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Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a homozygous GAA triplet repeat expansion in the frataxin gene. Cardiac involvement, usually manifesting as hypertrophic cardiomyopathy, can range from asymptomatic cases to severe cardiomyopathy with progressive deterioration of the left ventricular ejection fraction and chronic heart failure. The management of cardiac involvement is directed to prevent disease progression and cardiovascular complications. However, direct-disease therapies are not currently available for FRDA. The present review aims to describe the current state of knowledge regarding cardiovascular involvement of FRDA, focusing on clinical-instrumental features and management of cardiac manifestation.

BACKGROUND Neuroinflammation is proposed to accompany, or even contribute to, neuropathology in Friedreich ataxia (FRDA), with implications for disease treatment and tracking. OBJECTIVES To examine brain glial activation and systemic immune dysfunction in people with FRDA and quantify their relationship with symptom severity, duration, and onset age. METHODS Fifteen individuals with FRDA and 13 healthy controls underwent brain positron emission tomography using the translocator protein (TSPO) radioligand [18 F]-FEMPA, a marker of glial activation, together with the quantification of blood plasma inflammatory cytokines. RESULTS [18 F]-FEMPA binding was significantly increased in the dentate nuclei (d = 0.67), superior cerebellar peduncles (d = 0.74), and midbrain (d = 0.87), alongside increased plasma interleukin-6 (IL-6) (d = 0.73), in individuals with FRDA compared to controls. Increased [18 F]-FEMPA binding in the dentate nuclei, brainstem, and cerebellar anterior lobe correlated with earlier age of symptom onset (controlling for the genetic triplet repeat expansion length; all rpart

Background Friedreich ataxia is the most frequent hereditary ataxia worldwide. Subclinical visual and auditory involvement has been recognized in these patients, with co-occurrence of severe blindness and deafness being rare. Case report We describe a patient, homozygous for a 873 GAA expansion in the FXN gene, whose first symptoms appeared by the age of 8. At 22 years-old he developed sensorineural deafness, and at 26 visual impairment. Deafness had a progressive course over 11 years, until a stage of extreme severity which hindered communication. Visual acuity had a catastrophic deterioration, with blindness 3 years after visual impairment was first noticed. Audiograms documented progressive sensorineural deafness, most striking for low frequencies. Visual evoked potentials disclosed bilaterally increased P100 latency. He passed away at the age of 41 years old, at a stage of extreme disability, blind and deaf, in addition to the complete phenotype of a patient with Friedreich ataxia of more than 30 years duration. Discussion Severe vision loss and extreme deafness has been described in very few patients with Friedreich ataxia. Long duration, severe disease and large expanded alleles may account for such an extreme phenotype; nonetheless, the role of factors as modifying genes warrants further investigation in this subset of patients.

Objectives Friedreich ataxia (FRDA) is a rare disorder with progressive neurodegeneration and cardiomyopathy. Luvadaxistat (also known as TAK‐831; NBI‐1065844), an inhibitor of the enzyme d‐amino acid oxidase, has demonstrated beneficial effects in preclinical models relevant to FRDA. This phase 2, randomized, double‐blind, placebo‐controlled, parallel‐arm study evaluated the efficacy and safety of oral luvadaxistat in adults with FRDA. Methods Adult patients with FRDA were randomized 2:1:2 to placebo, luvadaxistat 75 mg twice daily (BID), or luvadaxistat 300 mg BID for 12 weeks. The primary endpoint changed from baseline at week 12 on the inverse of the time to complete the nine‐hole peg test (9‐HPT−1), a performance‐based measure of the function of the upper extremities and manual dexterity. Comparisons between luvadaxistat and placebo were made using a mixed model for repeated measures. Results Of 67 randomized patients, 63 (94%) completed the study. For the primary endpoint, there was no statistically significant difference in change from baseline on the 9‐HPT−1 (seconds−1) at week 12 between placebo (0.00029) and luvadaxistat 75 mg BID (−0.00031) or luvadaxistat 300 mg BID (−0.00059); least squares mean differences versus placebo (standard error) were −0.00054 (0.000746) for the 75 mg dose and −0.00069 (0.000616) for the 300 mg dose. Luvadaxistat was safe and well tolerated; the majority of reported adverse events were mild in intensity. Interpretation Luvadaxistat was safe and well tolerated in this cohort of adults with FRDA; however, it did not demonstrate efficacy as a treatment for this condition.

The monitoring of disease progression in certain neurodegenerative conditions can significantly be quantified with the help of objective assessments. The severity assessment of diseases like Friedreich ataxia (FRDA) are usually based on different subjective measures. The ability of a participant with FRDA to perform standard neurological tests is the most common way of assessing disease progression. In this feasibility study, an Ataxia Instrumented Measurement-Cup (AIM-C) is proposed to quantify the disease progression of 10 participants (mean age 39 years, onset of disease 16.3 years) in longitudinal timepoints. The device consists of a sensing system with the provision of extracting both kinetic and kinematic information while engaging in an activity closely associated with activities of daily living (ADL). A common functional task of simulated drinking was used to capture features that possesses disease progression information as well as certain other features which intrinsically correlate with commonly used clinical scales such as the modified Friedreich Ataxia Rating Scale (mFARS), the Functional Staging of Ataxia score and the ADL scale. Frequency and time-frequency domain features allowed the longitudinal assessment of participants with FRDA. Furthermore, both kinetic and kinematic measures captured clinically relevant features and correlated 85% with clinical assessments.

Aims To explore the feasibility of upper limbs cardiopulmonary exercise test (CPET) in Friedreich ataxia (FRDA) patients and to compare the results with sex, age, and body mass index (BMI) matched cohort of healthy controls (HC). Methods and results Cardiopulmonary exercise test was performed using an upper limbs cycle ergometer on fasting subjects. Peak oxygen uptake (peak VO2) was recorded as the mean value of VO2 during a 20 s period at the maximal effort of the test at an appropriate respiratory exchange rate. The ventilatory anaerobic threshold (AT) was detected by the use of the V-slope method. We performed echocardiography with an ultrasound system equipped with a 2.5 MHz multifrequency transducer for complete M-mode, two-dimensional, Doppler, and Tissue Doppler Imaging analyses. We studied 55 FRDA and 54 healthy matched controls (HC). Peak VO2 showed a significant 31% reduction in FRDA patients compared to HC (15.2 ± 5.7 vs. 22.0 ± 6.1 mL/kg/min; P Conclusions Upper limb CPET is useful in the assessment of exercise tolerance and a possible tool to determine the functional severity of the mitochondrial oxidative defect in patients with FRDA. The cardiopulmonary exercise test is an ideal functional endpoint for Phases II and III trials through a simple, non-invasive, and safe exercise test.

Objective Friedreich ataxia (FA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in models of FA. We investigated the safety and efficacy of omaveloxolone in patients with FA. Methods We conducted an international, double-blind, randomized, placebo-controlled, parallel-group, registrational phase 2 trial at 11 institutions in the United States, Europe, and Australia (NCT02255435, EudraCT2015-002762-23). Eligible patients, 16 to 40 years of age with genetically confirmed FA and baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomized 1:1 to placebo or 150mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone compared with those on placebo at 48 weeks. Results One hundred fifty-five patients were screened, and 103 were randomly assigned to receive omaveloxolone (n = 51) or placebo (n = 52), with 40 omaveloxolone patients and 42 placebo patients analyzed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (-1.55 ± 0.69) and placebo (0.85 ± 0.64) patients showed a difference between treatment groups of -2.40 ± 0.96 (p = 0.014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone. Interpretation In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FA. ANN NEUROL 2021;89:212-225.

