Novel human pathological mutations

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. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Naima Bouslam and Ahmed Bouhouche are co-first authors.