Spinocerebellar ataxia type 14: refining clinicogenetic diagnosis in a rare adult‐onset disorder

Objectives: Genetic variant classification is a challenge in rare adult-onset disorders as in SCA-PRKCG (prior spinocerebellar ataxia type 14) with mostly private conventional mutations and nonspecific phenotype. We here propose a refined approach for clinicogenetic diagnosis by including protein modeling and provide for confirmed SCA-PRKCG a comprehensive phenotype description from a German multi-center cohort, including standardized 3D MR imaging. Methods: This cross-sectional study prospectively obtained neurological, neuropsychological, and brain imaging data in 33 PRKCG variant carriers. Protein modeling was added as a classification criterion in variants of uncertain significance (VUS). Results: Our sample included 25 cases confirmed as SCA-PRKCG (14 variants, thereof seven novel variants) and eight carriers of variants assigned as VUS (four variants) or benign/likely benign (two variants). Phenotype in SCA-PRKCG included slowly progressive ataxia (onset at 4-50 years), preceded in some by early-onset nonprogressive symptoms. Ataxia was often combined with action myoclonus, dystonia, or mild cognitive-affective disturbance. Inspection of brain MRI revealed nonprogressive cerebellar atrophy. As a novel finding, a previously not described T2 hyperintense dentate nucleus was seen in all SCA-PRKCG cases but in none of the controls. Interpretation: In this largest cohort to date, SCA-PRKCG was characterized as a slowly progressive cerebellar syndrome with some clinical and imaging features suggestive of a developmental disorder. The observed non-ataxia movement disorders and cognitive-affective disturbance may well be attributed to cerebellar pathology. Protein modeling emerged as a valuable diagnostic tool for variant classification and the newly described T2 hyperintense dentate sign could serve as a supportive diagnostic marker of SCA-PRKCG

Spinocerebellar ataxia type 14: refining clinicogenetic diagnosis in a rare adult-onset disorder

OBJECTIVES: Genetic variant classification is a challenge in rare adult-onset disorders as in SCA-PRKCG (prior spinocerebellar ataxia type 14) with mostly private conventional mutations and nonspecific phenotype. We here propose a refined approach for clinicogenetic diagnosis by including protein modeling and provide for confirmed SCA-PRKCG a comprehensive phenotype description from a German multi-center cohort, including standardized 3D MR imaging. METHODS: This cross-sectional study prospectively obtained neurological, neuropsychological, and brain imaging data in 33 PRKCG variant carriers. Protein modeling was added as a classification criterion in variants of uncertain significance (VUS). RESULTS: Our sample included 25 cases confirmed as SCA-PRKCG (14 variants, thereof seven novel variants) and eight carriers of variants assigned as VUS (four variants) or benign/likely benign (two variants). Phenotype in SCA-PRKCG included slowly progressive ataxia (onset at 4-50 years), preceded in some by early-onset nonprogressive symptoms. Ataxia was often combined with action myoclonus, dystonia, or mild cognitive-affective disturbance. Inspection of brain MRI revealed nonprogressive cerebellar atrophy. As a novel finding, a previously not described T2 hyperintense dentate nucleus was seen in all SCA-PRKCG cases but in none of the controls. INTERPRETATION: In this largest cohort to date, SCA-PRKCG was characterized as a slowly progressive cerebellar syndrome with some clinical and imaging features suggestive of a developmental disorder. The observed non-ataxia movement disorders and cognitive-affective disturbance may well be attributed to cerebellar pathology. Protein modeling emerged as a valuable diagnostic tool for variant classification and the newly described T2 hyperintense dentate sign could serve as a supportive diagnostic marker of SCA-PRKCG

Deformation field morphometry study in a German multicenter SCA14 cohort reveals only a cerebellar volume deficit

