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Friedreich ataxia- pathogenesis and implications for therapies.

08:00 EDT 5th September 2019 | BioPortfolio

Summary of "Friedreich ataxia- pathogenesis and implications for therapies."

Friedreich ataxia is the most common of the hereditary ataxias. It is due to homozygous/compound heterozygous mutations in FXN. This gene encodes frataxin, a protein largely localized to mitochondria. In about 96% of affected individuals there is homozygosity for a GAA repeat expansion in intron 1 of the FXN gene. Studies of people with Friedreich ataxia and of animal and cell models, have provided much insight into the pathogenesis of this disorder. The expanded GAA repeat leads to transcriptional deficiency of the FXN gene. The consequent deficiency of frataxin protein leads to reduced iron-sulfur cluster biogenesis and mitochondrial ATP production, elevated mitochondrial iron, and oxidative stress. More recently, a role for inflammation has emerged as being important in the pathogenesis of Friedreich ataxia. These findings have led to a number of potential therapies that have been subjected to clinical trials or are being developed toward human studies. Therapies that have been proposed include pharmaceuticals that increase frataxin levels, protein and gene replacement therapies, antioxidants, iron chelators and modulators of inflammation. Whilst no therapies have yet been approved for Friedreich ataxia, there is much optimism that the advances in the understanding of the pathogenesis of this disorder since the discovery its genetic basis, will result in approved disease modifying therapies in the near future.

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This article was published in the following journal.

Name: Neurobiology of disease
ISSN: 1095-953X
Pages: 104606

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Medical and Biotech [MESH] Definitions

An autosomal recessive disease, usually of childhood onset, characterized pathologically by degeneration of the spinocerebellar tracts, posterior columns, and to a lesser extent the corticospinal tracts. Clinical manifestations include GAIT ATAXIA, pes cavus, speech impairment, lateral curvature of spine, rhythmic head tremor, kyphoscoliosis, congestive heart failure (secondary to a cardiomyopathy), and lower extremity weakness. Most forms of this condition are associated with a mutation in a gene on chromosome 9, at band q13, which codes for the mitochondrial protein frataxin. (From Adams et al., Principles of Neurology, 6th ed, p1081; N Engl J Med 1996 Oct 17;335(16):1169-75) The severity of Friedreich ataxia associated with expansion of GAA repeats in the first intron of the frataxin gene correlates with the number of trinucleotide repeats. (From Durr et al, N Engl J Med 1996 Oct 17;335(16):1169-75)

Therapies using arts or directed at the senses.

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Prenatal interventions to correct fetal anomalies or treat FETAL DISEASES in utero. Fetal therapies include several major areas, such as open surgery; FETOSCOPY; pharmacological therapy; INTRAUTERINE TRANSFUSION; STEM CELL TRANSPLANTATION; and GENE THERAPY.

Therapeutic practices which are not currently considered an integral part of conventional allopathic medical practice. They may lack biomedical explanations but as they become better researched some (PHYSICAL THERAPY MODALITIES; DIET; ACUPUNCTURE) become widely accepted whereas others (humors, radium therapy) quietly fade away, yet are important historical footnotes. Therapies are termed as Complementary when used in addition to conventional treatments and as Alternative when used instead of conventional treatment.

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