A 73-year-old woman had a long history of ataxia and unexplained visual loss. She had suffered a slow deterioration in her ability to walk since her 50s and dysarthria since her 60s. No cognitive disabilities were reported. Visual acuity was 20/50, right eye, and 20/80, left eye. Visual field results were not reliable. Macular drusen were present bilaterally (Fig. 3), and retinal autofluorescence was suggestive of central atrophy. The optic discs were normal. Fluorescein angiography showed mild granular appearance of the perifoveal retinal pigmentary epithelium (RPE). Macular OCT revealed bilateral macular atrophy with an abnormal foveal lamination pattern between the external layers. Focal thickening of the retinal pigment epithelium complex was present in the right eye (Fig. 4). Measurement of macular and global RNFL thickness was normal (Table 2).
A 55-year-old woman, with severe ataxia that began 13 years earlier complained of bilateral, progressive painless visual loss. Serial neurological examinations revealed slowly progressive kinetic and static cerebellar syndrome, associated with tetrapyramidal signs and speech and swallowing difficulties. Marked ponto-cerebellar atrophy was detected on magnetic resonance imaging (MRI). Visual acuity was 20/200, right eye, and 20/100, left eye. Visual fields showed bilateral central scotomas. Funduscopy revealed only mild granular appearance of the foveal RPE (Fig. 3). There was RNFL thinning on OCT (Table 2) and abnormal foveal cavitation was visible, between the outer segment layer and the layer representing the junction of the inner and outer segments. The layer corresponding to the retinal epithelium complex exhibited local foveal thickening (Fig. 4).
A 52-year-old man, with no visual complaints, had a history of slowly progressive cerebellar–pyramidal syndrome. MRI showed marked cerebellar atrophy, and genetic analysis confirmed SCA1 diagnosis. Other causes of genetic spinocerebellar ataxia were excluded (SCA 2, 3, 6, 7, 12, and 17). Visual acuity was 20/20 bilaterally. Macular visual field testing revealed asymptomatic, asymmetric central scotomas. Funduscopy was normal (Fig. 3), but OCT revealed central alteration of the photoreceptor outer segment layer, with focal thickening (Fig. 4). RNFL thickness was normal (Table 2).
Optic neuropathy has been reported previously as a cause of visual impairment in SCA1. Abe et al (10) reported 6 SCA1 patients from 3 families with decreased visual acuity and optic atrophy. Using OCT, Stricker et al (11) demonstrated significant thinning of temporal retinal nerve fibers, suggesting preferential involvement of the papillomacular bundle. Abnormalities of both latency and amplitude of VEPs also have been found in SCA1 patients (12–14). In most of these studies, the retinal function was tested using full-field ERG; mfERG was not performed.
Pathogenesis of SCA1 is due partly to direct mutation of the gene (6p22,3), translated into an abnormal protein (ataxin-1) that has an abnormally long stretch of glutamine. This leads to polyQ protein aggregation in the cell and aberrant protein interactions, with specific transcriptional complexes in the nucleus (25). Trinucleotide repeat disorder could exhibit other pathogenic manifestations, secondary to direct accumulation of the mutant messenger RNA in the nucleus, indirect gain of function (26), or inhibition of adjacent gene (27). In our patients, OCT demonstrated alterations of the external layers of the fovea, suggesting a loss of the structural integrity of the photoreceptors. Clinically, this foveolar lamination is compatible with an adult-onset vitelliform maculopathy, but the thinning of the whole macular area (including the surrounding perifoveolar retina) could be related to a cone dystrophy. Cone dystrophy is a clinically and genetically heterogeneous group, and no standard screening test has been developed. More than 10 different genes and loci have been identified in autosomal dominant cone dystrophy (https://sph.uth.edu/Retnet/sum-dis.htm#A-genes). Interestingly, a cluster of genes (GUCA1A, PRPH2) implicated in a spectrum of macular disease is located in 6p21.1, nearby SCA1 mutation. The gene GUCA1A (guanylate cyclase activator 1A) is implicated in cone dystrophy (COD3), which has phenotypic variability, even in the same family (28,29). The gene PRPH2 (Peripherin 2) has been also identified in adult-onset vitelliform macular dystrophy (30) or adult-onset foveomacular dystrophy (31). On inhibiting one of its promoters, CAG trinucleotide repeat could interfere with the regulation of one of these genes.
Establishing a definite association of a maculopathy with SCA1 is limited, in part, by our small patient sample size. More extensive study of relatives, especially those who do not have the SCA1 mutation, would be very informative. Other family members declined evaluation because most were free of symptoms and did not want genetic testing. However, none of them complained of neurological or visual symptoms. Whether there is truly a macular disorder associated with SCA1 awaits further study.
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