Ilaria Giordano

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.

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.

Cognition in Friedreich's ataxia: a behavioral and multimodal imaging study

Friedreichs ataxia (FRDA) is a spinocerebellar degenerative disorder, in which cognitive deficits are sparsely explored. In this behavioral and multimodal magnetic resonance imaging (MRI) study, we investigated the neurocognitive profile and cortico‐cerebellar dysfunctions underlying executive functioning in individuals with FRDA.

Predictors of survival in a Huntington's disease population from southern Italy.

BACKGROUND The primary aim of the present study was to determine the survival rates and identify predictors of disease duration in a cohort of Huntingtons disease (HD) patients from Southern Italy. METHODS All medical records of HD patients followed between 1977 and 2008 at the Department of Neurological Sciences of Federico II University in Naples were retrospectively reviewed and 135 patients were enrolled in the analysis. At the time of data collection, 41 patients were deceased (19 males and 22 females) with a mean ± SD age at death of 56.6 ± 14.9 years (range 18-83). RESULTS The median survival time was 20 years (95% CI: 18.3-21.7). Cox regression analysis showed that the number of CAG in the expanded allele (HR 1.09 for 1 point triplet increase, p=0.002) and age of onset (HR 1.05 for 1 point year increase, p=0.002) were independent and significant predictors of lower survival rates. CONCLUSIONS We believe that these findings are important for a better understanding of the natural history of the disease and may be relevant in designing future therapeutic trials.

Genetic screening for LRRK2 gene G2019S mutation in Parkinson's disease patients from Southern Italy.

Leuchine-rich repeat kinase 2 (LRRK2) gene mutations are a common cause of familial and sporadic Parkinson disease (PD). G2019S is the most frequent mutation of the LRRK2 gene and has been reported in about 5-6% of familial and 1-2% of sporadic PD cases. The aim of this study is to investigate the G2019S frequency in a series of 58 familial and 70 sporadic PD patients recruited from Campania, a region in Southern Italy. We identified one heterozygous G2019S mutation in a PD patient who also suffered from obsessive disorder and depression and presented hallucinations and delusional jealousy while he was treated with l-dopa, pramipexole, and amantadine. Brain (18)F-deoxy-glucose PET showed relative decrease of glucose metabolism in the caudate nuclei and to a lesser extent in cortical parietal/frontal regions. The patients mother also had PD and molecular analysis demonstrated that she carried the same mutation. G2019S mutation frequency is rather low in overall patients (0.8%) and in the familial group (1.7%), suggesting that it may be an uncommon cause of PD in Southern Italy.

Experience in a short-term trial with 4-aminopyridine in cerebellar ataxia.

4-Aminopyridine (4-AP) is a reversible blocker of voltagegated potassium channels. Its slow release form has been approved for symptomatic treatment of gait disorder in multiple sclerosis [2]. In a number of small studies, 4-AP and the related compound 3,4-diaminopyridine (3,4-AP) improved downbeat nystagmus and reduced attack frequency in episodic ataxia [9]. In addition, 4-AP decreased gait variability in patients with chronic cerebellar ataxia of different origin [7, 8]. Chronic treatment with 3,4-AP had beneficial effects in a mouse model of spinocerebellar ataxia type 1 (SCA1) [3]. We here report our clinical experiences with 4-AP in 16 patients with chronic cerebellar ataxia. As 4-AP is thought to exert its effect on ataxia by interfering with the activity of cerebellar Purkinje neurons, we treated patients with SCA1, SCA3, SCA6 and sporadic adult-onset ataxia of unknown origin (SAOA), as well as one with a POLG mutation. These disorders are characterized by prominent cerebellar cortical degeneration with Purkinje cell involvement. Three centers participated in the observations. After giving informed consent, 16 patients were treated with the slow release form of 4-AP (Fampyra , 2 9 10 mg/day). Nine of the patients were female. Three patients were diagnosed SCA1, three SCA6, two SCA3, one genetically nonidentified autosomal dominant cerebellar ataxia, one POLG mutation and six of them a SAOA. Age was 60 ± 11.3 years (mean ± SD), disease duration 16.3 ± 17.1 years. To assess the severity of ataxia, we used the Scale for the Assessment and Rating of Ataxia (SARA) [5]. In addition, patients underwent three timed coordination tests, the 8 m walk (8 MW), the 9-hole pegboard (9HPT), and the speech rate test (PATA rate). Performance in these tests allows calculating the SCA Functional Index (SCAFI) [6]. Results of the timed tests are expressed as Z scores. Neurological symptoms other than ataxia were assessed with the Inventory of Non-Ataxia Signs (INAS) [4]. Patients estimated their health-related quality of life on the visual analogue scale of the EQ-5D (EQ-VAS) [1]. Assessments were done at baseline, 4 h and 14 days after treatment. Although two patients discontinued 4-AP due to side effects, the compound was generally well tolerated. This view is also supported by the trend towards an improvement of the EQ-VAS after 14 days. In the remaining 14 patients, SARA (range: 0–40) improved from 14.3 ± 4.7 to 13.0 ± 4.6 points after 4 h (n = 11) and to 13.7 ± 4.6 points after 14 days (n = 14), but these differences failed I. Giordano (&) H. Jacobi M. Minnerop T. Klockgether Department of Neurology, University Hospital of Bonn, Sigmund-Freud-Strase 25, 53105 Bonn, Germany e-mail: ilaria_anna.giordano@ukb.uni-bonn.de

