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Friedreich's Ataxia is named after a German neurologist, Nikolaus Friedreich, who, in 1863, described this rare, inherited disease to the medical community.
"Ataxia," which refers to coordination problems such as clumsy or awkward movements and unsteadiness, occurs in many different diseases and conditions. The ataxia of Friedreich's ataxia results from the degeneration of nerve tissue in the spinal cord, in particular sensory neurons essential (through connections with the cerebellum) for directing muscle movement of the arms and legs. The spinal cord becomes thinner and nerve cells lose some of their myelin sheath (the insular covering on some nerve cells that helps conduct nerve impulses).
Friedreich's Ataxia is caused by an abnormality in one of the genes, called X25, located in the ninth chromosome pair. Genes are sets of instructions that tell the cells, containing chromosomes, how to build the proteins that enable these cells to carry out their various functions. These functions determine a person's physical characteristics, from the color of the hair and eyes to the organization of the nervous system.
Humans have two copies of each gene — one inherited from the mother and one from the father. Genes are located at a specific place on each of an individual's 46 chromosomes, which are tightly coiled chains of DNA containing millions of chemicals called bases. These bases — adenine, thymine, cytosine, and guanine — are abbreviated A, T, C, and G. Certain bases always "pair" together (A with T; C with G), and different combinations of base pairs join in sets of three to form coded messages.
These coded messages are "recipes" for making amino acids, the building blocks of proteins. By combining in long sequences, like long phone numbers, the paired bases tell each cell how to assemble different proteins. Proteins make up cells, tissues, and specialized enzymes that our bodies need to function normally. The protein that is altered in Friedreich's ataxia is called frataxin. This lack of frataxin protein causes the nerve cells within the tissues of the spinal cord and its brain connections, the heart and pancreas to degenerate, thereby reducing nerve signals to the muscles.
In 1996, an international group of scientists identified the cause of Friedreich's ataxia as a defect in a gene located on chromosome 9. Because of the inherited abnormal code, a particular sequence of bases (GAA) is repeated too many times. Normally, the GAA sequence is repeated 7 to 22 times, but in people with Friedreich's ataxia it can be repeated hundreds or even over a thousand times. This type of abnormality is called a triplet repeat expansion and has been implicated as the cause of several dominantly inherited diseases. Friedreich's ataxia is the first known recessive genetic disease that is caused by a triplet repeat expansion. Although about 98 percent of Friedreich's ataxia carriers have this particular genetic triplet repeat expansion, it is not found in all cases of the disease. A very small proportion of affected individuals have other gene coding defects responsible for causing disease.
The triplet repeat expansion apparently disrupts the normal assembly of amino acids into proteins, greatly reducing the amount of frataxin that is produced. Frataxin is found in the energy-producing parts of the cell called mitochondria. Research suggests that without a normal level of frataxin, certain cells in the body (especially brain, spinal cord, and muscle cells) cannot effectively produce energy and have a buildup of toxic byproducts leading to what is called "oxidative stress." This clue to the possible cause of Friedreich's ataxia came after scientists conducted studies using a yeast protein with a chemical structure similar to human frataxin. They found that the shortage of this protein in the yeast cell led to a toxic buildup of iron in the cell's mitochondria. When the excess iron reacted with oxygen, free radicals were produced. Although free radicals are essential molecules in the body's metabolism, they can also destroy cells and harm the body. Research continues on this subject.
Friedreich´s ataxia develops only when a person inherits the defective gene from both parents. This is called a recessive inheritance pattern. If only one parent contributes a defective gene, the child becomes a "carrier" of Friedreich's Ataxia but never develops the disorder.
Carriers appear neurologically normal, and sometimes may not know they are carriers until an afflicted child is born to them. It is estimated that 1 out of every 100 people is a carrier of the Friedreich's gene defect, and 1 of every 40,000 is affected with Friedreich's Ataxia. Each child of parents who are both carriers has a 25 percent chance of inheriting the disease.
