Brain Advance Access originally published online on June 9, 2005
Brain 2005 128(8):1855-1860; doi:10.1093/brain/awh535
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The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA Study Group
1 Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, 2 Gene Bank Parkinson Germany Bonn, Department of Neurology, University of Bonn, Bonn and Parkinson Competence Net e.V. (BMBF 01G19901), 3 Department of Neurology, Philipps University, Marburg, 4 Department of Neurology, University of Ulm, 5 Center of Medical Genetics, Munich, 6 GSF National Research Center for Environment and Health, Institute of Epidemiology, Neuherberg, Germany, 7 Department of Molecular Neuroscience and 8 Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, 9 Department of Medical Genetics, St George's Hospital, Tooting, London, 10 Academic Neurology Unit, Division of Genomic Medicine, University of Sheffield, Sheffield, UK, 11 Department of Neurology, University of Innsbruck, Innsbruck, Austria, 12 Institute of Human Genetics, University of Aarhus, Aarhus, Denmark, 13 Department of Neurological Sciences, University Federico II, Napoli, Italy, 14 Neurology Service, Institut Clinic Malaltias del Sistema Nervios, Hospital Clinic Universitari, University of Barcelona, Barcelona, Spain, 15 Istituto Nazionale Neurologico ‘C. Besta’, Milano, Italy and 16 Neuroscience Department, University of Lund, Lund, Sweden
Correspondence to: T. Gasser, Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, Hoppe-Seyler-Strasse 3, University of Tübingen, 72086 Tübingen, Germany E-mail: thomas.gasser{at}med.uni-tuebingen.de
The recent identification of fragile X-associated tremor ataxia syndrome (FXTAS) associated with premutations in the FMR1 gene and the possibility of clinical overlap with multiple system atrophy (MSA) has raised important questions, such as whether genetic testing for FXTAS should be performed routinely in MSA and whether positive cases might affect the specificity of current MSA diagnostic criteria. We genotyped 507 patients with clinically diagnosed or pathologically proven MSA for FMR1 repeat length. Among the 426 clinically diagnosed cases, we identified four patients carrying FMR1 premutations (0.94%). Within the subgroup of patients with probable MSA-C, three of 76 patients (3.95%) carried premutations. We identified no premutation carriers among 81 patients with pathologically proven MSA and only one carrier among 622 controls (0.16%). Our results suggest that, with proper application of current diagnostic criteria, FXTAS is very unlikely to be confused with MSA. However, slowly progressive disease or predominant tremor are useful red flags and should prompt the consideration of FXTAS. On the basis of our data, the EMSA Study Group does not recommend routine FMR1 genotyping in typical MSA patients.
Key Words: multiple system atrophy; FXTAS; fragile X; FMR1; premutation
Abbreviations: EMSA-SG = European Multiple System Atrophy Study Group; FMR1 = fragile site mental retardation 1 gene; FXTAS = fragile X tremor ataxia syndrome; KORA = Cooperative Health Research in the Region of Augsburg; MSA = multiple system atrophy; MSA-C = multiple system atrophy with predominant cerebellar ataxia; REM = rapid eye movement
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* These authors contributed equally to this work
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