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Background: Progressive loss of standing balance is a feature of Friedreich's ataxia (FRDA). Objectives: This study aimed to identify standing balance conditions and digital postural sway measures that best discriminate between FRDA and healthy controls (HC). We assessed test–retest reliability and correlations between sway measures and clinical scores. Methods: Twenty‐eight subjects with FRDA and 20 HC completed six standing conditions: feet apart, feet together, and feet tandem, both with eyes opened (EO) and eyes closed. Sway was measured using a wearable sensor on the lumbar spine for 30 seconds. Test completion rate, test–retest reliability with intraclass correlation coefficients, and areas under the receiver operating characteristic curves (AUCs) for each measure were compared to identify distinguishable FRDA sway characteristics from HC. Pearson correlations were used to evaluate the relationships between discriminative measures and clinical scores. Results: Three of the six standing conditions had completion rates over 70%. Of these three conditions, natural stance and feet together with EO showed the greatest completion rates. All six of the sway measures' mean values were significantly different between FRDA and HC. Four of these six measures discriminated between groups with >0.9 AUC in all three conditions. The Friedreich Ataxia Rating Scale Upright Stability and Total scores correlated with sway measures with P‐values <0.05 and r‐values (0.63–0.86) and (0.65–0.81), respectively. Conclusion: Digital postural sway measures using wearable sensors are discriminative and reliable for assessing standing balance in individuals with FRDA. Natural stance and feet together stance with EO conditions suggest use in clinical trials for FRDA. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Objectives: Friedreich ataxia (FRDA) is a rare genetic disorder caused by mutations in the FXN gene, leading to progressive coordination loss and other symptoms. The recently approved omaveloxolone targets this condition but is limited to patients over 16 years of age, highlighting the need for pediatric treatments due to the disorder's early onset and more rapid progression in children. This population also experiences increased non‐neurological complications; the FACHILD study aimed to augment and expand the knowledge about the natural history of the disease and clinical outcome assessments for trials in children in FRDA. Methods: The study enrolled 108 individuals aged 7–18 years with a confirmed FRDA diagnosis, with visits occurring from October 2017 to November 2022 across three institutions. Several measures were introduced to minimize the impact of the COVID‐19 pandemic, including virtual visits. Outcome measures centered on the mFARS score and its subscores, and data were analyzed using mixed models for repeated measures. For context and to avoid misinterpretation, the analysis was augmented with data from patients enrolled in the Friedreich's Ataxia Clinical Outcome Measures Study. Results: Results confirmed the general usefulness of the mFARS score in children, but also highlighted issues, particularly with the upper limb subscore (FARS B). Increased variability, limited homogeneity across study subgroups, and potential training effects might limit mFARS application in clinical trials in pediatric populations. Interpretation: The FARS E (Upright Stability) score might be a preferred outcome measure in this patient population. [ABSTRACT FROM AUTHOR]

Objective: Most individuals with Friedreich ataxia (FRDA) have homozygous GAA triplet repeat expansions in the FXN gene, correlating with a typical phenotype of ataxia and cardiomyopathy. A minority are compound heterozygotes carrying a GAA expansion on one allele and a mutation on the other. The study aim was to examine phenotypic variation among compound heterozygotes. Methods: Data on FXN mutations were obtained from the Friedreich Ataxia Clinical Outcome Measures Study (FA‐COMS). We compared clinical features in a single‐site FA‐COMS cohort of 51 compound heterozygous and 358 homozygous patients, including quantitative measures of cardiac, neurologic, and visual disease progression. Results: Non‐GAA repeat mutations were associated with reduced cardiac disease, and patients with minimal/no function mutations otherwise had a typical FRDA phenotype but with significantly more severe progression. The partial function mutation group was characterized by relative sparing of bulbar and upper limb function, as well as particularly low cardiac involvement. Other clinical features in this group, including optic atrophy and diabetes mellitus, varied widely depending on the specific type of partial function mutation. Interpretation: These data support that the typical FRDA phenotype is driven by frataxin deficiency, especially severe in compound heterozygotes with minimal/no function mutations, whereas the heterogeneous presentations of those with partial function mutations may indicate other contributing factors to FRDA pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Fatigue is a prevalent and debilitating symptom in neurological disorders, including spinocerebellar ataxias (SCAs). However, the risk factors of fatigue in the SCAs as well as its impact have not been well investigated. Objectives: To study the prevalence of fatigue in SCAs, the factors contributing to fatigue, and the influence of fatigue on quality of life. Methods: Fatigue was assessed in 418 participants with SCA1, SCA2, SCA3, and SCA6 from the Clinical Research Consortium for the Study of Cerebellar Ataxia using the Fatigue Severity Scale. We conducted multi‐variable linear regression models to examine the factors contributing to fatigue as well as the association between fatigue and quality of life. Results: Fatigue was most prevalent in SCA3 (52.6%), followed by SCA1 (36.7%), SCA6 (35.7%), and SCA2 (35.6%). SCA cases with fatigue had more severe ataxia and worse depressive symptoms. In SCA3, those with fatigue had a longer disease duration and longer pathological CAG repeat numbers. In multi‐variable models, depressive symptoms, but not ataxia severity, were associated with more severe fatigue. Fatigue, independent of ataxia and depression, contributed to worse quality of life in SCA3 and SCA6 at baseline, and fatigue continued affecting quality of life throughout the disease course in all types of SCA. Conclusions: Fatigue is a common symptom in SCAs and is closely related to depression. Fatigue significantly impacts patients' quality of life. Therefore, screening for fatigue should be considered a part of standard clinical care for SCAs. [ABSTRACT FROM AUTHOR]

