliosis is a condition in which a person's spine has an irregular curve. The curve is usually S- or C-shaped over three dimensions. In some, the degree of curve is stable, while in others, it increases over time. Mild scoliosis does not typically cause problems, but more severe cases can affect breathing and movement. Pain is usually present in adults, and can worsen with age. As the condition progresses, it may alter a person's life, and hence can also be considered a disability.
Hereditary spastic paraplegia (HSP) is a group of inherited diseases whose main feature is a progressive gait disorder. The disease presents with progressive stiffness (spasticity) and contraction in the lower limbs. HSP is also known as hereditary spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell disease, or Strumpell-Lorrain disease. The symptoms are a result of dysfunction of long axons in the spinal cord. The affected cells are the primary motor neurons; therefore, the disease is an upper motor neuron disease. HSP is not a form of cerebral palsy even though it physically may appear and behave much the same as spastic diplegia. The origin of HSP is different from cerebral palsy. Despite this, some of the same anti-spasticity medications used in spastic cerebral palsy are sometimes used to treat HSP symptoms.
Dysarthria is a speech sound disorder resulting from neurological injury of the motor component of the motor–speech system and is characterized by poor articulation of phonemes. In other words, it is a condition in which problems effectively occur with the muscles that help produce speech, often making it very difficult to pronounce words. It is unrelated to problems with understanding language, although a person can have both. Any of the speech subsystems can be affected, leading to impairments in intelligibility, audibility, naturalness, and efficiency of vocal communication. Dysarthria that has progressed to a total loss of speech is referred to as anarthria. The term dysarthria was formed from the Greek components dys- "dysfunctional, impaired" and arthr- "joint, vocal articulation".
Ataxia–telangiectasia, also referred to as ataxia–telangiectasia syndrome or Louis–Bar syndrome, is a rare, neurodegenerative disease causing severe disability. Ataxia refers to poor coordination and telangiectasia to small dilated blood vessels, both of which are hallmarks of the disease. A–T affects many parts of the body:
Degenerative disc disease (DDD) is a medical condition typically brought on by the aging process in which there are anatomic changes and possibly a loss of function of one or more intervertebral discs of the spine. DDD can take place with or without symptoms, but is typically identified once symptoms arise. The root cause is thought to be loss of soluble proteins within the fluid contained in the disc with resultant reduction of the oncotic pressure, which in turn causes loss of fluid volume. Normal downward forces cause the affected disc to lose height, and the distance between vertebrae is reduced. The anulus fibrosus, the tough outer layers of a disc, also weakens. This loss of height causes laxity of the longitudinal ligaments, which may allow anterior, posterior, or lateral shifting of the vertebral bodies, causing facet joint malalignment and arthritis; scoliosis; cervical hyperlordosis; thoracic hyperkyphosis; lumbar hyperlordosis; narrowing of the space available for the spinal tract within the vertebra ; or narrowing of the space through which a spinal nerve exits with resultant inflammation and impingement of a spinal nerve, causing a radiculopathy.
Idebenone is a drug that was initially developed by Takeda Pharmaceutical Company for the treatment of Alzheimer's disease and other cognitive defects. This has been met with limited success. The Swiss company Santhera Pharmaceuticals has started to investigate it for the treatment of neuromuscular diseases. In 2010, early clinical trials for the treatment of Friedreich's ataxia and Duchenne muscular dystrophy have been completed. As of December 2013 the drug is not approved for these indications in North America or Europe. It is approved by the European Medicines Agency (EMA) for use in Leber's hereditary optic neuropathy (LHON) and was designated an orphan drug in 2007.
Gerstmann–Sträussler–Scheinker syndrome (GSS) is an extremely rare, always fatal neurodegenerative disease that affects patients from 20 to 60 years in age. It is exclusively heritable, and is found in only a few families all over the world. It is, however, classified with the transmissible spongiform encephalopathies (TSE) due to the causative role played by PRNP, the human prion protein. GSS was first reported by the Austrian physicians Josef Gerstmann, Ernst Sträussler and Ilya Scheinker in 1936.
Spinocerebellar ataxia (SCA) is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a neurological condition in its own right. An estimated 150,000 people in the United States have a diagnosis of spinocerebellar ataxia at any given time. SCA is hereditary, progressive, degenerative, and often fatal. There is no known effective treatment or cure. SCA can affect anyone of any age. The disease is caused by either a recessive or dominant gene. In many cases people are not aware that they carry a relevant gene until they have children who begin to show signs of having the disorder.
