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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. 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. 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. 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. EU FP6 (EUROSCA), German Ministry of Education and Research (BMBF; GeneMove), Polish Ministry of Science, EU FP7 (NEUROMICS).

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. 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 inclusion 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. 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 0–1·0] 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). SCA2 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). 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 closer to the estimated onset of ataxia. Individuals in this early disease stage could be targeted in future preventive trials. ERA-Net E-Rare and Polish Ministry of Science and Higher Education.

Antisense oligonucleotides (ASOs) are single-stranded nucleic acid strings that can be used to selectively modify protein synthesis by binding complementary (pre-)mRNA sequences. By specific arrangements of DNA and RNA into a chain of nucleic acids and additional modifications of the backbone, sugar, and base, the specificity and functionality of the designed ASOs can be adjusted. Thereby cellular uptake, toxicity, and nuclease resistance, as well as binding affinity and specificity to its target (pre-)mRNA, can be modified. Several neurodegenerative diseases are caused by autosomal dominant toxic gain-of-function mutations, which lead to toxic protein products driving disease progression. ASOs targeting such mutations—or even more comprehensively, associated variants, such as single nucleotide polymorphisms (SNPs)—promise a selective degradation of the mutant (pre-)mRNA while sparing the wild type allele. By this approach, protein expression from the wild type strand is preserved, and side effects from an unselective knockdown of both alleles can be prevented. This makes allele-specific targeting strategies a focus for future personalized therapies. Here, we provide an overview of current strategies to develop personalized, allele-specific ASO therapies for the treatment of neurodegenerative diseases, such Huntington’s disease (HD) and spinocerebellar ataxia type 3 (SCA3/MJD).

The European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS) is a prospective international registry investigating the natural history of Friedreich’s 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. We enrolled patients with genetically confirmed Friedreich’s 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. Between Sept 15, 2010, and Nov 21, 2013, we enrolled 605 patients with Friedreich’s 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. 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 Friedreich’s ataxia. European Commission.

Blood biomarkers in degenerative ataxias are still largely missing. Here, we aimed to provide piloting proof-of-concept that serum Neurofilament light (NfL) could offer a promising peripheral blood biomarker in degenerative ataxias. Specifically, as a marker of neuronal damage, NfL might (1) help to differentiate multiple system atrophy of cerebellar type (MSA-C) from sporadic adult-onset ataxia (SAOA), and (2) show increases in repeat-expansion spinocerebellar ataxias (SCAs) which might be amenable to treatment in the future. To explore these two hypotheses, we measured serum NfL levels by single-molecule array (Simoa) technique in 115 subjects, comprising patients with MSA-C (n = 25), SAOA (n = 25), the most frequent repeat-expansion SCAs (SCA 1, 2, 3 and 6) (n = 20), and age-matched controls (n = 45). Compared to controls, NfL was significantly increased in MSA-C, with levels significantly higher than in SAOA (AUC = 0.74 (0.59–0.89), mean and 95% confidence interval, p = .004). NfL was also significantly increased in SCA patients as compared to controls (AUC = 0.91 (0.81–1.00), p < .001), including NfL increases in SCA1 and SCA3. These findings provide first proof-of-concept that NfL might provide a promising peripheral biomarker in degenerative ataxias, e.g. supporting the differentiation of MSA-C from SAOA, and indicating neuronal damage in repeat-expansion SCAs.

Friedreich's 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 Friedreich's ataxia database registry. Within the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) framework, we assessed a cohort of patients with genetically confirmed Friedreich's 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 Friedreich's Ataxia Rating Scale and EQ-5D. The Friedreich's 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. We enrolled 592 patients with genetically confirmed Friedreich's 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]). 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 Friedreich's ataxia, for which SARA might be the most suitable measure to monitor disease progression. European Commission.

Johannes Lemke, Holger Lerche and colleagues report the identification of de novo mutations in the potassium channel gene KCNA2 in patients with epileptic encephalopathies. The authors confirm in vitro that two mutations cause dominant loss of channel function, whereas the other two mutations induce gain-of-function effects, leading to permanently open channels. Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features 1 , 2 , 3 , 4 , 5 , 6 . Using next-generation sequencing, we identified four different de novo mutations in KCNA2 , encoding the potassium channel K V 1.2, in six isolated patients with epileptic encephalopathy (one mutation recurred three times independently). Four individuals presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild to moderate intellectual disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype showed almost complete loss of function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype. They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a new gene involved in human neurodevelopmental disorders through two different mechanisms, predicting either hyperexcitability or electrical silencing of K V 1.2-expressing neurons.

