Cognitive Impairment Is Part of the Phenotype of Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS).

BACKGROUND: Little is known about the impact of the cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) on cognition. OBJECTIVE: Our objective was to determine the frequency and severity of cognitive impairment in RFC1-positive patients and describe the pattern of deficits. METHODS: Participants underwent a comprehensive neuropsychological assessment. Volume of the cerebellum and its lobules was measured in those who underwent a 3 Tesla-magnetic resonance scan. RESULTS: Twenty-one patients underwent a complete assessment, including 71% scoring lower than the cutoff at the Montreal Cognitive assessment and 71% having a definite cerebellar cognitive affective/Schmahmann syndrome. Three patients had dementia and seven met the criteria of mild cognitive impairment. Severity of cognitive impairment did not correlate with severity of clinical manifestations. Performance at memory and visuospatial functions tests negatively correlated with the severity of cerebellar manifestations. CONCLUSION: Cognitive manifestations are frequent in RFC1-related disorders. They should be included in the phenotype and screened systematically. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A Review of Brain and Pituitary Gland MRI Findings in Patients with Ataxia and Hypogonadism.

The association of cerebellar ataxia and hypogonadism occurs in a heterogeneous group of disorders, caused by different genetic mutations often associated with a recessive inheritance. In these patients, magnetic resonance imaging (MRI) plays a pivotal role in the diagnostic workflow, with a variable involvement of the cerebellar cortex, alone or in combination with other brain structures. Neuroimaging involvement of the pituitary gland is also variable. Here, we provide an overview of the main clinical and conventional brain and pituitary gland MRI imaging findings of the most common genetic mutations associated with the clinical phenotype of ataxia and hypogonadism, with the aim of helping neuroradiologists in the identification of these disorders.

Uncertainty of Vowel Predictions as a Digital Biomarker for Ataxic Dysarthria.

Dysarthria is a common manifestation across cerebellar ataxias leading to impairments in communication, reduced social connections, and decreased quality of life. While dysarthria symptoms may be present in other neurological conditions, ataxic dysarthria is a perceptually distinct motor speech disorder, with the most prominent characteristics being articulation and prosody abnormalities along with distorted vowels. We hypothesized that uncertainty of vowel predictions by an automatic speech recognition system can capture speech changes present in cerebellar ataxia. Speech of participants with ataxia (N=61) and healthy controls (N=25) was recorded during the "picture description" task. Additionally, participants' dysarthric speech and ataxia severity were assessed on a Brief Ataxia Rating Scale (BARS). Eight participants with ataxia had speech and BARS data at two timepoints. A neural network trained for phoneme prediction was applied to speech recordings. Average entropy of vowel tokens predictions (AVE) was computed for each participant's recording, together with mean pitch and intensity standard deviations (MPSD and MISD) in the vowel segments. AVE and MISD demonstrated associations with BARS speech score (Spearman's rho=0.45 and 0.51), and AVE demonstrated associations with BARS total (rho=0.39). In the longitudinal cohort, Wilcoxon pairwise signed rank test demonstrated an increase in BARS total and AVE, while BARS speech and acoustic measures did not significantly increase. Relationship of AVE to both BARS speech and BARS total, as well as the ability to capture disease progression even in absence of measured speech decline, indicates the potential of AVE as a digital biomarker for cerebellar ataxia.

Imbalance and gait impairment in Parkinson's disease: discussing postural instability and ataxia.

Gait and balance difficulties pose significant clinical challenges in Parkinson's disease (PD). The impairment of physiological mechanisms responsible for maintaining natural orthostatism plays a central role in the pathophysiology of postural instability observed in PD. In addition to the well-known rigidity and abnormalities in muscles and joints, various brain regions involved in the regulation of posture, balance, and gait, such as the basal ganglia, cerebellum, and brainstem regions like the pontine peduncle nucleus, are affected in individuals with PD. The recognition of the cerebellum's role in PD has been increasingly acknowledged. Cortical areas and their connections are associated with freezing of gait, a type of frontal lobe ataxia commonly observed in PD. Furthermore, impairments in the peripheral nervous system, including those caused by levodopatherapy, can contribute to gait impairment and imbalance in PD patients. Consequently, individuals with PD may exhibit frontal ataxia, sensory ataxia, and even cerebellar ataxia as underlying causes of gait disturbances and imbalance, starting from the early stages of the disease. The complex interplay between dysfunctional brain regions, impaired cortical connections, and peripheral nervous system abnormalities contributes to the multifaceted nature of gait and balance difficulties in PD. Understanding the intricate mechanisms is crucial for the development of effective therapeutic approaches targeting these specific deficits in PD.