Objective: The natural history of Friedreich ataxia is being investigated in a multi‐center longitudinal study designated the Friedreich ataxia Clinical Outcome Measures Study (FACOMS). To understand the utility of this study in analysis of clinical trials, we performed a propensity‐matched comparison of data from the open‐label MOXIe extension (omaveloxolone) to that from FACOMS. Methods: MOXIe extension patients were matched to FACOMS patients using logistic regression to estimate propensity scores based on multiple covariates: sex, baseline age, age of onset, baseline modified Friedreich Ataxia Rating scale (mFARS) score, and baseline gait score. The change from baseline in mFARS at Year 3 for the MOXIe extension patients compared to the matched FACOMS patients was analyzed as the primary efficacy endpoint using mixed model repeated measures analysis. Results: Data from the MOXIe extension show that omaveloxolone provided persistent benefit over 3 years when compared to an untreated, matched cohort from FACOMS. At each year, in all analysis populations, patients in the MOXIe extension experienced a smaller change from baseline in mFARS score than matched FACOMS patients. In the primary pooled population (136 patients in each group) by Year 3, patients in the FACOMS matched set progressed 6.6 points whereas patients treated with omaveloxolone in MOXIe extension progressed 3 points (difference = −3.6; nominal p value = 0.0001). Interpretation: These results suggest a meaningful slowing of Friedreich ataxia progression with omaveloxolone, and consequently detail how propensity‐matched analysis may contribute to understanding of effects of therapeutic agents. This demonstrates the direct value of natural history studies in clinical trial evaluations. [ABSTRACT FROM AUTHOR]

Objective: Friedreich ataxia (FRDA) is an inherited condition caused by a GAA triplet repeat (GAA‐TR) expansion in the FXN gene. Clinical features of FRDA include ataxia, cardiomyopathy, and in some, vision loss. In this study, we characterize features of vision loss in a large cohort of adults and children with FRDA. Methods: Using optical coherence tomography (OCT), we measured peripapillary retinal nerve fiber layer (RNFL) thickness in 198 people with FRDA, and 77 controls. Sloan letter charts were used to determine visual acuity. RNFL thickness and visual acuity were compared to measures of disease severity obtained from the Friedreich Ataxia Clinical Outcomes Measures Study (FACOMS). Results: The majority of patients, including children, had pathologically thin RNFLs (mean = 73 ± 13 μm in FRDA; 98 ± 9 μm in controls) and low‐contrast vision deficits early in the disease course. Variability in RNFL thickness in FRDA (range: 36 to 107 μm) was best predicted by disease burden (GAA‐TR length X disease duration). Significant deficits in high‐contrast visual acuity were apparent in patients with an RNFL thickness of ≤68 μm. RNFL thickness decreased at a rate of −1.2 ± 1.4 μm/year and reached 68 μm at a disease burden of approximately 12,000 GAA years, equivalent to disease duration of 17 years for participants with 700 GAAs. Interpretation: These data suggest that both hypoplasia and subsequent degeneration of the RNFL may be responsible for the optic nerve dysfunction in FRDA and support the development of a vision‐directed treatment for selected patients early in the disease to prevent RNFL loss from reaching the critical threshold. [ABSTRACT FROM AUTHOR]

