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Standards of NGS Data Sharing and Analysis in Ataxias: Recommendations by the NGS Working Group of the Ataxia Global Initiative.

The Ataxia Global Initiative (AGI) is a worldwide multi-stakeholder research platform to systematically enhance trial-readiness in degenerative ataxias. The next-generation sequencing (NGS) working group of the AGI aims to improve methods, platforms, and international standards for ataxia NGS analysis and data sharing, ultimately allowing to increase the number of genetically ataxia patients amenable for natural history and treatment trials. Despite extensive implementation of NGS for ataxia patients in clinical and research settings, the diagnostic gap remains sizeable, as approximately 50% o…

Responsiveness of the Scale for the Assessment and Rating of Ataxia and Natural History in 884 Recessive and Early Onset Ataxia Patients.

OBJECTIVE: The Scale for the Assessment and Rating of Ataxia (SARA) is the most widely applied clinical outcome assessment (COA) for genetic ataxias, but presents metrological and regulatory challenges. To facilitate trial planning, we characterize its responsiveness (including subitem-level relations to ataxia severity and patient-focused outcomes) across a large number of ataxias, and provide first natural history data for several of them. METHODS: Subitem-level correlation and distribution-based analysis of 1,637 SARA assessments in 884 patients with autosomal recessive/early onset ataxia …

Clinical spectrum of early onset cerebellar ataxia with retained tendon reflexes: an autosomal recessive ataxia not to be missed.

Autosomal recessive cerebellar ataxias are a heterogeneous group of neurological disorders. In 1981, a neurological entity comprised by early onset progressive cerebellar ataxia, dysarthria, pyramidal weakness of the limbs and retained or increased upper limb reflexes and knee jerks was described. This disorder is known as early onset cerebellar ataxia with retained tendon reflexes. In this article, we aimed to call attention for the diagnosis of early onset cerebellar ataxia with retained tendon reflexes as the second most common cause of autosomal recessive cerebellar ataxias, after Friedrei…

Mapping of autosomal dominant cerebellar ataxia without the pathogenic PPP2R2B mutation to the locus for spinocerebellar ataxia 12.

OBJECTIVES: To map the disease locus and to identify a gene mutation in a Japanese family with autosomal dominant cerebellar ataxia. DESIGN: A genome-wide linkage analysis was performed using the Affymetrix genome-wide human single-nucleotide polymorphism array containing 909 622 single-nucleotide polymorphisms. Direct nucleotide sequencing of a candidate gene was performed. SETTING: Hokkaido University Graduate School of Medicine and Tokyo University Graduate School of Medicine. Patients  Four affected and 6 healthy individuals in a family with autosomal dominant cerebellar ataxia. RESULTS…

Dominantly inherited ataxias: lessons learned from Machado-Joseph disease/spinocerebellar ataxia type 3.

To date, nearly 30 distinct genetic forms of dominantly inherited ataxia are known to exist. Of these, Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is perhaps the most common in many regions of the world including the United States. This article discusses MJD/SCA3 as a paradigm example of the dominant ataxias, which are collectively known as the spinocerebellar ataxias. Using MJD/SCA3 as a starting point, the article reviews common clinical and genetic features of the SCAs and highlights new insights into molecular mechanisms, especially of the SCAs caused …

Соглашение между очной и телеоценкой масштабов атаксии у многочисленных склерозных пациентов с атаксией.

Все более важное значение для расширения доступа к медицинским услугам и облегчения последующих мероприятий в связи с пациентами приобретают оценки справочной информации. Цель этого исследования заключалась в сопоставлении личных и телеоценочных оценок Международной кооперативной шкалы по оценке атаксии (ИКАРС) и оценки и оценки атаксии (САРА) у пациентов, страдающих атактическим МУ, и в изучении их пригодности для телеоценки. Случайность определяет, какой метод будет использоваться в первую очередь для оценки участников. В оценках использовались ИКАРС и САРА. Очные оценки проводились в рамках

Совпадение в аннотации оригинала
BackgroundTele-assessments are becoming increasingly important to increase access to healthcare services and facilitate patient follow-up. W … s study was to compare the face-to-face and tele-assessment scores of the International Cooperative Ataxia Rating Scale (ICARS) and Assessment and Rating of Ataxia (SARA) in ataxic MS patients and to examine their suitability for tele-assessment.MethodsThe participants were assessed both online and face-to-face. Randomization determined which method woul …

Content Validity of the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) Instrument in Spinocerebellar Ataxia.

