Resumen: Introducción: La ARCA1/SCAR8 es una heredoataxia recesiva causada por mutaciones en el gen SYNE1, que fue descrita inicialmente en familias francocanadienses (Quebec) con un síndrome cerebeloso puro. En la actualidad se reporta cada vez más este tipo de ataxia en otras partes del mundo y con un fenotipo muy variable. Recientemente se han notificado casos de distrofia muscular, artrogriposis y miocardiopatía por mutaciones de este gen. Objetivos: Describir los hallazgos clínicos y moleculares en 3 familias españolas de diferente origen geográfico, las primeras en las que se confirmó el diagnóstico de ARCA1/SCAR8 con análisis molecular. Material y métodos: Evaluación clínica, pruebas paraclínicas y estudio genético en 4 pacientes (3 varones y una mujer), diagnosticados en distintos servicios de neurología españoles. Resultados: Los síntomas cerebelosos comenzaron en todos los casos en la tercera-cuarta décadas. Tras 15 años de evolución, 3 pacientes presentaban un síndrome cerebeloso puro similar a la descripción original, mientras que un paciente con más de 30 años de evolución presentaba también parálisis de mirada vertical, afectación piramidal y moderado deterioro cognitivo. El estudio de resonancia magnética mostró en todos los casos atrofia restringida al cerebelo. La secuenciación de SYNE1 permitió identificar distintas variantes patogénicas en cada familia. Conclusiones: La ARCA1/SCAR8 tiene una distribución mundial con una gran diversidad de mutaciones en SYNE1. Además de ataxia puede dar lugar a un complejo fenotipo de inicio y gravedad muy variable. Abstract: Introduction: Autosomal recessive spinocerebellar ataxia type 8 (ARCA1/SCAR8) is caused by mutations of the SYNE1 gene. The disease was initially described in families from Quebec (Canada) with a phenotype of pure cerebellar syndrome, but in recent years has been reported with a more variable clinical phenotype in other countries. Cases have recently been described of muscular dystrophy, arthrogryposis, and cardiomyopathy due to SYNE1 mutations. Objective: To describe clinical and molecular findings from 4 patients (3 men and one woman) diagnosed with ARCA1/SCAR8 from 3 Spanish families from different regions. Material and methods: We describe the clinical, paraclinical, and genetic results from 4 patients diagnosed with ARCA1/SCAR8 at different Spanish neurology departments. Results: Onset occurred in the third or fourth decade of live in all patients. After 15 years of progression, 3 patients presented pure cerebellar syndrome, similar to the Canadian patients; the fourth patient, with over 30 years’ progression, presented vertical gaze palsy, pyramidal signs, and moderate cognitive impairment. In all patients, MRI studies showed cerebellar atrophy. The genetic study revealed distinct pathogenic SYNE1 mutations in each family. Conclusions: ARCA1/SCAR8 can be found worldwide and may be caused by many distinct mutations in the SYNE1 gene. The disease may manifest with a complex phenotype of varying severity.

Introduction: Autosomal recessive spinocerebellar ataxia type 8 (ARCA1/SCAR8) is caused by mutations of the SYNE1 gene. The disease was initially described in families from Quebec (Canada) with a phenotype of pure cerebellar syndrome, but in recent years has been reported with a more variable clinical phenotype in other countries. Cases have recently been described of muscular dystrophy, arthrogryposis, and cardiomyopathy due to SYNE1 mutations. Objective: To describe clinical and molecular findings from 4 patients (3 men and one woman) diagnosed with ARCA1/SCAR8 from 3 Spanish families from different regions. Material and methods: We describe the clinical, paraclinical, and genetic results from 4 patients diagnosed with ARCA1/SCAR8 at different Spanish neurology departments. Results: Onset occurred in the third or fourth decade of live in all patients. After 15 years of progression, 3 patients presented pure cerebellar syndrome, similar to the Canadian patients; the fourth patient, with over 30 years' progression, presented vertical gaze palsy, pyrami-dal signs, and moderate cognitive impairment. In all patients, MRI studies showed cerebellar atrophy. The genetic study revealed distinct pathogenic SYNE1 mutations in each family. Conclusions: ARCA1/SCAR8 can be found worldwide and may be caused by many distinct muta-tions in the SYNE1 gene. The disease may manifest with a complex phenotype of varying severity. (c) 2019 Sociedad Espanola de Neurologia. Published by Elsevier Espana, S.L.U. All rights reserved.