Background: Friedreich's ataxia (FRDA), most commonly caused by a GAA triplet repeat (GAA‐TR) expansion in intron 1 of the FXN gene, is characterized by deficiency of frataxin protein and clinical features such as progressive ataxia, dysarthria, impaired proprioception and vibration, abolished deep tendon reflexes, Babinski sign, and vision loss in association with non‐neurological features such as skeletal anomalies, hearing loss, cardiomyopathy, and diabetes. Pathogenic GAA‐TRs range in size from 60 to 1500 triplets and negatively correlate with age of onset. Clinical severity is predicted by a combination of GAA‐TR length and disease duration (DD) via multivariable regressions, which cannot typically be used for the small sample sizes in most studies on this rare disease. Objective: We aimed to develop a single metric, which we call "disease burden" (DB), that encompasses both GAA‐TR length and DD for predicting disease features of FRDA in small sample sizes. Methods: Linear regression and multivariable regression analysis was used to determine correlation coefficients between different disease features of FRDA. Results: Using large datasets for validation, we found that DB predicts measures of neurological dysfunction in FRDA better than GAA‐TR length or DD. Analogous results were found using small datasets. Conclusions: FRDA DB is a novel metric of disease severity that has utility in small datasets to demonstrate correlations that would not otherwise be evident with either GAA‐TR or DD alone. This is important for discovering new biomarkers, as well as improving the prediction of severity of disease features in FRDA. © 2023 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The ever‐increasing body of ataxia research provides opportunities for large‐scale meta‐analyses, systematic reviews, and data aggregation. Because multiple standardized scales are used to quantify ataxia severity, harmonization of these measures is necessary for quantitative data pooling. We applied the modified Friedreich Ataxia Rating Scale (mFARS), the Scale for the Assessment and Rating of Ataxia (SARA), and the International Cooperative Ataxia Rating Scale (ICARS) to a large cohort of people with Friedreich's ataxia. We provide regression coefficients for scale interconversion and discuss the reliability of this approach, together with insights into the differential sensitivities of mFARS and SARA to disease progression. [ABSTRACT FROM AUTHOR]

Regioselectivities in cyclizations of 4-substituted 4-penten-1-oxyl radicals are investigated by density functional theory. The FMO interactions between the terminal carbon atom of the pi-bond and the O-radical center favor the 6-endo-trig reaction on the basis of lower transition state energies.

Background: Friedreich's ataxia is an inherited, progressive, neurodegenerative disease that typically begins in childhood. Disease severity is commonly assessed with rating scales, such as the modified Friedreich's Ataxia Rating Scale, which are usually administered in the clinic by a neurology specialist. Objective: This study evaluated the utility of home‐based, self‐administered digital endpoints in children with Friedreich's ataxia and unaffected controls and their relationship to standard clinical rating scales. Methods: In a cross‐sectional study with 25 participants (13 with Friedreich's ataxia and 12 unaffected controls, aged 6–15 years), home‐based digital endpoints that reflect activities of daily living were recorded over 1 week. Domains analyzed were hand motor function with a digitized drawing, automated analysis of speech with a recorded oral diadochokinesis test, and gait and balance with wearable sensors. Results: Hand‐drawing and speech tests were easy to conduct and generated high‐quality data. The sensor‐based gait and balance tests suffered from technical limitations in this study setup. Several parameters discriminated between groups or correlated strongly with modified Friedreich's Ataxia Rating Scale total score and activities of daily living total score in the Friedreich's ataxia group. Hand‐drawing parameters also strongly correlated with standard 9‐hole peg test scores. Interpretation: Deploying digital endpoints in home settings is feasible in this population, results in meaningful and robust data collection, and may allow for frequent sampling over longer periods of time to track disease progression. Care must be taken when training participants, and investigators should consider the complexity of the tasks and equipment used. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to characterize the incidence and progression of scoliosis in the natural history of Friedreich's ataxia (FRDA) and document the factors leading to the requirement for corrective surgery. Methods: Data on the prevalence of scoliosis and scoliosis surgery from up to 17 years of follow‐up collected during a large natural history study in FRDA (1116 patients at 4928 visits) were summarized descriptively and subjected to time to event analyses. Results: Well over 90% of early or typical FRDA patients (as determined by age of onset) developed intermediate to severe scoliosis, while patients with a later onset (>14 years) had no or much lower prevalence of scoliosis. Diagnosis of scoliosis occurs during the onset of ataxia and in rare cases even prior to that. Major progression follows throughout the growth phase and puberty, leading to the need for surgical intervention in more than 50% of individuals in the most severe subgroup. The youngest patients appear to delay surgery until the end of the growth period, leading to further progression before surgical intervention. Age of onset of FRDA before or after reaching 15 years sharply separated severe and relatively mild incidence and progression of scoliosis. Interpretation: Scoliosis is an important comorbidity of FRDA. Our comprehensive documentation of scoliosis progression in this natural history study provides a baseline for comparison as novel treatments become available. [ABSTRACT FROM AUTHOR]