Neurological gait assessment.

Gait disorders are a common feature of neurological disease. The gait examination is an essential part of the neurological clinical assessment, providing valuable clues to a myriad of causes. Understanding how to examine gait is not only essential for neurological diagnosis but also for treatment and prognosis. Here, we review aspects of the clinical history and examination of neurological gait to help guide gait disorder assessment. We focus particularly on how to differentiate between common gait abnormalities and highlight the characteristic features of the more prevalent neurological gait patterns such as ataxia, waddling, steppage, spastic gait, Parkinson's disease and functional gait disorders. We also offer diagnostic clues for some unusual gait presentations, such as dystonic, stiff-person and choreiform gait, along with red flags that help differentiate atypical parkinsonism from Parkinson's disease.

Natural History and Phenotypic Spectrum of GAA-FGF14 Sporadic Late-Onset Cerebellar Ataxia (SCA27B).

BACKGROUND: Heterozygous GAA expansions in the FGF14 gene have been related to autosomal dominant cerebellar ataxia (SCA27B-MIM:620174). Whether they represent a common cause of sporadic late-onset cerebellar ataxia (SLOCA) remains to be established. OBJECTIVES: To estimate the prevalence, characterize the phenotypic spectrum, identify discriminative features, and model longitudinal progression of SCA27B in a prospective cohort of SLOCA patients. METHODS: FGF14 expansions screening combined with longitudinal deep-phenotyping in a prospective cohort of 118 SLOCA patients (onset >40 years of age, no family history of cerebellar ataxia) without a definite diagnosis. RESULTS: Prevalence of SCA27B was 12.7% (15/118). Higher age of onset, higher Spinocerebellar Degeneration Functional Score, presence of vertigo, diplopia, nystagmus, orthostatic hypotension absence, and sensorimotor neuropathy were significantly associated with SCA27B. Ataxia progression was ≈0.4 points per year on the Scale for Assessment and Rating of Ataxia. CONCLUSIONS: FGF14 expansion is a major cause of SLOCA. Our natural history data will inform future FGF14 clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Consensus Paper: Ataxic Gait.

The aim of this consensus paper is to discuss the roles of the cerebellum in human gait, as well as its assessment and therapy. Cerebellar vermis is critical for postural control. The cerebellum ensures the mapping of sensory information into temporally relevant motor commands. Mental imagery of gait involves intrinsically connected fronto-parietal networks comprising the cerebellum. Muscular activities in cerebellar patients show impaired timing of discharges, affecting the patterning of the synergies subserving locomotion. Ataxia of stance/gait is amongst the first cerebellar deficits in cerebellar disorders such as degenerative ataxias and is a disabling symptom with a high risk of falls. Prolonged discharges and increased muscle coactivation may be related to compensatory mechanisms and enhanced body sway, respectively. Essential tremor is frequently associated with mild gait ataxia. There is growing evidence for an important role of the cerebellar cortex in the pathogenesis of essential tremor. In multiple sclerosis, balance and gait are affected due to cerebellar and spinal cord involvement, as a result of disseminated demyelination and neurodegeneration impairing proprioception. In orthostatic tremor, patients often show mild-to-moderate limb and gait ataxia. The tremor generator is likely located in the posterior fossa. Tandem gait is impaired in the early stages of cerebellar disorders and may be particularly useful in the evaluation of pre-ataxic stages of progressive ataxias. Impaired inter-joint coordination and enhanced variability of gait temporal and kinetic parameters can be grasped by wearable devices such as accelerometers. Kinect is a promising low cost technology to obtain reliable measurements and remote assessments of gait. Deep learning methods are being developed in order to help clinicians in the diagnosis and decision-making process. Locomotor adaptation is impaired in cerebellar patients. Coordinative training aims to improve the coordinative strategy and foot placements across strides, cerebellar patients benefiting from intense rehabilitation therapies. Robotic training is a promising approach to complement conventional rehabilitation and neuromodulation of the cerebellum. Wearable dynamic orthoses represent a potential aid to assist gait. The panel of experts agree that the understanding of the cerebellar contribution to gait control will lead to a better management of cerebellar ataxias in general and will likely contribute to use gait parameters as robust biomarkers of future clinical trials.

