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Friedreich's Ataxia
Published in Charles Theisler, Adjuvant Medical Care, 2023
In Friedreich’s ataxia (FA), nerve fibers in the spinal cord and peripheral nerves degenerate, becom ing thinner.1 The cerebellum also degenerates, but to a lesser extent. Nonetheless, cerebellar damage results in awkward, unsteady movements and impaired sensory functions. FA is an autosomal recessive inherited disease and is caused by a defect in a gene labeled FXN, which carries the genetic code for a protein called frataxin. Although rare, the disorder is the most common form of hereditary ataxia in the U.S., affecting about one in every 50,000 people.
Mitochondrial Dysfunction in Friedreich Ataxia
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Rosella Abeti, Annalisa Baccaro, Paola Giunti
The FXN gene is located in the chromosome 9q13 and the mutation impedes its transcription (Grabczyk and Usdin, 2000), reducing the level of downstream frataxin (FXN) protein in the cells. FXN is a mitochondrial protein located in the inner mitochondrial membrane and causing iron biogenesis deficiency. The range of GAA repeat expansion can span between 70 and 1700, however, the average patients have been shown to have around 600 and 900 repeats (Pandolfo, 2001).
Anaesthesia for a patient with Friedreich’s ataxia undergoing emergency tibia interlocking nail insertion
Published in Egyptian Journal of Anaesthesia, 2022
Friedreich's ataxia is a disorder that affects a gene (FXN) on chromosome 9, which produces an important protein (frataxin). Low frataxin levels lead to insufficient biosynthesis of iron–sulfur clusters that are needed for mitochondrial electron transport and iron metabolism. This leads to cell damage and degeneration. Degeneration occurs in sensory nerves more than motor nerves. Similar degenerative changes occur in cardiac cells and pancreatic cells causing left ventricular hypertrophy and dilatation and diabetes mellitus. Friedreich's ataxia is the most common inherited ataxia with a prevalence of 1 in 30,000–50,000 and a carrier frequency of 1 in 90–110. The classic Friedreich’s ataxia phenotype is due to a homozygous GAA (guanine, adenine, adenine) triplet repeat expansion in intron 1 of the frataxin gene [3–6].
Designing phase II clinical trials in Friedreich ataxia
Published in Expert Opinion on Emerging Drugs, 2021
Gene therapies for FRDA will be advancing to clinical trials in the next few years. In addition to all the challenges discussed in this review, gene therapies will have added hurdles to overcome. Gene therapy delivered via viral vectors elicits an immune response and can therefore only be administered to a person one time. Dose optimization in pre-clinical models is thus crucial. A second unique challenge for gene therapy is that administration of an exogenous FXN gene into a person eliminates the possibility of that person ever participating in future clinical trials. It would be impossible to tell if a trial drug was acting on the endogenous FXN genes, the exogenous gene, or both and would therefore cloud the data for future trials. Finally, viral vectors currently in pre-clinical development generally are directed to limited organ systems, that is, only the heart or only the nervous system. These last two issues require careful consideration of enrollment criteria for trials testing these agents and raise a few questions: Should only severely affected individuals in advanced stages of the disease be considered for initial trials? What are the best biomarkers and outcome measures to use in this subpopulation?
New developments in pharmacotherapy for Friedreich ataxia
Published in Expert Opinion on Pharmacotherapy, 2019
Alexandra Clay, Patrick Hearle, Kim Schadt, David R. Lynch
Since the discovery of FXN 23 years ago, the clinical diagnosis and evaluation of FRDA, as well as the understanding of the pathophysiology of the disease, have greatly evolved. Several clinical trials have occurred or are currently occurring, a rapid pace for a rare disease. Clinical trials and therapies to date are directed at the augmentation of mitochondrial function and alleviation of symptoms. Drugs that target mitochondria are not regarded as potential cures in FRDA since these drugs do not replace or increase low levels of frataxin. However, recent exploration of Nrf2 upregulators holds promise as a powerful new class of therapies directed toward improving the homeostatic response to the disease. A combination of therapies may produce significant improvements in quality of life and mitochondrial function, and slowing of disease progression.