Background In rare disorders diagnosis may be delayed due to limited awareness and unspecific presenting symptoms. Herein, we address the issue of diagnostic delay in Friedreich’s Ataxia (FRDA), a genetic disorder usually caused by homozygous GAA-repeat expansions. Methods Six hundred eleven genetically confirmed FRDA patients were recruited within a multicentric natural history study conducted by the EFACTS (European FRDA Consortium for Translational Studies, ClinicalTrials.gov -Identifier NCT02069509). Age at first symptoms as well as age at first suspicion of FRDA by a physician were collected retrospectively at the baseline visit. Results In 554 of cases (90.7%), disease presented with gait or coordination disturbances. In the others ( n = 57, 9.3%), non-neurological features such as scoliosis or cardiomyopathy predated ataxia. Before the discovery of the causal mutation in 1996, median time to diagnosis was 4(IQR = 2–9) years and it improved significantly after the introduction of genetic testing (2(IQR = 1–5) years, p < 0.001). Still, after 1996, time to diagnosis was longer in patients with a) non-neurological presentation (mean 6.7, 95%CI [5.5,7.9] vs 4.5, [4.2,5] years in those with neurological presentation, p = 0.001) as well as in b) patients with late-onset (3(IQR = 1–7) vs 2(IQR = 1–5) years compared to typical onset < 25 years of age, p = 0.03). Age at onset significantly correlated with the length of the shorter GAA repeat (GAA1) in case of neurological onset (r = − 0,6; p < 0,0001), but not in patients with non-neurological presentation (r = − 0,1; p = 0,4). Across 54 siblings’ pairs, differences in age at onset did not correlate with differences in GAA-repeat length (r = − 0,14, p = 0,3). Conclusions In the genetic era, presentation with non-neurological features or in the adulthood still leads to a significant diagnostic delay in FRDA. Well-known correlations between GAA1 repeat length and disease milestones are not valid in case of atypical presentations or positive family history.

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.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.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.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.