Symptoms usually begin in childhood or youth (age 5 through 25) as a result of deterioration in areas of the brain controlling muscle coordination, the spinal cord and nerves. In Late Onset FA (LOFA) symptoms may occur in the 20s or 30s. Symptoms include any combination, but not necessarily all of the following:
The symptoms may include:
Diagnosis is based on a person's medical history, family history and a complete neurological evaluation which includes an electromyography (EMG). An EMG is a test in which the electrical activity in muscle is analyzed after being amplified, displayed and recorded. To supplement the evaluation, various tests may be performed which assist in the diagnosis and rule out other possible disorders that may present similar symptoms.
Doctors diagnose Friedreich's ataxia by performing a careful clinical examination, which includes a medical history and a thorough physical examination. Tests that may be performed include:
As with many degenerative diseases of the nervous system, there is unfortunately no specific treatment. However, many of the following symptoms associated with Friedreich's Ataxia can be treated or controlled.
Symptoms and possible treatment method(s)
A wheelchair may be required for mobility.
Researchers are optimistic that they will soon be closer to understanding the causes of the disease, which eventually will help scientists develop effective treatments and prevention strategies for Friedreich's ataxia.
Studies reveal that frataxin is a mitochondrial protein that should normally be present in the nervous system, the heart, and the pancreas. Yet in patients with the disease, the amount of frataxin in affected cells of these tissues is severely reduced. There are abnormally high levels of iron in the heart tissue of people with Friedreich's ataxia. It is believed that the nervous system, heart, and pancreas may be particularly susceptible to damage from free radicals (produced when the excess iron reacts with oxygen) because once certain cells in these tissues are destroyed by free radicals they cannot be replaced. Nerve and muscle cells are particularly vulnerable to free radical damage. Free radicals have been implicated in other degenerative diseases such as Parkinson's and Alzheimer's diseases.
Based upon this information, scientists and physicians have tried to reduce the levels of free radicals, also called oxidants, using treatment with “antioxidants.” Several clinical studies in Europe suggest that antioxidants like coenzyme Q10, vitamin E, and idebenone may offer patients some limited benefit. There are currently clinical trials in the United States and Europe to evaluate the effectiveness of idebenone in patients with Friedreich’s ataxia.
Pioglitazone: It is known that the lack of frataxin affects the synthesis of iron-sulfur proteins within the cell. Besides this, lack of frataxin causes defective signalling of the superoxide dismutase, a key enzyme for the cell's antioxidant defenses. Because of this defective signalling, the cells exhibit hypersensitivity to all oxidative attack. This phenomenon explains for certain one aspect of in vivo pathology. On the other hand, Pioglitazone is known for activating a PPAR receptor, and this activation leads to the expression of many enzymes involved in mitochondrial metabolism, including the superoxide dismutases. Pioglitazone also shows a protective effect in models of neurological pathology, both in vitro and in vivo, when it inhibits inflammatory enzymes, activating anti-inflammatory genes, and reducing the activation of the microglia. In this form, Pioglitazone joins with a protein called MitoNEET, a protein of the mitochondria's external membrane; this protein increases the stability of the 2Fe-2S complexes. This neuroprotective agent is capable of crossing the blood-brain barrier. Pioglitazone is a drug commonly used in the treatment of type II diabetes. In December 2008, Dr. Pierre Rustin initiated a trial in France to explore the effects of Pioglitazone on neurological function in FA patients.
A0001 is the compound discovered by Edison Pharmaceuticals that shows important promise of improving mitochondrial function (which means energy production) in FA patients. Edison has now partnered with Penwest Pharmaceuticals for the purposes of advancing A0001 through clinical trials. The Edison-Penwest team initiated phase I of the A0001 trial in July 2008. The dose escalation for this phase will be done healthy volunteers-- in whom the dose escalation can be done much quicker than in FA patients. The plan is then to conduct the phase II in FA patients using the optimum dose.
