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Neurosciences
SCA7, from an ophthalmological point of view, can be assessed through numerous multimodal imaging techniques to evaluate and manage the follow-up of patients. Visual acuity is a fundamental parameter that should be monitored, and SDOCT, which is a rapid and non-invasive method, should be routinely performed to evaluate ophthalmic disease progression over time. Additional exams, including NIR imaging, can indicate photoreceptor loss and disruption of the RPE that are not readily evident with CFP.
- spinocerebellar ataxia
- SCA7
- ocular manifestations
- color fundus photography
1. Introduction
Spinocerebellar ataxias (SCAs) are genetic neurodegenerative diseases characterized by progressive loss of balance and coordination and often associated with additional symptoms such as slurred speech or progressive visual loss. Different subtypes are present within the SCA group, including SCA1, which is the most common with a prevalence of 1–5 per 1,000,000 individuals, SCA2, SCA3, SCA6, SCA7, and SCA17. Currently, 27 distinct SCA forms have been recognized, and more are added yearly. The genetic mutations associated with these can be grouped into three classes: CAG/polyglutamine (poly Q) ataxias with expansion; ataxias due to non-protein coding repeat expansions; and ataxias resulting from standard mutations. A genetic expansion in a CAG repeat sequence that translates into a poly Q tract is the pathophysiological basis for SCA7 [1,2].
Genetic studies have identified ATXN7, a gene found on chromosome 3, to be affected in SCA7. ATXN7 alleles typically have 4–35 CAG repeats, with most carrying 10 CAG repeats. SCA7 patients have mutant alleles with 36 or more CAG repeats and can reach more than 460 repeats [2,4,5]. A common feature in polyQ diseases is the intracellular accumulation of amyloid-like aggregates containing protein fragments bearing the polyQ expansion. In SCA7, large aggregates in cell nuclei are observed in numerous brain tissues; these are known as mutant ATXN7 (mATXN7) aggregates and are observed as nuclear inclusions (NI) by immunohistochemistry [6]. As in other polyQ diseases, such as Huntington’s disease, SCA7 patients show an inverse relationship between the number of CAG repeats and the age of disease presentation, whereas there is a direct relationship with the severity of neurological and ophthalmological symptoms [7]. Furthermore, successive generations present disease anticipation, mainly due to paternal transmission. On average, symptoms begin around 30 years of age; however, there is variability, with reported onset ranging from 1 month to 76 years [8]. CAG repeats <59 are more commonly associated with adult onset (age >30 years) with mainly cerebellar and ataxic findings. Repeats over 59 are typically associated with adolescent or young adult onset, and visual impairment is an early symptom. Juvenile and more aggressive forms have been diagnosed in patients with CAG expansion sizes between 60–100, and infantile forms, incompatible with life and associated with multiorgan failure, have been reported with repeat sizes ranging between 200–400 [7,9].
ATXN7 is a core component of SAGA complexes (Spt-Ada-Gcn5 Acetyltransferase) involved in chromatin remodeling. In particular, the C-terminus of ATXN7 extends into SAGA, interacting with proteins in the core module. SAGA is a large complex best described as a chromatin-modifying transcriptional coactivator complex which acetylates and deubiquitinates histones preparing for transcriptional activation [10]. The core module assists with pre-initiation complex assembly, while the splicing module assists with gene activation and transcript splicing.
Transcriptome analysis of SCA7 mouse retina models revealed an early and progressive downregulation of most photoreceptor-specific genes leading to a progressive reduction of electroretinography activity and retinal thinning. The expression profile of SCA7 in mouse cerebellum models showed the downregulation of genes involved in the maintenance and function of neuronal dendrites and myelin sheath. The postmortem cerebellum of SCA7 patients reveals neuronal loss in the Purkinje cell layer, dentate nuclei, and granule cell layer [2,6]. Mitochondrial activity has been analyzed in SCA7, and the results show that it is abnormal in mouse retina and presents a decreased electron transport chain activity and metabolic acidosis in muscle tissue [11]. In SCA7 knock-in and transgenic mouse models, mATXN7 accumulates faster in the nuclei of vulnerable neurons such as photoreceptors and Purkinje cells. mATXN7 nuclear inclusions also disrupt many cellular proteins and activities, thus contributing to pathogenesis. Proteasomes, chaperones, RNA binding proteins, transcription activators such as the CREB-binding protein, and subunits of the SAGA complex may therefore lose their biological functions [2].