Dominant optic atrophy (DOA) type 1 is an autosomal dominant disorder caused by mutations in the OPA1 gene, involved in mitochondrial integrity, resulting in damage to cells with high energy demands, like retinal ganglion cells.1, 2 Patients are diagnosed during their childhood suffering a progressive, symmetrical and irreversible loss of vision, usually moderate, caecocentral scotoma, and specific dyschromatopsia in the blue-yellow axis with optic discs atrophy, typically of its temporal side. However, there is an important phenotypic variability: development of symptoms at advanced ages, variable severity (from subclinical presentations to blind patients), asymmetric affectation, rapidly progressive deterioration, or even spontaneous recovery.3 Up to 20% of patients with heterozygous OPA1 mutations have extra-ophthalmologic abnormalities (DOA plus phenotypes) including neurosensory hearing loss, cerebellar ataxia, peripheral neuropathy, myopathy, spastic paraplegia, multiple sclerosis-like illnesses, and progressive external ophthalmoplegia.3 There are more than 200 OPA1 mutations reported, with many sporadic cases, but no clear genotype–phenotype correlation has been established. There is only one patient with an OPA1 mutation plus dystonia reported.4 She was a 42-year-old woman presented with progressive vision loss, polyneuropathy, hearing impairment, and cervical dystonia, and was a carrier of the heterozygous OPA1 mutation c.1345A > C (p.Thr449Pro). Here we present a Spanish patient with DOA and cervical dystonia carrying a novel OPA1 mutation. She noticed slowly and symmetric progressing loss of vision and color vision defect at the age of 40 years, and she was diagnosed with optic atrophy eight years later. She also developed at the age of 49 years a "no-no" head tremor preceding neck pain and stiffness, with involuntary spasms leading to an abnormal head posture, managed with botulinum toxin. An ophthalmological assessment showed paracentral scotomas on visual field examination and difficulty distinguishing blue and green colors. Fundus examination revealed bilateral optic nerve pallor more evident in the temporal side. Her visual acuity was 0,5 in both eyes. Neurological examination showed an increased tone of her left sternocleidomastoid muscle with a dystonic posture compatible with right torticollis. Cranial nerves, strength, and sensory function were intact. No cerebellar ataxia was noted. Deep tendon reflexes were within normal range, and plantar response was flexor bilaterally. No rigid-bradykinetic parkinsonism was noted, and she had a normal gait. The patient denied hearing impairment. Routine laboratory tests including serum copper, ceruloplasmin, and ferritin were normal. Visual evoked potentials were delayed. Brain MRI revealed bilateral optic nerve atrophy without contrast enhancement (Fig. 1), and OCT showed a decrease in the retinal nerve fiber layer in temporal sectors. Genetic screening was performed of the most frequent mitochondrial mutations in LHON (ND1: 3460G > A, ND4: 11778G > A, ND6: 14484 T > C) and the m.14459G > A mutation in ND6, associated with optic neuropathy plus dystonia,5 which was negative. Next-generation sequencing (Illumina) multi-gene panel analysis, including 170 genes related to nuclear DNA mutations with mitochondrial disturbance and dystonia, demonstrated heterozygosity for the base pair substitution in exon 22 (c.2060 T > A), causing the amino acid change (p.Val687Glu) in OPA1. The variant identified in the patient was a missense mutation that has not been previously reported in the literature or the databases consulted. Bioinformatic predictors (SIFT, PolyPhen2, MutationTaster, MutationAssessor, LRT, FATHMM, MetaSVM, CONDEL (ALAMMUT and ANNOVAR) suggested a deleterious effect. The panel also included OPA3, associated with Costeff optic atrophy syndrome and autosomal optic atrophy and cataract (ADOAC), TIMM8A associated with deafness-dystonia-optic neuronopathy syndrome (DDON) and other genes associated with optic atrophy such as WFS1, MFN2, or ATP1A3. The diagnosis of OPA1 was made based on a combination of clinical findings, electrophysiologic studies, and molecular genetic testing. The mother of the patient died a decade ago (80 years, without visual impairment). The 92-year-old father was diagnosed with ischemic optic neuropathy. He lives in another geographical region, so it is impossible to carry out a family segregation study, but we strongly suspect that he also carries the OPA1 mutation. The patient has a 30-year-old daughter carrier of the mutation, asymptomatic until the moment, but in annual follow-up. No other family members had similar symptoms. In summary, with this manuscript we describe a novel mutation of the OPA1 gene associated with DOA and cervical dystonia, expanding the genotype and phenotype in OPA1-related disorders. Differences in the effects of OPA1 mutations and external factors (environment, secondary nuclear genes) could be implied in the clinical phenotype.6 Neurodegenerative diseases with mitochondrial dysfunction as a final common pathway are associated with a great diversity in clinical manifestations, with complex phenotypes, and OPA1 is just one example. There are other conditions recently associated with dystonia and optic atrophy, such as spastic paraplegia type 77 or neurodegeneration with brain iron accumulation,8 possibly because of deleterious interactions of this gene variants and OPA1. 1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique. G.O-S: 1A, 1B, 1C, 3A. M.F-M.: 1A, 1B, 1C. E.L-V.: 3B. J.A.: 3B. Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that patient consent was not required for this work. Funding Sources and Conflicts of Interest: The authors declare that there are no conflicts of interest. Financial Disclosures for the previous 12 months: The authors have no conflict of interests to report in relation to the present manuscript.

BACKGROUND:Sensitive outcome measures for clinical trials on cerebellar ataxias are lacking. Most cerebellar ataxias progress very slowly and quantitative measurements are required to evaluate cerebellar dysfunction.METHODS:We evaluated two scales for rating cerebellar ataxias: the Composite Cerebellar Functional Severity (CCFS) Scale and Scale for the Assessment and Rating of Ataxia (SARA), in patients with spinocerebellar ataxia (SCA) and controls. We evaluated these scales for different diseases and investigated the factors governing the scores obtained. All patients were recruited prospectively.RESULTS:There were 383 patients with Friedreich's ataxia (FRDA), 205 patients with SCA and 168 controls. In FRDA, 31% of the variance of cerebellar signs with the CCFS and 41% of that with SARA were explained by disease duration, age at onset and the shorter abnormal repeat in the FXN gene. Increases in CCFS and SARA scores per year were lower for FRDA than for SCA (CCFS index: 0.123±0.123 per year vs 0.163±0.179, P<0.001; SARA index: 1.5±1.2 vs 1.7±1.7, P<0.001), indicating slower cerebellar dysfunction indexes for FRDA than for SCA. Patients with SCA2 had higher CCFS scores than patients with SCA1 and SCA3, but similar SARA scores.CONCLUSIONS:Cerebellar dysfunction, as measured with the CCFS and SARA scales, was more severe in FRDA than in patients with SCA, but with lower progression indexes, within the limits of these types of indexes. Ceiling effects may occur at late stages, for both scales. The CCFS scale is rater-independent and could be used in a multicentre context, as it is simple, rapid and fully automated.TRIAL REGISTRATION NUMBER:ClinicalTrials.gov: NCT02069509.