BackgroundFriedreich ataxia (FRDA) is the most frequent form of inherited ataxias. Vestibular and auditory assessments are not commonly part of the check up for these patients despite hearing and balance complaints. Screening of vestibular and auditory function was performed in a large group of young patients with genetically confirmed FRDA.MethodsOur study included 43 patients (7–24 years of age). A complete vestibular assessment was performed including the canals function evaluation at 3 head velocities (bithermal caloric test, earth vertical axis rotation (EVAR) and head impulse test (HIT)) and otolith function evaluation (cervical vestibular evoked myogenic potentials). Information regarding the hearing evaluation of the patients were also retrieved including impedance tympanometry, distortion product otoacoustic emissions (DPOAEs), air and bone conduction audiometry and auditory brainstem response (ABR).ResultsVestibular responses were impaired for canal responses (only at high and middle head velocities) and vestibulospinal otolithic responses. Abnormal neural conduction in the central auditory pathways was frequently observed. Oculomotor abnormalities were frequent, mostly hypermetric saccades and gaze instability. Inhibition of the vestibulo-ocular reflex by fixation was normal.ConclusionsWe show that Friedreich ataxia, even at onset, frequently associate saccadic intrusions, abnormal ABRs and decreased vestibulo-ocular and vestibulospinal responses progressing over time. These sensory impairments combined with ataxia further impair patient’s autonomy. These vestibular, auditory and visual impairments could be used as markers of the severity and progression of the disease. Adding vestibular and auditory testing to Friedreich patient’s evaluation may help physicians improve patient’s management.

To identify gait and balance measures that are responsive to change during the timeline of a clinical trial in Friedreich ataxia (FRDA), we administered a battery of potential measures three times over a 12-month period. Sixty-one ambulant individuals with FRDA underwent assessment of gait and balance at baseline, 6 months and 12 months. Outcomes included GAITRite® spatiotemporal gait parameters; Biodex Balance System Postural Stability Test (PST) and Limits of Stability; Berg Balance Scale (BBS); Timed 25-Foot Walk Test; Dynamic Gait Index (DGI); SenseWear MF Armband step and energy activity; and the Friedreich Ataxia Rating Scale Upright Stability Subscale (FARS USS). The standardised response mean (SRM) or correlation coefficients were reported as effect size indices for comparison of internal responsiveness. Internal responsiveness was also analysed in subgroups. SenseWear Armband daily step count had the largest effect size of all the variables over 6 months (SRM = -0.615), while the PST medial-lateral index had the largest effect size (SRM = 0.829) over 12 months. The FARS USS (SRM = 0.824) and BBS (SRM = -0.720) were the only outcomes able to detect change over 12 months in all subgroups. The DGI was the most responsive outcome in children, detecting a mean change of -2.59 (95% CI -3.52 to -1.66, p < 0.001, SRM = -1.429). In conclusion, the FARS USS and BBS are highly responsive and can detect change in a wide range of ambulant individuals with FRDA. However, therapeutic effects in children may be best measured by the DGI.

Friedreich ataxia is the most common form of hereditary ataxia. Heart involvement in Friedreich ataxia is common and can include increased left ventricular wall thickness, atrial fibrillation, and in the later stages, a reduction of left ventricular ejection fraction. We present the case of a 45-year-old man with a history of paroxysmal atrial fibrillation and a congestive heart failure, hypertension, age ⩾ 75 years, diabetes mellitus, stroke, vascular disease, age 65–74 years, and female sex (CHA2DS2-VASc) score of only 1 (because of reduced left ventricular ejection fraction) who presented with pneumonia and was also found to have atrial fibrillation with a rapid ventricular response. Despite already being on long-term therapy with a non-vitamin K-antagonist oral anticoagulant, a transesophageal echocardiogram showed a mobile floating thrombus in the left atrial appendage. In accordance with previous necropsy evidence of thrombosis and thromboembolism in Friedreich ataxia subjects who likely have had only non-sex-related CHA2DS2-VASc score ⩽1, this case suggests that the risk of thromboembolism in Friedreich ataxia subjects with atrial fibrillation may not be adequately predicted by the sole CHA2DS2-VASc score.

Friedreich ataxia is a progressive neurodegenerative disorder with reported abnormalities in cerebellar, brainstem, and cerebral white matter. White matter structure can be measured using in vivo neuroimaging indices sensitive to different white matter features. For the first time, we examined the relative sensitivity and relationship between multiple white matter indices in Friedreich ataxia to more richly characterize disease expression and infer possible mechanisms underlying the observed white matter abnormalities. Diffusion‐tensor, magnetization transfer, and T1‐weighted structural images were acquired from 31 individuals with Friedreich ataxia and 36 controls. Six white matter indices were extracted: fractional anisotropy, diffusivity (mean, axial, radial), magnetization transfer ratio (microstructure), and volume (macrostructure). For each index, whole‐brain voxel‐wise between‐group comparisons and correlations with disease severity, onset age, and gene triplet‐repeat length were undertaken. Correlations between pairs of indices were assessed in the Friedreich ataxia cohort. Spatial similarities in the voxel‐level pattern of between‐group differences across the indices were also assessed. Microstructural abnormalities were maximal in cerebellar and brainstem regions, but evident throughout the brain, while macroscopic abnormalities were restricted to the brainstem. Poorer microstructure and reduced macrostructural volume correlated with greater disease severity and earlier onset, particularly in peri‐dentate nuclei and brainstem regions. Microstructural and macrostructural abnormalities were largely independent. Reduced fractional anisotropy was most strongly associated with axial diffusivity in cerebral tracts, and magnetization transfer in cerebellar tracts. Multiple mechanisms likely underpin white matter abnormalities in Friedreich ataxia, with differential impacts in cerebellar and cerebral pathways.

