Abstract
Autosomal recessive spastic ataxias are a heterogeneous group of neurodegenerative diseases usually characterized by the early onset of cerebellar and pyramidal signs. With the collaboration of the clinical European and Mediterranean SPATAX network, we identified 15 families with 34 affected members presenting with ataxia and pyramidal signs or spasticity that were not linked to the ARSACS locus on chromosome 13. In an informative consanguineous Moroccan family, we mapped a novel locus, SAX2, to chromosome 17p13. The minimal linked interval lies in a region of 6.1 cM flanked by markers D17S1845/1583 and D17S1854 (Z max = 3.21). Three of the remaining 14 families were also possibly linked to SAX2. The overall clinical picture in nine patients was cerebellar ataxia with pyramidal signs and/or spasticity. Onset occurred before the age of 15 years in two families and in adulthood in the other two. Interestingly, in the largest SAX2 family, the presenting clinical sign was dysarthria, which is not common in other forms of inherited ataxias or spastic ataxias, whereas gait difficulties appeared later. Most cases also showed fasciculations suggesting that both lower and upper motor neurons are involved in the disease process. No mutations were found in the coding exons of KIF1C, ARRB2 and ANKFY1, three genes in the candidate region.
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Acknowledgments
We thank the members of the European and Mediterranean network dedicated to the Spastic Paraplegias and ATAXias (SPATAX) for recruiting several families. The authors wish to thank the families that participated in this study as well as Ms Nawal Benammar and Drs M. Abada-Bendib, S. Forlani, D. Grid, M. Koenig, I. Leber, J. F. Lemaire, S. Poea, M. Ruberg and P. Vondracek for their help. This study was supported by grants from the French National Institute for Health and Medical Research (INSERM), the Neurogenetic Moroccan Association (AMNG), the Verum Foundation (to A Brice), The French Agency for Research (to AD), the “Pôle de Compétences en Neurogénétique au Maroc” (PCNG) and the GIS/Rare Diseases Institute (to AD and GS). NB and HA received fellowships from the Foundation of Friedreich Ataxia (AFAF, France) and the French Association against Myopathies (AFM, France). SK was the recipient of a fellowship from the Tom-Walhig Foundation (Germany) and the Verum Foundation (Germany).
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Naima Bouslam and Ahmed Bouhouche are co-first authors.
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Supplementary table 1: Pairwise and multipoint LOD scores calculated in all families using an autosomal recessive mode of transmission with 95% penetrance. Alpha (% of unlinked families) and HLOD (homogeneity LOD scores) were calculated with ALLEGRO assuming heterogeneity of linkage. Grey = non-excluded LOD scores (DOC 89 kb)
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Bouslam, N., Bouhouche, A., Benomar, A. et al. A novel locus for autosomal recessive spastic ataxia on chromosome 17p. Hum Genet 121, 413–420 (2007). https://doi.org/10.1007/s00439-007-0328-0
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DOI: https://doi.org/10.1007/s00439-007-0328-0