Project JPCOFUND/0002/2015

ESMI - European Initiative for Spinocerebellar Ataxia Type 3/Machado-Joseph Disease

The objectives of this project are
• establish the world's largest cohort of preclinical and mildly ataxic SCA3 mutation carriers, pooling and expanding existing SCA3 cohorts,
• develop a model of disease evolution in SCA3 that conceives of the preclinical stage (pre-ataxia) and the ataxia stage as the gradual manifestation of a disease process,
• develop new functional tests based on movement recording that complement clinical scales and can detect and quantify subtle coordination deficits,
• study the effects of lifestyle and gender on the evolution of the disease,
• develop easily extractable MRI markers that indicate brain pathology before the onset of clinically manifest ataxia and reflect disease progression,
• develop new biochemical markers of disease and progression based on RNA profiles and ataxin-3 measurement.

ESMI - European Initiative for Spinocerebellar Ataxia Type 3/Machado-Joseph Disease

Spinocerebellar ataxia type 3 (SCA3) / Machado-Joseph disease (MJD) is the most frequent dominant hereditary ataxia a

worldwide. It is caused by the expansion of CAG repeats, located in the ATXN3 gene, which encode the amino acid glutamine. No

is there currently any treatment for SCA3; advanced understanding of the molecular mechanisms underlying SCA3

potentiates, however, the development of new therapeutic approaches, leading to the fact that currently, in SCA3, there is

entering a phase of intense experimentation activity. For interventional studies to be possible in SCA3, a

availability of large groups of subjects, including asymptomatic carriers of the mutation and patients in the initial phase of the disease,

seems to be mandatory. To this end, the European Initiative for Spinocerebellar Ataxia Type 3/Machado's Disease-

Joseph (ESMI) intends to create an extensive cohort that can be used in clinical trials, which brings together 7 European cohorts and

a cohort from the USA, representing, as a whole, more than 800 individuals. Existing data will be integrated into a database of

common data and standardized and de

controlled quality. An important part of the ESMI will be the development and validation of assessment tools

innovative and disease biomarkers, including a new highly sensitive battery of motor tests, activity measures

sensor-based ambulatory, automated volumetric assessment (MRI), diffusion tensor imaging (DTI) and markers

peripheral blood and CSF, based on transcriptional profile and measurement of ataxin-3. In addition, the impact of lifestyle

on the evolution of the disease will be evaluated, using appropriate questionnaires. By exploring the data obtained in this cohort, it will be

a model of evolution of SCA3 disease was developed, which conceives of the preclinical state (pre-ataxia) and the phase with ataxia as a

progressive manifestation of a disease process, which will take lifestyle factors into account. The investigation to be

developed has an impact not only on the feasibility and design of intervention studies, but also on the health care of

routine, as new instruments (such as automated activity measurement and MRI analysis)

can be used in the diagnosis and routine treatment of patients with ataxia. European and national patient organizations

with ataxia are directly involved in the planning and management of this project.

The objective will be to achieve the highest possible level of compliance and standardization. On the other hand, we will try to ensure continuity where possible to allow for joint analysis of existing and newly acquired data. The core elements of the ESMI clinical assessment program will be the Scale for Assessment. In the statistical analysis, a particular emphasis will be placed on the longitudinal analysis of quantitative data with the ultimate goal of developing a disease evolution model that takes into account both preclinical and clinical subjects and corrects for dropout. In addition to previous studies, data from patients and carriers of preclinical mutations will not be analyzed separately, but on a common time scale, starting with birth.