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Cardiac Hypertrophy, Heart Failure and Cardiomyopathy
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
Friedreich's ataxia initially presents with central nervous symptoms before puberty. About 50% of cases die of cardiac disease in the third and fourth decades. Many will have cor pulmonale due to respiratory failure but cardiac hypertrophic and dilated phenotypes occur. DCM and arrhythmia are associated with higher mortality, whereas HCM is not. The gene responsible is on chromosome 9 and codes for a 210 amino acid protein frataxin. This frataxin gene impacts on the ability of the encoded protein to participate in mitochondrial oxidative phosphorylation. Mitochondria proliferate but remain dysfunctional. The length of the repeat sequence is directly related to the degree of LVH. The conduction disease seen in Friedriech's ataxia patients is thought to be a result of fibrotic myocardial replacement and scarring, which predispose the patient to atrioventricular conduction blocks and atrial or ventricular arrhythmias.
Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
The GAA repeat represses transcription of frataxin mRNA by altering local chromatin structure.32 Frataxin appears to be a nuclear encoded mitochondrial protein important for normal production of cellular energy. Reduced frataxin in spinal cord, heart, and pancreas has been postulated to cause neuronal degeneration, cardiomyopathy, and an increased risk of diabetes by altering iron homeostasis in cells and their mitochondria.
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].
Emerging therapies in Friedreich’s Ataxia
Published in Expert Review of Neurotherapeutics, 2020
Theresa A. Zesiewicz, Joshua Hancock, Shaila D. Ghanekar, Sheng-Han Kuo, Carlos A. Dohse, Joshua Vega
Friedreich’s ataxia (FRDA) is a progressive, neurodegenerative disorder and the most common autosomal recessive ataxia worldwide, affecting approximately 1 in 50,000 people. Approximately 1 in 100 people carry an allele of mutated frataxin (FXN) gene, which encodes for the frataxin protein. FRDA is caused by biallelic intronic GAA repeat expansion in the FXN gene on chromosome 9 [1], ranging from 66 to approximately 1300 GAA repeats [2]. The expanded intronic GAA repeats lead to transcriptional silencing of FXN, causing a deficiency of frataxin protein. The length of the GAA repeat in the shorter allele (GAA1) correlates with disease severity at the age of onset [3]. A small subset of FRDA patients might have one allele with GAA repeat expansions and one allele of point mutation of the FXN gene. Genetic testing is available for FRDA diagnosis confirmation.
New developments in pharmacotherapy for Friedreich ataxia
Published in Expert Opinion on Pharmacotherapy, 2019
Alexandra Clay, Patrick Hearle, Kim Schadt, David R. Lynch
Friedreich ataxia (FRDA), an autosomal recessive neurodegenerative disorder that affects roughly 1 in 50,000 people of European descent, is the most common inherited ataxia [1–3]. Affected individuals have mutations on both alleles of the FXN gene, which encodes the protein frataxin. The most common genetic mutation of FRDA (96% of all abnormal alleles) is an expanded GAA trinucleotide repeat in the first intron of the gene. Abnormal alleles contain 66 to 1500 GAA repeats in the FXN gene, while normal alleles contain fewer than 33 consecutive GAA repeats [1–3]. Point mutations in the FXN gene constitute most of the remaining 4% of mutations [1–9]. In very rare instances, the affected individuals are compound heterozygous for an exonic deletion and an expansion [7,10]. Carriers of a single abnormal allele exhibit lower frataxin levels than controls, but do not develop clinical symptoms [11,12].