INTRODUCTION In this study we assessed the effect of methylprednisolone on safety, tolerability, and ability in Friedreich ataxia (FRDA). METHODS The study was an open-label trial of pulse methylprednisolone on 11 participants with FRDA. All participants followed a 28-day treatment cycle, repeated 7 times. Patients were assessed with the timed 25-foot walk (T25FW), 1-minute walk (1MW), the Friedreich Ataxia Rating Scale (FARS), and the 9-hole peg test (9HPT). Efficacy was tested by comparing baseline and week 26 visits, separated into adult and pediatric groups. RESULTS In comparisons of participants' baseline and week 26 visits, only the pediatric cohort's 1MW score showed change (P

Friedreich ataxia (FRDA) is the commonest hereditary ataxia in Caucasians. Most patients are homozygous for expanded GAA triplet repeats in the first intron of the frataxin (FXN) gene, involved in mitochondrial iron metabolism. Here, we used magnetoencephalography (MEG) to characterize the main determinants of FRDA-related changes in intrinsic functional brain architecture., info:eu-repo/semantics/published

Speech and language disorders are prominent signs in Friedreich ataxia (FRDA), which significantly impact on patients' quality of life. Despite such relevance, several issues regarding phenomenology, assessment, and treatment are still unmet. In this short review, we thus analyzed the existing literature to summarize what is known about the features of speech and language disorders in FRDA, which methods are used for evaluation and rating, and what are the available therapeutic strategies and future direction of scientific research in this field, in order to highlight critical aspects for a better clinical approach to the problem. FRDA patients often present dysarthria, resulting from central and peripheral causes and additional primary language disorders. Speech disturbances have peculiar characteristics, although variable among patients, and progress along the disease course. Assessment relies on multiple but not specific clinical scales, some of which can also reflect the general severity of ataxia; classical instrumental investigations and novel technologies allow more accurate measurements of several speech parameters, which could found application as potential disease's biomarkers. No successful treatments exist for communication disorders of FRDA patients; however, the tailored speech training or the non-invasive neuromodulation appear as the most reliable therapeutic options to be validate in future trials.

Friedreich ataxia (FRDA) is a multisystem neurodegenerative disorder and the most common hereditary ataxia. Dysphagia (swallowing impairment) is present in 98% of individuals with FRDA and is characterized by lingual and pharyngeal dysfunction (manifesting in impaired bolus preparation and transfer, and post-swallow residue in the mouth and pharynx), delayed swallow initiation, and entry of material into the airway (penetration/aspiration). Dysphagia severity correlates with disease severity and duration however no longitudinal studies describe changes in function in FRDA. The aim of this study was to investigate the progression of dysphagia in FRDA over one year. Fifty-nine individuals with FRDA and confirmed dysphagia were recruited and 23 of them underwent a second assessment 12 months later. Assessments of swallowing related quality of life, oral motor function (Frenchay Dysarthria Assessment 2nd Ed [FDA-2]) and functional swallowing via videofluoroscopy were conducted. Trials of thin liquid, puree and biscuit were interpreted using the Bethlehem Assessment Scale and the Penetration-Aspiration Scale by two blinded raters. Data from the videofluoroscopy revealed a decline in tongue function, pharyngeal clearance and cricopharyngeal function on solid food. However, severity of penetration/aspiration did not increase. Swallowing-related quality of life and oral-motor function remained stable. A decline in function was observed at three anatomical sites considered important for safe and effective swallowing (tongue, pharyngeal, and cricopharyngeal). However, these deficits did not translate into any meaningful functional decline in swallowing related health over 12 months for individuals with FRDA.

Friedreich's ataxia (FRDA) is a rare autosomal-recessive slowly progressive neurodegenerative disorder. As common clinical measures for this devastating disease lack sensitivity, we explored whether (a) the quantitative motor assessments of the Q-Motor battery can enhance clinical characterisation of FRDA; (b) clinical measures can predict Q-Motor outcomes and (c) Q-Motor is sensitive to longitudinal change. At baseline 29 patients and 23 controls and in a 1-year follow-up 14 patients and 6 controls were included. The Q-Motor included lift (manumotography), finger tapping (digitomotography) and pronate/supinate (dysdiadochomotography) tasks. To model responses, a search of generalised linear models was conducted, selecting best fitting models, using demographic and clinical data as predictors. Predictors from selected models were used in linear mixed models to investigate longitudinal changes. Patients with FRDA performed worse than controls on most measures. Modelling of the pronate/supinate task was dominated by SCAFI (SCA functional index) subtasks, while tapping task and lift task models suggested a complex relationship with clinical measures. Longitudinal modelling implied minor changes from baseline to follow-up, while clinical scales mainly showed no change in this sample. Overall Q-Motor likely has favourable properties for assessing distinct motor aspects in severe FRDA as it can be administered in wheelchair-bound patients. Further longitudinal research is warranted to fully characterise its relation to routinely used measures and scales for FRDA.

Friedreich ataxia (FRDA) has a significant effect on hand function which in turn, may compromise independence and quality of life. This study sought to identify the extent of muscle weakness, spasticity and changes in joint range in the hands of individuals with FRDA. We used the Modified Tardieu Scale (MTS), testing of muscle strength and goniometry to examine hand function in 19 individuals with FRDA. Relationships between clinical measures of disease severity, functional independence and measures of hand function were also explored. We found evidence for both upper and lower motor neuron impairment in this population. Thirteen (68.0%) participants had spasticity in the dominant wrist and finger flexors, and seven (36.8%) had contracture in at least one joint of either hand. Sixteen (84.3%) participants demonstrated weakness in the intrinsic musculature of the hands and the majority demonstrated some degree of hyperextension at the metacarpophalangeal joints of either hand. Significant correlations were found between functional independence capacity and clinical parameters, and components of spasticity and weakness in both the dominant and non-dominant hands. Moreover, spasticity and weakness in the dominant hand were shown to be significant predictors of reduced functional independence capacity. This study highlights for the first time the incidence of upper limb spasticity which, in combination with weakness and contracture, suggests a multifactorial source of hand dysfunction in people with FRDA.

Background Friedreich ataxia is the most commonly inherited ataxia; nearly 60% of deaths are cardiac in nature, with one in eight deaths due to arrhythmia. Additional or irregular heartbeats, measured as ectopy, can be quantified using portable heart rhythm monitoring. We sought to describe the ectopic burden in Friedreich ataxia. Methods Using a natural history study of patients with Friedreich ataxia at a single center, we analyzed portable heart rhythm monitors (Holters). Ectopic burden was defined as the proportion of atrial or ventricular ectopic beats over total beats. Results Of 456 patients, 131 had Holters. Sixty-eight (52.0%) were male, median age of symptom onset was 8.0 years (5.0 to 13.0, n = 111), median age at time of Holter was 17.3 years (interquartile range [IQR] 12.9 to 22.8, n = 129), and median duration of illness was 8.7 years (IQR 5.3 to 11.6, n = 110). Median GAA length on the shorter FXN allele was 706.0 (IQR 550.0 to 840.0, n = 112). Eight (7.8%, n = 103) had diminished cardiac function, and 74 (74.0%, n = 100) had ventricular hypertrophy. Ninety patients (83.0%) had atrial ectopy (supraventricular ectopy [SVE]): 85 (78.0%) with rare SVE (>0% to 5%) and five (5.0%) with frequent SVE (>10%). Twenty-five (19.0%) had supraventricular runs, and one (0.8%) had atrial fibrillation/flutter. Forty-five (41.0%) had ventricular ectopy (VE): 43 (39.0%) with rare VE (0% to 5%) and two (2.0%) with moderate VE (5% to 10%). Compared with patients with none and rare SVE, patients with frequent SVE had longer disease duration (18.3 versus 4.6 versus 9.0 years, P = 0.0005). Conclusion Patients with longer disease duration had higher rates of SVE. Heart rhythm monitoring may be considered for risk stratification; however, longitudinal analysis is needed.

