Friedreich Ataxia: current status and future prospects

Bürk, Katrin

doi:10.1186/s40673-017-0062-x

Cited by 128 publications

(118 citation statements)

References 128 publications

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“…This difference provides a plausible explanation for DM‐related differences in physical function, especially since the neurological burden represented by FARS score captures mostly ataxia, with minimal FA‐associated neuropathy. In contrast to DM‐related neuropathy, the neuropathy related to FA is static, and typically has already reached maximal severity at presentation in individuals with FA 6, 9, 36. One limitation of this analysis is that self‐reported comorbidities were not verified, and some participants may have comorbidities of which they are unaware and/or were not inclined to report.…”

Section: Discussionmentioning

confidence: 99%

Impact of diabetes in the Friedreich ataxia clinical outcome measures study

McCormick

Farmer

Perlman

et al. 2017

Ann Clin Transl Neurol

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ObjectiveFriedreich ataxia (FA) is a progressive neuromuscular disorder caused by GAA triplet repeat expansions or point mutations in the FXN gene. FA is associated with increased risk of diabetes mellitus (DM). This study assessed the age‐specific prevalence of FA‐associated DM and its impact on neurologic outcomes.Research Design and MethodsParticipants were 811 individuals with FA from 12 international sites in a prospective natural history study (FA Clinical Outcome Measures Study, FACOMS). Physical function was assessed, using validated instruments. Multivariable regression analyses examined the independent association of DM with outcomes.ResultsMean age of participants was 30.1 years (SD 15.3, range: 7–82), 50% were female, and 94% were non‐Hispanic white. 9% (42/459) of adults and 3% (10/352) of children had DM. Individuals with FA‐associated DM were older (P < 0.001), had longer GAA repeat length on the least affected FXN allele (P = 0.037), and more severe FA (P = 0.0001). Of individuals with DM, 65% (34/52) were taking insulin. Even after accounting statistically for both age and GAA repeat length, DM was independently associated with greater FA symptom burden (P = 0.010), reduced capacity to perform activities of daily living (P = 0.021), and a decrease of 0.33 SDs on a composite performance measure (95% CI: −0.56–0.11, P = 0.004); the relative impact of DM was most apparent in younger individuals.Conclusions DM‐associated FA has an independent adverse impact on well‐being in affected individuals, particularly at younger ages. In future, evidence‐based approaches for identification and management of FA‐related DM may improve both health and function.

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Section: Discussionmentioning

confidence: 99%

Impact of diabetes in the Friedreich ataxia clinical outcome measures study

McCormick

Farmer

Perlman

et al. 2017

Ann Clin Transl Neurol

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“…FXN gene does not seem to possess cancer driver properties (Davoli et al, 2013), and an increased risk of tumor has been apparently excluded in FRDA patients (Bürk, 2017;Martelli et al, 2012). However, alteration of FXN levels has been found in different types of cancer, as reported in the Cancer Genome Atlas (Hutter & Zenklusen, 2018), and several cases of FRDA are associated with the occurrence of neoplastic diseases and alteration of DNA in peripheral blood cells (Ackroyd, Shorthouse & Stephenson, 1996;Barr, Page & Taylor, 1986;Deutsch, Seyer, Perlman, Yu, & Lynch, 2012;Haugen et al, 2010;Kidd et al, 2001;Misiakos et al, 2011;Ramos, Latash, Hurvitz, & Brown, 1997).…”

Section: Discussionmentioning

confidence: 99%

Characterization of human frataxin missense variants in cancer tissues

et al. 2019

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Human frataxin is an iron‐binding protein involved in the mitochondrial iron–sulfur (Fe–S) clusters assembly, a process fundamental for the functional activity of mitochondrial proteins. Decreased level of frataxin expression is associated with the neurodegenerative disease Friedreich ataxia. Defective function of frataxin may cause defects in mitochondria, leading to increased tumorigenesis. Tumor‐initiating cells show higher iron uptake, a decrease in iron storage and a reduced Fe–S clusters synthesis and utilization. In this study, we selected, from COSMIC database, the somatic human frataxin missense variants found in cancer tissues p.D104G, p.A107V, p.F109L, p.Y123S, p.S161I, p.W173C, p.S181F, and p.S202F to analyze the effect of the single amino acid substitutions on frataxin structure, function, and stability. The spectral properties, the thermodynamic and the kinetic stability, as well as the molecular dynamics of the frataxin missense variants found in cancer tissues point to local changes confined to the environment of the mutated residues. The global fold of the variants is not altered by the amino acid substitutions; however, some of the variants show a decreased stability and a decreased functional activity in comparison with that of the wild‐type protein.