Ataxia in a Movement Disorders Outpatient Clinic: a Single-Center Experience in Turkey.

The etiology may not be determined in patients with ataxia despite detailed evaluations. The aim of this study was to investigate the clinical and laboratory characteristics of a large cohort of patients with adult-onset ataxia of different etiologies, particularly, undetermined etiologies despite extensive clinical, genetic, laboratory, electrophysiological, and imaging investigations. The medical records of all patients diagnosed with ataxia of subacute-chronic onset between January 2011 and March 2021 were reviewed retrospectively. The records of patients with symptom onset after 16 years of age were included in the study. In all patients, clinical and demographic findings were noted. Etiologies were classified as acquired, hereditary, degenerative (multiple system atrophy-cerebellar, MSA-C), functional, and undetermined. During the study period, we determined 74 patients with ataxia and 59 (35 males) patients met the study criteria. The age range was 22-87 years. The etiologies were hereditary (n = 19), acquired (n = 14), MSA-C (n = 9), functional (n = 2), and undetermined (n = 15). The patients with hereditary etiologies and undetermined causes were significantly younger at admission and at symptom onset (p = 0.001 and p = 0.000). There was a significant delay until diagnosis in patients with hereditary etiologies compared to other etiologies. In acquired etiologies, axial findings (71.4%) were more prominent whereas extremity and axial findings were more common in patients with hereditary etiologies (83.3%, p = 0.030). There were systemic and radiological indicators such as hearing loss, juvenile cataract, or dentate hyperintensity in certain disorders. Hereditary etiologies are as common as acquired or degenerative etiologies in adults. However, they have an earlier onset and delayed diagnosis. Therefore, we should recognize the extracerebellar neurological, systemic, and neuroimaging findings.

Multimodal Mobility Assessment Predicts Fall Frequency and Severity in Cerebellar Ataxia.

This cohort study aims to evaluate the predictive validity of multimodal clinical assessment and quantitative measures of in- and off-laboratory mobility for fall-risk estimation in patients with cerebellar ataxia (CA).Occurrence, severity, and consequences of falling were prospectively assessed for 6 months in 93 patients with hereditary (N = 36) and sporadic or secondary (N = 57) forms of CA and 63 healthy controls. Participants completed a multimodal clinical and functional fall risk assessment, in-laboratory gait examination, and a 2-week inertial sensor-based daily mobility monitoring. Multivariate logistic regression analyses were performed to evaluate the predictive capacity of all clinical and in- and off-laboratory mobility measures with respect to fall (1) status (non-faller vs. faller), (2) frequency (occasional vs. frequent falls), and (3) severity (benign vs. injurious fall) of patients. 64% of patients experienced one or recurrent falls and 65% of these severe fall-related injuries during prospective assessment. Mobility impairments in patients corresponded to a mild-to-moderate ataxic gait disorder. Patients' fall status and frequency could be reliably predicted (78% and 81% accuracy, respectively), primarily based on their retrospective fall status. Clinical scoring of ataxic symptoms and in- and off-laboratory gait and mobility measures improved classification and provided unique information for the prediction of fall severity (84% accuracy).These results encourage a stepwise approach for fall risk assessment in patients with CA: fall history-taking readily and reliably informs the clinician about patients' general fall risk. Clinical scoring and instrument-based mobility measures provide further in-depth information on the risk of recurrent and injurious falling.

Translation, Cross-Cultural Adaptation, and Validation to Brazilian Portuguese of the Cerebellar Cognitive Affective/Schmahmann Syndrome Scale.