Aims: Current guidelines recommend opportunistic screening for atrial fibrillation (AF) but the prognosis of individuals is unclear. The aim of this investigation is to determine prevalence and 1-year outcome of individuals with screen-detected AF.Methods and Results: We performed a prospective, pharmacy-based single time point AF screening study in 7107 elderly citizens (≥65 years) using a hand-held, single-lead electrocardiogram (ECG) device. Prevalence of AF was assessed, and data on all-cause death and hospitalization for cardiovascular (CV) causes were collected over a median follow-up of 401 (372; 435) days. Mean age of participants was 74 ± 5.9 years, with 58% (N = 4130) of female sex. Automated heart rhythm analyses identified AF in 432 (6.1%) participants, with newly diagnosed AF in 3.6% of all subjects. During follow-up, 62 participants (0.9%) died and 390 (6.0%) were hospitalized for CV causes. Total mortality was 2.3% in participants with a screen-detected AF and 0.8% in subjects with a normal ECG [hazard ratio (HR) 2.94; 95% confidence interval (CI) 1.49-5.78; P = 0.002]; hospitalization for CV causes occurred in 10.6% and 5.5%, respectively (HR 2.08; 95% CI 1.52-2.84; P < 0.001). Compared with subjects without a history of AF at baseline and a normal ECG, participants with newly diagnosed or known AF had a significantly higher mortality risk with HRs of 2.64 (95% CI 1.05-6.66; P = 0.04) and 2.68 (95% CI 1.44-4.97; P = 0.002), respectively. After multivariable adjustment, screen-detected AF remained a significant predictor of death or hospitalization for CV causes.Conclusion: Pharmacy-based, automated AF screening in elderly citizens identified subjects with unknown AF and an excess mortality risk over the next year. [ABSTRACT FROM AUTHOR]

The modified Friedreich Ataxia Rating Scale (mFARS) is a disease specific, exam‐based neurological rating scale commonly used as a outcome measure in clinical trials. While extensive clinimetric testing indicates it's validity in measuring disease progression, formal test–retest reliability was lacking. To fill this gap, we acquired results from screening and baseline visits of several large clinical trials and calculated intraclass correlation coefficients, coefficients of variance, standard error, and the minimally detectable changes. This study demonstrated excellent test–retest reliability of the mFARS, and it's upright stability subscore. [ABSTRACT FROM AUTHOR]

Research has been conducted on C (sub)3 -symmetric tripodal ligand possessing central mesitylene-derived core and chiral biaryl subunits. The authors describe the enantioselective synthesis of this ligand.

The authors investigated the correlation of protan and tritan color vision with disease characteristics in Leber hereditary optic neuropathy (LHON). The authors also characterized the therapeutic potential of idebenone in protecting patients from developing dyschromatopsia in LHON.Color contrast data of 39 LHON patients participating in a randomized, double-blind placebo-controlled intervention study were evaluated. Patients reported disease onset <5 years before enrolment and were genetically confirmed. Protan and tritan color contrast sensitivity was measured using a computer graphics method in patients receiving idebenone (Catena; 900 mg/d; N = 28) or placebo (N = 11) for 6 months.Mean age of patients was 28.1 years, 87.2% were men, 76.9% carried the m11778G>A mutation, and mean duration since onset was 2 years. Assessing protan and tritan color vision at baseline revealed a high degree of color confusion even in young patients (<25 years) and with a short history of disease (<1 year). Treatment with idebenone improved tritan color vision compared with placebo (P = 0.008 at week 24); a similar trend was seen for protan. The effect of idebenone was most prominent in patients with discordant visual acuity (interocular difference of logMAR >0.2). In this subgroup, the treatment effect at week 24 was 20.4% (P = 0.005) in favor of idebenone for the tritan color domain and 13.5% (P = 0.067) for the protan domain.This study confirms that protan and tritan color confusion is an early symptom in LHON. Treatment with idebenone can protect from loss of color vision, particularly in patients who are at imminent risk of further vision loss. [ABSTRACT FROM AUTHOR]