Objective Previous studies have demonstrated that suppression of Nrf2 in Friedreich ataxia tissues contributes to excess oxidative stress, mitochondrial dysfunction, and reduced ATP production. Omaveloxolone, an Nrf2 activator and NF‐kB suppressor, targets dysfunctional inflammatory, metabolic, and bioenergetic pathways. The dose‐ranging portion of this Phase 2 study assessed the safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia patients (NCT02255435). Methods Sixty‐nine Friedreich ataxia patients were randomized 3:1 to either omaveloxolone or placebo administered once daily for 12 weeks. Patients were randomized in cohorts of eight patients, at dose levels of 2.5–300 mg/day. Results Omaveloxolone was well tolerated, and adverse events were generally mild. Optimal pharmacodynamic changes (noted by changes in ferritin and GGT) were observed at doses of 80 and 160 mg/day. No significant changes were observed in the primary outcome, peak work load in maximal exercise testing (0.9 ± 2.9 W, placebo corrected). At the 160 mg/day dose, omaveloxolone improved the secondary outcome of the mFARS by 3.8 points versus baseline (P = 0.0001) and by 2.3 points versus placebo (P = 0.06). Omaveloxolone produced greater improvements in mFARS in patients that did not have musculoskeletal foot deformity (pes cavus). In patients without this foot deformity, omaveloxolone improved mFARS by 6.0 points from baseline (P

OBJECTIVE: To provide a systematic evaluation of the broad clinical variability in Friedreich ataxia (FRDA), a multisystem disorder presenting mainly with afferent ataxia but also a complex phenotype of nonataxia symptoms. METHODS: From the large database of the European Friedreich's Ataxia Consortium for Translational Studies, 650 patients with genetically confirmed FRDA were included. Detailed data of medical history documentation, questionnaires, and reports on clinical features were analyzed to provide in-depth description of the clinical profile and frequency rates of phenotypical features with a focus on differences between typical-onset and late-onset FRDA. Logistic regression modeling was used to identify predictors for the presence of the most common clinical features. RESULTS: The most frequent clinical features beyond afferent ataxia were abnormal eye movements (90.5%), scoliosis (73.5%), deformities of the feet (58.8%), urinary dysfunction (42.8%), cardiomyopathy and cardiac hypertrophy (40.3%), followed by decreased visual acuity (36.8%); less frequent features were, among others, depression (14.1%) and diabetes (7.1%). Most of these features were more common in the typical-onset group compared to the late-onset group. Logistic regression models for the presence of these symptoms demonstrated the predictive value of GAA repeat length on the shorter allele and age at onset, but also severity of ataxia signs, sex, and presence of neonatal problems. CONCLUSIONS: This joint European effort demonstrates the multisystem nature of this neurodegenerative disease encompassing most the central nervous, neuromuscular, cardiologic, and sensory systems. A distinct and deeper knowledge of this rare and chronic disease is highly relevant for clinical practice and designs of clinical trials., SCOPUS: ar.j, info:eu-repo/semantics/published

Effective monitoring of the progression of neurodegenerative conditions can be significantly improved by objective assessments. Clinical assessments of conditions such as Friedreich's Ataxia (FA), currently rely on subjective measures commonly practiced in clinics as well as the ability of the affected individual to perform conventional tests of the neurological examination. In this study, we propose an ataxia measuring device, in the form of a pressure canister capable of sensing certain kinetic and kinematic parameters of interest to quantify the impairment levels of participants particularly when engaged in an activity that is closely associated with daily living. In particular, the functional task of simulated drinking was utilised to capture characteristic features of disability manifestation in terms of diagnosis (separation of individuals with FA and controls) and severity assessment of individuals diagnosed with the debilitating condition of FA. Time and frequency domain analysis of these biomarkers enabled the classification of individuals with FA and control subjects to reach an accuracy of 98% and a correlation level reaching 96% with the clinical scores.

COVID-19 outbreak profoundly impacted on daily-life of patients with neurodegenerative diseases, including those with ataxia. Effects on interventional trials have been recently described. Conversely, changes in physical activity programs, which are crucial in care of ataxic patients, have not been assessed yet.Here we used a structured electronic survey to interview twenty patients with Friedreich ataxia (FA) on changes in physical activity during the lockdown in Italy.Regular physiotherapy was interrupted for most patients and up to 60% of them referred a substantial worsening of self-perceived global health. However, FA patients (especially those mildly affected) adopted voluntarily home-based training strategies and, in 30% of cases, used technology-based tools (TBTs) for exercise.COVID-19 crisis thus disclosed the urgent need to support ataxic patients improving systems for remote physical activity and technology-based assistance.

The progression of neurodegenerative conditions can be effectively monitored and improved by using objective assessments. The conditions such as Friedreich Ataxia (FA) are clinically assessed by means of subjective measures commonly practised in clinics. Here, we propose a device capable of measuring ataxia, in the form of a `cup' capable of sensing certain kinematic parameters of interest while engaging in an activity that is closely related to daily living. In this study, the functional task of 'drinking' was utilised to diagnose participants with FA and capture features in terms of diagnosis (separation) and correlation with the clinical scales. Frequency domain analysis was incorporated enabling the classification of control subjects and FA patients to an accuracy of 88% with a correlation of 90% with the clinical scores.

Friedreich ataxia (FRDA), the most common of the inherited ataxias, is a degenerative disease that progressively affects walking and other functions leading to significant impairment associated with a shortened lifespan. It is important to monitor the progression of ataxia over periods of time for clinical and therapeutic interventions. This study was aimed at investigating the use of our instrumented measurement scheme of utilizing a motion detecting spoon in a self-feeding activity to quantify the longitudinal effect of FRDA on upper limb function. Forty individuals diagnosed with FRDA (32.8±14.9 years old) were recruited in a 12-month longitudinal study consisting of equal number of males and females (20). A set of biomarkers was extracted from the temporal and texture analysis of the movement time series data that objectively detected subtle changes during follow-up testing. The results indicated that both analyses generated features that resembled clinical ratings. Although the diagnosis and severity related performances were readily observed by temporal features, the longitudinal progression was better captured by the textural features (p = 0.029). The estimation of severity by mean of random forest regression model and LASSO exhibited a high degree of parity with the standard clinical scale (rho = 0.73, p < 0.001).

The objective assessment of motor impairment resulting from neurological disorders forms the basis for effective rehabilitation and therapeutic programs. Such assessments conducted through the engagement of suitable daily activities can serve as an effective surrogate measure for the assessment of independent living. This study considers an instrumented spoon in the assessment of upper-limb functionality through the self-feeding activity of a group of individuals clinically diagnosed with the debilitating condition, Friedreich ataxia (FRDA). Thirty-five subjects with FRDA (34 ± 14 years old) and 14 age-matched healthy subjects performed three cycles of self-feeding consisting of grasping, scooping, transferring food to mouth and returning the spoon. Parameters relating to the feeding rate, trajectory of the rotation, range of motion and movement variability with specific attention to each segment were considered for the capture of ataxia pertaining to the disability. Movement variability measured by Dynamic Time Warping (DTW) resulted in an average accuracy of 96% in the diagnosis of ataxia (separation of the two cohorts). The severity of ataxia estimated using a combination of features from Random Forest (RF) increased the correlation with the clinical estimates of ataxia by 13% and achieved higher coefficient (0.72 in patient scale) than the currently used tests (Box & Block, Pegboard). While the overall results provided an objective, daily activity based means of capturing intrinsic abnormalities, the different segments of the task demonstrated the presence of ataxia in a spatial context concurring with relevant clinical observations.