INTRODUCTION:Variant detection protocols for clinical next-generation sequencing (NGS) need application-specific optimization. Our aim was to analyze the performance of single nucleotide variant (SNV) and copy number (CNV) detection programs on an NGS panel for a rare disease.METHODS:Thirty genes were sequenced in 83 patients with hereditary spastic paraplegia. The variant calls obtained with LifeScope, GATK UnifiedGenotyper and GATK HaplotypeCaller were compared with Sanger sequencing. The calling efficiency was evaluated for 187 (56 unique) SNVs and indels. Five multiexon deletions detected by multiple ligation probe assay were assessed from the NGS panel data with ExomeDepth, panelcn.MOPS and CNVPanelizer software.RESULTS:There were 48/51 (94%) SNVs and 1/5 (20%) indels consistently detected by all the calling algorithms. Two SNVs were not detected by any of the callers because of a rare reference allele, and one SNV in a low coverage region was only detected by two algorithms. Regarding CNVs, ExomeDepth detected 5/5 multi-exon deletions, panelcn.MOPs 4/5 and only 3/5 deletions were accurately detected by CNVPanelizer.CONCLUSIONS:The calling efficiency of NGS algorithms for SNVs is influenced by variant type and coverage. NGS protocols need to account for the presence of rare variants in the reference sequence as well as for ambiguities in indel calling. CNV detection algorithms can be used to identify large deletions from NGS panel data for diagnostic applications; however, sensitivity depends on coverage, selection of the reference set and deletion size. We recommend the incorporation of several variant callers in the NGS pipeline to maximize variant detection efficiency.

Background Spinocerebellar 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. Methods Seventeen patients with SCA3 underwent systematic anamnesis, neurological and SARA assessment, visual evaluation of 123 I-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. Results The 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. Conclusions Pattern recognition approaches are useful tools to describe clinical phenotypes of ataxias and to identify particular configurations of cerebellar signs.

Objective: Endothelial dysfunction is associated with arterial stiffness, a factor that is increasingly recognised as an important determinant of cardiovascular risk. High-flow organs such as the brain and kidneys are particularly sensitive to excessive pressure and flow pulsatility. High, local blood flow is associated with low microvascular impedance, which facilitates the penetration of excessive pulsatile energy into the microvascular bed leading to tissue damage. Systemic endothelial dysfunction and arterial stiffness have been demonstrated in peripheral vessels in associated vasculitis (AAV). Although, the brain involvement is not infrequent in AAV, it has not been evaluated previously. Our aim is to evaluate the involvement of the brain microvasculature in AAV. Methods: Twenty-three patients with inactive AAV were studied. Brain blood flow was assessed by transcranial Doppler (TCD) and single-photon positron emission tomography (SPECT), structural brain involvement by brain MRI and cognitive scores by Montreal Cognitive Assessment (MoCA) test. Results: Lower mean flow velocity (MFV) was associated to altered SPECT perfusion, higher white matter changes (WMC), lower MoCA scores and younger age (p < 0.05). Middle cerebral artery pulsatility index (MCA-PI) was related to hypertension, diabetes, lower scores on MoCA, increased vasculitis damage index (VDI) and perfusion impairment in SPECT (p < 0.05). These data were reproduced for all intracranial arteries. Up to 88.9% of patients had WMC on MRI. A higher lesion load was associated with age, decreased MoCA and fewer MFV with higher PI. The multivariable linear regression analysis showed that the greater the lesion loads, greater the bifrontal atrophy, MCA-PI and lower MoCA scores. Up to 60.9% of patients presented a decreased MoCA score (p = 0.012). It appeared to be related to VDI (p = 0.04), WMC (p = 0.004) and altered SPECT (p = 0.05). Conclusions: The alterations in brain perfusion SPECT, the presence of white matter lesions on MRI, as well as increased PI and RI with lower MFV of the cerebral vessels in TCD suggest the presence of microangiopathy in asymptomatic AAV that could lead to cognitive impairment.