2. Multimodal Ophthalmic Imaging in Spinocerebellar Ataxia Type 7
SCA7 is the only spinocerebellar ataxia that seems to be associated with a decrease in visual acuity owing to retinal degeneration. In patients with SCA7, the retina develops in health before showing a progressive reduction of electroretinographic activity, retinal thinning, and silencing of genes specific to photoreceptors. CRX (cone-rod homeobox protein) dysfunction, a key transcription factor of photoreceptor genes, is central to rod and cone dystrophy. CRX requires interaction with ATXN7 and SAGA for its transactivation activity on photoreceptor gene promoters. Additionally, dysregulation of transcriptional programs controlling the maintenance of mature photoreceptors has been found. In histological sections, SCA7 photoreceptors progressively lose their outer segments and cell polarity, acquire a round cell shape, and die via a mechanism of dark degeneration in response to mATXN7 toxicity [6,9,13]. Postmortem retinal sections reveal the almost complete loss of photoreceptors and the considerable loss of bipolar and ganglion cells resulting in severe thinning of the nuclear and plexiform layers. In addition, damage in the Bruch’s membrane, hypertrophy or degeneration of the retinal pigmentary epithelium, and optic nerve hypomyelination can be observed [2].
The ocular manifestations of SCA7 are numerous; therefore, routine ophthalmological examination is not always sufficient to assess early retinal changes that can be demonstrated with multimodal imaging.
Numerous studies present shared characteristics of BCVA, CFP, and SDOCT as the most commonly used techniques, together with some form of color vision testing and visual field examination. Various authors reported the electrophysiological exams of patients. Less diffuse imaging techniques in the study of SCA7 are FAF, fluorescein angiography (FA), and NIR. Some studies focused on specular microscopy to analyze the morphology and cell density of the corneal endothelium.
Central vision is compromised first and then progresses to complete blindness [3]. Visual acuity was converted to decimals, and the mean BCVA was 0.14 ± 0.36 in the patients reported in the study; therefore, in line with previous studies, the central vision was significantly affected. For many SCA7 patients, visual symptoms are an early manifestation of the disease, occurring before or starting together with the ataxic symptomatology. Abe et al. described a phenomenon of ophthalmologic anticipation where decreased visual acuity due to macular dysfunction started earlier in younger generations compared to older patients [14]. Around 15% of patients included in the review were younger than 18 years of age and had a visual acuity that ranged from no light perception to 0.3.
Color perception has been reported as one of the earlier ophthalmological signs. Different studies [13,14,15,16,17,18,19] studied color perception utilizing Ishihara color tests or Farnsworth’s color test, when visual acuity permitted color testing, and described different degrees of color blindness. Four of the six patients studied by Abe et al. had tritan color blindness with loss of blue cones [14], whereas other studies indicated more aspecific color alterations. In a large case series by Velazquez et al., partial or total color blindness was commonly found in patients with adult-onset disease (above 18 years of age), while total blindness was present in nearly all patients with early onset forms (younger than 18 years of age) but in only one-third of patients with adult onset [20].
The spectrum in ocular movement anomalies is extensive, often linked to cerebellar and brainstem impairments. While many patients exhibited no discernible ocular movement disorders, the ones affected typically presented with traits such as saccadic smooth pursuit, elongated saccades, saccadic dysmetria, and eccentric gaze jerk nystagmus [13,19].
Funduscopic findings described by authors vary from normal–subnormal appearing maculae to Bull’s eye maculopathy and diffuse retinal atrophy. Several authors proposed a classification system for describing the fundus appearance of SCA7 patients. Campos et al. in 2000 classified retinal findings into three groups: mild retinopathy when loss of foveal reflex, moderate retinopathy with granular appearance and pigment changes of the RPE, and severe retinopathy with clinically evident atrophy [13]. More recently, in 2021, Marianelli et al. proposed a slightly different staging system composed of four stages, where CFP and SDOCT findings were classified together. Stage 0 was represented by normal CFP, with preserved foveal reflex and standard SDOCT; stage 1 showed abnormalities in macular pigmentation with a granular appearance in CFP and subfoveal cavitation on SDOCT; stage 2 was when macular atrophy was evident both on CFP and SDOCT; in stage 3, atrophic lesions were observed on the macular region, around the optic disc, and at the peripheral retina and SDOCT, it presented with diffuse photoreceptor layer atrophy [21]. This grading system is specific and easily applicable; for example, patients 1 and 3 from the case series presented herein could be classified as stage 1, whereas patient 2 would fit in stage 3.
