Friedreich's ataxia (FRDA or FA) is an
autosomal-recessive genetic disease that causes difficulty walking, a loss of sensation 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
A mobility aid is a device designed to assist walking or otherwise improve the mobility of people with a mobility impairment.
There are various walking aids which can help people with impaired ability to walk, and wheelchairs or mobility scoot ...
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 mellitus
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
.
The condition is caused by mutations in the ''FXN'' gene on
chromosome 9
Chromosome 9 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome, as they normally do with all chromosomes. Chromosome 9 spans about 138 million base pairs of nucleic acids (the building blocks of D ...
, which makes a protein called
frataxin
Frataxin is a protein that in humans is encoded by the FXN gene.
It is located in the mitochondrion and Frataxin mRNA is mostly expressed in tissues with a high metabolic rate. The function of frataxin is not clear but it is involved in assemb ...
. In FRDA, cells produce less frataxin.
Degeneration of
nerve tissue
Nervous tissue, also called neural tissue, is the main tissue component of the nervous system. The nervous system regulates and controls body functions and activity. It consists of two parts: the central nervous system (CNS) comprising the brain ...
in the
spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the sp ...
causes the
ataxia
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. Ataxia is a clinical manifestation indicating dysfunction of ...
; particularly affected are the
sensory neurons
Sensory neurons, also known as afferent neurons, are neurons in the nervous system, that convert a specific type of stimulus, via their receptors, into action potentials or graded potentials. This process is called sensory transduction. The ...
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
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...
.
No effective treatment is known, but several therapies are in trials. FRDA shortens life expectancy due to heart disease, but some people can live into their 60s or older.
FRDA affects one in 50,000 people in the United States and is the most common inherited ataxia. Rates are highest in people of Western European descent. The condition is named after German physician
Nikolaus Friedreich, who first described it in the 1860s.
Symptoms
Symptoms typically start between the ages of 5 and 15, but in late-onset FRDA, they may occur after age 25 years.
The symptoms are broad, but consistently involve gait and limb ataxia, dysarthria and loss of lower limb reflexes.
Classical symptoms
There is some variability in symptom frequency, onset and progression. All individuals with FRDA develop
neurological symptoms
A neurological disorder is any disorder of the nervous system. Structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves can result in a range of symptoms. Examples of symptoms include paralysis, muscle weaknes ...
, including
dysarthria
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 ...
and loss of lower limb reflexes, and more than 90% present with ataxia.
Cardiac issues are very common with early onset FRDA .
Most individuals develop heart problems such as
enlargement of the heart, symmetrical
hypertrophy
Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number.Updated by Linda J. ...
,
heart murmurs
Heart murmurs are unique heart sounds produced when blood flows across a heart valve or blood vessel. This occurs when turbulent blood flow creates a sound loud enough to hear with a stethoscope. Turbulent blood flow is not smooth. The sound di ...
,
atrial fibrillation,
tachycardia
Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ( ...
,
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.
Other symptoms
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.
Hearing loss is present in about 10.9% of cases.
Some patients report bladder and bowel symptoms.
Advanced stages of disease are associated with
supraventricular tachyarrhythmias
Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (s ...
, most commonly
atrial fibrillation.
Other later stage symptoms can include,
cerebellar
The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cereb ...
effects such as
nystagmus
Nystagmus is a condition of involuntary (or voluntary, in some cases) eye movement. Infants can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in reduced or limited vision. Due to the invol ...
, fast
saccadic eye movements,
dysmetria
Dysmetria ( en, wrong length) is a lack of coordination of movement typified by the undershoot or overshoot of intended position with the hand, arm, leg, or eye. It is a type of ataxia. It can also include an inability to judge distance or scale.
...
and loss of coordination (
truncal ataxia
Truncal ataxia (or trunk ataxia) is a wide-based "drunken sailor" gait characterised by uncertain starts and stops, lateral deviations and unequal steps. It is an instability of the trunk and often seen during sitting. It is most visible when sh ...
, and
stomping gait).
Symptoms can involve the dorsal column such as the loss of
vibratory sensation and
proprioceptive sensation.
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.
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.
Early-onset cases
Non-neurological symptoms such as
scoliosis,
pes cavus
Pes cavus, also known as high arch, is a human foot type in which the sole of the foot is distinctly hollow when bearing weight. That is, there is a fixed plantar flexion of the foot. A high arch is the opposite of a flat foot and is somewhat ...
