The objective of this study was to investigate predictors of survival in FA. Within a prospective registry established by the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS; ClinicalTrials.gov identifier NCT02069509), genetically confirmed FA patients were enrolled at 11 tertiary centers and followed in yearly intervals. Overall survival was investigated applying the Kaplan-Meier method, life tables, and log-rank test. Prognostic factors were explored applying Cox proportional hazards regression and subsequently a risk score was built to assess for discrimination and calibration performance. Between September 2010 and March 2017, 631 FA patients were enrolled. Median age at inclusion was 31 (range, 6-76) years. Until December 2022, 44 patients died and 119 terminated the study for other reasons. The 10-year cumulative survival rate was 87%. In a multivariable analysis, the disability stage (hazard ratio [HR] 1.51, 95% CI 1.08-2.12, P = 0.02), history of arrhythmic disorder (HR 2.93, 95% CI 1.34-6.39, P = 0.007), and diabetes mellitus (HR 2.31, 95% CI 1.05-5.10, P = 0.04) were independent predictors of survival. GAA repeat lengths did not improve the survival model. A risk score built on the previously described factors plus the presence of left ventricular systolic dysfunction at echocardiography enabled identification of four trajectories to prognosticate up to 10-year survival (log-rank test P < 0.001). Arrhythmias, progressive neurological disability, and diabetes mellitus influence the overall survival in FA. The authors built a survival prognostic score which identifies patients meriting closer surveillance and who may benefit from early invasive cardiac monitoring and therapy.
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Scientific News
FARA funds research progress
In this section, you will find the most recent FA research publications, many of which are funded by FARA, as well as information on upcoming conferences and symposiums. You can search for articles by date using the archive box in the right hand column. To locate FARA Funded or Supported Research, click the hyperlink in the right hand column. You may also search for specific content using key words or phrases in the search button at the top right of your screen. Please be sure to visit other key research sections of our website for information on FARA's Grant Program and the Treatment Pipeline.
Predictors of Survival in Friedreich's Ataxia: A Prospective Cohort Study
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Generation and characterization of two human iPSC lines, IGIBi014-A and IGIBi015-A, from Friedreich's ataxia (FRDA) patients with pathogenic (GAA/TTC)n repeat expansion in first intron of the Frataxin (FXN) gene
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Friedreich's ataxia (FRDA) is a rare neurodegenerative disorder caused by over expansion of GAA repeats in the first intron of the FXN gene. Here, the authors generated two iPSC lines from FRDA patients with biallelic expansion of GAA repeats in the first intron of FXN gene. Both iPSC lines demonstrated characteristics of pluripotency, normal karyotypes (46, XY), the capacity to differentiate into all three germ layers, and the ability to sustain the GAA repeat expansion with decreased FXN mRNA expression.
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Unraveling the genetic landscape of undiagnosed cerebellar ataxia in Brazilian patients
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Hereditary ataxias (HAs) encompass a diverse and genetically intricate group of rare neurodegenerative disorders, presenting diagnostic challenges. Whole-exome sequencing (WES) has significantly improved diagnostic success. This study aimed to elucidate genetic causes of cerebellar ataxia within a diverse Brazilian cohort. Biological samples were collected from individuals with sporadic or familial cerebellar ataxia, spanning various ages and phenotypes, excluding common SCAs and Friedreich ataxia. RFC1 biallelic AAGGG repeat expansion was screened in all patients. For AAGGG-negative cases, WES targeting 441 ataxia-related genes was performed, followed by ExpansionHunter analysis for repeat expansions, including the recently described GGC-ZFHX3. Variant classification adhered to ClinGen guidelines, yielding definitive or probable diagnoses. The study involved 76 diverse Brazilian families. 16 % received definitive diagnoses, and another 16 % received probable ones. RFC1-related ataxia was predominant, with two definitive cases, followed by KIF1A (one definitive and one probable) and SYNE-1 (two probable). Early-onset cases exhibited higher diagnostic rates. ExpansionHunter improved diagnosis by 4 %. GGC-ZFHX3 repeat expansion was not detected in this cohort. This study highlights diagnostic complexities in cerebellar ataxia, even with advanced genetic methods. RFC1, KIF1A, and SYNE1 emerged as prevalent mutations. ZFHX3 repeat expansion seem to be rare in Brazilian population. Early-onset cases showed higher diagnostic success. WES coupled with ExpansionHunter holds promise as a primary diagnostic tool, emphasizing the need for broader NGS accessibility in Brazil.
