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

Ann Clin Transl Neurol. 2021 Apr;8(4):774-789. doi: 10.1002/acn3.51315. Epub 2021 Mar 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Cross-Sectional Studies
  • Disease Progression
  • Female
  • Humans
  • Male
  • Prospective Studies
  • Protein Kinase C / genetics*
  • Spinocerebellar Ataxias / diagnosis*
  • Spinocerebellar Ataxias / genetics*
  • Spinocerebellar Ataxias / physiopathology*


  • protein kinase C gamma
  • Protein Kinase C

Supplementary concepts

  • Spinocerebellar ataxia 14

Grants and funding

This work was funded by Deutsche Forschungsgemeinschaft grant 390688087; NeuroCure Cluster of Excellence grant EXC 257; EU Horizon 2020 grant 779257.