Spinal muscular atrophy (SMA) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting. It is usually diagnosed in infancy or early childhood and if left untreated it is the most common genetic cause of infant death. It may also appear later in life and then have a milder course of the disease. The common feature is progressive weakness of voluntary muscles, with arm, leg and respiratory muscles being affected first. Associated problems may include poor head control, difficulties swallowing, scoliosis, and joint contractures.
A trinucleotide repeat expansion, also known as a triplet repeat expansion, is the DNA mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder. These are labelled in dynamical genetics as dynamic mutations. Triplet expansion is caused by slippage during DNA replication, also known as "copy choice" DNA replication. Due to the repetitive nature of the DNA sequence in these regions, 'loop out' structures may form during DNA replication while maintaining complementary base pairing between the parent strand and daughter strand being synthesized. If the loop out structure is formed from the sequence on the daughter strand this will result in an increase in the number of repeats. However, if the loop out structure is formed on the parent strand, a decrease in the number of repeats occurs. It appears that expansion of these repeats is more common than reduction. Generally, the larger the expansion the more likely they are to cause disease or increase the severity of disease. Other proposed mechanisms for expansion and reduction involve the interaction of RNA and DNA molecules.
Kyphoscoliosis describes an abnormal curvature of the spine in both the coronal and sagittal planes. It is a combination of kyphosis and scoliosis. This musculoskeletal disorder often leads to other issues in patients, such as under-ventilation of lungs, pulmonary hypertension, difficulty in performing day-to-day activities, psychological issues emanating from anxiety about acceptance among peers, especially in young patients. It can also be seen in syringomyelia, Friedreich's ataxia, spina bifida, kyphoscoliotic Ehlers–Danlos syndrome (kEDS), and Duchenne muscular dystrophy due to asymmetric weakening of the paraspinal muscles.
Frataxin is a protein that in humans is encoded by the FXN gene.
Copper deficiency, or hypocupremia, is defined either as insufficient copper to meet the needs of the body, or as a serum copper level below the normal range. Symptoms may include fatigue, decreased red blood cells, early greying of the hair, and neurological problems presenting as numbness, tingling, muscle weakness, and ataxia. The neurodegenerative syndrome of copper deficiency has been recognized for some time in ruminant animals, in which it is commonly known as "swayback". Copper deficiency can manifest in parallel with vitamin B12 and other nutritional deficiencies.
Spinal disease refers to a condition impairing the backbone. These include various diseases of the back or spine ("dorso-"), such as kyphosis. Dorsalgia refers to back pain. Some other spinal diseases include spinal muscular atrophy, ankylosing spondylitis, scoliosis, lumbar spinal stenosis, spina bifida, spinal tumors, osteoporosis and cauda equina syndrome.
Autosomal dominant cerebellar ataxia (ADCA) is a form of spinocerebellar ataxia inherited in an autosomal dominant manner. ADCA is a genetically inherited condition that causes deterioration of the nervous system leading to disorder and a decrease or loss of function to regions of the body.
Omaveloxolone, sold under the brand name Skyclarys, is a medication used for the treatment of Friedreich's ataxia. It is taken by mouth.
Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant disorder, which, like other spinocerebellar ataxias, is characterized by neurological symptoms including dysarthria, hypermetric saccades, and ataxia of gait and stance. This cerebellar dysfunction is progressive and permanent. First onset of symptoms is normally between 30 and 40 years of age, though juvenile onset can occur. Death typically occurs within 10 to 30 years from onset.
Cerebellar degeneration is a condition in which cerebellar cells, otherwise known as neurons, become damaged and progressively weaken in the cerebellum. There are two types of cerebellar degeneration; paraneoplastic cerebellar degeneration, and alcoholic or nutritional cerebellar degeneration. As the cerebellum contributes to the coordination and regulation of motor activities, as well as controlling equilibrium of the human body, any degeneration to this part of the organ can be life-threatening. Cerebellar degeneration can result in disorders in fine movement, posture, and motor learning in humans, due to a disturbance of the vestibular system. This condition may not only cause cerebellar damage on a temporary or permanent basis, but can also affect other tissues of the central nervous system, those including the cerebral cortex, spinal cord and the brainstem.