Episodic ataxia and severe infantile phenotype in spinocerebellar ataxia type 14: expansion of the phenotype and novel mutations

doi:10.1007/s00415-021-10712-5

. 2022 Mar;269(3):1476-1484.

doi: 10.1007/s00415-021-10712-5. Epub 2021 Jul 22.

Episodic ataxia and severe infantile phenotype in spinocerebellar ataxia type 14: expansion of the phenotype and novel mutations

Giovanna De Michele^#¹, Daniele Galatolo^#², Serena Galosi³, Andrea Mignarri⁴, Gabriella Silvestri^{5

6}, Carlo Casali⁷, Vincenzo Leuzzi³, Ivana Ricca², Melissa Barghigiani², Alessandra Tessa², Ettore Cioffi⁷, Caterina Caputi³, Vittorio Riso^{5

6}, Maria Teresa Dotti⁴, Francesco Saccà¹, Giuseppe De Michele¹, Sirio Cocozza⁸, Alessandro Filla⁹, Filippo M Santorelli²

Affiliations

¹ Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, Via Sergio Pansini 5, 80131, Naples, Italy.
² Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS), Fondazione Stella Maris, Pisa, Italy.
³ Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy.
⁴ Department of Medicine, Surgery and Neuroscience, Neurology and Neurometabolic Unit, University of Siena, Siena, Italy.
⁵ Department of Neurosciences, Faculty of Medicine and Surgery, Catholic University of Sacred Heart, Rome, Italy.
⁶ Neurology Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.
⁷ Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy.
⁸ Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
⁹ Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, Via Sergio Pansini 5, 80131, Naples, Italy. afilla@unina.it.

^# Contributed equally.

PMID: 34292398
PMCID: PMC8857164
DOI: 10.1007/s00415-021-10712-5

Episodic ataxia and severe infantile phenotype in spinocerebellar ataxia type 14: expansion of the phenotype and novel mutations

Giovanna De Michele et al. J Neurol. 2022 Mar.

. 2022 Mar;269(3):1476-1484.

doi: 10.1007/s00415-021-10712-5. Epub 2021 Jul 22.

Authors

Affiliations

¹ Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, Via Sergio Pansini 5, 80131, Naples, Italy.
² Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS), Fondazione Stella Maris, Pisa, Italy.
³ Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy.
⁴ Department of Medicine, Surgery and Neuroscience, Neurology and Neurometabolic Unit, University of Siena, Siena, Italy.
⁵ Department of Neurosciences, Faculty of Medicine and Surgery, Catholic University of Sacred Heart, Rome, Italy.
⁶ Neurology Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.
⁷ Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy.
⁸ Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
⁹ Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, Via Sergio Pansini 5, 80131, Naples, Italy. afilla@unina.it.

^# Contributed equally.

PMID: 34292398
PMCID: PMC8857164
DOI: 10.1007/s00415-021-10712-5

Abstract

Introduction: Spinocerebellar ataxia type 14 (SCA14) is a dominantly inherited neurological disorder characterized by slowly progressive cerebellar ataxia. SCA14 is caused by mutations in PRKCG, a gene encoding protein kinase C gamma (PKCγ), a master regulator of Purkinje cells development.

Methods: We performed next-generation sequencing targeted resequencing panel encompassing 273 ataxia genes in 358 patients with genetically undiagnosed ataxia.

Results: We identified fourteen patients in ten families harboring nine pathogenic heterozygous variants in PRKCG, seven of which were novel. We encountered four patients with not previously described phenotypes: one with episodic ataxia, one with a spastic paraparesis dominating her clinical manifestations, and two children with an unusually severe phenotype.

Conclusions: Our study broadens the genetic and clinical spectrum of SCA14.

Keywords: Broadened phenotype; NGS targeted resequencing panel; Novel mutations; PRKCG; Spinocerebellar ataxia type 14.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

**Fig. 1**
Variants associated with ataxia so far described in the protein kinase C γ coded by *PRKCG*. Pathogenic or likely pathogenic variants identified in this study are boxed (novel ones are indicated in italics). It should be noticed that the splicing variant c.285C > G and two large-scale deletions previously associated with SCA14 are not reported in this figure. Legend: 1A and C1B = cysteine-rich regions, C2 = Ca²⁺ sensitive region, C3 = kinase region, C4 = substrate recognition region

**Fig. 2**
Family trees of the ten kindreds. Boxes are men and circles women. Full symbols indicated affected individuals. Empty symbols indicated not tested or wild-type relatives