Cerebellar cognitive affective syndrome (CCAS) is characterized by deficits in executive functions, language processing, spatial orientation, and affect regulation in patients with cerebellar disease. The symptoms can occur isolated or along with motor and coordination symptoms. The aim of our study was to translate and culturally adapt the CCAS scale to Brazilian Portuguese and validate the scale in our population. We performed a cross-sectional study with patients with primary and secondary ataxia. The study included 111 individuals, aged between 20 and 80 years, of both genders, 20 without cognitive and/or affective complaints who participated in the pre-test phase, 40 with cerebellar disease (hereditary/neurodegenerative ataxia or acquired/secondary cerebellar ataxia), and 51 healthy controls with no evidence of cognitive impairment and no affective symptoms matched for sex, age, and educational level. The scale was translated, culturally adapted, and validated. Statistical analysis of the data was performed, with association tests, mean comparison, and ROC curve analysis. Based on the analysis of the ROC curve, optimal cutoff values ​were found for each subitem of the scale. The translated and adapted scale has good internal consistency, is reproducible, has good reliability, and has the potential to be a reliable tool for screening cognitive symptoms in patients with cerebellar disease.

Dengue fever presenting as acute cerebellar ataxia: Case report and literature review.

Dengue fever has been associated with several neurological complications, cerebellar involvement being among the rarest of them. Here, we describe the case of a 70-year-old female who presented a cerebellar syndrome during the first day of an arboviral infection, posteriorly confirmed as dengue fever. Among the seven other cases in which the relationship between dengue virus and ataxia was reported, only in one cerebellar presentation occurred as early. Onset, course, and prognosis, as well as the adequate investigation and management of these patients, are discussed. While the disease pattern is not better characterized by future studies, differential diagnosis and close follow-up are essential tools for guaranteeing good outcomes.

Clinical and Genetic Characterization of Brazilian Patients with Ataxia and Oculomotor Apraxia.

BACKGROUND: Ataxia with oculomotor apraxia (AOA) is characterized by early-onset cerebellar ataxia associated with oculomotor apraxia. AOA1, AOA2, AOA3, and AOA4 subtypes may present pathogenic variants in APTX, SETX, PIK3R5, and PNKP genes, respectively. Mutations in XRCC1 have been found to cause autosomal recessive spinocerebellar ataxia-26 (SCAR26) now considered AOA5. OBJECTIVES: To examine a cohort of Brazilians with autosomal recessive cerebellar ataxia plus oculomotor apraxia and determine the frequencies of AOA subtypes through genetic investigation. METHODS: We evaluated clinical, biomarkers, electrophysiological, and radiological findings of 52 patients with AOA phenotype and performed a genetic panel including APTX, SETX, PIK3R5, PNKP, and XRCC1. RESULTS: We found pathogenic variants in SETX (15 patients), PNKP (12), and APTX (5). No mutations in PIK3R5 or XRCC1 were identified. CONCLUSIONS: AOA2 and AOA4 were the most common forms of AOA in Brazil. Mutations in PIK3R5 and XRCC1 were not part of this genetic spectrum. © 2022 International Parkinson and Movement Disorder Society.

Novel Homozygous Truncating Variant Widens the Spectrum of Early-Onset Multisystemic SYNE1 Ataxia.