Friedreich ataxia (FRDA) is a multisystem autosomal recessive disease with progressive clinical course involving the neuromuscular and endocrine system. Diabetes mellitus (DM) is one typical non-neurological manifestation, caused by beta cell failure and insulin resistance. Because of its rarity, knowledge on DM in FRDA is limited. Based on data from 200,301 patients with DM of the German-Austrian diabetes registry (DPV) and two exemplary patient reports, characteristics of patients with DM and FRDA are compared with classical type 1 or type 2 diabetes. Diabetes phenotype in FRDA is intermediate between type 1 and type 2 diabetes with ketoacidosis being frequent at presentation and blood glucose levels similar to T1Dm but higher than in T2Dm (356 ± 165 and 384 ± 203 mg/dl). 63.2% of FRDA patients received insulin monotherapy, 21% insulin plus oral antidiabetics and 15.8% lifestyle change only, applying similar doses of insulin in all three groups. FRDA patients did not show overweight and HbA1c levels were even lower than in T1Dm or T2Dm patients, respectively, indicating good overall diabetes control. FRDADm can be controlled by individualized treatment regimen with insulin or oral antidiabetics. Patients with DM in FRDA may show a relevant risk to ketoacidotic complications, which should be avoided.

Background: Friedreich&rsquo, s ataxia (FA) is a rare autosomal recessive mitochondrial disease resulting of a triplet repeat expansion guanine-adenine-adenine (GAA) in the frataxin (FXN) gene, exhibiting progressive cerebellar ataxia, diabetes and cardiomyopathy. We aimed to determine the relationship between cardiac biomarkers, serum N-terminal pro-brain natriuretic peptide (NT-proBNP), and serum cardiac high-sensitivity troponin (hsTnT) concentrations, and the extent of genetic abnormality and cardiac parameters. Methods: Between 2013 and 2015, 85 consecutive genetically confirmed FA adult patients were prospectively evaluated by measuring plasma hsTnT and NT-proBNP concentrations, electrocardiogram, and echocardiography. Results: The 85 FA patients (49% women) with a mean age of 39 &plusmn, 12 years, a mean disease onset of 17 &plusmn, 11 years had a mean SARA (Scale for the Assessment and Rating of Ataxia) score of 26 &plusmn, 10. The median hsTnT concentration was 10 ng/L (3 to 85 ng/L) and 34% had a significant elevated hsTnT &ge, 14 ng/L. Increased septal wall thickness was associated with increased hsTnT plasma levels (p &lt, 0.001). The median NT-proBNP concentration was 31 ng/L (5 to 775 ng/L) and 14% had significant elevated NT-proBNP &ge, 125 ng/L. Markers of increased left ventricular filling pressure (trans mitral E/A and lateral E/E&rsquo, ratio) were associated with increased NT-proBNP plasma levels (p = 0.01 and p = 0.01). Length of GAA or the SARA score were not associated with hsTnT or NT-proBNP plasma levels. Conclusion: hsTnT was increased in 1/3 of the adult FA and associated with increased septal wall thickness. Increased NT-proBNP remained a marker of increased left ventricular filling pressure. This could be used to identify patients that should undergo a closer cardiac surveillance.

The present study evaluates serum neurofilament light chain (NfL) as a biomarker of disease features in Friedreich’s ataxia (FRDA). NfL levels from serum of 117 subjects (85 FRDA patients, 13 carriers, and 19 controls) were assayed and correlated with disease features such as smaller GAA repeat length (GAA1), age, sex, and level of neurological dysfunction. Mean serum NfL levels were higher in FRDA patients than in carriers or unaffected controls in two independent cohorts of subjects. In longitudinal samples from FRDA patients drawn monthly or 1 year apart, values changed minimally. No difference was noted between carriers and controls. NfL levels correlated positively with age in controls and carriers of similar age, (Rs = 0.72, p

Friedreich ataxia (FRDA) is a progressive autosomal recessive disease. While motor dysfunction is the primary neurological hallmark, little is known about the underlying neurobiological changes associated with motor deficits over the course of disease. We investigated the hypothesis that progressive functional changes in both the cerebellum and cerebrum are related to longitudinal changes in performance on complex motor tasks in individuals with FRDA. Twenty-two individuals with FRDA and 28 controls participated over 24 months. The longitudinal investigation included finger tapping tasks with different levels of complexity (i.e., visually cued, multi-finger; self-paced, single finger), performed in conjunction with fMRI acquisitions, to interrogate changes in the neurobiology of motor and attentional brain networks including the cerebellum and cerebrum. We demonstrated evidence for significant longitudinal decreased cerebral fMRI activity over time in individuals with FRDA, relative to controls, during an attentionally-demanding motor task (visually cued tapping of multiple fingers) in six cerebral regions: right and left superior frontal gyri, right superior temporal gyrus, right primary somatosensory area, right anterior cingulate cortex, and right medial frontal gyrus. Importantly, longitudinal decreased activity was associated with more severe disease status at baseline, higher GAA1 repeat length and earlier age of onset. These findings suggest a dynamic pattern of neuronal activity in motor, attention and executive control networks over time in individuals with FRDA, which is associated with increased disease severity at baseline, increased GAA1 repeat length and earlier age at onset.

To evaluate autonomic symptoms and function in Friedreich's Ataxia (FRDA).Twenty-eight FRDA patients and 24 controls underwent clinical/electrophysiological testing. We employed the Friedreich's Ataxia Rating Scale (FARS) and the Scales for Outcomes in Parkinson's Disease: Autonomic Questionnaire-SCOPA-AUT to estimate the intensity of ataxia and autonomic complaints, respectively. Cardiovagal tests and the quantitative sudomotor axonal reflex, Q-SART, were then assessed in both groups.In the patient group, there were 11 men with mean age of 31.5 ± 11.1 years. Mean SCOPA-AUT score was 15.1 ± 8.1. Minimum RR interval at rest was shorter in the FRDA group (Median 831.3 × 724.0 ms, p 0.001). The 30:15 ratio, Valsalva index, E:I ratio, low and high frequency power presented no differences between patients and controls (p 0.05). Sweat responses were significantly reduced in patients for all sites tested (forearm 0.389 × 1.309 µL; proximal leg 0.406 × 1.107 µL; distal leg 0.491 × 1.232 µL; foot 0.265 × 0.708 µL; p value 0.05). Sweat volumes correlated with FARS scores.We found abnormal sudomotor but normal heart rate variability in FRDA. Small cholinergic post-ganglionic fibers are affected in the disease.Quantification of sudomotor function might be a biomarker for FRDA.

Friedreich ataxia (FRDA) is an autosomal recessive spinocerebellar ataxia caused by mutations of FXN. Hypotonus and hyporeflexia of the lower extremities are observed in most FRDA patients. Patients with hyperreflexia, called Friedreich ataxia with retained reflexes (FARR), have also been identified. We herein report the case of a 16-year-old Nepalese boy presenting with early-onset ataxia with prominent spasticity and hyperreflexia of the legs. Mutational analyses established the diagnosis of FRDA presenting as FARR. A haplotype analysis revealed that expanded alleles of the patient shared a common haplotype with Indian and European FRDA patients, suggesting that the mutation descended from a common founder.