The functional Scale for the Assessment and Rating of Ataxia (f-SARA) assesses Gait, Stance, Sitting, and Speech. It was developed as a potentially clinically meaningful measure of spinocerebellar ataxia (SCA) progression for clinical trial use. Here, we evaluated content validity of the f-SARA. Qualitative interviews were conducted among individuals with SCA1 (n = 1) and SCA3 (n = 6) and healthcare professionals (HCPs) with SCA expertise (USA, n = 5; Europe, n = 3). Interviews evaluated symptoms and signs of SCA and relevance of f-SARA concepts for SCA. HCP cognitive debriefing was conducted.…

The Development of a New Patient-Reported Outcome Measure in Recessive Ataxias: The Person-Reported Ataxia Impact Scale.

Autosomal recessive cerebellar ataxias (ARCAs) are inherited neurological disorders that can affect both the central and peripheral nervous systems. To assess the effects of interventions according to the perception of people affected, patient-reported outcome measures (PROMs) must be available. This paper presents the development process of the Person-Reported Ataxia Impact Scale (PRAIS), a new PROM in recessive ataxias, and the documentation of its content validity, interpretability, and construct validity (structural and discriminant). The development followed the PROMIS framework and the F…

Frequency of GAA-FGF14 Ataxia in a Large Cohort of Brazilian Patients With Unsolved Adult-Onset Cerebellar Ataxia.

OBJECTIVES: Intronic FGF14 GAA repeat expansions have recently been found to be a common cause of hereditary ataxia (GAA-FGF14 ataxia; SCA27B). The global epidemiology and regional prevalence of this newly reported disorder remain to be established. In this study, we investigated the frequency of GAA-FGF14 ataxia in a large cohort of Brazilian patients with unsolved adult-onset ataxia. METHODS: We recruited 93 index patients with genetically unsolved adult-onset ataxia despite extensive genetic investigation and genotyped the FGF14 repeat locus. Patients were recruited across 4 different regi…

Comparison of an expanded ataxia interactome with patient medical records reveals a relationship between macular degeneration and ataxia.

Spinocerebellar ataxias 6 and 7 (SCA6 and SCA7) are neurodegenerative disorders caused by expansion of CAG repeats encoding polyglutamine (polyQ) tracts in CACNA1A, the alpha1A subunit of the P/Q-type calcium channel, and ataxin-7 (ATXN7), a component of a chromatin-remodeling complex, respectively. We hypothesized that finding new protein partners for ATXN7 and CACNA1A would provide insight into the biology of their respective diseases and their relationship to other ataxia-causing proteins. We identified 118 protein interactions for CACNA1A and ATXN7 linking them to other ataxia-causing prot…

The Pattern and Staging of Brain Atrophy in Spinocerebellar Ataxia Type 2 (SCA2): MRI Volumetrics from ENIGMA-Ataxia.

OBJECTIVE: Spinocerebellar ataxia type 2 (SCA2) is a rare, inherited neurodegenerative disease characterised by progressive deterioration in both motor coordination and cognitive function. Atrophy of the cerebellum, brainstem, and spinal cord are core features of SCA2, however the evolution and pattern of whole-brain atrophy in SCA2 remain unclear. We undertook a multi-site, structural magnetic resonance imaging (MRI) study to comprehensively characterize the neurodegeneration profile of SCA2. METHODS: Voxel-based morphometry analyses of 110 participants with SCA2 and 128 controls were undert…

Quantitative Speech Assessment in Ataxia-Consensus Recommendations by the Ataxia Global Initiative Working Group on Digital-Motor Markers.

Dysarthria is a common and debilitating symptom of many neurodegenerative diseases, including those resulting in ataxia. Changes to speech lead to significant reductions in quality of life, impacting the speaker in most daily activities. Recognition of its importance as an objective outcome measure in clinical trials for ataxia is growing. Its viability as an endpoint across the disease spectrum (i.e. pre-symptomatic onwards) means that trials can recruit ambulant individuals and later-stage individuals who are often excluded because of difficulty completing lower limb tasks. Here we discuss t…

Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain.