Multisystemic SYNE1 ataxia: confirming the high frequency and extending the mutational and phenotypic spectrum

Sir, We recently reported in Brain a large multi-centre study suggesting that truncating SYNE1 mutations are a recurrent cause of recessive ataxia also outside Quebec (23/434 = 5.3% of patients with unexplained early-onset ataxia) (Synofzik et al. , 2016). Moreover, this study indicated that SYNE1 ataxia might commonly present with complex multisystemic phenotypes rather than pure cerebellar ataxia, including in particular motor neuron and brainstem dysfunction (Synofzik et al. , 2016). However, confirmation of both the frequency estimate and the complex phenotypic spectrum is still lacking, raising the question whether these findings indeed represent systematic results rather than just exceptional or coincidental associations. Here, we now report the mutational and phenotypic findings on SYNE1 from a second, independent ataxia series of 116 patients. These findings not only confirm the high frequency of SYNE1 ataxia and extend both the mutational spectrum (seven novel index patients, 12 novel SYNE1 mutations) and the multisystemic phenotypic spectrum, including amyotrophic lateral sclerosis (ALS)-like motor neuron features, they also indicate that muscle immunohistochemistry might provide a valuable diagnostic biomarker for clarifying the pathogenic contribution of SYNE1 missense variants. This observation may have consequences for clinical SYNE1 diagnostics, as diagnostic tests are urgently needed for clarifying the role of the ubiquitous SYNE1 missense variants with unknown clinical significance (VUS), which are frequently found in neurological and non-neurological patients and controls (Synofzik et al. , 2016). Index subjects ( n = 116) with unexplained degenerative ataxia compatible with autosomal recessive inheritance (no ataxia in the parental generation) and negative for trinucleotide repeat expansions causing Friedreich’s ataxia (FRDA) were compiled from three sources: the Early Onset Ataxia Consortium ( n = 88), the ataxia centre Antwerp, Belgium ( n = 9), and the ataxia centre Milano, Italy ( n = 19). All subjects originated from European, Middle East or Mediterranean countries. This …

Clinical and genetic characteristics of sporadic adult-onset degenerative ataxia

Objective: To define the clinical phenotype and natural history of sporadic adult-onset degenerative ataxia and to identify putative disease-causing mutations. Methods: The primary measure of disease severity was the Scale for the Assessment and Rating of Ataxia (SARA). DNA samples were screened for mutations using a high-coverage ataxia-specific gene panel in combination with next-generation sequencing. Results: The analysis was performed on 249 participants. Among them, 83 met diagnostic criteria of clinically probable multiple system atrophy cerebellar type (MSA-C) at baseline and another 12 during follow-up. Positive MSA-C criteria (4.94 ± 0.74, p < 0.0001) and disease duration (0.22 ± 0.06 per additional year, p = 0.0007) were associated with a higher SARA score. Forty-eight participants who did not fulfill MSA-C criteria and had a disease duration of >10 years were designated sporadic adult-onset ataxia of unknown etiology/non-MSA (SAOA/non-MSA). Compared with MSA-C, SAOA/non-MSA patients had lower SARA scores (13.6 ± 6.0 vs 16.0 ± 5.8, p = 0.0200) and a slower annual SARA increase (1.1 ± 2.3 vs 3.3 ± 3.2, p = 0.0013). In 11 of 194 tested participants (6%), a definitive or probable genetic diagnosis was made. Conclusions: Our study provides quantitative data on the clinical phenotype and progression of sporadic ataxia with adult onset. Screening for causative mutations with a gene panel approach yielded a genetic diagnosis in 6% of the cohort. ClinicalTrials.gov registration: NCT02701036.

E03 Determinants of survival in Huntington's disease

Background and aims The precise knowledge of the natural history of Huntingtons disease (HD) and the impact of variables that may modify the rate of survival are essential for counselling of patients and design of future therapeutic trials. Failure to use survival analyses methodology in previous studies may have produced serious bias in estimates of the survival rates in the disease. The aim of the present study was to examine the determinants of survival in HD. Methods We retrospectively reviewed 309 medical records of all HD patients and at risk subjects between 1977 and 2008 followed at the Department of Neurological Sciences of ‘Federico II’ University in Naples. Inclusion criteria were manifest signs and symptoms and positive molecular testing for HD (CAG triplet number >35). Demographic and clinical data were collected at the first evaluation and at follow-up although the last day we examined the patient in 2008. Results A total of 135 patients were included in the study. The remaining 174 subjects were excluded for the following reasons: gene test missing (n=84), lack of traceability (n=71), premanifest state (n=16) and refusal to participate in the study (n=3). At the time of data collection, 94 patients were still living and 41 patients were deceased (19 males and 22 females) with an average death age of 56.55 years±14.94 (mean±SD, range 18–83). Mean follow-up time after diagnosis was 145 months (range 12–552). Higher survival probabilities were registered in patients with CAG repeat length ≤47 (n=101, 75% of the cohort; p=0.015) and with onset ≤41 (n=74, 55% of the cohort; p=0.046). The individual contribution of each covariate was assessed using a Cox analysis and the final model was generated considering only the significant ones. Conclusions Survival time was longer in patients with a triplet repeat size of the mutant allele ≤47 and with onset of the disease ≤41 years of age. No significant impact either of the size of the wild-type allele or its interaction with the expanded allele was found in the survival rates. Larger studies using the appropriate statistical tool are necessary to better understand the disease duration determinants in HD.

Nonataxia symptoms in Friedreich Ataxia: Report from the Registry of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS)

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.