We aimed to screen for Pompe disease in patients with unclassified limb-girdle muscular dystrophy (LGMD) or asymptomatic hyperCKemia using dried blood spot (DES) assays. Subsequently, we aimed to calculate the diagnostic delay between initial symptom presentation and the diagnosis. A prospective, multicenter, observational study was conducted in 348 patients: 146 with unclassified LGMD and 202 with asymptomatic or paucisymptomatic hyperCKemia. We quantified levels of acid alpha-glucosidase (GAA) from dried blood spots analyzed fiuorometrically. The test was positive in 20 patients, and Pompe disease was confirmed by-genetic testing in 16. Undiagnosed Pompe disease was detected in 7.5% of patients with LGMD and 111 2.5% of patients with persistent, idiopathic elevation of serum creatine kinase. The c.-32-13 T > G mutation was found most commonly. The diagnostic delay was 15 years on average. In conclusion, DBS tests are useful and reliable screening tools for Pompe disease. We recommend the dried blood spot test to be included in the diagnostic work-up of patients with unclassified myopathies with proximal weakness and/or hyperCKemia of unknown cause and, when positive, to define the diagnosis, it will have to be confirmed by biochemical and/or molecular genetic analysis. (C) 2015 Elsevier B.V. All rights reserved.

Pompe disease is frequently underdiagnosed and diagnosed with a big delay, usually measured in years.An early diagnosis is important because enzyme replacement therapy seems to be more effective in less affected patients. PATIENTS AND METHODSTo screen patients suffering from late-onset Pompe disease (LOPD), we performed a dried blood spot (DBS) in 248 patients: 146 patients with unclassifi ed limb-girdle myopathy and 202 wi th asymptomatic hyperCKemia.

IMPORTANCE:Little is known of glutamic acid decarboxylase antibodies (GAD-abs) in the paraneoplastic context. Clinical recognition of such cases will lead to prompt tumor diagnosis and appropriate treatment.OBJECTIVE:To report the clinical and immunological features of patients with paraneoplastic neurological syndromes (PNS) and GAD-abs.DESIGN, SETTING, AND PARTICIPANTS:Retrospective case series study and immunological investigations conducted in February 2014 in a center for autoimmune neurological disorders. Fifteen cases with GAD65-abs evaluated between 1995 and 2013 who fulfilled criteria of definite or possible PNS without concomitant onconeural antibodies were included in this study.MAIN OUTCOMES AND MEASURES:Analysis of the clinical records of 15 patients and review of 19 previously reported cases. Indirect immunofluorescence with rat hippocampal neuronal cultures and cell-based assays with known neuronal cell-surface antigens were used. One hundred six patients with GAD65-abs and no cancer served as control individuals.RESULTS:Eight of the 15 patients with cancer presented as classic paraneoplastic syndromes (5 limbic encephalitis, 1 paraneoplastic encephalomyelitis, 1 paraneoplastic cerebellar degeneration, and 1 opsoclonus-myoclonus syndrome). When compared with the 106 non-PNS cases, those with PNS were older (median age, 60 years vs 48 years; P = .03), more frequently male (60% vs 13%; P < .001), and had more often coexisting neuronal cell-surface antibodies, mainly against γ-aminobutyric acid receptors (53% vs 11%; P < .001). The tumors more frequently involved were lung (n = 6) and thymic neoplasms (n = 4). The risk for an underlying tumor was higher if the presentation was a classic PNS, if it was different from stiff-person syndrome or cerebellar ataxia (odds ratio, 10.5; 95% CI, 3.2-34.5), or if the patient had coexisting neuronal cell-surface antibodies (odds ratio, 6.8; 95% CI, 1.1-40.5). Compared with the current series, the 19 previously reported cases had more frequent stiff-person syndrome (74% vs 13%; P = .001) and better responses to treatment (79% vs 27%; P = .005). Predictors of improvement in the 34 patients (current and previously reported) included presentation with stiff-person syndrome and the presence of a thymic tumor.CONCLUSIONS AND RELEVANCE:Patients with GAD-abs must be screened for an underlying cancer if they have clinical presentations different from those typically associated with this autoimmunity or develop classic PNS. The risk for cancer increases with age, male sex, and the presence of coexisting neuronal cell-surface antibodies.

Background 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.Methods 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.Findings 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]).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 Friedreich's ataxia, for which SARA might be the most suitable measure to monitor disease progression.

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 (cm(2)) 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.