Deformation field morphometry study in a German multicenter SCA14 cohort reveals only acerebellar volume deficitPeter Pieperhoff1, Tanja Schmitz-Hübsch2, Elena Schlapakow3, Silke Lux4, Peter Bauer5, HannaGärtner6, Mehmet Eylem Kirlangic7, Dagmar Timmann-Braun8, Vincent Gras9, Matthis Synofzik10,Nadim Jon Shah9, Ludger Schöls11, Ute Kopp12, Thomas Klockgether13, Katrin Amunts14, SarahDoss15, Martina Minnerop161Research Centre Jülich, Institute of Neuroscience and Medicine (INM-1), Jülich, Germany2Charité – Universitätsmedizin Berlin, Klinik für Neurologie, NeuroCure Clinical Research Center,Berlin, Germany3Universitätsklinikum Bonn, Klinik für Neurologie, Bonn, Germany4Research Centre Jülich, Institute of Neuroscience and Medicine (INM-1, INM-4), Jülich, Germany5Universität Tübingen, Institut für Medizinische Genetik und angewandte Genomik, Tübingen,Germany6Forschungszentrum Jülich, Institut für Neurowissenschaften und Medizin (INM-1), Jülich, Germany7Research Centre Jülich, Institute of Neuroscience and Medicine (INM-1, INM-2, INM-4, INM-8),Jülich, Germany8Universitätsklinikum Duisburg-Essen, Neurologie, Essen, Germany9Research Centre Jülich, Institute of Neuroscience and Medicine (INM-4), Jülich, Germany10Universitätsklinik Tübingen, Hertie-Institut für klinische Hirnforschung; Deutsches Zentrum fürNeurodegenerative Erkrankungen (DZNE), Sektion Klinische Neurogenetik, Klinik für Neurologie,Tübingen, Germany11Universitätsklinikum Tübingen, Hertie-Institut für klinische Hirnforschung; Deutsches Zentrum fürNeurodegenerative Erkrankungen (DZNE), Sektion Klinische Neurogenetik, Klinik für Neurologie,Tübingen, Germany12Charité – Universitätsmedizin Berlin, Klinik für Neurologie, Berlin, Germany13Universitätsklinikum Bonn, Klinik und Poliklinik für Neurologie, Deutsches Zentrum fürNeurodegenerative Erkrankungen (DZNE), Bonn, Germany14Heinrich-Heine-University Düsseldorf, C. and O. Vogt Institute for Brain Research, Düsseldorf,RWTH Aachen University, Department of Psychiatry, Psychotherapy and Psychosomatics, Aachen,Research Centre Jülich, Institute of Neuroscience and Medicine (INM-1, INM-4), Jülich, Jülich,Germany15Charité – Universitätsmedizin Berlin, Neurologie, NeuroCure Center for Excellence, Berlin, Germany16Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich, Department of Neurology,University Hospital Bonn, Center for Movement Disorders and Neuromodulation, Department ofNeurology and Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich-Heine University, Jülich/Bonn/Düsseldorf, GermanyBackground: Since its genetic definition in 2003, the rare autosomal dominant spinocerebellar ataxiatype 14 (SCA14), a late onset progressive disorder caused by mutations in protein kinase C gamma(PKCγ), is increasingly recognized among patients with hitherto undefined SCAs in Germany. Patientsmostly present with a slowly progressive cerebellar ataxia, but reports on additional symptoms(cognitive decline, hyperreflexivity, myoclonus, dystonia) might reflect extracerebellar damage.Aims: Analysing the pattern of brain atrophy on magnetic resonance (MR) images by deformationbasedmorphometry (DBM) in the largest reported and genetically heterogeneous SCA14 sampleenrolled in a coordinated study at two German university ataxia clinics.Question: Case series reported mild to severe cerebellar midline atrophy and sometimes additionalpontine, brainstem or cerebral atrophy. Are these findings supported in a first analysis on group level?Methods: T1-weighted MR images (3T, MPRAGE sequence, voxel-size: 1x1x1 mm³) of 18 clinicallywell-characterized SCA14-patients (7 m, age 52.1 ± 12.3 years, disease duration 21.0 ± 12.5 years)and matched healthy controls were compared with DBM. The registration algorithm simulated anelastic deformation of each (source) brain, such that the structural similarity with the reference brainwas maximized. This yielded a 3D-deformation field encoding the anatomical differences betweensource and reference brain. Maps of voxel-wise volume differences between each source andreference brain were computed and statistically analysed in each voxel and in regions-of-interest asdefined by the AAL and JuBrain atlas (pR).In particular, the volume of the dorsal motor part of the dentate nucleus was reduced as was theinterposed nucleus bilaterally.Conclusions: Volume deficits found in the cerebellar cortex are in line with the reported highexpression of PKCγ in Purkinje cells. The most pronounced findings in anterior lobe and interposednucleus bilaterally fit well to the clinical finding of prominent ataxia of gait and stance. Althoughextracerebellar (EC) symptoms were present (dystonia/myoclonus), volume deficits were restricted tothe cerebellum. This may point to functional EC changes not associated with volume deficits, butpotentially detectable by other methods, or to a cerebellar involvement in the pathogenesis of dystoniaand myoclonus in SCA14. Correlation analyses of imaging with clinical data currently underway willyield further insights into structure-function relationships