With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA3), easily accessible, cross-species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in ataxic and preataxic subjects of two independent multicentricSCA3 cohorts and in aSCA3 knock-in mouse model. AtaxicSCA3 subjects showed increased levels of both NfL andpNfH. In preataxic subjects, NfL levels increased with proximity to the individual expected onset of ataxia, with significant NfL elevations already 7.5 years before onset. Cross-sectional NfL levels correlated with both disease severity and longitudinal disease progression. Blood NfL andpNfHincreases in humanSCA3 were each paralleled by similar changes inSCA3 knock-in mice, here also starting already at the presymptomatic stage, closely following ataxin-3 aggregation and preceding Purkinje cell loss in the brain. Blood neurofilaments, particularly NfL, might thus provide easily accessible, cross-species validated biomarkers in both ataxic and preataxicSCA3, associated with earliest neuropathological changes, and serve as progression, proximity-to-onset and, potentially, treatment-response markers in both human and preclinical SCA3 trials.

Background Spinocerebellar ataxias (SCAs) are autosomal dominant neurodegenerative diseases. Our aim was to study the conversion to manifest ataxia among apparently healthy carriers of mutations associated with the most common SCAs (SCA1, SCA2, SCA3, and SCA6), and the sensitivity of clinical and functional measures to detect change in these individuals. Methods In this prospective, longitudinal, observational cohort study, based at 14 referral centres in seven European countries, we enrolled children or siblings of patients with SCA1, SCA2, SCA3, or SCA6. Eligible individuals were those without ataxia, defined by a score on the Scale for the Assessment and Rating of Ataxia (SARA) of less than 3; participants had to be aged 18-50 years for children or siblings of patients with SCA1, SCA2, or SCA3, and 35-70 years for children or siblings of patients with SCA6. Study visits took place at recruitment and after 2, 4, and 6 years (plus or minus 3 months). We did genetic testing to identify mutation carriers, with results concealed to the participant and dinical investigator. We assessed patients with clinical scales, questionnaires of patient-reported outcome measures, a rating of the examiner's confidence of presence of ataxia, and performance-based coordination tests. Conversion to ataxia was defined by an SARA score of 3 or higher. We analysed the association of factors at baseline with conversion to ataxia and the evolution of outcome parameters on temporal scales (time from inclusion and time to predicted age at ataxia onset) in the context of mutation status and conversion status. This study is registered with ClinicalTrials.gov, NCT01037777. Findings Between Sept 13, 2008, and Oct 28, 2015, 302 participants were enrolled. We analysed data for 252 participants with at least one follow-up visit. 83 (33%) participants were from families affected by SCA1, 99 (39%) by SCA2, 46 (18%) by SCA3, and 24 (10%) by SCA6. In participants who carried SCA mutations, 26 (52%) of 50 SCA1 carriers, 22 (59%) of 37 SCA2 carriers, 11 (42%) of 26 SCA3 carriers, and two (13%) of 15 SCA6 carriers converted to ataxia. One (3%) of 33 SCA1 non-carriers and one (2%) of 62 SCA2 non-carriers converted to ataxia. Owing to the small number of people who met our criteria for ataxia, subsequent analyses could not be done in carriers of the SCA6 mutation. Baseline factors associated with conversion were age (hazard ratio 1.13 [95% CI 1. 03-1. 24]; p=0.011), CAG repeat length (1.25 [1- 11-1. 41]; p=0 . 0002), and ataxia confidence rating (1.72 [1.23-2.41]; p=0 . 0015) for SCA1; age (1.08 [1.02-1-14]; p=0.0077) and CAG repeat length (1.65 [1.27-2.13]; p=0.0001) for SCA2; and age (1.27 [1.09-1.50]; p=0.0031), confidence rating (2.60 [1.23-5.47]; p=0.012), and double vision (14.83 [245-102.44]; p=0 . 0063) for SCA3. From the time of indusion, the SARA scores of SCA1, SCA2, and SCA3 mutation carriers increased, whereas they remained stable in non-carriers. On a timescale defined by the predicted time of ataxia onset, SARA progression in SCA1, SCA2, and SCA3 mutation carriers was non-linear, with marginal progression before ataxia and increasing progression after ataxia onset. Interpretation Our study provides quantitative data on the conversion of non-ataxic SCA1, SCA2, and SCA3 mutation carriers to manifest ataxia. Our data could prove useful for the design of preventive trials aimed at delaying the onset of ataxia by aiding sample size calculations and stratification of study participants. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Background Spinocerebellar ataxias are rare dominantly inherited neurodegenerative diseases that lead to severe disability and premature death. Objective To quantify the impact of disease progression measured by the Scale for the Assessment and Rating of Ataxia on survival, and to identify different profiles of disease progression and survival. Methods Four hundred sixty-two spinocerebellar ataxia patients from the EUROSCA prospective cohort study, suffering from spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, and spinocerebellar ataxia type 6, and who had at least two measurements of Scale for the Assessment and Rating of Ataxia score, were analyzed. Outcomes were change over time in Scale for the Assessment and Rating of Ataxia score and time to death. Joint model was used to analyze disease progression and survival. Results Disease progression was the strongest predictor for death in all genotypes: An increase of 1 standard deviation in total Scale for the Assessment and Rating of Ataxia score increased the risk of death by 1.28 times (95% confidence interval: 1.18-1.38) for patients with spinocerebellar ataxia type 1; 1.19 times (1.12-1.26) for spinocerebellar ataxia type 2; 1.30 times (1.19-1.42) for spinocerebellar ataxia type 3; and 1.26 times (1.11-1.43) for spinocerebellar ataxia type 6. Three subgroups of disease progression and survival were identified for patients with spinocerebellar ataxia type 1: "severe" (n = 13; 12%), "intermediate" (n = 31; 29%), and "moderate" (n = 62; 58%). Patients in the severe group were more severely affected at baseline with higher Scale for the Assessment and Rating of Ataxia scores and frequency of nonataxia signs compared to those in the other groups. Conclusion Rapid ataxia progression is associated with poor survival of the most common spinocerebellar ataxia. Theses current results have implications for the design of future interventional studies of spinocerebellar ataxia. (c) 2019 International Parkinson and Movement Disorder Society

