Author Affiliations: Department of Ophthalmology, Hôpitaux Universitaires, Geneva (Dr Vaclavik), and Jules-Gonin Eye Hospital, University of Lausanne, Lausanne (Drs Vaclavik, Borruat, Ambresin, and Munier), Switzerland.
The dominantly inherited ataxias, or spinocerebellar ataxias (SCAs), are a group of neurodegenerative disorders characterized by ataxia, oculomotor disturbances, and variable other neurological features such as pyramidal and extrapyramidal tract, basal ganglia, or brainstem dysfunction.1 The number of known SCA subtypes continues to grow and currently includes at least 27 subtypes,2 numbered in the order of discovery of the defective gene. Spinocerebellar ataxia type 1 (SCA1) typically presents in the fourth decade (age range, 4-74 years) with dysarthria, handwriting difficulties, and limb ataxia.3 Several ocular manifestations have been described in the early stage of the disease: gaze-evoked nystagmus, impairment of vestibulo-ocular reflex, and abnormal saccades are common findings.4 Reduced visual acuity with optic atrophy has been described in patients with SCA1,5 and 1 patient exhibited a rod-cone dystrophy.6
We report the anatomical and functional characteristics of a novel progressive maculopathy in 2 unrelated patients with ataxia and genetically confirmed SCA1.
A 62-year-old Pakistani man had a progressive gait disturbance and weakness in his feet since he was aged 40 years. Clinical and genetic testing confirmed SCA1 (heterozygote 43 CAG trinucleotide repeat expansion in ATXN1). His vision started to decline at age 54 years, and his visual acuity was 20/200 OU at the time of referral. Ocular motility examination revealed mild abnormalities (saccadic pursuit, hypermetric saccades, and decreased saccadic velocity), all compatible with cerebellar dysfunction.
Fundus examination showed bilateral areas of hypopigmented retinal pigment epithelium within the macula. Autofluorescence imaging revealed an unusual appearance of the maculae with central mild hyperautofluorescence surrounded by a ring of hypoautofluorescence. Time-domain optical coherence tomography disclosed bilateral hyporeflective foveal cavities corresponding to the loss of the highly reflective inner segment–outer segment junction as well as thinning of the outer nuclear layer. Outside the macula, the retina was within normal range. Fluorescein angiography showed small areas of patchy hyperfluorescence in the macula, corresponding to areas of depigmented retinal pigment epithelium without any leakage in late stages. Goldmann kinetic manual perimetry revealed a relative central scotoma bilaterally (Figure 1). Full-field electroretinographic results were within normal limits under photopic and scotopic conditions. The family history revealed that similar neurological symptoms were present in 3 deceased siblings (2 brothers and 1 sister).
Figure 1. Findings from patient 1. A and B, Funduscopy revealed bilateral hypopigmented fovea with a patchy area of depigmented retinal pigmented epithelium mostly within the right macula; the optic nerve head, retinal vessels, and peripheral retina appeared normal bilaterally. C and D, Fundus autofluorescence imaging showed a central hyperautofluorescence surrounded by a ring of hypoautofluorescence. E and F, Time-domain optical coherence tomography disclosed bilateral hyporeflective cavities with global thinning of the underlying neuroretina. G and H, Fluorescein angiography showed small areas of patchy hyperfluorescence mostly in the right macula, corresponding to the areas of depigmented retinal pigment epithelium without any leakage at later phases. I and J, Goldmann kinetic perimetry showed a moderate concentric loss of sensitivity with a partial central scotoma in both eyes. K and L, Multifocal electroretinography demonstrated decreased electrical potential within the central 7° to 10° of each eye. Outside that central area, the potentials were normal.
A 61-year-old Italian man had SCA with mainly limb ataxia and dysarthria. A progressive decline of visual function bilaterally was noticed. At age 60 years, his visual acuity was 20/200 OD and 25/200 OS. Ocular motility examination revealed saccadic pursuit without any nystagmus. The saccades were hypermetric with normal velocities. The findings were also compatible with cerebellar dysfunction. Results on fundus examination, autofluorescence, Spectralis spectral-domain optical coherence tomography (Heidelberg Engineering), fundus fluorescein angiography, Goldmann visual field, and multifocal electroretinography were very similar to those of patient 1 (Figure 2). Full-field electroretinographic results were within normal limits under photopic and scotopic conditions. Genetic testing confirmed heterozygote 46 CAG trinucleotide repeat expansion in ATXN1. No other affected family members have been described and his only daughter was negative.
Figure 2. Findings from patient 2. A and B, Funduscopy showed very subtle abnormalities with bilateral hypopigmented fovea. C and D, Autofluorescence imaging showed a central hyperautofluorescence surrounded by a ring of hypofluorescence at both maculae. E and F, Spectral-domain optical coherence tomography showed bilateral loss of the inner segment–outer segment junction band at the fovea and marked thinning of the outer nuclear layer. G and H, Fluorescein angiography showed very subtle hyperfluorescence in the macula, with mild pooling in the late phase. I and J, Goldmann kinetic perimetry showed a normal peripheral sensitivity with a partial central scotoma in both eyes. K and L, Multifocal electroretinography demonstrated a central depression of electrical potentials within the central 5°, more in the left eye.
We describe a novel retinal phenotype in 2 patients from 2 unrelated families with genetically confirmed SCA1.
Loss of vision in patients with SCA is not frequently reported and can result from either optic neuropathy or retinopathy.5,6 Spinocerebellar ataxia type 7 is distinct from other SCAs by the nearly universal presence of retinal degeneration, characterized by early involvement of the macula and cone function.7
Within the fovea, Spectralis spectral-domain optical coherence tomography confirmed a loss of photoreceptors, presumably cones. The retinal pigment epithelial layer under the fovea was still intact in patient 2 with a more recent loss of vision. Both patients also had bilateral foveal spaces or cavities, similar to those reported previously in achromatopsia, blue-cone monochromacy, and cone dystrophy.8
The causative gene in SCA1 is located on the short arm of chromosome 6 and encodes the protein ataxin 1 (ATXN1), which harbors a prolonged and unstable CAG repeat sequence.9 Although the neuronal injury in this syndrome is thought to result from the cellular toxic effects of the polyglutamine product at a protein level,9 the pathogenesis of the maculopathy in SCA1 is not clear.
To understand the mechanism underlying the foveal phenotype found in patients with SCA1, we checked the gene expression in the retina. Although this information is not yet known in humans, we found that there is no retinal expression of the murine counterpart in the recently published database of the transcriptional code for adult retinal cell types.10 Based on this, one could indirectly argue that ATXN1 plays a role in formation of the fovea and maintenance of the foveal cones.
To conclude, this is the first report of a bilateral maculopathy with otherwise normal peripheral retinal anatomy and function in patients with genetically confirmed SCA1. Our data suggest that ATXN1 should be screened in all patients with SCA and decreasing vision. The findings extend the range of ophthalmologic phenotypes and provide important information to assist the management of families in whom SCA1 is suspected.
Correspondence: Dr Munier, Jules-Gonin Eye Hospital, Avenue de France 15, 1004 Lausanne, Switzerland (email@example.com).
Author Contributions: Drs Vaclavik and Borruat contributed equally to the work and share first authorship.
Conflict of Interest Disclosures: None reported.
Funding/Support: This work was supported by grant 320030-127558 from the Swiss National Science Foundation (Dr Munier).
Previous Presentation: This paper was presented at the Atlantic Coast Fan Club Meeting; January 20, 2012; New York, New York; and the Société Française d’Oculogénétique Francophone Annual Meeting; December 2-3, 2011; Lausanne, Switzerland.
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