ATXN7-Related Cone-Rod Dystrophy: The Integrated Functional Evaluation of the Cerebellum (CERMOI) Study.

Importance: Reliable biomarkers with diagnostic and prognostic values are needed for upcoming gene therapy trials for spinocerebellar ataxias. Objective: To identify ophthalmological biomarkers in a sample of spinocerebellar ataxia type 7 (SCA7) carriers. Design, Setting, and Participants: This article presents baseline data from a cross-sectional natural history study conducted in Paris, France, reference centers for rare diseases from May 2020 to April 2021. Data were analyzed from September to December 2022. Fifteen adult ATXN7 pathogenic expansion carriers (9 with preataxia and 6 with ataxia) were included, all with a Scale for the Assessment and Rating of Ataxia (SARA) score of 15 of 40 or lower. Patients were recruited at the Paris Brain Institute, and all contacted patients accepted to participate in the study. Main Outcomes and Measures: Three visits (baseline, 6 months, and 12 months) were planned, including neurological examination (SARA and Composite Cerebellar Functional Severity Score), ophthalmological examination (best-corrected visual acuity, microperimetry, full-field electroretinogram, optical coherence tomography, and fundus autofluorescence imaging), and neurofilament light chain (NfL) measurements. Here we report the baseline ophthalmic data from the cohort and determine whether there is a correlation between disease scores and ophthalmic results. Results: Among the 15 included SCA7 carriers (median [range] age, 38 [18-60] years; 8 women and 7 men), 12 displayed cone or cone-rod dystrophy, with the number of CAG repeats correlating with disease severity (ρ, 0.73, 95% CI, 0.34 to 0.90; P < .001). Two patients with cone-rod dystrophy exhibited higher repeat numbers and greater ataxia scores (median [range] SARA score, 9 [7-15]) compared to those with only cone dystrophy (median [range] SARA score, 2 [0-5]). A correlation emerged for outer nuclear layer thickness with SARA score (ρ, -0.88; 95% CI, -0.96 to -0.59; P < .001) and NfL levels (ρ, -0.87; 95% CI, -0.86 to 0.96; P < .001). Moreover, ataxia severity was correlated with visual acuity (ρ: 0.89; 95% CI, 0.68 to 0.96; P < .001) and retinal sensitivity (ρ, -0.88; 95% CI, -0.96 to 0.59; P < .001). Conclusions and Relevance: In this cross-sectional study, retinal abnormalities were found at preataxic stages of the disease. Most of the carriers presented with cone dystrophy and preserved rod function. The outer nuclear layer thickness correlated with SARA score and plasma NfL levels suggesting nuclear layer thickness to be a biomarker of disease severity. These findings contribute to understanding the dynamics of SCA7-related retinal dystrophy and may help lay the groundwork for future therapeutic intervention monitoring and clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04288128.

Extreme Interocular Asymmetry in an Atypical Case of a Hydroxychloroquine-Related Retinopathy.

Background and Objectives: Long-term hydroxychloroquine (HCQ) therapy can lead to retinal toxicity. Typically, it is characterized by a bull's eye maculopathy. More recently, a "pericentral" form of HCQ retinopathy that predominantly affects patients of Asian descent has been described. To our knowledge, this is the first reported case where such an asymmetry between the right and the left eye in the toxicity profile is observed. Case presentation: The patient presented with a 12-year exposure to HCQ at a daily dose of 4.35 mg/kg. She presented an inferior pericentral-only phenotype of HCQ toxicity on the right eye and a perifoveal-only toxicity on the left eye. Modest progression of toxicity was observed on both eyes over the seven years of follow-up, despite drug discontinuation. Conclusions: To our knowledge, this is the first time that two different phenotypes of HCQ-related retinopathy are found in the same patient, challenging our understanding of the pathophysiology of HCQ retinal toxicity.