To study the long-term evolution of patient-reported outcome measures (PROMs) in the most common spinocerebellar ataxias (SCAs), we analyzed 8 years follow-up data of the EUROSCA Natural History Study, a cohort study of 526 patients with SCA1, SCA2, SCA3 and SCA6.

In a patient with marked symptoms of Huntington disease after the huntingtin testing, which gave normal result, a whole exome sequencing (WES) has been performed based on an international collaboration. A homozygous G>A nucleotid change in the exon 34 of the VPS13A gene has been detected with WES, a mutation resulting in a premature stop codon at the position 1301. This change is a known pathogenic mutation. The aim of this article is to draw attention on the importance of the WES in the diagnosis of rare neurological diseases without any specific symptoms.

Background: Spinocerebellar ataxias (SCAs) are dominantly inherited, progressive ataxia disorders. Disease progression could be preceded by weight loss.Objectives: We aimed to study the course of weight loss in patients who had the most common SCAs (SCA1, SCA2 SCA3, and SCA6). Additional objectives were to identify subgroups of weight evolution, to determine the factors influencing these evolutions, and to assess the impact of these evolutions on disease progression.Methods: In total, 384 patients from the EUROSCA prospective cohort study were analyzed who had SCA1, SCA2, SCA3, or SCA6 and at least 3 measurements of weight. Age was used as a time scale. Clinical outcomes were body mass index (BMI) and the Scale for the Assessment and Rating Ataxia (SARA), with scores ranging from 0 to 40. We used a linear mixed model to analyze the course of BMI and a latent class mixed model to identify subgroup BMI evolution.Results: Overall, BMI declined over time (-0.11 0.03 kg/m(2) per decade; P = 0.0009). Three subgroups of BMI evolution were identified: decreasing BMI (n = 88; 23%), increasing BMI (n = 70; 18%) and stable BMI (n = 226; 59%). Patients in the decreasing BMI group were more severely affected at baseline with higher SARA scores and a higher frequency of non-ataxia signs (especially motor symptoms) compared with those in the other groups. Weight loss was associated with faster disease progression (5.7 +/- 0.7 SARA points per decade; P = 0.036).Conclusions: The current data have substantial implications for the design of future interventional studies in SCA, as they provide a basis for patient stratification and emphasize the usefulness of BMI as a biomarker for monitoring disease progression.

