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| Item Type: | Article |
|---|---|
| Title: | Spinocerebellar ataxia type 14: refining clinicogenetic diagnosis in a rare adult-onset disorder |
| Creators Name: | Schmitz-Hübsch, T., Lux, S., Bauer, P., Brandt, A.U., Schlapakow, E., Greschus, S., Scheel, M., Gärtner, H., Kirlangic, M.E., Gras, Vi., Timmann, D., Synofzik, M., Giorgetti, A., Carloni, P., Shah, J.N., Schöls, L., Kopp, U., Bußenius, L., Oberwahrenbrock, T., Zimmermann, H., Pfueller, C., Kadas, E.M., Rönnefarth, M., Grosch, A.S., Endres, M., Amunts, K., Paul, F., Doss, S. and Minnerop, M. |
| 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. |
| Keywords: | Age of Onset, Cross-Sectional Studies, Disease Progression, Prospective Studies, Protein Kinase C, Spinocerebellar Ataxias |
| Source: | Annals of Clinical and Translational Neurology |
| ISSN: | 2328-9503 |
| Publisher: | Wiley |
| Volume: | 8 |
| Number: | 4 |
| Page Range: | 774-789 |
| Date: | April 2021 |
| Official Publication: | https://doi.org/10.1002/acn3.51315 |
| PubMed: | View item in PubMed |
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