, cardiomyopathy and diabetes are more frequent amongst the early-onset cases.
Genetics
FRDA is an autosomal-recessive disorder that affects a gene (''FXN'') on chromosome 9, which produces an important protein called frataxin.
In 96% of cases, the mutant ''FXN'' gene has 90–1,300 GAA
trinucleotide repeat expansion
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 muta ...
s in
intron 1 of both
alleles
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chrom ...
.
This expansion causes
epigenetic changes and formation of
heterochromatin near the repeat.
The length of the shorter GAA repeat is correlated with the age of onset and disease severity.
The formation of heterochromatin results in reduced
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
of the gene and low levels of frataxin. People with FDRA might have 5-35% of the frataxin protein compared to healthy individuals.
Heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
carriers of the mutant FXN gene have 50% lower frataxin levels, but this decrease is not enough to cause symptoms.
In about 4% of cases, the disease is caused by a (
missense
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
Substitution of protein from DNA mutations
Missense mu ...
,
nonsense
Nonsense is a communication, via speech, writing, or any other symbolic system, that lacks any coherent meaning. Sometimes in ordinary usage, nonsense is synonymous with absurdity or the ridiculous. Many poets, novelists and songwriters have u ...
, or
intronic
An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene ...
)
point mutation
A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequence ...
, with an expansion in one
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
and a
point mutation
A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequence ...
in the other.
A missense point mutation can have milder symptoms.
Depending on the point mutation, cells can produce no frataxin, nonfunctional frataxin, or frataxin that is not properly localized to the mitochondria.
Pathophysiology
FRDA affects the nervous system, heart, pancreas, and other systems.
Degeneration of nerve tissue in the spinal cord causes ataxia.
The sensory neurons essential for directing muscle movement of the arms and legs through connections with the cerebellum are particularly affected.
The disease primarily affects the spinal cord and
peripheral nerves
The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain an ...
.
The spinal cord becomes thinner and nerve cells lose some
myelin sheath
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...
.
The diameter of the spinal cord is smaller than that of unaffected individuals mainly due to smaller dorsal root ganglia.
The
motor neurons of the spinal cord are affected to a lesser extent than sensory neurons.
In peripheral nerves, a loss of large myelinated sensory fibers occurs.
Structures in the brain are also affected by FRDA, notably the dentate nucleus of the cerebellum.
The heart often develops some fibrosis, and over time, develops left-ventricle hypertrophy and dilatation of the left ventricle.
Frataxin
The exact role of frataxin remains unclear.
Frataxin assists
iron-sulfur protein
Iron–sulfur proteins (or iron–sulphur proteins in British spelling) are proteins characterized by the presence of iron–sulfur clusters containing sulfide-linked di-, tri-, and tetrairon centers in variable oxidation states. Iron–sulfur cl ...
synthesis in the electron transport chain to generate
adenosine triphosphate
Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms o ...
, 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
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
(ROS) to maintain normal processes.
One result of frataxin deficiency is mitochondrial iron overload, which damages many proteins due to effects on cellular metabolism.
Without frataxin, the energy in the mitochondria falls, and excess iron creates extra ROS, leading to further cell damage.
[ 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.]
Diagnosis
Balance difficulty, loss of proprioception, an absence of reflexes, and signs of other neurological problems are common signs from a physical examination. Diagnostic tests are made to confirm a physical examination such as electromyogram
Electromyography (EMG) is a technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an instrument called an electromyograph to produce a record called an electromyogram. An electromyog ...
, nerve conduction studies
A nerve conduction study (NCS) is a medical diagnostic test commonly used to evaluate the function, especially the ability of electrical conduction, of the motor and sensory nerves of the human body. These tests may be performed by medical spec ...
, electrocardiogram, echocardiogram
An echocardiography, echocardiogram, cardiac echo or simply an echo, is an ultrasound of the heart.
It is a type of medical imaging of the heart, using standard ultrasound or Doppler ultrasound.
Echocardiography has become routinely used in th ...
, blood tests for elevated glucose levels and vitamin E levels, and scans such as X-ray radiograph for scoliosis. MRI
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...
and CT scans of brain and spinal cord are done to rule out other neurological conditions.[ ] Finally, a genetic test
Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, o ...
is conducted to confirm.