Abstract: In a patient with marked symptoms of Huntington disease after the huntingtin testing, which gave normal result, a whole exome sequencing (WES) has been performed based on an international collaboration. A homozygous G>A nucleotid change in the exon 34 of the VPS13A gene has been detected with WES, a mutation resulting in a premature stop codon at the position 1301. This change is a known pathogenic mutation. The aim of this article is to draw attention on the importance of the WES in the diagnosis of rare neurological diseases without any specific symptoms. Orv Hetil. 2017; 158(42): 1681–1684.

Background Defects of the slow myosin heavy chain isoform coding MYH7 gene primarily cause skeletal myopathies including Laing Distal Myopathy, Myosin Storage Myopathy and are also responsible for cardiomyopathies. Scapuloperoneal and limb-girdle muscle weakness, congenital fiber type disproportion, multi-minicore disease were also reported in connection of MYH7 . Pathogeneses of the defects in the head and proximal rod region of the protein are well described. However, the C-terminal mutations of the MYH7 gene are less known. Moreover, only two articles describe the phenotypic impact of the elongated mature protein product caused by termination signal loss. Case presentation Here we present a male patient with an unusual phenotypic variant of early-onset and predominant involvement of neck muscles with muscle biopsy indicating myopathy and sarcoplasmic storage material. Cardiomyopathic involvements could not be observed. Sequencing of MYH7 gene revealed a stop-loss mutation on the 3-prime end of the rod region, which causes the elongation of the mature protein. Conclusions The elongated protein likely disrupts the functions of the sarcomere by multiple functional abnormalities. This elongation could also affect the thick filament degradation leading to protein deposition and accumulation in the sarcomere, resulting in the severe myopathy of certain axial muscles. The phenotypic expression of the detected novel MYH7 genotype could strengthen and further expand our knowledge about mutations affecting the structure of MyHCI by termination signal loss in the MYH7 gene.

Absztrakt: Egy Huntington-betegsegre utalo tunetegyuttest produkalo betegben a huntingtin mutacio negativ volta miatt nemzetkozi kollaboracio kereten belul exom-szekvenalas (whole exome sequencing – WES) keszult. Betegunkben a WES soran a VPS13A gen 34 exonjaban egy homozigota G>A cseret detektaltunk, ami az 1301-es kodonon egy prematurus stopkodont eredmenyez. Az elteres ismert patogen mutacio. Kozlemenyunkben a modszer fontossagara szeretnenk ramutatni nagyon ritka, nem specifikus megjelenest mutato neurologiai korkepek diagnosztikajaban. Orv Hetil. 2017; 158(42): 1681–1684. | Abstract: In a patient with marked symptoms of Huntington disease after the huntingtin testing, which gave normal result, a whole exome sequencing (WES) has been performed based on an international collaboration. A homozygous G>A nucleotid change in the exon 34 of the VPS13A gene has been detected with WES, a mutation resulting in a premature stop codon at the position 1301. This change is a known pathogenic mutation. The aim of this article is to draw attention on the importance of the WES in the diagnosis of rare neurological diseases without any specific symptoms. Orv Hetil. 2017; 158(42): 1681–1684.

