Retinal Architecture in Autosomal Recessive Spastic Ataxia of Charlevoix‐Saguenay (ARSACS): Insights into Disease Pathogenesis and Biomarkers

Abstract

Background Autosomal recessive spastic ataxia of Charlevoix‐Saguenay (ARSACS) causes unique retinal abnormalities, which have not been systematically investigated. Objective To deeply phenotype the retina in ARSACS in order to better understand its pathogenesis and identify potential biomarkers. Methods We evaluated 29 patients with ARSACS, 66 with spinocerebellar ataxia (SCA), 38 with autosomal recessive cerebellar ataxia (ATX), 22 with hereditary spastic paraplegia (SPG), 21 cases of papilledema, and 20 healthy controls (total n = 196 subjects). Participants underwent visual acuity assessment, intraocular pressure measurement, fundoscopy, and macular and peripapillary optical coherence tomography (OCT). Macular layers thicknesses in ARSACS were compared with those of age‐matched healthy controls. Ophthalmologists analyzed the scans for abnormal signs in the different patient groups. Linear regression analysis was conducted to look for associations between retinal changes and age, age at onset, disease duration, and Scale for the Assessment and Rating of Ataxia (SARA) scores in ARSACS. Results Only patients with ARSACS exhibited peripapillary retinal striations (82%) on fundoscopy, and their OCT scans revealed foveal hypoplasia (100%), sawtooth appearance (89%), papillomacular fold (86%), and macular microcysts (18%). Average peripapillary retinal nerve fiber layer (pRNFL) was thicker in ARSACS than in SCA, ATX, SPG, and controls; a cut‐off of 121 μm was 100% accurate in diagnosing ARSACS. All macular layers were thicker in ARSACS when compared to healthy controls. RNFL thickness in the inferior sector of the macula positively correlated with SARA scores. Conclusions Retinal abnormalities are highly specific for ARSACS, and suggest retinal hyperplasia due to abnormal retinal development. OCT may provide potential biomarkers for future clinical trials. © 2021 International Parkinson and Movement Disorder Society

Hsp90 Inhibition: A Promising Therapeutic Approach for ARSACS

“…However, the further examination of 13 heterozygous carriers revealed that this thickness (115.5 µm) was just below the 119 µm threshold for distinguishing ARSACS from non-ARSACS patients [21]. A recent study suggests that this cut-off should be increased to 121 µm to provide 100% accuracy in diagnosing ARSACS [22].…”

Altered retinal structure and function in Spinocerebellar ataxia type 3

“…In fact, patients with Spinocerebellar ataxia type 7 show macular dysfunction and morphological retinal alterations 22,56,57 . Importantly, previous studies reported that patients with Spinocerebellar ataxia type 3 also reveal thinning of the NFL, GCL and macula [29][30][31]58 , but whether the retinal function is affected in patients with this disease remained uncovered. We, therefore, sought to evaluate both the anatomy and function of the retina in patients with Spinocerebellar ataxia type 3 and in a transgenic mouse model.…”

“…In healthy individuals, ATXN3 harbors 12 to about 51 CAGs, whereas in patients with Spinocerebellar ataxia type 3 the gene contains an expanded (CAG) n tract that ranges from ~60 to 87 triplets 3,4 . Intermediate length alleles (45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60) show incomplete penetrance or differential clinical presentation 5 . The length of the ATXN3 expanded CAG repeat correlates directly with phenotypic severity and disease progression rate, and indirectly with the age at onset of the first clinical manifestations [6][7][8][9][10][11] .…”

Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration

“…Since the retina may be an excellent source of potential surrogate biomarkers in ARSACS, Rezende Filho et al (2021) performed fundoscopy (another simple cost-effective technique) and OCT on patients with ARSACS and other forms of ataxia (spinocerebellar ataxia, autosomal recessive cerebellar ataxia, hereditary spastic paraplegia). The investigated retinal nerve fiber thickening in ARSACS by fundoscopy provided false negative data, suggesting that this method has lower sensitivity than OCT [ 130 ].…”

“…All ARSACS patients presented foveal hypoplasia, in addition to other impairments, such as retinal hyperplasia, sawtooth appearance or papillomacular fold. The above results suggest that monitoring neurophysiological abnormalities could yield promising biomarkers for ARSACS diagnosis [ 72 , 130 ], such as nerve conduction or nerve ultrasonography. Nerve enlargement and peripheral demyelination may be useful biomarkers in ARSACS [ 35 , 36 ].…”