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“…Current strategies for the treatment of FRDA mainly focused on correcting frataxin expression, which intervenes the pathogenetic cascade downstream of frataxin deficiency, enhance antioxidant expression, and even some further gene or protein replacement or cellular therapies 6,33 . In fact, no therapies have been proven to cure or slow disease progression effectively 34 .…”

Section: Discussionmentioning

confidence: 99%

Long-term voluntary running prevents the onset of symptomatic Friedreich’s ataxia in mice

Zhao

Lewellen

Wilson

et al. 2020

Sci Rep

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the common clinical symptoms of Friedreich's ataxia (FRDA) include ataxia, muscle weakness, type 2 diabetes and heart failure, which are caused by impaired mitochondrial function due to the loss of frataxin (FXN) expression. Endurance exercise is the most powerful intervention for promoting mitochondrial function; however, its impact on FRDA has not been studied. Here we found that mice with genetic knockout and knock-in of the Fxn gene (KIKO mice) developed exercise intolerance, glucose intolerance and moderate cardiac dysfunction at 6 months of age. These abnormalities were associated with impaired mitochondrial respiratory function concurrent with reduced iron regulatory protein 1 (Irp1) expression as well as increased oxidative stress, which were not due to loss of mitochondrial content and antioxidant enzyme expression. Importantly, long-term (4 months) voluntary running in KIKO mice starting at a young age (2 months) completely prevented the functional abnormalities along with restored Irp1 expression, improved mitochondrial function and reduced oxidative stress in skeletal muscle without restoring Fxn expression. We conclude that endurance exercise training prevents symptomatic onset of FRDA in mice associated with improved mitochondrial function and reduced oxidative stress. These preclinical findings may pave the way for clinical studies of the impact of endurance exercise in FRDA patients.Friedreich's ataxia (FRDA) is the most common autosomal recessive ataxia in the Caucasian population 1-4 with detrimental clinical symptoms, including ataxia, muscle weakness, type 2 diabetes and heart failure 5,6 . These symptoms usually first appear in childhood or adolescence and worsen over time. A hypertrophic cardiomyopathy is an important clinical trait, which contributes significantly to disability and early death 7,8 . A high percentage of FRDA patients have glucose intolerance or diabetes mellitus 4 , and exercise capacity is usually severely diminished 9 , leading to wheelchair binding within 10 to 20 years after the disease onset 10 .FRDA is caused by GAA repeat expansions in both alleles of the frataxin (FXN) gene within intron 1 located in chromosome 9 11,12 from normally around 5-30 to >90 6,12 . The GAA expansion mutations lead to reduced expression of frataxin, a mitochondrial protein, which is involved in assembly of iron-sulfur clusters (ISC) and/or function as an iron chaperone or an iron storage protein 13 . Although the precise function of frataxin is not entirely clear yet, substantial evidence shows that frataxin deficiency leads to inefficient use of iron during ISC synthesis, inhibition of ISC formation and/or increased production of reactive oxygen species (ROS) via the Fenton reaction, resulting in iron deposition, mitochondrial dysfunction and oxidative damage 14,15 . It is these abnormal functions in the metabolically active tissues/organs that eventually lead to the onset of clinical symptoms. Unfortunately, no pharmacologic treatment up to date has been proven to impede FRDA progression ...

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Friedreich Ataxia: current status and future prospects

Cited by 128 publications

References 128 publications

Impact of diabetes in the Friedreich ataxia clinical outcome measures study

Impact of diabetes in the Friedreich ataxia clinical outcome measures study

Characterization of human frataxin missense variants in cancer tissues

Long-term voluntary running prevents the onset of symptomatic Friedreich’s ataxia in mice

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