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

Giovanna De Michele,Daniele Galatolo,Caterina Caputi,Maria Teresa Dotti,Andrea Mignarri,Serena Galosi,Giuseppe De Michele,Filippo M Santorelli,Vittorio Riso,Sirio Cocozza,Alessandro Filla,Vincenzo Leuzzi,Francesco Saccà,Melissa Barghigiani,Ettore Cioffi,Carlo Casali,Alessandra Tessa,Ivana Ricca,Gabriella Silvestri

doi:10.1007/s00415-021-10712-5

Abstract

IntroductionSpinocerebellar 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.MethodsWe performed next-generation sequencing targeted resequencing panel encompassing 273 ataxia genes in 358 patients with genetically undiagnosed ataxia.ResultsWe 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.ConclusionsOur study broadens the genetic and clinical spectrum of SCA14.

Highlights

Spinocerebellar ataxia type 14 (SCA14) is a dominantly inherited neurological disorder characterized by slowly progressive cerebellar ataxia
In a multicenter Italian study addressing the etiology of inherited ataxias and related disorders, we investigated 358 index patients with genetically undiagnosed ataxias, both familial (17%) and sporadic (83%) from 16 neurological centers belonging to ITASPAX network using a targeted resequencing multigene panel (TRP) in nextgeneration sequencing (NGS)
We describe fourteen patients in ten families harbouring variants of pathogenic significance in PRKCG gene

Summary

Introduction

Spinocerebellar ataxia type 14 (SCA14) is a dominantly inherited neurological disorder characterized by slowly progressive cerebellar ataxia. Spinocerebellar ataxia type 14 (SCA14, OMIM 605,361) is a rare disorder with a frequency varying from 1 to 7% of all non-polyQ autosomal dominant cerebellar ataxias [1,2,3,4]. It is caused by mutations in the PRKCG gene coding for the Giovanna De Michele and Daniele Galatolo contributed to this work. SCA14 phenotype is that of a slowly progressive ataxia, rarely associated with severe disabilities. MRI shows a variable atrophy of the cerebellum, more marked in the vermis, without other abnormalities in brainstem and cerebral cortex [3]

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