A phase I/II study of iron chelator Deferiprone began at a number of international sites such as France, Belgium, the UK, Italy and Spain in 2008. ApoPharma is working with FA clinicians in Canada and Australia regarding additional sites. This trial is based on very promising results in a pilot study conducted in France. For 6 months, each patient received two doses of Deferiprone per day. At the end of the trial, 8 of the 9 patients showed an improvement in their neurological disorders as a result of the reduction in iron present in the cerebellum. These improvements first of all concerned sensitivity and sphincter disorders, such as incontinence or constipation, followed by performance of movements and speech, and finally walking and balance.
EPO is a hormone produced in our bodies and is also an approved drug used to increase red blood cells. In an explorative open-label clinical pilot study, an Austrian team found an evidence for clinical improvement together with a persistent increase of frataxin levels and a reduction of oxidative stress parameters in patients with FRDA receiving chronic treatment with rhuEPO. Safety monitoring with regular blood cell counts and parameters of iron metabolism is a potential limitation of this approach.
HDAC inhibitors are the compounds discovered for FA by Dr. Joel Gottesfeld of The Scripps Research Institute in La Jolla, California. These HDAC inhibitors act at the DNA/gene level and increase frataxin in cells from FA patients and in FA animal models. The pharmaceutical company Repligen is now working with the active HDAC inhibitors that have been identified, doing pharmacokinetic and toxicology studies to learn more and identify the most effective compounds. A library of derivatives that can be screened for potential treatments has been established, and toxicity studies are going well.
Pilot study of Varenicline (Chantix(R)) in the treatment of FA: Chantix is a smoking-cessation drug. Dr. Theresa Zesiewicz, a neurologist and movement disorders specialist from the University of South Florida in Tampa found that Chantix® may have a positive effect on ataxia while treating a single fragile X tremor/ataxia patient-smoker and then two patients with spinocerebellar ataxia (SCA 3 and SCA 14). These single-patient and two-patient case reports were very recently published in the medical literature. Dr. Zesiewicz only has information on treating a few patients and is currently trying to understand how this drug can work on symptoms of ataxia.
Several other compounds may be brought to clinical trials in the near future. To check for current trials, go to the following website: www.clinicaltrials.gov.
The reports on this website are for informational and educational purposes only. It is not intended to replace or contradict your medical doctor's advice and should not be used, interpreted, or relied upon as professional medical advice. Please consult a qualified physician regarding specific medical concerns or treatment.
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Currently, BabelFAmily is financing two promising research projects aimed at finding a cure for Friedreich's Ataxia. Whenever you make a donation to us or purchase a copy of "The legacy of Marie Schlau", this is where all funds raised will be devoted to:
1) Gene Therapy for Friedreich's Ataxia research project:
The project is the result of an initiative of Spanish people affected by this rare disease who are grouped in GENEFA in collaboration with the Spanish Federation of Ataxias and the BabelFAmily. The Friedreich’s Ataxia Research Alliance (FARA), one of the main patients’ associations in the United States now joins the endeavour.
2) Frataxin delivery research project:
The associations of patients and families Babel Family and the Asociación Granadina de la Ataxia de Friedreich (ASOGAF) channel 80,000 euros of their donations (50% from each organisation) into a new 18-month project at the Institute for Research in Biomedicine (IRB Barcelona). The project specifically aims to complete a step necessary in order to move towards a future frataxin replacement therapy for the brain, where the reduction of this protein causes the most damage in patients with Friedreich’s Ataxia.
The study is headed by Ernest Giralt, head of the Peptides and Proteins Lab, who has many years of experience and is a recognised expert in peptide chemistry and new systems of through which to delivery drugs to the brain, such as peptide shuttles—molecules that have the capacity to carry the drug across the barrier that surrounds and protects the brain. Since the lab started its relation with these patients’ associations in 2013*, it has been developing another two projects into Friedrich’s Ataxia.