Investigation of Visual System Involvement in Spinocerebellar Ataxia Type 14

Thomas Klockgether,Thomas Ihl,Sarah Doss,Alexander U Brandt,Ella M Kadas,Hanna G Zimmermann,Martina Minnerop,Timm Oberwahrenbrock,Friedemann Paul,Jan Schroeter,Matthias Endres,Tanja Schmitz-Hübsch

doi:10.1007/s12311-020-01130-w

Abstract

Spinocerebellar ataxia type 14 (SCA-PRKCG, formerly SCA14) is a rare, slowly progressive disorder caused by conventional mutations in protein kinase Cγ (PKCγ). The disease usually manifests with ataxia, but previous reports suggested PRKCG variants in retinal pathology. To systematically investigate for the first time visual function and retinal morphology in patients with SCA-PRKCG. Seventeen patients with PRKCG variants and 17 healthy controls were prospectively recruited, of which 12 genetically confirmed SCA-PRKCG patients and 14 matched controls were analyzed. We enquired a structured history for visual symptoms. Vision-related quality of life was obtained with the National Eye Institute Visual Function Questionnaire (NEI-VFQ) including the Neuro-Ophthalmic Supplement (NOS). Participants underwent testing of visual acuity, contrast sensitivity, visual fields, and retinal morphology with optical coherence tomography (OCT). Measurements of the SCA-PRKCG group were analyzed for their association with clinical parameters (ataxia rating and disease duration). SCA-PRKCG patients rate their vision-related quality of life in NEI-VFQ significantly worse than controls. Furthermore, binocular visual acuity and contrast sensitivity were worse in SCA-PRKCG patients compared with controls. Despite this, none of the OCT measurements differed between groups. NEI-VFQ and NOS composite scores were related to ataxia severity. Additionally, we describe one patient with a genetic variant of uncertain significance in the catalytic domain of PKCγ who, unlike all confirmed SCA-PRKCG, presented with a clinically silent epitheliopathy. SCA-PRKCG patients had reduced binocular vision and vision-related quality of life. Since no structural retinal damage was found, the pathomechanism of these findings remains unclear.

Highlights

The spinocerebellar ataxias (SCA) denote the group of autosomal dominantly inherited ataxias clinically characterized by cerebellar syndrome and non-cerebellar involvement of varying degrees [1, 2]
After consideration of exclusion criteria, twelve SCAPRKCG patients (9 members of 4 families and 3 singular cases) and 14 healthy controls (HCs) were available for analysis (Fig. 1)
Some difficulty in horizontal or vertical gaze was seen in two SCA-PRKCG patients, though one of them was excluded from analysis due to glaucoma

Summary

Introduction

The spinocerebellar ataxias (SCA) denote the group of autosomal dominantly inherited ataxias clinically characterized by cerebellar syndrome and non-cerebellar involvement of varying degrees [1, 2]. SCA-PRKCG (formerly SCA14) was one of the first SCAs in which a conventional mutation was described as causative [7]. The protein kinase C gamma (PKCγ) is only expressed in neurons of the brain and the spinal cord and is abundant in Purkinje cells [10]. It exhibits distinct dissemination in the visual system [11,12,13,14,15], especially in the human retina [14, 15]. PKCγ-knockout mice show an enlarged ganglion cell and inner nuclear layer, which was histologically caused by empty spaces between cells [17]

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