SCA14 in Norway, two families with autosomal dominant cerebellar ataxia and a novel mutation in the PRKCG gene Introduction Spinocerebellar ataxia type 14 (SCA14, OMIM; Mendelian Inheritance in Man 605361) is an autosomal dominant neurodegenerative disorder characterized by a mild and slowly progressive form of cerebellar ataxia. Additional symptoms and signs such as myoclonus, spasticity, hyperref- lexia, dystonia, tremor and cognitive decline are described in patients (1–10). The disorder is rare, representing 1.5% of the French autosomal dom- inant cerebellar ataxia (ADCA) families (3) and 4% of the Dutch ADCA families (7). Age at onset is reported highly variable from early childhood to the sixth decade of life. SCA14 is associated with mutations in the protein kinase c c gene (PRKCG) at chromosome 19q13.4. The gene is composed of 18 exons and encodes protein kinase Cc (PKCc), which is a protein expressed in the brain and particularly in the Purkinje cells. The PKCc protein is believed to affect many cellular pathways that regulate cell-cycle control, proliferation, apop- tosis and cellular adhesion (11). To date, 23 mutations are reported (1–9, 12–18) (Table 1), mostly missense mutations, but also an in-frame deletion in exon 4 and a deletion of a termination-codon-containing region in exon 18. Eighteen of the 23 mutations are concentrated in the regulatory C1 domain of the gene, and most mutations are clustered in exon 4. It is not clear how these mutations lead to loss of Purkinje cells and cerebellar dysfunction, but one study has shown that mutations increase the PKCc protein activity by reducing a pseudo-substrate to Acta Neurol Scand DOI: 10.1111/j.1600-0404.2011.01504.x Ó 2011 John Wiley & Sons A ⁄ S ACTA NEUROLOGICA SCANDINAVICA Koht J, Stevanin G, Durr A, Mundwiller E, Brice A, Tallaksen CME. SCA14 in Norway, two families with autosomal dominant cerebellar ataxia and a novel mutation in the PRKCG gene. Acta Neurol Scand: DOI: 10.1111/j.1600-0404.2011.01504.x. Ó 2011 John Wiley & Sons A ⁄ S. Objectives – Despite a similar prevalence of autosomal dominant cerebellar ataxia (ADCA) in Norway compared to other European countries, less than 10% of the families are explained by the CAG trinucleotide expansions. We wanted to find the occurence of SCA14 in the dominant ataxia population and describe the phenotype. Methods – We screened a large dominant cerebellar ataxia cohort for mutations in the PRKCG gene. Patients were evaluated according to a standard clinical protocol for ataxia patients. Results – A novel mutation was found in two families, a C to A transversion altering Histidine to a Glutamine at codon 139, located in a highly concerved region in the gene. It completely co-segregated with the affected family members and was not seen in 576 control chromosomes. Genetic analysis revealed common alleles at three microsatellite markers between these two families suggesting a shared ancestral chromosome. Affected subjects displayed a mild, slowly progressive cerebellar syndrome that included gait and limb ataxia and saccadic pursuit and head tremor in one. Age at onset ranged from 10 to 45 years. Conclusions – These are the first families with SCA14 reported from Scandinavia and a new mutation in the PRKCG gene. The occurrence in the Norwegian dominant ataxia cohort is 3.5%. J. Koht 1,2,3 , G. Stevanin 1,4,5 , A. Durr 1,4,5 , E. Mundwiller 1,4 , A. Brice 1,4,5 , C. M. E. Tallaksen 2,3 1 INSERM U975, Paris, France; 2 Faculty of Medicine, University of Oslo, Oslo, Norway; 3 Department of Neurology, Oslo University Hospital, Oslo, Norway; 4 UPMC Univ. Paris 6, UMR_S975, Centre de Recherche de lÕInstitut du Cerveau et de la Moelle Øpinire, CNRS 7225, Groupe Hospitalier PitiØ- SalpÞtrire, Paris, France; 5 APHP, Groupe Hospitalier PitiØ SalpÞtrire, DØpartement de GØnØtique et CytogØnØtique, Paris, France Key words: Ataxia; PRKCG; SCA; SCA14 J. Koht, Department of Neurology, Faculty of Medicine, Oslo University Hospital, Ullevål, 0407 Oslo, Norway Tel.: +47 23015969 or +4791632024 Fax: +47 23027455 e-mail: jeanette.koht@medisin.uio.no Accepted for publication February 2, 2011 1