title: Biological and clinical characteristics of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 in the longitudinal RISCA study: analysis of baseline data.
abstract: BACKGROUND
  Spinocerebellar ataxias (SCAs) are autosomal, dominantly inherited, fully penetrant neurodegenerative diseases. Our aim was to study the preclinical stage of the most common SCAs: SCA1, SCA2, SCA3, and SCA6.
  
  
  METHODS
  Between Sept 13, 2008, and Dec 1, 2011, offspring or siblings of patients with SCA1, SCA2, SCA3, or SCA6 were enrolled into a prospective, longitudinal observational study at 14 European centres. To be eligible for inclusion in our study, individuals had to have no ataxia and be aged 18-50 years if directly related to individuals with SCA1, SCA2, or SCA3, or 35-70 years if directly related to individuals with SCA6. We did anonymous genetic testing to identify mutation carriers. We assessed participants with clinical scales, questionnaires, and performance-based coordination tests. In eight of the 14 centres, participants underwent MRI. We analysed relations between outcome variables and time from onset (defined as the difference between present age and estimated age at ataxia onset). This study is registered with ClinicalTrials.gov, number NCT01037777.
  
  
  RESULTS
  276 participants met inclusion criteria and agreed to participate, of whom 12 (4%) were excluded from final analysis because DNA samples were missing or genotyping failed. Estimated time from onset was -9 years (IQR -13 to -6) in 50 carriers of the SCA1 mutation, -12 years (-15 to -9) in 31 SCA2 mutation carriers, -8 years (-11 to -6) in 26 SCA3 mutation carriers, and -18 years (-22 to -16) in 16 SCA6 mutation carriers. Compared with non-carriers of each mutation, SCA1 mutation carriers had higher median scores on the scale for the assessment and rating of ataxia (SARA; 0·5 [IQR 0-1·0] vs 0 [0-0]; p=0·0052), as did SCA2 mutation carriers (0·5 [0-2·0] vs 0 [0-0·5]; p=0·0037). SCA2 mutation carriers had lower SCA functional index scores than did non-carriers (-0·43 [-0·91 to -0·07] vs 0·09 [-0·30 to 0·56]; p=0·0007). SCA2 mutation carriers had worse composite cerebellar functional scores than did their non-carrier counterparts (0·915 [0·861-0·959] vs 0·849 [0·764-0·886]; p=0·0039). All other differences between carriers and non-carriers were non-significant. In SCA1 and SCA2 mutation carriers, SARA scores were increased in participants who were closer to the estimated age at onset (SCA1: r=0·36, p=0·0112; SCA2: r=0·50, p=0·0038). 83 individuals (30%) underwent MRI. Voxel-based morphometry showed grey-matter loss in the brainstem and cerebellum in SCA1 and SCA2 mutation carriers, and normalised brainstem volume was lower in SCA2 mutation carriers (median 0·015, range 0·012-0·016) than in non-carriers (0·019, 0·017-0·021; p=0·0107).
  
  
  CONCLUSIONS
  Preclinical SCA1 and SCA2 mutation carriers seem to have mild coordination deficits and abnormalities in the brain that are more common in carriers who are closer to the estimated onset of ataxia. Individuals in this early disease stage could be targeted in future preventive trials.
  
  
  BACKGROUND
  ERA-Net E-Rare and Polish Ministry of Science and Higher Education.
authors.affiliation: Department of Neurology, University Hospital of Bonn, Bonn, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Jacobi
authors.forename: Kathrin
authors.initials: K
authors.lastname: Reetz
authors.forename: Sophie Tezenas
authors.initials: ST
authors.lastname: du Montcel
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
authors.forename: Caterina
authors.initials: C
authors.lastname: Mariotti
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Nanetti
authors.forename: Maria
authors.initials: M
authors.lastname: Rakowicz
authors.forename: Anna
authors.initials: A
authors.lastname: Sulek
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.forename: Perrine
authors.initials: P
authors.lastname: Charles
authors.forename: Alessandro
authors.initials: A
authors.lastname: Filla
authors.forename: Antonella
authors.initials: A
authors.lastname: Antenora
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.forename: Julia
authors.initials: J
authors.lastname: Schicks
authors.forename: Jon
authors.initials: J
authors.lastname: Infante
authors.forename: Jun-Suk
authors.initials: JS
authors.lastname: Kang
authors.forename: Dagmar
authors.initials: D
authors.lastname: Timmann
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Fabio
authors.forename: Marcella
authors.initials: M
authors.lastname: Masciullo
authors.forename: Laszlo
authors.initials: L
authors.lastname: Baliko
authors.forename: Bela
authors.initials: B
authors.lastname: Melegh
authors.forename: Sylvia
authors.initials: S
authors.lastname: Boesch
authors.forename: Katrin
authors.initials: K
authors.lastname: Bürk
authors.forename: Annkathrin
authors.initials: A
authors.lastname: Peltz
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dufaure-Garé
authors.forename: Thomas
authors.initials: T
authors.lastname: Klockgether
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D001933:Brain Stem / Q000473:pathology; D004247:DNA / Q000097:blood / Q000235:genetics; D018450:Disease Progression; D005060:Europe; D005260:Female; D006304:Health Status; D006579:Heterozygote; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics / Q000502:physiology; D009460:Neurologic Examination; D009483:Neuropsychological Tests; D011446:Prospective Studies; D012148:Restless Legs Syndrome / Q000150:complications; D012306:Risk; D012893:Sleep Wake Disorders / Q000209:etiology; D020754:Spinocerebellar Ataxias / Q000175:diagnosis* / Q000503:physiopathology / Q000523:psychology; D055815:Young Adult
chemical_list: D004247:DNA