SDOCT is perhaps one of the most effective ophthalmological imaging methods to evaluate patients with SCA7, as it gives information on retinal thickness and a clear image of the state of the external retinal layers. In 2002, Aleman et al. were among the first to present the SDOCT characteristics of three patients with SCA7, describing foveal and parafoveal thinning with an abnormally low reflectivity splitting of the outer retina-choroidal complex [22]. Other authors, including Park et al., later confirmed these findings, describing foveal thinning with focal disruption of the ellipsoid zone and central loss of the outer segment-RPE interdigitation zone [29]. In 2021, Zou et al. described the presence of hyperreflective dots as a common finding in outer retinal and choroidal vessel layers. These hyperreflective dots seemed to correspond to the coarse granular appearance on the 633-nm scanning laser ophthalmoscope (SLO) images while remaining undetectable on CFP and with fundus autofluorescence. These authors also described that “these dots were not visible in the early stages of disease, were appreciated in an intermediate phase, and became less evident in more advanced retinopathy” [30]. It would be interesting to histopathologically study these aggregates to understand if they could represent photoreceptors that are losing polarity and undergoing dark degeneration or if perhaps they could represent mATXN7 aggregates.
Few authors reported FAF and FA while monitoring patients with SCA7. Zou et al. presented FAF images of three patients, two with a hypofluorescent patch in the macular area with a surrounding hyperfluorescent ring and one with more advanced retinopathy showing a dark area of macular atrophy with mottled autofluorescence in the posterior pole [30]. Ahn et al. described a bull’s eye macular configuration with FA in one patient [32]. This was not the case for a patient with foveal thinning at SDOCT, described by Park et al., where fundus examination, FA, and FAF were normal [29].
As SCA7 patients have significant foveal disruption, visual field examinations reflect this with the presence of commonly described central scotomas [14,16,18,27,29]. Miller et al. performed visual field analysis on eight patients; only one had a normal Humphrey visual field, three had generalized depression, and four presented a central scotoma [20].
Electrophysiological examination is of apparent interest in understanding this pathology that affects the photoreceptors. Velázquez-Pérez et al., in 2015, conducted the most extensive case series using VEP in SCA7 patients. Documenting that impaired VEP was more frequent in patients with early-onset (71.42%) than adult-onset disease (36%). Compared with healthy controls, the most found alteration was a marked prolongation of P100 mean latency [20]. Numerous studies focused on full-field ERG, and results obtained generally demonstrated a prolonged 30-Hz flicker implicit time, with extinguished cone responses in more severely affected patients, indicating a widespread cone photoreceptor degeneration [14,15,16,17,18,19,22,25,27,28,30]. Results reported on scotopic responses were less consistent. Katagiri et al. recorded preserved rod responses in one patient [18]; Miller et al. performed full-field ERG on four patients who had affected cone responses, while only one patient showed a combination of cone and rod degeneration [19]. On other occasions, the scotopic response decreased to some degree or as much as the photopic response, suggestive of cone-rod dystrophy [11,19,22,25,27,30,31]. Multifocal ERG (mfERG), evaluating the cone function in localized areas of the macular region, recorded significantly reduced amplitudes within the foveal area; in more advanced patients, amplitudes were reduced even in the outer mfERG areas [17]. Horton et al. proposed four stages of SCA7 disease using ERG as one of the critical biomarkers. Stage 0 patients were gene positive and asymptomatic, with normal physiology (deep tendon reflexes and/or ERG); stage 1 patients had hyperreflexia or abnormal ERG; stage 2 patients had mild disease and slow progression; stage 3 patients showed rapid disease evolution [36].
3. Conclusions
SCA7, from an ophthalmological point of view, can be assessed through numerous multimodal imaging techniques to evaluate and manage the follow-up of patients. Visual acuity is a fundamental parameter that should be monitored, and SDOCT, which is a rapid and non-invasive method, should be routinely performed to evaluate ophthalmic disease progression over time. Additional exams, including NIR imaging, can indicate photoreceptor loss and disruption of the RPE that are not readily evident with CFP. Electrophysiological tests are longer examinations and more difficult for patients to undergo; however, they give essential results on the state of cone and rod dystrophy that could be paramount in guiding future genetic therapies [37,38].
This entry is adapted from the peer-reviewed paper 10.3390/life13112169
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