Friedreich ataxia is an inherited neurodegenerative disease, with cerebral and cerebellar pathology evident. Despite an increased understanding of its neuropathology, disease progression in this disease remains poorly understood. This study aimed to characterise longitudinal change in brain structure using a multi-modal approach across cerebral and cerebellar grey and white matter. T1-weighted, diffusion-tensor, and magnetisation transfer magnetic resonance images were obtained from 28 individuals with Friedreich ataxia and 29 age- and gender-matched controls at two time-points, 2 years apart. Region-of-interest and exploratory between-group comparisons assessed changes in brain macrostructure (cerebellar lobule volume, cerebral cortical thickness/gyrification, brain white matter volume) and microstructure (white matter fractional anisotropy, mean/axial/radial diffusivity, magnetisation transfer ratio). Rates of change were correlated against change in neurological severity, Time 1 severity, and onset age. Individuals with Friedreich ataxia had a greater rate of white matter volume loss than controls in the superior cerebellar peduncles and right peri-thalamic/posterior cerebral regions, and greater reduction in left primary motor cortex gyrification. Greater cerebellar/brainstem white matter volume loss and right dorsal premotor gyrification loss was observed amongst individuals with less severe neurological symptoms at Time 1. Conversely, cerebral atrophy and changes in axial diffusivity were observed in individuals with more severe Time 1 symptoms. Progression in radial diffusivity was more pronounced amongst individuals with earlier disease onset. Greater right ventral premotor gyrification loss correlated with greater neurological progression. Heterogeneity in Friedreich ataxia progression is observed at the neurobiological level, with evidence of earlier cerebellar and later cerebral degeneration.

BACKGROUND: The Friedreich Ataxia Rating Scale (FARS) and the Scale for the Assessment and Rating of Ataxia (SARA) are commonly used neurological rating scales in Friedreich ataxia (FRDA). The modified Friedreich Ataxia Rating Scale (mFARS) has been accepted as an appropriate outcome measure for clinical trials in FRDA. OBJECTIVES: The COVID‐19 pandemic has resulted in limited face‐to‐face interactions with individuals involved in natural history studies and clinical trials. The aim of this study was to determine the validity of conducting the mFARS and SARA through video. METHODS: Individuals who had the mFARS administered face‐to‐face in the previous 6 months were invited to participate. Participants were sent instructions and asked to have a carer present to assist. The mFARS and SARA were then administered by video. Differences between face‐to‐face and video scores and the reliability between scores obtained face‐to‐face and by video were examined. RESULTS: The mFARS and SARA were conducted by video with 19 individuals. Excellent test–retest reliability was seen in the mFARS lower limb coordination (ICC = 0.96, 95% CI 0.90–0.98) and upright stability sections (ICC = 0.97, 95% CI 0.93–0.99), total mFARS (ICC = 0.97, 95% CI 0.92–0.99) and SARA scores (ICC = 0.98, 95% CI 0.95–0.99). CONCLUSIONS: Excellent test–retest reliability was demonstrated in the majority of the mFARS sections, and in the total mFARS and SARA scores, suggesting that video is a valid method of conducting these scales. This method enables inclusion of participants who are unable to travel to study sites. A larger cohort will be required to further validate the use of video mFARS and SARA for future studies.

A 36-year-old woman with a clinical history of Friedreich ataxia and hypertrophic cardiomyopathy was found unexpectedly dead at her home. The heart showed asymmetric left ventricular hypertrophy, with an interventricular septal thickness of 20–25 mm (the remainder of the left ventricular wall measured 15 mm). Histologically, both ventricles had irregular areas of marked myocyte hypertrophy with associated interstitial fibrosis and focal myofibre disarray. There was neuronal loss within the dentate nucleus of the cerebellum, with vacuolation and axonal loss in the dorsal columns and spinocerebellar tracts of the upper cervical spinal cord. Death was due to hypertrophic cardiomyopathy complicating Friedreich ataxia. Other causes of death in this condition include embolic stroke, cerebral haemorrhage, aspiration pneumonia, renal failure, diabetic ketoacidosis, myocardial infarction, generalised inanition and trauma. Sudden death due to cardiac disease, resulting in presentation for medicolegal autopsy, may be the presenting feature at all ages, including childhood.

Continuous and objective assessment is essential for accurate monitoring of the progression of neurodegenerative conditions such as Friedreich ataxia. However, current clinical assessments predominantly rely on the ability of the affected individual to complete specific clinical tests which may not capture the intricate kinematic details associated with ataxia Moreover, such testing often consists of a level of subjectivity of the assessing clinician. In this paper, we propose an objective measuring instrument, in the form of a spoon, equipped with the Internet-of-Things (IoT) based system and relevant machine learning techniques to quantitatively assess impairment levels while engaged in routine daily activity. In a clinical study involving individuals diagnosed with Friedreich ataxia, movement patterns during a simulated eating task were captured and kinematic biomarkers were extracted that were consistent with the frequently-used clinical rating scales. Multivariate analysis of these biomarkers allows us to accurately classify individuals with Friedreich ataxia and control subjects to an accuracy of 91%. Furthermore, the kinematic information captured from the spoon can be used to introduce an alternative assessment scheme with a greater sensitivity to ataxic movements and with less inter-rater discrepancy.

Friedreich ataxia is an autosomal recessive neurodegenerative disease associated with a high diabetes prevalence. No treatment is available to prevent or delay disease progression. Friedreich ataxia is caused by intronic GAA trinucleotide repeat expansions in the frataxin-encoding FXN gene that reduce frataxin expression, impair iron-sulfur cluster biogenesis, cause oxidative stress, and result in mitochondrial dysfunction and apoptosis. Here we examined the metabolic, neuroprotective and frataxin-inducing effects of glucagon-like-peptide 1 (GLP-1) analogs in in vivo and in vitro models and in Friedreich ataxia patients. The GLP-1 analog exenatide improved glucose homeostasis of frataxin-deficient mice through enhanced insulin content and secretion in pancreatic β-cells. Exenatide induced frataxin and iron-sulfur cluster-containing proteins in β-cells and brain, and was protective to sensory neurons in dorsal root ganglia. GLP-1 analogs also induced frataxin expression, reduced oxidative stress and improved mitochondrial function in Friedreich ataxia patients' induced pluripotent stem cell-derived β-cells and sensory neurons. The frataxin-inducing effect of exenatide was confirmed in a pilot trial in Friedreich ataxia patients, showing modest frataxin induction in platelets over a 5-week treatment course. Taken together, GLP-1 analogs improve mitochondrial function in frataxin-deficient cells and induce frataxin expression. Our findings identify incretin receptors as a therapeutic target in Friedreich ataxia., info:eu-repo/semantics/published

Friedreich ataxia (FRDA) is a chronic, progressive and highly disabling cerebellar degenerative disease. Despite this, little attention has been paid to the health-related quality of life (HRQOL) in this disease. The aim of the present study was to assess FRDA patients’ perception of HRQOL and to determine the influence of depression, and demographic and clinical variables. The sample consisted of 62 patients with genetically confirmed FRDA. The SF-36 Health Survey was used to assess HRQOL. Depressive symptoms were evaluated with the Beck Depression Inventory-II. FRDA patients’ mean scores were significantly lower than the values for the Spanish population in all SF36 dimensions. Average z scores ranged from − 5.5 in physical functioning to − 0.48 in mental health. Age and clinical variables were significant predictors of HRQOL in only several dimensions, whereas BDI scores were able to predict a significant percentage of variance in all SF36 dimensions, except physical functioning. Our study demonstrates the high impact of Friedreich ataxia on quality of life. This impact does not only occur in those aspects most related to motor disability but it is also present in non-motor dimensions. Depressive symptomatology is the most relevant variable for predicting quality of life.

