Spinocerebellar ataxia Type 7 (SCA-7) is part of a group of inherited neurodegenerative diseases that belong to autosomal dominant cerebellar ataxias. Autosomal dominant cerebellar ataxias are further divided into three subtypes: I–III. Spinocerebellar ataxia Type 7 belongs to Type II, which is described as ataxia with retinal degeneration and is the only SCA within the Subtype II.1,2 Genetically, SCA-7 has been linked to chromosome 3p12-13 and found to have a repeating pattern of (CAG)n resulting in the expansion of the coding region.1,3 Genetic anticipation is strongly associated with SCA-7, which is described as an earlier age of onset and a more severe progression of the disease in successive generations.1,3,4 Visually, the degree of retinopathy can vary from mild to severe, correlating with the number of CAG repeats. The purpose of this article is to present a case study and review of SCA-7.
A 5-year-old African American female, previously healthy, first presented to the emergency room with worsening of shaking, decreased ability to walk, and progressive vision loss. On presentation, her motor skills had progressively regressed to the inability to balance properly, requiring assistance in ambulation. She had full muscle strength proven on electromyography; however, she was unable to coordinate her movements and a broad-based ataxic gait was observed. At her healthy baseline, she was able to participate in ballerina activities without any problems. The patient was also noted to have developed developmental and language regression from her baseline. Visually, she was able to track but was found to have impaired smooth pursuit eye movements. Metabolic disorder and mass lesions were ruled out with subsequent testing and imaging which allowed for a diagnosis of cerebellar ataxia with developmental regression.
During the patient's hospitalization, there was concern for SCA hereditary disorder, and ophthalmology was requested for ocular examination. Her examination results showed hand motion visual acuity in both eyes with normal anterior segment. Fundus examination showed hypopigmentation and atrophy of the macula, arterial attenuation and straightening, and widespread pigmentary changes involving the midperipheral retina (Figure 1). Flash visually evoked potential and electroretinogram were attempted with the patient under anesthesia, but results of the analysis were unreliable. Spectral domain optical coherence tomography was attempted but unsuccessful because of patient's age and inability to fixate. Subsequent testing showed loss of the ability to differentiate color. Hereditary disorder workup was performed, showing a negative ataxia autosomal recessive panel, whereas the autosomal dominant ataxia panel was abnormal with expanded 96 CAG repeats on the ATXN7 gene.
The patient's father, a 27-year-old healthy African American male, also had poor visual acuity of 20/150 in both eyes and carried a diagnosis of possible solar retinopathy. Interestingly, he denied any sun gazing, laser beam injury, or welding activity. His retinal examination suggested foveal atrophy, with bilateral parafoveal pigmentary changes, and mild temporal pallor of the optic nerves (Figure 2). Optical coherence tomography revealed foveal thinning, bilateral symmetric optically empty fovea with loss of the outer foveal reflectivity. Structurally, there were bilateral foveal cavitations, loss of the ellipsoid zone (measuring 410 μm in right eye and 480 μm in left eye), and preservation of the external limiting membrane (Figure 3). He subsequently underwent genetic testing and was also found to have expanded 47 CAG repeats on the ataxin-7 gene. This milder form of retinopathy and “outer foveal cavitation” on optical coherence tomography has been described by Agarwal et al to be associated with SCA-7.5,6 His diagnosis was subsequently changed to cone–rod degeneration associated with SCA-7.
All forms of SCA are characterized by variable degeneration of cerebellar cortex, basal ganglia, brainstem, spinal cord, and peripheral nerves. Within the autosomal dominant cerebellar ataxia groups, there are only several that present with ocular findings. Spinocerebellar ataxia Type 3 can present with nystagmus, ophthalmoplegia, and bulging eyes.2 Spinocerebellar ataxia Type 7 or olivopontocerebellar atrophy with retinal degeneration is the only SCA consistently associated with retinal degeneration.4 It should be mentioned that there are three case reports of SCA-1 reporting retinal maculopathy; however, this is not a typical characteristic finding of SCA-1.7 The molecular basis of SCA-7 is based on the expansion of CAG repeats in the ataxin-7 gene. This gene has been shown to suppress cone–rod homeobox protein transactivation, which contributes to controlling the level of activity of photoreceptor-specific genes, including rhodopsin and color opsin.8 Suppression of this protein results in loss of cone photoreceptor cells and the resulting funduscopic, electroretinography, and optical coherence tomography findings. Initial funduscopic findings may be mild and may lead to misdiagnosis of disease, as in the case of our father. However with continued expansion of CAG repeats due to parent–child transmission, there is an anticipated progressive worsening of retinopathy in successive generations.9 Johansson et al10 reported the negative correlation between age of onset and CAG repeats in 17 Swedish patients with SCA-7.
Visual symptoms of SCA-7 are variable and can present either before or after neurologic symptoms. Symptoms are usually reduced central vision or abnormal color vision with eventual peripheral vision loss. Visual acuity ranges from 20/60 to hand motion.4 Funduscopic macular changes can range from a mild granular pigment mottling to severe bull's eye maculopathy and peripheral pigmentary retinopathy.9 Late-stage temporal optic nerve pallor has also been documented in case series.11 Electrophysiological testing shows early cone dysfunction followed by rod dysfunction in later stages, resulting in a cone–rod dystrophy.12 Differential diagnosis of this disease should include the following etiologies: Genetic (cone dystrophy associated with RP1LI or KCNV2 mutation, achromatopsia, stargardt, neuronal ceroid lipofucinosis, Bardet–Biedl syndrome, and retinitis pigmentosa), Degenerative (juxtafoveal macular telangiectasia Type II), Toxic (tamoxifen toxicity and popper's usage), Tractional (vitreomacular traction and resolved macular hole), and Iatrogenic (solar retinopathy, laser beam injury and welder maculopathy).
Our case study is unique in the diagnosis of the daughter with SCA-7, which helped diagnose her father with SCA-7. Findings were confirmed with genetic testing of expanded CAG repeats displaying the genetic anticipation as expected in this disorder. Fundus images also demonstrate the successive worsening in pigmentary retinopathy from father to child. The variable presentation and subsequent sequela of SCA-7 demonstrate the importance of early retinal evaluation in the diagnosis and management of this disease. Early detection will be beneficial to the patient and their family for effective counseling and visual rehabilitation.
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Keywords:© 2017 by Ophthalmic Communications Society, Inc.
CAG repeats; inherited retinal dystrophy; spinocerebellar ataxia Type 7 (SCA-7); optical coherence tomography (OCT); outer foveal cavitation; cone-rod degeneration