Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: a longitudinal cohort study.

Abstract

BACKGROUND:

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.

METHODS:

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.

FINDINGS:

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.

INTERPRETATION:

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.

FUNDING:

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

• Authors: Heike Jacobi, Sophie Tezenas du Montcel, Peter Bauer, Paola Giunti, Arron Cook, Robyn Labrum, Michael H Parkinson, Alexandra Durr, Alexis Brice, Perrine Charles, Cecilia Marelli, Caterina Mariotti, Lorenzo Nanetti, Marta Panzeri, Maria Rakowicz, Anna Sulek, Anna Sobanska, Tanja Schmitz-Hübsch, Ludger Schöls, Holger Hengel, Laszlo Baliko, Bela Melegh, Alessandro Filla, Antonella Antenora, Jon Infante, José Berciano, Bart P van de Warrenburg, Dagmar Timmann, Sandra Szymanski, Sylvia Boesch, Jun-Suk Kang, Massimo Pandolfo, Jörg B Schulz, Sonia Molho, Alhassane Diallo, Thomas Klockgether
• Journal: The Lancet. Neurology (Lancet Neurol) Vol. 14 Issue 11 Pg. 1101-8 (Nov 2015) ISSN: 1474-4465 [Electronic] England
• PMID: 26377379 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• ATXN1 protein, human
• ATXN2 protein, human
• Ataxin-1
• Ataxin-2
• CACNA1A protein, human
• Calcium Channels
• Repressor Proteins
• ATXN3 protein, human
• Ataxin-3

Topics

• Adult
• Ataxin-1 (genetics)
• Ataxin-2 (genetics)
• Ataxin-3 (genetics)
• Calcium Channels (genetics)
• Cohort Studies
• Disease Progression
• Female
• Humans
• Male
• Middle Aged
• PubMed (statistics & numerical data)
• Repressor Proteins (genetics)
• Spinocerebellar Ataxias (classification, genetics, physiopathology)
• Young Adult