**Fig. 3**
MRI: Representative brain MRI findings in SCA 14 patients. Brain MRI scans of four SCA14 patients (A: Pt. 13; B: Pt. 2; C: Pt. 8; D: Pt. 1). In the first two columns, from left to right, T1-weighted sagittal (with the exception, in B of a T2-weighted sequence) and coronal T2-weighted images showing the absence (A), the presence of moderate (B; C) and severe (D) cerebellar atrophy, respectively. In the third column axial Fluid Attenuated Inversion Recovery (FLAIR) images showing the absence of supratentorial signal changes, as well as preserved cerebral volumes (finding also visible in the other columns). The arrows in B indicate the presence of a mild T2-weighted hyperintensity affecting both dentate nuclei

See this image and copyright information in PMC

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References

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[1] Klebe S, Durr A, Rentschler A, Hahn-Barma V, Abele M, Bouslam N, Schöls L, Jedynak P, Forlani S, Denis E, Dussert C, Agid Y, Bauer P, Globas C, Wüllner U, Brice A, Riess O, Stevanin G. New mutations in protein kinase Cgamma associated with spinocerebellar ataxia type 14. Ann Neurol. 2005;58:720–729. doi: 10.1002/ana.20628. - DOI - PubMed

[2] Klebe S, Durr A, Rentschler A, Hahn-Barma V, Abele M, Bouslam N, Schöls L, Jedynak P, Forlani S, Denis E, Dussert C, Agid Y, Bauer P, Globas C, Wüllner U, Brice A, Riess O, Stevanin G. New mutations in protein kinase Cgamma associated with spinocerebellar ataxia type 14. Ann Neurol. 2005;58:720–729. doi: 10.1002/ana.20628. - DOI - PubMed

[3] Chelban V, Wiethoff S, Fabian-Jessing BK, Haridy NA, Khan A, Efthymiou S, Becker EBE, O'Connor E, Hersheson J, Newland K, Hojland AT, Gregersen PA, Lindquist SG, Petersen MB, Nielsen JE, Nielsen M, Wood NW, Giunti P, Houlden H. Genotype-phenotype correlations, dystonia and disease progression in spinocerebellar ataxia type 14. Mov Disord. 2018;33:1119–1129. doi: 10.1002/mds.27334. - DOI - PMC - PubMed

[4] Chelban V, Wiethoff S, Fabian-Jessing BK, Haridy NA, Khan A, Efthymiou S, Becker EBE, O'Connor E, Hersheson J, Newland K, Hojland AT, Gregersen PA, Lindquist SG, Petersen MB, Nielsen JE, Nielsen M, Wood NW, Giunti P, Houlden H. Genotype-phenotype correlations, dystonia and disease progression in spinocerebellar ataxia type 14. Mov Disord. 2018;33:1119–1129. doi: 10.1002/mds.27334. - DOI - PMC - PubMed

[5] Koht J, Stevanin G, Durr A, Mundwiller E, Brice A, Tallaksen CM. SCA14 in Norway, two families with autosomal dominant cerebellar ataxia and a novel mutation in the PRKCG gene. Acta Neurol Scand. 2014;125:116–122. doi: 10.1111/j.1600-0404.2011.01504.x. - DOI - PubMed

[6] Koht J, Stevanin G, Durr A, Mundwiller E, Brice A, Tallaksen CM. SCA14 in Norway, two families with autosomal dominant cerebellar ataxia and a novel mutation in the PRKCG gene. Acta Neurol Scand. 2014;125:116–122. doi: 10.1111/j.1600-0404.2011.01504.x. - DOI - PubMed

[7] Chen DH, Bird TD, Raskind WH (2005, updated 2020) Spinocerebellar Ataxia Type 14. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1399/ - PubMed

[8] Chen DH, Bird TD, Raskind WH (2005, updated 2020) Spinocerebellar Ataxia Type 14. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1399/ - PubMed

[9] Chen DH, Brkanac Z, Verlinde CL, Tan XJ, Bylenok L, Nochlin D, Matsushita M, Lipe H, Wolff J, Fernandez M, Cimino PJ, Bird TD, Raskind WH. Missense mutations in the regulatory domain of PKC gamma: a new mechanism for dominant nonepisodic cerebellar ataxia. Am J Hum Genet. 2003;72:839–849. doi: 10.1086/373883. - DOI - PMC - PubMed

[10] Chen DH, Brkanac Z, Verlinde CL, Tan XJ, Bylenok L, Nochlin D, Matsushita M, Lipe H, Wolff J, Fernandez M, Cimino PJ, Bird TD, Raskind WH. Missense mutations in the regulatory domain of PKC gamma: a new mechanism for dominant nonepisodic cerebellar ataxia. Am J Hum Genet. 2003;72:839–849. doi: 10.1086/373883. - DOI - PMC - PubMed

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Episodic ataxia and severe infantile phenotype in spinocerebellar ataxia type 14: expansion of the phenotype and novel mutations

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Episodic ataxia and severe infantile phenotype in spinocerebellar ataxia type 14: expansion of the phenotype and novel mutations

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