To assess with magnetoencephalography the developmental vs progressive character of the impairment of spinocortical proprioceptive pathways in Friedreich ataxia (FRDA)., info:eu-repo/semantics/published

Dorsal root ganglia, dorsal roots (DR), and dorsal root entry zones (DREZ) are vulnerable to frataxin deficiency in Friedreich ataxia (FA). A previously unrecognized abnormality is the intrusion of astroglial tissue into DR. Segments of formalin-fixed upper lumbar spinal cord of 13 homozygous and 2 compound heterozygous FA patients were sectioned longitudinally to represent DREZ and stained for glial fibrillary acidic protein (GFAP), S100, vimentin, the central nervous system (CNS)-specific myelin protein proteolipid protein, the peripheral nervous system (PNS) myelin proteins PMP-22 and P0, and the Schwann cell proteins laminin, alpha-dystroglycan, and periaxin. Normal DREZ showed short, sharply demarcated, dome-like extensions of CNS tissue into DR. The Schwann cell-related proteins formed tight caps around these domes. In FA, GFAP-, S100-, and vimentin-reactive CNS tissue extended across DREZ and into DR over much longer distances by breaching the CNS-PNS barrier. The transition between PNS and CNS myelin proteins was disorganized. During development, neural-crest derived boundary cap cells provide guidance to dorsal root ganglia axons growing into the dorsal spinal cord and at the same time block the inappropriate intrusion of CNS glia into DR. It is likely that frataxin is required during a critical period of permissive (axons) and nonpermissive (astroglia) border-control.

Upper limb function for people with Friedreich ataxia determines capacity to participate in daily activities. Current upper limb measures available do not fully capture impairments related to Friedreich ataxia. We have developed an objective measure, the Ataxia Instrumented Measure-Spoon (AIM-S), which consists of a spoon equipped with a BioKin wireless motion capture device, and algorithms that analyse these signals, to measure ataxia of the upper limb during the pre-oral phase of eating. The aim of this study was to evaluate the AIM-S as a sensitive and functionally relevant clinical outcome for use in clinical trials. A prospective longitudinal study evaluated the capacity of the AIM-S to detect change in upper limb function over 48 weeks. Friedreich ataxia clinical severity, performance on the Nine-Hole Peg Test and Box and Block Test and responses to a purpose-designed questionnaire regarding acceptability of AIM-S were recorded. Forty individuals with Friedreich ataxia and 20 control participants completed the baseline assessment. Thirty individuals with Friedreich ataxia completed the second assessment. The sensitivity of the AIM-S to detect deterioration in upper limb function was greater than other measures. Patient-reported outcomes indicated the AIM-S reflected a daily activity and was more enjoyable to complete than other assessments. The AIM-S is a more accurate, less variable measure of upper limb function in Friedreich ataxia than existing measures. The AIM-S is perceived by individuals with Friedreich ataxia to be related to everyday life and will permit individuals who are non-ambulant to be included in future clinical trials.

Friedreich ataxia (FRDA) has been associated with functional abnormalities in cerebral and cerebellar networks, particularly in the ventral attention network. However, how functional alterations change with disease progression remains largely unknown. Longitudinal changes in brain activation, associated with working memory performance (N-back task), and grey matter volume were assessed over 24 months in 21 individuals with FRDA and 28 healthy controls using functional and structural magnetic resonance imaging, respectively. Participants also completed a neurocognitive battery assessing working memory (digit span), executive function (Stroop, Haylings), and set-shifting (Trail Making Test). Individuals with FRDA displayed significantly increased brain activation over 24 months in ventral attention brain regions, including bilateral insula and inferior frontal gyrus (pars triangularis and pars opercularis), compared with controls, but there was no difference in working memory (N-back) performance between groups. Moreover, there were no significant differences in grey matter volume changes between groups. Significant correlations between brain activations and both clinical severity and age at disease onset were observed in FRDA individuals only at 24 months. There was significant longitudinal decline in Trail Making Test (TMT) difference score (B-A) in individuals with FRDA, compared with controls. These findings provide the first evidence of increased longitudinal activation over time in the cerebral cortex in FRDA, compared with controls, despite comparable working memory performance. This finding represents a possible compensatory response in the ventral attention network to help sustain working memory performance in individuals with FRDA.

Background: This study compared functional and structural visual changes in Friedreich ataxia (FRDA) patients with healthy controls (HC) and correlated these changes with neurological disability. Methods: Eight FRDA Spanish patients and eight HC were selected from 2014 to 2018. Best corrected visual acuity (BCVA), visual field (VF), optic coherence tomography (OCT), and neurological disability measured by &ldquo, scale for the assessment and rating of ataxia&rdquo, (SARA) were taken in a basal exploration and repeated after 6 months. A linear mixed analysis and Bonferroni p-value correction were performed. Results: FRDA baseline and follow-up patients showed statistically significant decreases in BCVA, VF, and OCT parameters compared with the HC. Some of the VF measurements and most of the OCT parameters had an inverse mild-to-strong correlation with SARA. Moreover, the analysis of the ROC curve demonstrated that the peripapillary retinal nerve fiber layer (pRNFL) average thickness was the best parameter to discriminate between FRDA patients and HC. Conclusions: The follow-up study showed a progression in OCT parameters. Findings showed a sequential effect in pRNFL, ganglion cell complex (GCC), and macula. The VF and the OCT could be useful biomarkers in FRDA, both for their correlation with neurological disease as well as for their ability to evaluate disease progression.

