Thesis defense Sascha Vermeer (Donders Series 83)

5 April 2012

Promotors: Prof.dr. N.V.A.M. Knoers, Prof.dr. H.P.H. Kremer

Copromotors: Dr. H. Scheffer, dr. B.P.C. van de Warrenburg

Clinical and genetic characterisation of Autosomal Recessive Cerebellar Ataxias

With the project entitled “Clinical and genetic characterisation of autosomal recessive cerebellar ataxias” we could identify Dutch patients with the rare neurodegenerative disorder called ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay). In total we identified 23 Dutch patients from 16 different families. By performing detailed neurological examination in many ARSACS patients in our clinic we have characterized a specific uniform phenotype for ARSACS in a Dutch cohort. As mutation scanning of the entire SACS gene, involved in ARSACS, is now possible we expect to identify more ARSACS patients.

Furthermore by combining SNP array-based linkage analysis and targeted resequencing of relevant sequences in the linkage interval using next generation sequencing technology we identified a novel gene (ANO10) involved in a rather pure autosomal recessive cerebellar ataxia (ARCA). Mutations could be identified in three different families originating from the Netherlands, France and Serbia. ANO10 encodes a putative calcium-activated chloride channel, this adds another pathway to the list of pathophysiological mechanisms that may cause cerebellar ataxia.