Background--This cross-sectional study provides a practical approach for the clinical assessment of Friedreich ataxia (FA) cardiomyopathy (FA-CM). Methods and Results--A comprehensive cardiac assessment, including standard echocardiography, color Doppler myocardial imaging, cardiac magnetic resonance imaging, ECG, and exercise stress testing, was performed in 205 FA patients. To assess myocardial hypertrophy in FA-CM, the end-diastolic interventricular septal wall thickness (IVSTd) was found to be the best echocardiographic parameter compared with cardiac magnetic resonance imaging-determined left ventricular mass. With the use of this parameter, 4 groups of patients with FA-CM could be defined. Patients with normal values for IVSTd (31.7%) were classified as having no FA-CM. Patients with an IVSTd exceeding the predicted normal IVSTd were classified as having mild FA-CM (40%) if IVSTd exceeded the normal value by < 18% or as having intermediate FA-CM (16.1%) if IVSTd exceeded the normal value by ≥18%. Patients with ejection fraction <50% were classified as having severe FA-CM (12.2%). In addition to increased myocardial mass, severe FA-CM was further characterized by dilatation of the left ventricle, reduced systolic strain rate of the posterior wall, and ECG abnormalities. Regional myocardial function correlated negatively with FA-CM groups. Younger patients had a tendency for more advanced FA-CM. Importantly, no clear correlation was found between FA-CM groups and neurological function. Conclusions--We provide and describe a readily applicable clinical grouping of the cardiomyopathy associated with FA based on echocardiographic IVSTd and ejection fraction data. Because no distinct interrelations between FA-CM and neurological status could be determined, regular follow-up of potential cardiac involvement in FA patients is essential in clinical practice. [ABSTRACT FROM AUTHOR]

Short-chain quinones have been investigated as therapeutic molecules due to their ability to modulate cellular redox reactions, mitochondrial electron transfer and oxidative stress, which are pathologically altered in many mitochondrial and neuromuscular disorders. Recently, we and others described that certain short-chain quinones are able to bypass a deficiency in complex I by shuttling electrons directly from the cytoplasm to complex III of the mitochondrial respiratory chain to produce ATP. Although this energy rescue activity is highly interesting for the therapy of disorders associated with complex I dysfunction, no structure-activity-relationship has been reported for short-chain quinones so far. Using a panel of 70 quinones, we observed that the capacity for this cellular energy rescue as well as their effect on lipid peroxidation was influenced more by the physicochemical properties (in particular logD) of the whole molecule than the quinone moiety itself. Thus, the observed correlations allow us to explain the differential biological activities and therapeutic potential of short-chain quinones for the therapy of disorders associated with mitochondrial complex I dysfunction and/or oxidative stress. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase 4 (DP4) inhibitors are currently under intensive investigation in late-stage clinical trials as a treatment for type II diabetes. Lack of selectivity toward the related enzymes DP8 and DP9 has recently emerged as a possible source of drug-induced toxicity. Unlike DP4, X-ray structures of DP8 and DP9 are not yet available. As an aid to understanding the structural basis for selectivity, the authors have constructed homology models of DP8 and DP9 based on the X-ray coordinates of DP4. Accurate sequence alignment reveals common structural features indicative for a well-preserved overall fold comprising two domains, namely, a hydrolase domain and a so-called β-propeller, which together form the active site deeply buried within the protein. The conformation of two loops inside this deep cavity is particularly relevant for the active sites. The authors used a published protocol for loop prediction based on conformational sampling and energy analysis to generate plausible solutions for these two loops. The predictive power of the approach was successfully evaluated for the template protein DP4 and two additional known structures from the same protein family, namely, FAP and DPX. The authors also show that inclusion of the covalent ligand NVP-728 greatly enhances the refinement. Based on the established evaluation protocol, the corresponding loops of DP8 and DP9 were predicted and the resulting active sites were compared with DP4. In particular, the authors conclude that differences in the P2-pocket are relevant for the design of selective DP4 inhibitors. The loss of key interactions in DP8 and DP9 as predicted from their models is consistent with the selectivity profile of the DP4 clinical candidate MK-431. Proteins 2007. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background: Friedreich's Ataxia (FA) is a neuromuscular disorder caused by either GAA triplet repeat expansions of both alleles of the gene frataxin, or less commonly, by a point mutation in one allele and triplet expansion on the other. FA is associated with an increased incidence of diabetes (DM), but risk factors and management are not well described. Objective: To report the prevalence of, identify risk factors for, and describe management of DM in FA using the large (N=1,020) multi-site, longitudinal, observational FA Outcomes Measures Study (FACOMS). Methods: FACOMS was queried for self-reported DM status and the modified FA Rating Scale (mFARS), which rates severity. For the subset at the Children's Hospital of Philadelphia (CHOP), past medications were noted via EMR. Point mutation status and mFARS were compared in DM vs. non DM with chi-square and Wilcoxon signed rank tests, respectively. Independent risk factors for DM were tested by logistic regression including mFARS, age, point mutation, and age of FA diagnosis (dx). Results: Median age of FA dx was 14y (IQR 10-21), 5.7% had a point mutation, and 8.8% had DM. In those with DM, median age at DM dx was 27y (IQR 17-41) and mean HbA1c since dx was 7% (SD 1). Point mutations were more common in DM vs. non DM (13.9% vs. 4.9%; p<0.001). Those with DM had more severe disease (median mFARS, 70, IQR 58,78) vs. without (55, IQR 41,68) (p<0.001). In logistic regression, severe disease (mFARS 4th vs. 1st quartile, OR 4.54, 95%CI: 1.75,11.77, p=0.002), older age (OR 1.05, 95%CI: 1.02,1.07, p<0.001), and point mutation (OR 4.49, 95%CI: 2.11,9.53, p<0.001) were associated with a greater risk of DM. In FACOMS, 76% (61/80 with DM and current medication data) used insulin. At CHOP, 47% (14/30 with DM and past medication data) had ever tried Metformin. Conclusions: DM in FA was associated with more severe disease, older age, and a point mutation. Many require insulin. Future studies will evaluate the pathophysiology of FA-related DM to inform screening practices and management decisions. Disclosure: J. Tamaroff: None. A. DeDio: None. K.L. Wade: None. C. Rummey: None. S.E. Pinney: None. D. Lynch: None. A. Kelly: None. S. McCormack: Advisory Panel; Self; Reata Pharmaceuticals, Rhythm Pharmaceuticals. Other Relationship; Self; Levo Pharmaceuticals. Funding: National Institutes of Health (T32DK063688-16); Uplifting Athletes; McCormack Children's Hospital of Pittsburgh Metabolism, Nutrition, and Development Research Affinity Group; McCormack Friedreich's Ataxia Research Alliance [ABSTRACT FROM AUTHOR]

