Irene Sanz-Gallego

Biological and clinical characteristics of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) cohort: a cross-sectional analysis of baseline data.

BACKGROUND Friedreichs ataxia is a rare autosomal recessive neurodegenerative disorder. Here we report cross-sectional baseline data to establish the biological and clinical characteristics for a prospective, international, European Friedreichs ataxia database registry. METHODS Within the European Friedreichs Ataxia Consortium for Translational Studies (EFACTS) framework, we assessed a cohort of patients with genetically confirmed Friedreichs ataxia. The primary outcome measure was the Scale for the Assessment and Rating of Ataxia (SARA) and secondary outcome measures were the Inventory of Non-Ataxia Signs (INAS), the performance-based coordination test Spinocerebellar Ataxia Functional Index (SCAFI), the neurocognitive phonemic verbal fluency test, and two quality-of-life measures: the activities of daily living (ADL) part of the Friedreichs Ataxia Rating Scale and EQ-5D. The Friedreichs ataxia cohort was subdivided into three groups: early disease onset (≤14 years), intermediate onset (15-24 years), and late onset (≥25 years), which were compared for clinical characteristics and outcome measures. We used linear regression analysis to estimate the annual decline of clinical outcome measures based on disease duration. This study is registered with ClinicalTrials.gov, number NCT02069509. FINDINGS We enrolled 592 patients with genetically confirmed Friedreichs ataxia between Sept 15, 2010, and April 30, 2013, at 11 sites in seven European countries. Age of disease onset was inversely correlated with the number of GAA repeats in the frataxin (FXN) gene: every 100 GAA repeats on the smaller repeat allele was associated with a 2·3 year (SE 0·2) earlier onset. Regression analyses showed significant estimated annual worsening of SARA (regression coefficient 0·86 points [SE 0·05], INAS (0·14 points [0·01]), SCAFI Z scores (-0·09 [0·01]), verbal fluency (-0·34 words [0·07]), and ADL (0·64 points [0·04]) during the first 25 years of disease; the regression slope for health-related quality-of-life state from EQ-5D was not significant (-0·33 points [0·18]). For SARA, the predicted annual rate of worsening was significantly higher in early-onset patients (n=354; 1·04 points [0·13]) and intermediate-onset patients (n=137; 1·17 points [0·22]) than in late-onset patients (n=100; 0·56 points [0·10]). INTERPRETATION The results of this cross-sectional baseline analysis of the EFACTS cohort suggest that earlier disease onset is associated with larger numbers of GAA repeats and more rapid disease progression. The differential estimated progression of ataxia symptoms related to age of onset have implications for the design of clinical trials in Friedreichs ataxia, for which SARA might be the most suitable measure to monitor disease progression. FUNDING European Commission.

Deferiprone in Friedreich ataxia: A 6-Month randomized controlled trial.

We conducted a 6‐month, randomized, double‐blind, placebo‐controlled study to assess safety, tolerability, and efficacy of deferiprone in Friedreich ataxia (FRDA).

Progression characteristics of the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS): a 2 year cohort study

BACKGROUND The European Friedreichs Ataxia Consortium for Translational Studies (EFACTS) is a prospective international registry investigating the natural history of Friedreichs ataxia. We used data from EFACTS to assess disease progression and the predictive value of disease-related factors on progression, and estimated sample sizes for interventional randomised clinical trials. METHODS We enrolled patients with genetically confirmed Friedreichs ataxia from 11 European study sites in Austria, Belgium, France, Germany, Italy, Spain, and the UK. Patients were seen at three visits-baseline, 1 year, and 2 years. Our primary endpoint was the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes were the Inventory of Non-Ataxia Signs (INAS), the Spinocerebellar Ataxia Functional Index (SCAFI), phonemic verbal fluency (PVF), and the quality of life measures activities of daily living (ADL) and EQ-5D-3L index. We estimated the yearly progression for each outcome with linear mixed-effect modelling. This study is registered with ClinicalTrials.gov, number NCT02069509, and follow-up assessments and recruitment of new patients are ongoing. FINDINGS Between Sept 15, 2010, and Nov 21, 2013, we enrolled 605 patients with Friedreichs ataxia. 546 patients (90%) contributed data with at least one follow-up visit. The progression rate on SARA was 0·77 points per year (SE 0·06) in the overall cohort. Deterioration in SARA was associated with younger age of onset (-0·02 points per year [0·01] per year of age) and lower SARA baseline scores (-0·07 points per year [0·01] per baseline point). Patients with more than 353 GAA repeats on the shorter allele of the FXN locus had a higher SARA progression rate (0·09 points per year [0·02] per additional 100 repeats) than did patients with fewer than 353 repeats. Annual worsening was 0·10 points per year (0·03) for INAS, -0·04 points per year (0·01) for SCAFI, 0·93 points per year (0·06) for ADL, and -0·02 points per year (0·004) for EQ-5D-3L. PVF performance improved by 0·99 words per year (0·14). To detect a 50% reduction in SARA progression at 80% power, 548 patients would be needed in a 1 year clinical trial and 184 would be needed for a 2 year trial. INTERPRETATION Our results show that SARA is a suitable clinical rating scale to detect deterioration of ataxia symptoms over time; ADL is an appropriate measure to monitor changes in daily self-care activities; and younger age at disease onset is a major predictor for faster disease progression. The results of the EFACTS longitudinal analysis provide suitable outcome measures and sample size calculations for the design of upcoming clinical trials of Friedreichs ataxia. FUNDING European Commission.