Other diagnoses might include Charcot-Marie-Tooth types 1 and 2, ataxia with vitamin E deficiency
Vitamin E deficiency in humans is a very rare condition, occurring as a consequence of abnormalities in dietary fat absorption or metabolism rather than from a diet low in vitamin E. Collectively the EARs, RDAs, AIs and ULs for vitamin E and other ...
, ataxia-oculomotor apraxia types 1 and 2, and other early-onset ataxias.
Management
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.
Rehabilitation
Physical therapy typically includes intensive motor coordination, balance, and stabilization training to preserve gains. Low intensity strengthening exercises are incorporated to maintain functional use of the upper and lower extremities. Stretching and muscle relaxation exercises can be prescribed to help manage spasticity and prevent deformities. 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. Speech therapy can improve voice quality.
Devices
Well-fitted orthoses
Orthotics ( el, Ορθός, translit=ortho, lit=to straighten, to align) is a medical specialty that focuses on the design and application of orthoses, or braces. An is "an externally applied device used to influence the structural and functio ...
can promote correct posture, support normal joint alignment, stabilize joints during walking, improve range of motion and gait, reduce spasticity
Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles ...
, and prevent foot deformities and scoliosis.
Functional electrical stimulation
Functional electrical stimulation (FES) is a technique that uses low-energy electrical pulses to artificially generate body movements in individuals who have been paralyzed due to injury to the central nervous system. More specifically, FES can ...
or transcutaneous nerve stimulation devices may alleviate symptoms.[
As progression of ataxia continues, assistive devices such as a cane, walker, or wheelchair may be required for mobility and independence. A ]standing frame
A standing frame (also known as a stand, stander, standing technology, standing aid, standing device, standing box, tilt table) is assistive technology that can be used by a person who relies on a wheelchair for mobility. A standing frame provide ...
can help reduce the secondary complications of prolonged use of a wheelchair.
Medication and surgery
Cardiac abnormalities can be controlled with ACE inhibitors such as enalapril
Enalapril, sold under the brand name Vasotec among others, is an ACE inhibitor medication used to treat high blood pressure, diabetic kidney disease, and heart failure. For heart failure, it is generally used with a diuretic, such as furose ...
, ramipril
Ramipril, sold under the brand name Altace among others, is an ACE inhibitor type medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It can also be used as a preventative medication in patients over 55 yea ...
, lisinopril
Lisinopril is a medication of the angiotensin-converting enzyme (ACE) inhibitor and is used to treat high blood pressure, heart failure, and after heart attacks. For high blood pressure it is usually a first-line treatment. It is also used t ...
, or trandolapril
Trandolapril is an ACE inhibitor used to treat high blood pressure. It may also be used to treat other conditions. It is similar in structure to another ACE Inhibitor, Ramipril but has a cyclohexane group. It also is a pro-drug and must get metabo ...
, sometimes used in conjunction with beta blockers
Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms, and to protect the heart from a second heart attack after a first heart attack ( secondary prevention). They are ...
. Affected people who also have symptomatic congestive heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...
may be prescribed eplerenone
Eplerenone, sold under the brand name Inspra, is an aldosterone antagonist type of potassium-sparing diuretic that is used to treat chronic heart failure and high blood pressure, particularly for patients with resistant hypertension due to ele ...
or digoxin to keep cardiac abnormalities under control.[
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
The Achilles tendon or heel cord, also known as the calcaneal tendon, is a tendon at the back of the lower leg, and is the thickest in the human body. It serves to attach the plantaris, gastrocnemius (calf) and soleus muscles to the calcaneus ( ...
can improve independence and mobility to alleviate equinus deformity.[ An automated ]implantable cardioverter-defibrillator
An implantable cardioverter-defibrillator (ICD) or automated implantable cardioverter defibrillator (AICD) is a device implantable inside the body, able to perform defibrillation, and depending on the type, cardioversion and pacing of the h ...
can be implanted after a severe heart failure.[
]
Prognosis
The disease evolves differently in different people.[ In general, those diagnosed at a younger age or with longer GAA triplet expansions tend to have more severe symptoms.][
Congestive heart failure and abnormal heart rhythms are the leading causes of death, but people with fewer symptoms can live into their 60s or older.]