Background: Loss of hand dexterity has a profound impact on disability in patients with cerebellar, pyramidal, or extrapyramidal diseases. Analysis of multiple finger tapping (FT) parameters can contribute to identify the underlying physiopathology, while providing a quantitative clinical assessment tool, particularly in patients not reliably evaluated using clinical rating scales. Here, we used an automated method of FT analysis in Friedreich ataxia (FRDA) to disentangle cerebellar (prominent FT rate variability), extrapyramidal (FT progressive amplitude reduction without slowing of tapping rate), and pyramidal (progressive decrease of FT rate and amplitude) contribution to upper limb loss of dexterity. FT parameters were then related to FRDA clinical parameters and upper limbs motor evoked potential (MEPs). Methods: Twenty-four FRDA patients and matched healthy subjects performed FT with the dominant hand for 90 seconds. FT rate, FT rate variability, FT amplitude, and linear regressions of FT movement parameters were automatically computed. Eleven patients underwent MEPs, measured at the first dorsal interosseous of the dominant hand to determine central motor conduction time (CMCT). Results: FRDA patients had slower and more regular FT rate than controls. Eleven FRDA patients showed FT rate slowing. Those patients had longer disease duration and higher Scale for the Assessment and Rating of Ataxia (SARA) scores. Seven patients with FT rate slowing had MEP and all displayed prolonged CMCT, whereas the 4 other patients with constant FT rate had normal CMCT. Conclusion: This study provides evidence for a prominent involvement of pyramidal dysfunction in upper limb dexterity loss as well as a potential outcome measure for clinical studies in FRDA., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Recent studies have suggested the presence of a significant atrophy affecting the cerebellar cortex in Friedreich ataxia (FRDA) patients, an area of the brain long considered to be relatively spared by neurodegenerative phenomena. Cognitive deficits, which occur in FRDA patients, have been associated with cerebellar volume loss in other conditions. The aim of this study was to investigate the correlation between cerebellar volume and cognition in FRDA. Methods: Nineteen FRDA patients and 20 healthy controls (HC) were included in this study and evaluated via a neuropsychological examination. Cerebellar global and lobular volumes were computed using the Spatially Unbiased Infratentorial Toolbox (SUIT). Furthermore, a cerebellar voxel-based morphometry (VBM) analysis was also carried out. Correlations between MRI metrics and clinical data were tested via partial correlation analysis. Results: FRDA patients showed a significant reduction of the total cerebellar volume (p = 0.004), significantly affecting the Lobule IX (p = 0.001). At the VBM analysis, we found a cluster of significant reduced GM density encompassing the entire lobule IX (p = 0.003). When correlations were probed, we found a direct correlation between Lobule IX volume and impaired visuo-spatial functions (r = 0.58, p = 0.02), with a similar correlation that was found between the same altered function and results obtained at the VBM (r = 0.52; p = 0.03). Conclusions: With two different image analysis techniques, we confirmed the presence of cerebellar volume loss in FRDA, mainly affecting the posterior lobe. In particular, Lobule IX atrophy correlated with worse visuo-spatial abilities, further expanding our knowledge about the physiopathology of cognitive impairment in FRDA.

Children with Friedreich’s ataxia (FA) are at risk of perioperative morbidity and mortality from severe unpredictable heart failure. There is currently no clear way of identifying patients at highest risk. We used myocardial perfusion reserve (MPR), an MRI technique used to assess the maximal myocardial blood flow above baseline, to help determine potential surgical risk in FA subjects. In total, seven children with genetically confirmed FA, ages 8–17 years, underwent MPR stress testing using regadenoson. Six of the seven demonstrated impaired endocardial perfusion during coronary hyperemia. The same six were also found to have evidence of ongoing myocardial damage as illustrated by cardiac troponin I leak (range 0.04–0.17 ng/mL, normal

Friedreich’s ataxia (FA) is one of the most prevalent variants of the inherited ataxias. The disease is characterized by complicated phenotype that includes neurological signs (ataxia, sensory polyneuropathy, dysarthria, disorders of deep sensitivity, areflexia, pyramid symptoms with lower extremities involvement, vegetative disorders, sometimes — psychopathological symptoms), cardiological disorders (cardiomyopathy, heart failure, arrhythmias), and disorders of carbohydrate metabolism, and skeletal deformities. If neurological disorders lead to significant decrease of life quality and disability, cardiovascular complications are the main cause of fatal outcome in FA. It is worthy to mention that involvement of the heart into pathological process might long remain undiagnosed. Recently, most of abroad and local publications on FA are related to neurological presentation. Cardiovascular side of the problem in the scientific society remains underestimated, regardless the risk of sudden death and of heart failure (due to symmetric myocardial hypertrophy with the areas of intramyocardial fibrosis) being high. We present clinical and genetic observation of a 27-year old patient with FA, moderate neurological disorders and severe myocardial hypertrophy. The article is focused on the contemporary clinical and diagnostic aspects of FA associated cardiomyopathy.

Objectives The Medical Outcomes Study 36 item Short-Form Health Survey (SF-36) is one of the most commonly used patient reported outcome measure. This study aimed to examine the relationship between SF-36 version 2 (SF-36V2) summary scores and Friedreich ataxia (FRDA) clinical characteristics, and to investigate the responsiveness of the scale, in comparison with the Friedreich Ataxia Rating Scale (FARS), over 1, 2 and 3 years. Materials and Methods Descriptive statistics were used to examine the characteristics of the cohort at baseline and years 1, 2 and 3. Correlations between FRDA clinical characteristics and SF-36V2 summary scores were reported. Responsiveness was measured using paired t tests. Results We found significant correlations between the physical component summary (PCS) of the SF-36V2 and various FRDA clinical parameters but none for the mental component summary. No significant changes in the SF-36V2 were seen over 1 or 2 years; however, PCS scores at Year 3 were significantly lower than at baseline (−3.3, SD [7.6], P=.01). FARS scores were found to be significantly greater at Years 1, 2 and 3 when compared to baseline. Conclusions Our findings suggest that despite physical decline, individuals with FRDA have relatively stable mental well-being. This study demonstrates that the SF-36V2 is unlikely to be a useful tool for identifying clinical change in FRDA therapeutic trials.

Patients with Friedreich ataxia typically die of cardiomyopathy, marked by myocardial fibrosis and abnormal left ventricular (LV) geometry. We measured procollagen I carboxyterminal propeptide (PICP), a serum biomarker of collagen production, and characterized genotypes, phenotypes, and outcomes in these patients. Twenty-nine patients with Friedreich ataxia (mean age, 34.2 ± 2.2 yr) and 29 healthy subjects (mean age, 32.5 ± 1.1 yr) underwent serum PICP measurements. Patients underwent cardiac magnetic resonance imaging and outcome evaluations at baseline and 12 months. Baseline PICP values were significantly higher in the patients than in the control group (1,048 ± 77 vs 614 ± 23 ng/mL; P We conclude that PICP, a serum marker of collagen synthesis, is elevated in Friedreich ataxia and indicates baseline abnormal LV geometry and subsequent dilation. Cardiac magnetic resonance and PICP warrant consideration as complementary biomarkers in therapeutic trials of Friedreich ataxia cardiomyopathy.

Friedreich ataxia is a progressive degenerative disease with neurologic and cardiac involvement. This study characterizes comorbid medical conditions in a large cohort of patients with Friedreich ataxia. Patient diagnoses were collected in a large natural history study of 641 subjects. Prevalence of diagnoses in the cohort with Friedreich ataxia was compared with prevalence in the population without Friedreich ataxia. Ten patients (1.6%) had inflammatory bowel disease, 3.5 times more common in this cohort of individuals with Friedreich ataxia than in the general population. Four subjects were growth hormone deficient, reflecting a prevalence in Friedreich ataxia that is 28 times greater than the general population. The present study identifies specific diagnoses not traditionally associated with Friedreich ataxia that are found at higher frequency in this disease. These associations could represent coincidence, shared genetic background, or potentially interactive disease mechanisms with Friedreich ataxia.