Background Spinocerebellar ataxias are dominantly inherited neurodegenerative diseases. As potential treatments for these diseases are being developed, precise knowledge of their natural history is needed. We aimed to study the long-term disease progression of the most common spinocerebellar ataxias: SCA1, SCA2, SCA3, and SCA6. Furthermore, we aimed to establish the order and occurrence of non-ataxia symptoms, and identify predictors of disease progression.Methods In this longitudinal cohort study (EUROSCA), we enrolled men and women with positive genetic testing for SCA1, SCA2, SCA3, or SCA6 and with progressive, otherwise unexplained ataxia who were aged 18 years or older from 17 ataxia referral centres in ten European countries. Patients were seen every year for 3 years, and at irregular intervals thereafter. The primary outcome was the scale for the assessment and rating of ataxia (SARA), and the inventory of non-ataxia signs (INAS). We used linear mixed models to analyse progression. To account for dropouts, we applied a pattern-mixture model. This study is registered with ClinicalTrials.gov, number NCT02440763.Findings Between July 1, 2005, and Aug 31, 2006, 526 patients with SCA1, SCA2, SCA3, or SCA6 were enrolled. We analysed data for 462 patients with at least one follow-up visit. Median observation time was 49 months (IQR 35-72). SARA progression data were best fitted with a linear model in all genotypes. Annual SARA score increase was 2.11 (SE 0.12) in patients with SCA1, 1.49 (0.07) in patients with SCA2, 1.56 (0.08) in patients with SCA3, and 0.80 (0.09) in patients with SCA6. The increase of the number of non-ataxia signs reached a plateau in SCA1, SCA2, and SCA3. In patients with SCA6, the number of non-ataxia symptoms increased linearly, but more slowly than in patients with SCA1, SCA2, and SCA3 (p<0.0001). Factors that were associated with faster progression of the SARA score were short duration of follow-up (p=0.0179), older age at inclusion (0.04 [SE 0.02] per additional year; p=0.0476), and longer repeat expansions (0.06 [SE 0.02] per additional repeat unit; p=0.0128) in SCA1, short duration of follow-up (p<0.0001), lower age at onset (-0.02 [SE 0.01] per additional year; p=0.0014), and lower baseline SARA score (-0.02 [SE 0.01] per additional SARA point; p=0.0083) in SCA2, and lower baseline SARA score (-0.03 [SE 0.01] per additional SARA point; p=0.0195) in SCA6. In SCA3, we did not identify factors that affected progression of the SARA score.Interpretation Our study provides quantitative data on the progression of the most common spinocerebellar ataxias based on a follow-up period that exceeds those of previous studies. Our data could prove useful for sample size calculation and patient stratification in interventional trials.

INTRODUCTIONHereditary spastic paraplegia is the overall term for clinically and genetically diverse disorders characterized with progressive and variable severe lower extremity spasticity. The most common causes of autosomal dominantly inherited hereditary spastic paraplegias are different mutations of the spastin gene with variable incidence in different ethnic groups, ranging between 15-40%. Mutations in the spastin gene lead to loss of spastins function, causing progressive neuronal failure, which results in axon degeneration finally.AIMThe molecular testing of spastin gene is available in the institution of the authors since January, 2014. The experience gained with the examination of the first eleven patients is described in this article.METHODAfter polymerase chain reaction, Sanger sequencing was performed to examine the 17 exons of the spastin gene. Multiplex ligation-dependent probe amplification was performed to detect greater rearrangements in the spastin gene. Eight of the patients were examined in the genetic counseling clinic of the authors and after detailed phenotype assessment spastin gene testing was obtained. The other three patients were referred to the laboratory from different outpatient clinics.RESULTSOut of the 11 examined patients, four different pathogenic mutations were found in 5 patients.CONCLUSIONSThe first Hungarian data, gained with the examination of spastin gene are presented in this article. The five patients, in whom mutations were detected, represent 45.5% of all tested patients with hereditary spastic paraplegia, which is similar to those published in the international literature. Molecular testing and subsequent detailed genotype-phenotype correlations of the Hungarian patients may serve valuable new information about the disease, which later on may influence our therapeutic possibilities and decisions.