There are currently no drugs known to rescue the function of Kv1.1 voltage-gated potassium channels carrying loss-of-function sequence variants underlying the inherited movement disorder, Episodic Ataxia 1 (EA1). The Kwakwaka'wakw First Nations of the Pacific Northwest Coast used Fucus gardneri (bladderwrack kelp), Physocarpus capitatus (Pacific ninebark) and Urtica dioica (common nettle) to treat locomotor ataxia. Here, we show that extracts of these plants enhance wild-type Kv1.1 current, especially at subthreshold potentials. Screening of their constituents revealed that gallic acid and tan…

Brain Structure and Degeneration Staging in Friedreich Ataxia: Magnetic Resonance Imaging Volumetrics from the ENIGMA-Ataxia Working Group.

OBJECTIVE: Friedreich ataxia (FRDA) is an inherited neurological disease defined by progressive movement incoordination. We undertook a comprehensive characterization of the spatial profile and progressive evolution of structural brain abnormalities in people with FRDA. METHODS: A coordinated international analysis of regional brain volume using magnetic resonance imaging data charted the whole-brain profile, interindividual variability, and temporal staging of structural brain differences in 248 individuals with FRDA and 262 healthy controls. RESULTS: The brainstem, dentate nucleus region, …

Non-paraneoplastic Autoimmune Cerebellar Ataxia with Sensory Ataxia Associated with the Anti-Ca/ARHGAP26 Antibody: A Case Report.

Primary (non-paraneoplastic) autoimmune cerebellar ataxia is immune-mediated and often responds to immunotherapy. The anti-Ca/ARHGAP26 antibody is a rare cause; reported experience comprises individual cases and small series, in which peripheral polyneuropathy but not central deep-sensory involvement is recognized. We report a man in his 50s with one month of subacute, progressive gait instability who had both cerebellar and deep-sensory ataxia. Proprioception and vibration sense were markedly impaired in the arms. Nerve conduction studies showed a steeply length-dependent axonal neuropathy: s…

Spinocerebellar Ataxia Type 27B can be Suspected Based on Clinical Phenotype: The Massachusetts General Hospital Ataxia Center Experience.

Spinocerebellar Ataxia type 27B (SCA27B) is caused by an intronic GAA repeat expansion in the fibroblast growth factor 14 (FGF14) gene. The core clinical phenotype is a slowly progressive, adult-onset cerebellar ataxia, often with downbeat nystagmus (DBN) and episodic worsening. We tested whether clinical phenotyping could predict this genetic disorder. We screened the Massachusetts General Hospital Ataxia Center registry (n = 3,182) for patients with a) isolated DBN, b) DBN with ataxia, and c) autosomal dominant cerebellar ataxia (ADCA) that had eluded genetic diagnosis. Patient histories, ex…

A precocious cerebellar ataxia and frequent Fever episodes in a 16-month-old infant revealing ataxia-telangiectasia syndrome.

Ataxia-telangiectasia (AT) is the most frequent progressive cerebellar ataxia in infancy and childhood. Immunodeficiency which includes both cellular and humoral arms has variable severity. Since the clinical presentation is extremely variable, a high clinical suspicion will allow an early diagnosis. Serum alpha-fetoprotein is elevated in 80-85% of patients and therefore could be used as a screening tool. Here, we present a case of a 5-year-old female infant who was admitted to our department at the age of 16 months because of gait disorders and febrile episodes that had begun at 5 months afte…

Early onset cerebellar ataxia with retained tendon reflexes. Clinical, electrophysiological and MRI observations in comparison with Friedreich's ataxia.

Fourteen patients with the clinical diagnosis of early onset cerebellar ataxia with retained tendon reflexes (EOCA) were examined and compared with 11 patients with Friedreich's ataxia (FA). The mean age of onset in EOCA was 15.9 +/- 6.0 yrs (FA: 14.0 +/- 5.7 yrs). Annual progression rate and the percentage of patients who were wheelchair-bound was lower in EOCA as compared with FA, although the difference did not reach statistical significance. The latency until becoming wheelchair-bound, however, was significantly longer in EOCA than in FA. The segregation ratio in EOCA was significantly low…