A BS TRACT: Background: The cerebellar ataxia, neuropathy, and vestibular areflexia syndrome was initially described in the early 1990s as a late-onset slowly progressive condition. Its underlying genetic cause was recently mapped to the RFC1 gene, and additional reports have expanded on the phenotypic manifestations related to RFC1, although little is known about the pattern and extent of structural brain abnormalities in this condition.Objective: The aim is to characterize the structural signature of brain damage in RFC1-related disorder, correlating the findings with clinical symptoms and normal brain RFC1 expression. Methods: We recruited 22 individuals with molecular confirmation of RFC1 expansions and submitted them to high-resolution 3T magnetic resonance imaging scans. We performed multimodal analyses to assess separately cerebral and cerebellar abnormalities within gray and white matter (WM). The results were compared with a group of 22 age-and sex-matched controls. Results:The mean age and disease duration of patients were 62.8 and 10.9 years, respectively. Ataxia, sensory neuronopathy, and vestibular areflexia were the most frequent manifestations, but parkinsonism and pyramidal signs were also noticed. We found that RFC1-related disorder is characterized by widespread and relatively symmetric cerebellar and basal ganglia atrophy. There is brainstem volumetric reduction along all its segments. Cerebral WM is also involved-mostly the corpus callosum and deep tracts, but cerebral cortical damage is rather restricted. Conclusion: This study adds new relevant insights into the pathophysiological mechanisms of RFC1-related disorder. It should no longer be considered a purely cerebellar and sensory pathway disorder. Basal ganglia and deep cerebral WM are additional targets of damage.

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

A BS TRACT: Background: Spinal cord has been considered the main target of damage in hereditary spastic paraplegias (HSPs), but mounting evidence indicates that the brain is also affected. Despite this, little is known about the brain signature of HSPs, in particular regarding stratification for specific genetic subtypes. Objective: We aimed to characterize cerebral and cerebellar damage in five HSP subtypes (9 SPG3A, 27 SPG4, 10 SPG7, 9 SPG8, and 29 SPG11) and to uncover the clinical and gene expression correlates. Methods: We obtained high-resolution brain T1 and diffusion tensor image (DTI) datasets in this cross-sectional case-control study (n = 84). The MRICloud, FreeSurfer, and CERES-SUIT pipelines were employed to assess cerebral gray (GM) and white matter (WM) as well as the cerebellum. Results: Brain abnormalities were found in all but one HSP group (SPG3A), but the patterns were gene-specific: basal ganglia, thalamic, and posterior WM involvement in SPG4; diffuse WM and cerebellar involvement in SPG7; cortical thinning at the motor cortices and pallidal atrophy in SPG8; and widespread GM, WM, and deep cerebellar nuclei damage in SPG11. Abnormal regions in SPG4 and SPG8 matched those with higher SPAST and WASHC5 expression, whereas in SPG7 and SPG11 this concordance was only noticed in the cerebellum. Conclusions: Brain damage is a conspicuous feature of HSPs (even for pure subtypes), but the pattern of abnormalities is genotype-specific. Correlation between brain structural damage and gene expression maps is different for autosomal dominant and recessive HSPs, pointing to distinct pathophysiological mechanisms underlying brain damage in these subgroups of the disease.

Background Neurodegeneration affects the brain and peripheral nervous system in spinocerebellar ataxia type 3 (SCA3). As the retina is also involved, studying the retinal architecture in a cohort of patients could reveal clinically relevant biomarkers. Objective The aim is to investigate retinal architecture in SCA3 to identify potential biomarkers. Methods We evaluated 38 patients with SCA3 and 25 healthy age‐matched controls, who underwent visual acuity assessment, intraocular pressure measurement, and fundoscopy and macular and peripapillary spectral domain optical coherence tomography (SD‐OCT). We measured the peripapillary retinal nerve fiber layer (pRNFL) thickness in each quadrant of the temporal‐superior‐nasal‐inferior‐temporal chart and the macular layer thicknesses in each sector of the inner circle of the Early Treatment Diabetic Retinopathy Study (IC‐ETDRS) grid. Linear regression analysis was employed to test the associations between retinal parameters and age, disease duration, CAG repeats, and SARA (Scale of the Assessment and Rating of Ataxia) and ICARS (International Cooperative Ataxia Rating Scale) scores in SCA3. Results In all sectors, except for the temporal quadrant, pRNFL was significantly thinner in SCA3 patients than in controls. Average total macular, ganglion cell layer (GCL), and inner plexiform layer (IPL) thicknesses were significantly decreased in SCA3 patients in comparison to controls. The average total macular thickness and the average thicknesses of RNFL, GCL, and IPL negatively correlated with ICARS scores, whereas average GCL and IPL thicknesses negatively correlated with SARA scores. Conclusions The retinal ganglion cells, their dendrites, and axons are selectively affected in SCA3 patients. The RNFL, GCL, and IPL thicknesses in SD‐OCT correlate with the clinical phenotype and represent potential biomarkers for future clinical trials and natural history studies. © 2021 International Parkinson and Movement Disorder Society

The present study aimed to characterize clinical and molecular data of a large cohort of subjects with childhood-onset hereditary spastic paraplegias (HSPs). A multicenter historical cohort was performed at five centers in Brazil, in which probands and affected relatives' data from consecutive families with childhood-onset HSP (onset < 12 years-old) were reviewed from 2011 to 2020. One hundred and six individuals (83 families) with suspicion of childhood-onset HSP were evaluated, being 68 (50 families) with solved genetic diagnosis, 6 (5 families) with candidate variants in HSP-related genes and 32 (28 families) with unsolved genetic diagnosis. The most common childhood-onset subtype was SPG4, 11/50 (22%) families with solved genetic diagnosis; followed by SPG3A, 8/50 (16%). Missense pathogenic variants in SPAST were found in 54.5% of probands, favoring the association of this type of variant to childhood-onset SPG4. Survival curves to major handicap and cross-sectional Spastic Paraplegia Rating Scale progressions confirmed the slow neurological deterioration in SPG4 and SPG3A. Most common complicating features and twenty variants not previously described in HSP-related genes were reported. These results are fundamental to understand the molecular and clinical epidemiology of childhood-onset HSP, which might help on differential diagnosis, patient care and guiding future collaborative trials for these rare diseases.