Background The most common spinocerebellar ataxias (SCA)—SCA1, SCA2, SCA3, and SCA6—are caused by (CAG)n repeat expansion. While the number of repeats of the coding (CAG)n expansions is correlated with the age at onset, there are no appropriate models that include both affected and preclinical carriers allowing for the prediction of age at onset. Methods We combined data from two major European cohorts of SCA1, SCA2, SCA3, and SCA6 mutation carriers: 1187 affected individuals from the EUROSCA registry and 123 preclinical individuals from the RISCA cohort. For each SCA genotype, a regression model was fitted using a log-normal distribution for age at onset with the repeat length of the alleles as covariates. From these models, we calculated expected age at onset from birth and conditionally that this age is greater than the current age. Results For SCA2 and SCA3 genotypes, the expanded allele was a significant predictor of age at onset (−0.105±0.005 and −0.056±0.003) while for SCA1 and SCA6 genotypes both the size of the expanded and normal alleles were significant (expanded: −0.049±0.002 and −0.090±0.009, respectively; normal: +0.013±0.005 and −0.029±0.010, respectively). According to the model, we indicated the median values (90% critical region) and the expectancy (SD) of the predicted age at onset for each SCA genotype according to the CAG repeat size and current age. Conclusions These estimations can be valuable in clinical and research. However, results need to be confirmed in other independent cohorts and in future longitudinal studies. ClinicalTrials.gov, number NCT01037777 and NCT00136630 for the French patients.

Background Spinocerebellar ataxias (SCAs) are autosomal, dominantly inherited, fully penetrant neurodegenerative diseases. Our aim was to study the preclinical stage of the most common SCAs: SCA1, SCA2, SCA3, and SCA6.Methods Between Sept 13,2008, and Dec 1,2011, offspring or siblings of patients with SCA1, SCA2, SCA3, or SCA6 were enrolled into a prospective, longitudinal observational study at 14 European centres. To be eligible for indusion in our study, individuals had to have no ataxia and be aged 18-50 years if directly related to individuals with SCA1, SCA2, or SCA3, or 35-70 years if directly related to individuals with SCA6. We did anonymous genetic testing to identify mutation carriers. We assessed participants with clinical scales, questionnaires, and performance-based coordination tests. In eight of the 14 centres, participants underwent MRI. We analysed relations between outcome variables and time from onset (defined as the difference between present age and estimated age at ataxia onset). This study is registered with ClinicalTrials.gov, number NCT01037777.Findings 276 participants met inclusion criteria and agreed to participate, of whom 12 (4%) were excluded from final analysis because DNA samples were missing or genotyping failed. Estimated time from onset was -9 years (IQR -13 to -6) in 50 carriers of the SCA1 mutation, -12 years (-15 to -9) in 31 SCA2 mutation carriers, -8 years (-11 to -6) in 26 SCA3 mutation carriers, and -18 years (-22 to -16) in 16 SCA6 mutation carriers. Compared with non-carriers of each mutation, SCA1 mutation carriers had higher median scores on the scale for the assessment and rating of ataxia (SARA; 0-5 [IQR 0-1-01 vs 0 [0-0]; p=0.0052), as did SCA2 mutation carriers (0.5 [0-2.0] vs 0 [0-0.5]; p=0.0037). S CA2 mutation carriers had lower SCA functional index scores than did non-carriers (-0.43 [-0.91 to -0.07] vs 0.09 [-0.30 to 0-56]; p=0.0007). SCA2 mutation carriers had worse composite cerebellar functional scores than did their non-carrier counterparts (0.915 [0.861-0.959] vs 0-849 [0-764-0-886]; p=0-0039). All other differences between carriers and non-carriers were non-significant. In SCA1 and SCA2 mutation carriers, SARA scores were increased in participants who were closer to the estimated age at onset (SCA1: r=0.36, p=0-0112; SCA2: r=0.50, p=0.0038). 83 individuals (30%) underwent MRI. Voxel-based morphometry showed grey-matter loss in the brainstem and cerebellum in SCA1 and SCA2 mutation carriers, and normalised brainstem volume was lower in SCA2 mutation carriers (median 0.015, range 0.012-0.016) than in non-carriers (0.019, 0.017-0.021; p=0-0107).Interpretation Preclinical SCA1 and SCA2 mutation carriers seem to have mild coordination deficits and abnormalities in the brain that are more common in carriers who are doser to the estimated onset of ataxia. Individuals in this early disease stage could be targeted in future preventive trials.