Triple therapy with deferiprone, idebenone and riboflavin in Friedreich's ataxia – open-label trial

The objective of the study was to test the efficacy, safety and tolerability of triple therapy with deferiprone, idebenone and riboflavin in Friedreichs ataxia (FRDA) patients in a clinical pilot study.

Patterns of motor signs in spinocerebellar ataxia type 3 at the start of follow-up in a reference unit

BackgroundSpinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder that affects the cerebellar system and other subcortical regions of the brain. As for other cerebellar diseases, the severity of this type of ataxia can be assessed with the Scale for Assessment and Rating of Ataxia (SARA) which gives a total score that reflects functional impairment out of 8 cerebellar function tests. SCA3 patients score profile is heterogeneous on at the start of follow up. This study investigates possible patterns in those profiles and analyses the impact of other usually concurrent signs of impairment of extracerebellar motor systems in that profile variability by means of multivariate statistical approaches.MethodsSeventeen patients with SCA3 underwent systematic anamnesis, neurological and SARA assessment, visual evaluation of 123I-Ioflupane (DaTSCAN) single-photon emission computed tomography (SPECT) imaging and electrophysiological studies (nerve conduction and electromyography). Patterns in the profiles of SARA item scores were investigated by hierarchical clustering after multivariate correspondence analysis. A network analysis was used to represent relationships between SARA item scores, clinical, genetic and neurological examination parameters as well as abnormalities of DaTSCAN SPECT imaging and electrophysiological studies.ResultsThe most frequently altered SARA items in all patients are gait and stance, and three profiles of SCA3 patients can be distinguished depending mainly on their degree of impairment in those two items. Other SARA items like the score on heel-shin slide contribute less to the classification. Network analysis shows that SARA item scores configure a single domain that is independent of the size of the mutated expanded allele and age of onset, which are, in turn closely and inversely correlated. The severity of cerebellar dysfunction is correlated with longer disease duration, altered visual evaluation of DaTSCAN SPECT imaging and decreased patellar reflexes. Neither the presence of pyramidal or extrapyramidal signs nor the intensity of polyneuropathy is correlated with the SARA items scores.ConclusionsPattern recognition approaches are useful tools to describe clinical phenotypes of ataxias and to identify particular configurations of cerebellar signs.

Substantia Nigra Echogenicity in Hereditary Ataxias With and Without Nigrostriatal Pathology: a Pilot Study

Our objective was to determine whether substantia nigra (SN) hyperechogenicity is greater in spinocerebellar ataxias (SCA) with nigrostriatal affectation than in ataxias without it. A cross-sectional case-control study analyzing four groups of patients was conducted: 1) nigrostriatal ataxias (SCA3 and SCA6), 2) nigrostriatal healthy controls matched by age and sex, 3) non-nigrostriatal ataxias (FRDA and SCA7), and 4) non-nigrostriatal healthy controls matched by age and sex. All the patients underwent a transcranial ultrasound performed by an experienced sonographer blinded to the clinical, genetic, and neuroimaging data. The SN area was measured and compared in the four groups. The SN area was also correlated with clinical features and genetic data in the two ataxia groups. We examined 12 patients with nigrostriatal ataxia (11 SCA3 and 1 SCA6), 12 nigrostriatal healthy control patients, 7 patients with non-nigrostriatal ataxia (5 FRDA and 2 SCA7), and 7 non-nigrostriatal healthy control patients. The median (IQR) SN area (cm2) was greater in the nigrostriatal ataxias compared with the controls (right SN, 0.43 [0.44] vs. 0.11 [0.25]; P = 0.001; left SN, 0.32 [0.25] vs. 0.11 [0.16]; P = 0.001), but was similar among the non-nigrostriatal ataxias and controls. There were no statistically significant differences in the SN area between the nigrostriatal and non-nigrostriatal ataxias, although there was a tendency for a greater left SN area in the nigrostriatal compared with the non-nigrostriatal ataxias (0.32 [0.25] vs. 0.16 [0.24], P = 0.083). SN echogenicity is markedly greater in ataxias with nigrostriatal pathology than in controls. The role of SN hyperechogenicity in differentiating ataxias with and without nigrostriatal pathology should be elucidated in future studies.