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Tezenas du Montcel S, Charles P, Goizet C, et al. Factors Influencing Disease Progression in Autosomal Dominant Cerebellar Ataxia and Spastic Paraplegia. Arch Neurol. 2012;69(4):500–508. doi:10.1001/archneurol.2011.2713
Author Affiliations: Department of Biostatistics and Medical Informatics and Pitié-Salpêtrière Charles-Foix Clinical Research Unit (Dr Tezenas du Montcel), Department of Genetics and Cytogenetics, Medical Genetics Unit (Drs Charles, Marelli, Ribai, Vincitorio, Anheim, Tchikviladzé, Brice, and Durr), Department of Neurology (Drs Charles, Tchikviladzé, Le Ber, Tallaksen, and Brice), and Department of Genetics and Cytogenetics, Molecular and Cellular Neurogenetics Unit (Dr Cazeneuve), Pitié-Salpêtrière Hospital, Assistance Publique–Hôpitaux de Paris (AP-HP), UMR-S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (Drs Marelli, Le Ber, Tallaksen, Brice, and Durr) and ER4, Modelling in Clinical Research (Dr Tezenas du Montcel), Université Pierre et Marie Curie–Paris6, Inserm, U975 (Drs Marelli, Le Ber, Tallaksen, Brice, and Durr), Cnrs, UMR 7225 (Drs Marelli, Le Ber, Tallaksen, Brice, and Durr), Paris, Department of Medical Genetics, Pellegrin Hospital, Bordeaux CHU Hospitals, and Laboratory of Human Genetics, University Victor Segalen Bordeaux 2, Bordeaux (Dr Goizet), Service of Neurology, Carémeau Hospital, CHU Nimes, Nimes (Dr Le Bayon), Departments of Neurology and Genetics and Inserm Unit 614, Rouen University Hospital, Rouen (Dr Guyant-Maréchal), Service of Neurology C, Pierre Wertheimer Neurological Hospital, Lyon Hospitals, Lyon (Dr Vandenberghe), Department of Neurology, EA4559, IFR114 IMPRT, Université Lille Nord de France, Faculté Lille 2, CHU Lille, Lille (Dr Devos), and Department of Genetics, La Timone Hospital, Marseille Hospitals, Marseille (Dr N’Guyen), France.
Objectives To evaluate disease progression and determine validity of clinical tools for therapeutic trials.
Design Prospective cohort study (36 months).
Setting Referral center.
Patients One hundred sixty-two patients with autosomal dominant cerebellar ataxia and 64 with hereditary spastic paraplegia.
Main Outcome Measures 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.
Trial Registration clinicaltrials.gov Identifier: NCT00136630
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