Spinocerebellar ataxia type 14: refining clinicogenetic diagnosis in a rare adult‐onset disorder
Year: 2021
Type: article
Study design: Observational Study
Abstract: 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.
DOI: 10.1002/acn3.51315
Authors: Tanja Schmitz‐Hübsch, Silke Lux, Peter Bauer, Alexander U. Brandt, Elena Schlapakow, Susanne Greschus, Michael Scheel, Hanna Gärtner, Mehmet E. Kirlangic, Vincent Gras, Dagmar Timmann, Matthis Synofzik, Alejandro Giorgetti, Paolo Carloni, Jon N. Shah, Ludger Schöls, Ute Kopp, Lisa Bußenius, Timm Oberwahrenbrock, Hanna Zimmermann, Caspar Pfueller, Ella‐Maria Kadas, Maria Rönnefarth, Anne‐Sophie Grosch, Matthias Endres, Katrin Amunts, Friedemann Paul, Sarah Doss, Martina Minnerop
Institutions: Max Delbrück Center, Humboldt-Universität zu Berlin, NeuroCure Cluster of Excellence, Freie Universität Berlin, Charité – Universitätsmedizin Berlin, University Hospital Bonn, Centogene (Germany), University of Tübingen, University of California, Irvine, University of Bonn, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Forschungszentrum Jülich, Technische Universität Ilmenau, Essen University Hospital, University of Duisburg-Essen, German Center for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Verona, German Research School for Simulation Sciences, RWTH Aachen University, University Medical Center Hamburg-Eppendorf, German Centre for Cardiovascular Research, Center for Stroke Research Berlin, Heinrich Heine University Düsseldorf, University of Nebraska Medical Center
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,463
OpenAlex ID: W3136338554