Pathogenic variants in the SYNE1 gene are associated with a phenotypic spectrum spanning from late-onset, slowly progressive, relatively pure ataxia to early-onset, fast progressive multisystemic disease. Since its first description in 2007 as an adult-onset ataxia in French Canadian families, subsequent identification of patients worldwide has widened the clinical spectrum and increased the number of identified pathogenic variants. We report a 20-year-old Faroese female with early-onset progressive gait problems, weakness, dysphagia, slurred speech, orthostatic dizziness, and urge incontinence. Neurological examination revealed mild cognitive deficits, dysarthria, broken slow pursuit, hypometric saccades, weakness with spasticity, hyperreflexia, absent ankle reflexes, ataxia, and wide-based, spastic gait. Magnetic resonance imaging displayed atrophy of the cerebellum, brainstem, and spinal cord. Severely prolonged central motor conduction time and lower motor neuron involvement was demonstrated electrophysiologically. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scan showed hypometabolism of the cerebellum and right frontal lobe. Muscle biopsy revealed chronic neurogenic changes and near-absent immunostaining for Nesprin-1. Next-generation sequencing revealed a previously undescribed homozygous truncating, likely pathogenic variant in the SYNE1 gene. The patient's mother and paternal grandfather were heterozygous carriers of the variant. Her father's genotype was unobtainable. We expand the list of likely pathogenic variants in SYNE1 ataxia with a novel homozygous truncating variant with proximity to the C-terminus and relate it to a phenotype comprising early-onset cerebellar deficits, upper and lower motor neuron involvement and cognitive deficits. Also, we report novel findings of focally reduced frontal lobe FDG-PET uptake and motor evoked potential abnormalities suggestive of central demyelination.

The posterior fossa syndrome questionnaire: using science to inform practice.

INTRODUCTION: Up to 34% of patients with medulloblastoma develop posterior fossa syndrome (PFS) following brain tumor resection and have increased risk of long-term neurocognitive impairments. Lack of agreement in conceptualization and diagnosis of PFS calls for improvements in diagnostic methods. The current study aimed to describe psychometric properties of a new posterior fossa syndrome questionnaire (PFSQ). METHODS: The PFSQ was informed by prior research and developed by a multidisciplinary team with subject matter expertise. Participants (N = 164; 63.4% Male; 78.7% White; Mage at diagnosis = 10.38 years, SD = 5.09, range 3-31 years) included patients with newly diagnosed medulloblastoma enrolled in the SJMB12 clinical trial. Forty-four patients (26.8%) were classified as having PFS based on attending physician's post-surgical yes/no report. A PFSQ was completed by a neurologist within 2 weeks of coming to St. Jude Children's Research Hospital for adjuvant treatment, irrespective of suspicion for PFS. RESULTS: PFSQ items ataxia (100.00%), dysmetria (95.45%), and speech/language changes (79.55%) were most sensitive. However, ataxia (26.50%) and dysmetria (46.61%) demonstrated low specificity. Speech/language changes (81.36%), mutism (95.76%), orofacial apraxia (98.29%) and irritability (96.61%) had high specificity. A principal component analysis found four components: (1) speech/language changes, (2) apraxias (including mutism), (3) motor/oromotor, and (4) emotional lability. CONCLUSIONS: The PFSQ is a dimensional diagnostic approach that can be used to improve diagnostic consistency across clinical and research groups to help accelerate understanding of PFS etiology, identify surgical correlates of risk, predict long-term impairments, and develop targeted interventions. Additional measure validation, including correlation with symptom resolution, is required.

Clinical heterogeneity in patients with myoclonus associated to COVID-19.

OBJECTIVE: This study aims to report the clinical heterogeneity of myoclonus in 6 patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: Patient data were obtained from medical records from the University Hospital Dr. Josep Trueta, Girona, Spain. RESULTS: Six patients (5 men and 1 woman, aged 60-76 years) presented with different myoclonus phenotypes. All of them had a medical history of hypertension and overweight. The latency of myoclonus appearance ranged from 1 to 129 days. The phenotype most observed was generalized myoclonus. Special phenotypes such as painful legs and moving toes syndrome with jerking feet, Lazarus sign-like, action myoclonus/ataxia syndrome, and segmental myoclonus secondary to myelitis have been described too. Levetiracetam and clonazepam were medications most used successfully. Two patients died for complications not related to myoclonus. CONCLUSIONS: Our 6 cases highlight the heterogeneity of the clinical spectrum of myoclonus associated to COVID-19 (MYaCO). MYaCO pathogenesis is suspected to be due to an immune-mediated para- or post-infectious phenomenon; nevertheless, further research is needed to elucidate this hypothesis.

Postinfectious SARS-CoV-2 Opsoclonus-Myoclonus-Ataxia Syndrome.