Introduction: Friedreich ataxia (FRDA) is a recessive neurodegenerative disease characterized by progressive ataxia, dyscoordination, and loss of vision. The variable length of the pathogenic GAA triplet repeat expansion in the FXN gene in part explains the interindividual variability in the severity of disease. The GAA repeat expansion leads to epigenetic silencing of FXN; therefore, variability in properties of epigenetic effector proteins could also regulate the severity of FRDA. Methods: In an exploratory analysis, DNA from 88 individuals with FRDA was analyzed to determine if any of five non-synonymous SNPs in HDAC s/ SIRT s predicted FRDA disease severity. Results suggested the need for a full analysis at the rs352493 locus in SIRT6 ( p .Asn46Ser). In a cohort of 569 subjects with FRDA, disease features were compared between subjects homozygous for the common thymine SIRT6 variant (TT) and those with the less common cytosine variant on one allele and thymine on the other (CT). The biochemical properties of both variants of SIRT6 were analyzed and compared. Results: Linear regression in the exploratory cohort suggested that an SNP (rs352493) in SIRT6 correlated with neurological severity in FRDA. The follow-up analysis in a larger cohort agreed with the initial result that the genotype of SIRT6 at the locus rs352493 predicted the severity of disease features of FRDA. Those in the CT SIRT6 group performed better on measures of neurological and visual function over time than those in the more common TT SIRT6 group. The Asn to Ser amino acid change resulting from the SNP in SIRT6 did not alter the expression or enzymatic activity of SIRT6 or frataxin, but iPSC-derived neurons from people with FRDA in the CT SIRT6 group showed whole transcriptome differences compared to those in the TT SIRT6 group. Conclusion: People with FRDA in the CT SIRT6 group have less severe neurological and visual dysfunction than those in the TT SIRT6 group. Biochemical analyses indicate that the benefit conferred by T to C SNP in SIRT6 does not come from altered expression or enzymatic activity of SIRT6 or frataxin but is associated with changes in the transcriptome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rodden, Rummey, Dong, Lagedrost, Regner, Brocht, Bushara, Delatycki, Gomez, Mathews, Murray, Perlman, Ravina, Subramony, Wilmot, Zesiewicz, Bolotta, Domissy, Jespersen, Ji, Soragni, Gottesfeld and Lynch.)