Epidemiology
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. Males and females are affected equally. The estimated carrier prevalence is 1:100. A 1990–1996 study of Europeans calculated the incidence rate was 2.8:100,000. The prevalence rate of FRDA in Japan is 1:1,000,000.
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
The Franco-Cantabrian region (also ''Franco-Cantabric region'') is a term applied in archaeology and history to refer to an area that stretches from Asturias, in northern Spain, to Aquitaine and Provence in Southern France. It includes the southe ...
during the last ice age.
History
The condition is named after the 1860s German pathologist
Pathology is the study of the causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in t ...
and neurologist
Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...
, Nikolaus Friedreich. Friedreich reported the disease in 1863 at the University of Heidelberg
}
Heidelberg University, officially the Ruprecht Karl University of Heidelberg, (german: Ruprecht-Karls-Universität Heidelberg; la, Universitas Ruperto Carola Heidelbergensis) is a public research university in Heidelberg, Baden-Württemberg, ...
. Further observations appeared in a paper in 1876.
Frantz Fanon
Frantz Omar Fanon (, ; ; 20 July 1925 – 6 December 1961), also known as Ibrahim Frantz Fanon, was a French West Indian psychiatrist, and political philosopher from the French colony of Martinique (today a French department). His works have b ...
wrote his medical thesis on FRDA, in 1951.
A 1984 Canadian study traced 40 cases to one common ancestral couple arriving in New France
New France (french: Nouvelle-France) was the area colonized by France in North America, beginning with the exploration of the Gulf of Saint Lawrence by Jacques Cartier in 1534 and ending with the cession of New France to Great Britain and Spa ...
in 1634.
FRDA was first linked to a GAA repeat expansion on chromosome 9 in 1996.
Research
Active research is ongoing to find a treatment. 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. The Friedreich's Ataxia App is the only global community app which enables novel forms of research.
As of May 2021, research continues along the following paths.
Improve mitochondrial function and reduce oxidative stress
* Reata Pharmaceuticals
Reata Pharmaceuticals, Inc. is a pharmaceutical company based in Plano, Texas. Founded in 2002, Reata is primarily focused on investigating experimental oral antioxidative and anti-inflammatory drugs, which dually activate the antioxidative trans ...
developed RTA 408 ( Omaveloxolone or Omav) to target activation of a transcriptional factor, Nrf2
Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the ''NFE2L2'' gene. NRF2 is a basic leucine zipper (bZIP) protein that may reg ...
. Nrf2 is decreased in FRDA cells.[.]
* PTC-743 (formerly EPI-743) is being developed by PTC Therapeutics. PTC-743 is a para-benzoquinone and targets the NAD(P)H dehydrogenase (quinone 1)
NAD(P)H dehydrogenase uinone1 is an enzyme that in humans is encoded by the ''NQO1'' gene. This protein-coding gene is a member of the NAD(P)H dehydrogenase (quinone) family and encodes a 2-electron reductase (enzyme). This FAD-binding protein ...
(NQO1) enzyme to increase the biosynthesis of glutathione
Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pe ...
.
* Retrotope is advancing RT001. RT001 is a deuterated synthetic homologue of ethyl linoleate, an essential omega-6
Omega-6 fatty acids (also referred to as ω-6 fatty acids or ''n''-6 fatty acids) are a family of polyunsaturated fatty acids that have in common a final carbon-carbon double bond in the ''n''-6 position, that is, the sixth bond, counting from ...
polyunsaturated fatty acid which is one of the major components of lipid membrane
The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...
s, particularly in mitochondria. Oxidation damage might be reduced if the polyunsaturated fatty acid
Polyunsaturated fatty acids (PUFAs) are fatty acids that contain more than one double bond in their backbone. This class includes many important compounds, such as essential fatty acids and those that give drying oils their characteristic proper ...
s in the lipids were made more rigid and less susceptible to oxidation by the replacement of hydrogen
Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxic ...
atoms with the heavy hydrogen isotope deuterium
Deuterium (or hydrogen-2, symbol or deuterium, also known as heavy hydrogen) is one of two stable isotopes of hydrogen (the other being protium, or hydrogen-1). The nucleus of a deuterium atom, called a deuteron, contains one proton and one ...
.
