Brain Advance Access originally published online on August 20, 2009
Brain 2009 132(10):2688-2698; doi:10.1093/brain/awp211
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Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients
1 Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, Université de Strasbourg, INSERM, Illkirch, France 2 Department of Neurology, Hôpital Civil, Strasbourg, France 3 AP-HP, Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique, F-75013, Paris, France 4 Faculté de Médecine, Université de Lubumbashi, Lubumbashi, République Démocratique du Congo 5 Department of Neurology, Hospital S.Sebastião, Santa Maria da Feira, Portugal, and UnIGENe, IBMC, UP, Porto, Portugal 6 Division of Paediatric Neurology, College of Medicine, King Saud University, Riyadh, Saudi Arabia 7 Laboratoire de Diagnostic Génétique, Nouvel Hôpital Civil, Strasbourg, France 8 Department of Human Genetics, Ruhr-University, 44780 Bochum, Germany 9 Research Division for Clinical Neurogenetics Centre of Neurology and Hertie-Institute for Clinical Brain Research, Hoppe-Seyler-Str. 3, D – 72076 Tübingen 10 BMC – Institute for Molecular and Cell Biology, ICBAS; Univ. Porto, Portugal 11 Université Victor Segalen Bordeaux 2, Laboratoire de Génétique Humaine, CHU Bordeaux, Service de Génétique médicale, Bordeaux 33076 France 12 INSERM, CRicm UMRS975 (formely INSERM UMR_S679), F-75013, Paris, France 13 UPMC Univ Paris 06, CRicm UMRS975 (formely INSERM UMR_S679), F-75005, Paris, France 14 University of Oslo, Faculty of Medicine, Norway 15 Service of Neurology, Hospital Universitario Miguel Servet, Zaragoza, Spain 16 Department of Neurology, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium 17 Institute of Endemic Diseases, Faculty of Medicine, University of Khartoum, Sudan 18 Laboratoire de Recherche en Neurosciences, Service de Neurologie, CHU Mustapha, Place du 1er Mai, Alger, Algeria 19 Laboratoire de Biologie Cellulaire et Moléculaire, Université de Bab Ezzouar, Alger, Algérie 20 Service de Neurologie, Hôpital de Narbonne, France 21 Service de Neurologie, Hôpital Benbadis CHU Constantine, Algerie 22 Service de Pédiatrie, Hôpital La Timone-Enfants, Marseille, France 23 Department of Neurology and Neuromuscular Disease, CHU La Timone, Marseille, France 24 The Adelaide and Meath Hospital University of Dublin, Tallaght, Dublin 24 25 Department of Neurology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan
Correspondence to: Dr. Mathieu Anheim, Consultation de Neurogénétique, Groupe Hospitalier de la Pitié-Salpêtrière, 47-83, bd de l’Hôpital, 75651, Paris E-mail: anheim{at}titus.u-strasbg.fr
Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 µg/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 µg/l, P = 0.0004; itself higher than the normal level (3.4 µg/l, range from 0.5 to 17.2 µg/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level 
7 µg/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia ataxic patient to be affected with AOA2 with AFP levels 7 µg/l is 46%. Therefore, selection of patients with an AFP level above 7 µg/l for senataxin gene sequencing is a good strategy for AOA2 diagnosis. Pyramidal signs and dystonia were more frequent and disease was less severe with missense mutations in the helicase domain of senataxin gene than with missense mutations out of helicase domain and deletion and nonsense mutations (P = 0.001, P = 0.008 and P = 0.01, respectively). The lack of pyramidal signs in most patients may be explained by masking due to severe motor neuropathy.
Key Words: ataxia; oculomotor apraxia; polyneuropathy; alpha-feto-protein; cerebellar atrophy
Abbreviations: AFP, alpha-feto-protein; ALS4, amyotrophic lateral sclerosis; AOA1, ataxia with oculomotor apraxia type 1; AOA2, ataxia with oculomotor apraxia type 2; ARCA, autosomal recessive cerebellar ataxia; AT, ataxia-telangiectasia; DD, disease duration; HD, helicase domain; OMA, occasional oculomotor apraxia; SDFS, spinocerebellar degeneration functional score corrected; SETX, Senataxin gene
Received March 6, 2009. Revised June 15, 2009. Accepted June 26, 2009.