The m.8344A>G mutation in the MTTK gene, which encodes the mitochondrial transfer RNA for lysine, is traditionally associated with myoclonic epilepsy and ragged-red fibres (MERRF), a multisystemic mitochondrial disease that is characterised by myoclonus, seizures, cerebellar ataxia, and mitochondrial myopathy with ragged-red fibres. We studied the clinical and paraclinical phenotype of 34 patients with the m.8344A>G mutation, mainly derived from the nationwide mitoREGISTER, the multicentric registry of the German network for mitochondrial disorders (mitoNET). Mean age at symptom onset was 24.5 years ±10.9 (6–48 years) with adult onset in 75 % of the patients. In our cohort, the canonical features seizures, myoclonus, cerebellar ataxia and ragged-red fibres that are traditionally associated with MERRF, occurred in only 61, 59, 70, and 63 % of the patients, respectively. In contrast, other features such as hearing impairment were even more frequently present (72 %). Other common features in our cohort were migraine (52 %), psychiatric disorders (54 %), respiratory dysfunction (45 %), gastrointestinal symptoms (38 %), dysarthria (36 %), and dysphagia (35 %). Brain MRI revealed cerebral and/or cerebellar atrophy in 43 % of our patients. There was no correlation between the heteroplasmy level in blood and age at onset or clinical phenotype. Our findings further broaden the clinical spectrum of the m.8344A>G mutation, document the large clinical variability between carriers of the same mutation, even within families and indicate an overlap of the phenotype with other mitochondrial DNA-associated syndromes.

Cholestenoic acids are formed as intermediates in metabolism of cholesterol to bile acids, and the biosynthetic enzymes that generate cholestenoic acids are expressed in the mammalian CNS. Here, we evaluated the cholestenoic acid profile of mammalian cerebrospinal fluid (CSF) and determined that specific cholestenoic acids activate the liver X receptors (LXRs), enhance islet-1 expression in zebrafish, and increase the number of oculomotor neurons in the developing mouse in vitro and in vivo. While 3β,7α-dihydroxycholest-5-en-26-oic acid (3β,7α-diHCA) promoted motor neuron survival in an LXR-dependent manner, 3β-hydroxy-7-oxocholest-5-en-26-oic acid (3βH,7O-CA) promoted maturation of precursors into islet-1+ cells. Unlike 3β,7α-diHCA and 3βH,7O-CA, 3β-hydroxycholest-5-en-26-oic acid (3β-HCA) caused motor neuron cell loss in mice. Mutations in CYP7B1 or CYP27A1, which encode enzymes involved in cholestenoic acid metabolism, result in different neurological diseases, hereditary spastic paresis type 5 (SPG5) and cerebrotendinous xanthomatosis (CTX), respectively. SPG5 is characterized by spastic paresis, and similar symptoms may occur in CTX. Analysis of CSF and plasma from patients with SPG5 revealed an excess of the toxic LXR ligand, 3β-HCA, while patients with CTX and SPG5 exhibited low levels of the survival-promoting LXR ligand 3β,7α-diHCA. Moreover, 3β,7α-diHCA prevented the loss of motor neurons induced by 3β-HCA in the developing mouse midbrain in vivo.Our results indicate that specific cholestenoic acids selectively work on motor neurons, via LXR, to regulate the balance between survival and death.

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 multicentric SCA3 cohorts and in a SCA3 knock‐in mouse model. Ataxic SCA3 subjects showed increased levels of both NfL and pNfH. 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 and pNfH increases in human SCA3 were each paralleled by similar changes in SCA3 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 preataxic SCA3, associated with earliest neuropathological changes, and serve as progression, proximity‐to‐onset and, potentially, treatment‐response markers in both human and preclinical SCA3 trials. Synopsis This cross‐species study establishes neurofilament blood levels (NfL/pNfH) as biomarkers of neuronal damage in spinocerebellar ataxia type 3 (SCA3) in humans and mice, both at the manifest and premanifest disease stage. NfL levels capture proximity to symptom onset and disease progression. Blood levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) were assessed in manifest and premanifest subjects of two multicentric SCA3 cohorts and in SCA3 knock‐in mice. NfL and pNfH levels were increased at the manifest disease stage, with NfL levels reflecting both clinical disease severity and disease progression. NfL elevations in the premanifest stage were present already 7.5 years before the individual expected onset, with levels increasing further in temporal proximity to symptom onset. NfL and pNfH increases in the SCA3 mouse model started also already at the premanifest stage, closely following ataxin‐3 aggregation and even preceding Purkinje cell loss in the brain. Graphical Abstract This cross‐species study establishes neurofilament blood levels (NfL/pNfH) as biomarkers of neuronal damage in spinocerebellar ataxia type 3 (SCA3) in humans and mice, both at the manifest and premanifest disease stage. NfL levels capture proximity to symptom onset and disease progression.