Modulation of frataxin controlled metabolic pathways
* Dimethyl fumarate
Dimethyl fumarate (DMF) is the methyl ester of fumaric acid and is named after the earth smoke plant (''Fumaria officinalis''). Dimethyl fumarate combined with three other fumaric acid esters (FAEs) is solely licensed in Germany as an oral thera ...
has been shown to increase frataxin levels in FRDA cells, mouse models, and humans. DMF showed an 85% increase in frataxin expression over 3 months in multiple sclerosis .
Frataxin replacements or stabilizers
* EPO mimetics are orally available peptide imitations of erythropoietin. They are small molecules erythropoietin receptor agonists designed to activate the tissue-protective erythropoietin receptor.
* Etravirine
Etravirine (ETR, brand name Intelence, formerly known as TMC125) is a drug used for the treatment of HIV. Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI). Unlike the currently available agents in the class, resistance to o ...
, an antiviral drug used to treat HIV, was found in a drug repositioning
Drug repositioning (also called drug repurposing) involves the investigation of existing drugs for new therapeutic purposes.
Repurposing achievements
A number of successes have been achieved, the foremost including sildenafil (Viagra) for ere ...
screening to increase frataxin levels in peripheral cells. Fratagene Therapeutics is developing a small molecule called RNF126 to inhibit an enzyme which degrades frataxin.
Increase frataxin gene expression
* Resveratrol might improve mitochondrial function.
* Nicotinamide
Niacinamide or Nicotinamide (NAM) is a form of vitamin B3 found in food and used as a dietary supplement and medication. As a supplement, it is used by mouth to prevent and treat pellagra (niacin deficiency). While nicotinic acid (niacin) may ...
(vitamin B3) was found effective in preclinical FRDA models and well tolerated.
* An RNA-based approach might unsilence the FXN gene and increase the expression of frataxin. Non-coding RNA (ncRNA
A non-coding RNA (ncRNA) is a functional RNA molecule that is not translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Abundant and functionally important types of non ...
) could be responsible for directing the localized epigenetic silencing of the FXN gene.
* Lentivirus-mediated delivery of the FXN gene has been shown to increase frataxin expression and prevent DNA damage in human and mouse fibroblasts
A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells ...
.
* CRISPR Therapeutics received a grant from the Friedreich's Ataxia Research Alliance
The Friedreich's Ataxia Research Alliance (FARA) is a 501(c)(3), non-profit, tax-exempt organization formed to support the research on Friedreich's ataxia
Friedreich's ataxia (FRDA or FA) is an autosomal-recessive genetic disease that c ...
to investigate gene editing as a potential treatment for the disease in 2017.
Society and culture
'' The Cake Eaters'' is a 2007 independent drama film that stars Kristen Stewart
Kristen Jaymes Stewart (born April 9, 1990) is an American actress. The world's highest-paid actress in 2012, she has received various accolades, including a British Academy Film Award and a César Award, in addition to nominations for an Aca ...
as a young woman with FRDA.
'' 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.
Dynah Haubert spoke at the 2016 Democratic National Convention
The 2016 Democratic National Convention was a presidential nominating convention, held at the Wells Fargo Center in Philadelphia, Pennsylvania, from July 25 to 28, 2016. The convention gathered delegates of the Democratic Party, the majo ...
about supporting Americans with disabilities.
Geraint Williams in an athlete affected by FRDA who is known for scaling Mount Kilimanjaro in an adaptive wheelchair.
Shobhika Kalra is an activist with FRDA who helped build over 1000 wheelchair ramps across the United Arab Emirates
The United Arab Emirates (UAE; ar, اَلْإِمَارَات الْعَرَبِيَة الْمُتَحِدَة ), or simply the Emirates ( ar, الِْإمَارَات ), is a country in Western Asia ( The Middle East). It is located at t ...
in 2018 to try to make Dubai
Dubai (, ; ar, دبي, translit=Dubayy, , ) is the most populous city in the United Arab Emirates (UAE) and the capital of the Emirate of Dubai, the most populated of the 7 emirates of the United Arab Emirates.The Government and Politics of ...
fully wheelchair-friendly by 2020.
References
External links
Friedreich's Ataxia Global Patient Registry
NIH's FRDA information page
{{DEFAULTSORT:Friedreich's Ataxia
Systemic atrophies primarily affecting the central nervous system
Autosomal recessive disorders
Mitochondrial diseases
Trinucleotide repeat disorders
Rare diseases