title: Factors influencing disease progression in autosomal dominant cerebellar ataxia and spastic paraplegia.
abstract: OBJECTIVE
  To evaluate disease progression and determine validity of clinical tools for therapeutic trials.
  
  
  METHODS
  Prospective cohort study (36 months).
  
  
  METHODS
  Referral center.
  
  
  METHODS
  One hundred sixty-two patients with autosomal dominant cerebellar ataxia and 64 with hereditary spastic paraplegia.
  
  
  METHODS
  The quantitative Composite Cerebellar Functional Severity Score with the writing test (CCFSw) and Scale for the Assessment and Rating of Ataxia (SARA) score.
  
  
  RESULTS
  Disease worsened in patients with SCA1, SCA2, and SCA3 mutations (mean [SE] increase in CCFSw, +0.014 [0.005] to +0.025 [0.004] per year), improved in patients with SPG4 mutations (mean [SE] increase in CCFSw, -0.012 [0.003] per year; P = .02), and remained stable in patients with SCA6, SCA7, or other SCA mutations (mean [SE] increase in CCFSw, -0.015 [0.011] to +0.009 [0.013] per year) or hereditary spastic paraplegia with other SPG mutations (mean [SE] increase in CCFSw, -0.005 [0.005] per year). Progression was faster in patients with SCA2 mutations and normal alleles with 22 or fewer repeats (P = .02) and in patients with SCA3 mutations with parkinsonism and/or dystonia at baseline (P = .003). Whereas CCFSw distinguished between patients with ataxia and spasticity, SARA scores increased in both groups. A 2-arm trial with SARA score as the outcome measure would require 57 patients with SCA2 mutations, 70 with SCA1 mutations, and 75 with SCA3 mutations per group to detect a 50% reduction in disease progression (power, 80%; α = .05).
  
  
  CONCLUSIONS
  Disease progressed faster in SCA s with polyglutamine expansions in SCA1, 2, and 3 than the other groups. Both outcome measures are suitable for therapeutic trials; SARA requires fewer patients to attain the same power, but CCFSw needs less stratification. We demonstrate that the choice of clinical outcome measure is critical for reliable evaluation of progression in neurodegenerative diseases.
authors.affiliation: Department of Biostatistics and Medical Informatics, and Pitié-Salpêtrière Charles-Foix Clinical Research Unit, Hôpital Pitié-Salpêtrière, 47 boulevard de l'Hôpital, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Tezenas du Montcel
authors.forename: Perrine
authors.initials: P
authors.lastname: Charles
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.forename: Cecilia
authors.initials: C
authors.lastname: Marelli
authors.forename: Pascale
authors.initials: P
authors.lastname: Ribai
authors.forename: Carlo
authors.initials: C
authors.lastname: Vincitorio
authors.forename: Mathieu
authors.initials: M
authors.lastname: Anheim
authors.forename: Lucie
authors.initials: L
authors.lastname: Guyant-Maréchal
authors.forename: Alice
authors.initials: A
authors.lastname: Le Bayon
authors.forename: Nadia
authors.initials: N
authors.lastname: Vandenberghe
authors.forename: Maya
authors.initials: M
authors.lastname: Tchikviladzé
authors.forename: David
authors.initials: D
authors.lastname: Devos
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Ber
authors.forename: Karine
authors.initials: K
authors.lastname: N'Guyen
authors.forename: Cécile
authors.initials: C
authors.lastname: Cazeneuve
authors.forename: Chantal
authors.initials: C
authors.lastname: Tallaksen
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
mesh_terms: D000328:Adult; D000368:Aged; D000067696:Ataxin-1; D000067699:Ataxin-3; D000067528:Ataxins; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000503:physiopathology; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D010264:Paraplegia / Q000235:genetics* / Q000503:physiopathology; D010455:Peptides / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D012189:Retrospective Studies; D012720:Severity of Illness Index; D014956:Writing; D055815:Young Adult
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3