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Clinical stage and plasma neurofilament concentration in adults with Friedreich ataxia
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The authors evaluated the axonal protein neurofilament light in plasma (p-NfL) as a possible biomarker for disease severity in FRDA. All possible genetically confirmed FRDA cases in the Västra Götaland Region (VGR) of Sweden were searched and each patient was investigated clinically. Blood samples were obtained for analysis of p-NfL. Eight patients were found, corresponding to 1/170.000 adults in the VGR, and 5 of these participated in the study. Three out of the five FRDA patients displayed a small or moderate increase in the p-NfL value, compared to the age-adjusted cut-offs for p-NfL established in the Clinical Neurochemistry Laboratory at the authors’ hospital. The two others were the oldest and most severely affected, displayed normal values according the cut-off values. The cohort is too small to make any statistically significant correlation between the five p-NfL values with regard to disease severity. FRDA is less prevalent in this region of Sweden than could be assumed. In concordance with previous studies from other authors, it was found that p-NfL may be increased in patients with FRDA, but less so in older more clinically affected patients. Thus, the authors conclude that on an individual basis, p-NFL is of uncertain clinical value as a suitable biomarker.
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A kinetic model of iron trafficking in growing Saccharomyces cerevisiae cells; applying mathematical methods to minimize the problem of sparse data and generate viable autoregulatory mechanisms
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Iron is an essential transition metal for all eukaryotic cells, and its trafficking throughout the cell is highly regulated. However, the overall cellular mechanism of regulation is poorly understood despite knowing many of the molecular players involved. Here, an ordinary-differential-equations (ODE) based kinetic model of iron trafficking within a growing yeast cell was developed that included autoregulation. The 9-reaction 8-component in-silico cell model was solved under both steady-state and time-dependent dynamical conditions. The ODE for each component included a dilution term due to cell growth. Conserved rate relationships were obtained from the null space of the stoichiometric matrix, and the reduced-row-echelon-form was used to distinguish independent from dependent rates. Independent rates were determined from experimentally estimated component concentrations, cell growth rates, and the literature. Simple rate-law expressions were assumed, allowing rate-constants for each reaction to be estimated. Continuous Heaviside logistical functions were used to regulate rate-constants. These functions acted like valves, opening or closing depending on component "sensor" concentrations. Two cellular regulatory mechanisms were selected from 134,217,728 possibilities using a novel approach involving 6 mathematically-defined filters. Three cellular states were analyzed including healthy wild-type cells, iron-deficient wild-type cells, and a frataxin-deficient strain of cells characterizing the disease Friedreich's Ataxia. The model was stable toward limited perturbations, as determined by the eigenvalues of Jacobian matrices. Autoregulation allowed healthy cells to transition to the diseased state when triggered by a mutation in frataxin, and to the iron-deficient state when cells are placed in iron-deficient growth medium. The in-silico phenotypes observed during these transitions were similar to those observed experimentally. The model also predicted the observed effects of hypoxia on the diseased condition. A similar approach could be used to solve ODE-based kinetic models associated with other biochemical processes operating within growing cells.
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- Human frataxin, the Friedreich ataxia deficient protein, interacts with mitochondrial respiratory chain
- A modified mouse model of Friedreich's ataxia with conditional Fxn allele homozygosity delays onset of cardiomyopathy
- Novel intragenic deletion within the FXN gene in a patient with typical phenotype of Friedreich ataxia: may be more prevalent than we think?
- Recent progress and applications of small molecule inhibitors of Keap1-Nrf2 axis for neurodegenerative diseases
- Structural peculiarities of tandem repeats and their clinical significance