Treatable Ataxia: a comprehensive case series study

Autosomal recessive cerebellar ataxias are a group of heterogeneous early-onset progressive disorders that some of them are treatable. We performed 4-year-follow up for 25 patients that considered as treatable ataxia in the literature. According to our study, patients would benefit from early detection of treatable ataxia, close observation, and follow-up.

Identifying Gene Mutations in Autosomal Recessive Cerebellar Ataxias and Extending the Mutational Spectrum in China

Background: Autosomal recessive cerebellar ataxias (ARCA) are heterogeneous, complex, disabling neurodegenerative diseases characterized by autosomal recessive inheritance and cerebellar ataxia. Numerous mutations are described in several populations. However, in China, few data are available concerning ARCA. In this study, we aimed to identify ARCA-associated ataxia by targeted next-generation sequencing or whole-exome sequencing in a Chinese cohort, trying to determine clinical and genetic characteristics of Chinese patients with ARCA.Results: We identified 15 different mutations in 7 unrelated patients, of which 12 were novel, including seven missense mutations, three frameshift mutations, two splicing mutations, two nonsense mutations, and one inframe deletion mutation. The most frequent gene was ATM (3 patients), followed by SACS (2 patients), SYNE1 (2 patients), and SETX (1 patient). Specifically, 1 patient harbored mutations in both ATM and SYNE1. The phenotype was mainly cerebellar ataxia in all these cases. However, peripheral neuropathy, dystonia, oculomotor abnormalities, pyramidal tract dysfunction, cognitive impairment, and epilepsy were also revealed. Patients who harbored different gene mutations showed mutational heterogeneity. Conclusions: Our results indicate that ARCA-associated gene mutations are uncommon with additional clinical features in the Chinese population, and advanced sequencing is required to aid the diagnosis of undetermined cerebellar ataxia in Chinese patients.

The ARCA Registry: A Collaborative Global Platform for Advancing Trial Readiness in Autosomal Recessive Cerebellar Ataxias

Autosomal recessive cerebellar ataxias (ARCAs) form an ultrarare yet expanding group of neurodegenerative multisystemic diseases affecting the cerebellum and other neurological or non-neurological systems. With the advent of targeted therapies for ARCAs, disease registries have become a precious source of real-world quantitative and qualitative data complementing knowledge from preclinical studies and clinical trials. Here, we review the ARCA Registry, a global collaborative multicenter platform (>15 countries, >30 sites) with the overarching goal to advance trial readiness in ARCAs. It presents a good clinical practice (GCP)- and general data protection regulation (GDPR)-compliant professional-reported registry for multicenter web-based capture of cross-center standardized longitudinal data. Modular electronic case report forms (eCRFs) with core, extended, and optional datasets allow data capture tailored to the participating site's variable interests and resources. The eCRFs cover all key data elements required by regulatory authorities [European Medicines Agency (EMA)] and the European Rare Disease (ERD) platform. They capture genotype, phenotype, and progression and include demographic data, biomarkers, comorbidity, medication, magnetic resonance imaging (MRI), and longitudinal clinician- or patient-reported ratings of ataxia severity, non-ataxia features, disease stage, activities of daily living, and (mental) health status. Moreover, they are aligned to major autosomal-dominant spinocerebellar ataxia (SCA) and sporadic ataxia (SPORTAX) registries in the field, thus allowing for joint and comparative analyses not only across ARCAs but also with SCAs and sporadic ataxias. The registry is at the core of a systematic multi-component ARCA database cluster with a linked biobank and an evolving study database for digital outcome measures. Currently, the registry contains more than 800 patients with almost 1,500 visits representing all ages and disease stages; 65% of patients with established genetic diagnoses capture all the main ARCA genes, and 35% with unsolved diagnoses are targets for advanced next-generation sequencing. The ARCA Registry serves as the backbone of many major European and transatlantic consortia, such as PREPARE, PROSPAX, and the Ataxia Global Initiative, with additional data input from SPORTAX. It has thus become the largest global trial-readiness registry in the ARCA field.