To assess the clinical spectrum of ataxia and cerebellar oculomotor deficits in the most common spinocerebellar ataxias (SCAs), we analysed the baseline data of the EUROSCA natural history study, a multicentric cohort study of 526 patients with either spinocerebellar ataxia type 1, 2, 3 or 6. To quantify ataxia symptoms, we used the Scale for the Assessment and Rating of Ataxia (SARA). The presence of cerebellar oculomotor signs was assessed using the Inventory of Non-Ataxia Symptoms (INAS). In a subgroup of patients, in which magnetic resonance images (MRIs) were available, we correlated MRI morphometric measures with clinical signs on an exploratory basis. The SARA subscores posture and gait (items 1–3), speech (item 4) and the limb kinetic subscore (items 5–8) did not differ between the genotypes. The scores of SARA item 3 (sitting), 5 (finger chase) and 6 (nose–finger test) differed between the subtypes whereas the scores of the remaining items were not different. In SCA1, ataxia symptoms were correlated with brainstem atrophy and in SCA3 with both brainstem and cerebellar atrophy. Cerebellar oculomotor deficits were most frequent in SCA6 followed by SCA3, whereas these abnormalities were less frequent in SCA1 and SCA2. Our data suggest that vestibulocerebellar, spinocerebellar and pontocerebellar circuits in SCA1, SCA2, SCA3 and SCA6 are functionally impaired to almost the same degree, but at different anatomical levels. The seemingly low prevalence of cerebellar oculomotor deficits in SCA1 and SCA2 is most probably related to the defective saccadic system in these disorders.

As stroke is the third leading cause of death after heart failure and tumors worldwide, cerebrovascular diseases reached substantial attention. In the past few years, significant progression has been seen in identification of genetic variants in the background of stroke and other cerebrovascular and cardiovascular events. Examination of these variants is a new approach to recognize pathogenesis of disorders that hopefully helps in future prevention and prospects of screening and, optimistically, it contributes to special care of patients susceptible for stroke. In the background of ischemic stroke several genetic variants have been identified, which localize in genes encoding proteins involved in hemostasis, renin-angiotensin system and lipid metabolism. The number of these variants exponentially increases permanently due to rapid spreading of genome wide association studies. The goal of this review is to summarize the results of genetic studies on ischemic stroke. Here the authors focus on genetic variants which can have major role in personalized medicine and prevention of stroke.

Spinocerebellar ataxia type 2 (SCA2) is a progressive autosomal dominantly inherited cerebellar ataxia and is assigned to the CAG repeat or polyglutamine diseases. Recent morphological studies characterized the pathoanatomical features in heterozygous SCA2 patients and revealed severe neuronal loss in a large variety of cerebellar and extra-cerebellar brain sites. In the present study, we examined the brain pathoanatomy of a monozygous twin of a large Hungarian SCA2 family with pathologically extended CAG repeats in both SCA2 alleles. This unique patient was in the initial clinical stage of SCA2 and died almost 3 years after SCA2 onset. Upon pathoanatomical investigation, we observed loss of giant Betz pyramidal cells in the primary motor cortex, degeneration of sensory thalamic nuclei, the Purkinje cell layer, and deep cerebellar nuclei, as well as select brainstem nuclei (i.e., substantia nigra, oculomotor nucleus, reticulotegmental nucleus of the pons, facial, lateral vestibular, and raphe interpositus nuclei, inferior olive). All of these degenerated brain gray matter structures are known as consistent targets of the underlying pathological process in heterozygous SCA2 patients. Since they were already involved in our patient within 3 years after disease onset, we think that we were for the first time able to identify the early brain targets of the pathological process of SCA2.