BACKGROUND: The opsoclonus-myoclonus-ataxia syndrome (OMAS) represents a pathophysiology and diagnostic challenge. Although the diverse etiologies likely share a common mechanism to generate ocular, trunk, and limb movements, the underlying cause may be a paraneoplastic syndrome, as the first sign of cancer, or may be a postinfectious complication, and thus, the outcome depends on identifying the trigger mechanism. A recent hypothesis suggests increased GABAA receptor sensitivity in the olivary-oculomotor vermis-fastigial nucleus-premotor saccade burst neuron circuit in the brainstem. Therefore, OMAS management will focus on immunosuppression and modulation of GABAA hypersensitivity with benzodiazepines. METHODS: We serially video recorded the eye movements at the bedside of 1 patient with SARS-CoV-2-specific Immunoglobulin G (IgG) serum antibodies, but twice-negative nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR). We tested cerebrospinal fluid (CSF), serum, and nasopharyngeal samples. After brain MRI and chest, abdomen, and pelvis CT scans, we treated our patient with clonazepam and high-dose Solu-MEDROL, followed by a rituximab infusion after her formal eye movement analysis 10 days later. RESULTS: The recordings throughout her acute illness demonstrated different eye movement abnormalities. While on high-dose steroids and clonazepam, she initially had macrosaccadic oscillations, followed by brief ocular flutter during convergence the next day; after 10 days, she had bursts of opsoclonus during scotopic conditions with fixation block but otherwise normal eye movements. Concern for a suboptimal response to high-dose Solu-MEDROL motivated an infusion of rituximab, which induced remission. An investigation for a paraneoplastic etiology was negative. CSF testing showed elevated neuron-specific enolase. Serum IgG to Serum SARS-CoV2 IgG was elevated with negative RT-PCR nasopharyngeal testing. CONCLUSION: A recent simulation model of macrosaccadic oscillations and OMAS proposes a combined pathology of brainstem and cerebellar because of increased GABAA receptor sensitivity. In this case report, we report 1 patient with elevated CSF neuronal specific enolase, macrosaccadic oscillations, ocular flutter, and OMAS as a SARS-CoV-2 postinfectious complication. Opsoclonus emerged predominantly with fixation block and suppressed with fixation, providing support to modern theories on the mechanism responsible for these ocular oscillations involving cerebellar-brainstem pathogenesis.

[Clinical characteristics and prognosis of patients with anti-glutamic acid decarboxylase antibody-related cerebellar ataxia].

The clinical data, diagnosis, treatment, and prognosis of 10 patients with anti-glutamic acid decarboxylase (GAD) antibody-related cerebellar ataxia in Department of Neurology, Peking Union Medical College Hospital, from May 2015 to November 2021 were retrospectively analyzed. There were 8 female patients with a median age of 55 years old. Patients mainly presented with gait ataxia (10/10), dizziness (8/10), diplopia (6/10), and dysarthria (5/10). Four of them were complicated with other autoimmune disease, including vitiligo (3/4), Hashimoto thyroiditis (1/4), thrombocytopenia (1/4), and small cell lung cancer (1/4). All patients received immunotherapy, 6 out of 10 exhibited a good response, and half of them had satisfied functional prognosis. Patients of anti-GAD antibody-related cerebellar ataxia may be complicated with other autoimmune diseases, but underlying tumor is rare. More than half of patients have a good response to immunotherapy and satisfied prognosis.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): genetic and clinical aspects.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) typically presents in middle life with a combination of neuropathy, ataxia and vestibular disease, with patients reporting progressive imbalance, oscillopsia, sensory disturbance and a dry cough. Examination identifies a sensory neuropathy or neuronopathy and bilaterally impaired vestibulo-ocular reflex. The underlying genetic basis is of biallelic AAGGG expansions in the second intron of replication factor complex subunit 1 (RFC1). The frequency and phenotype spectrum of RFC1 disease is expanding, ranging from typical CANVAS to site-restricted variants affecting the sensory nerves, cerebellum and/or the vestibular system. Given the wide phenotype spectrum of RFC1, the differential diagnosis is broad. RFC1 disease due to biallelic AAGGG expansions is probably the most common cause of recessive ataxia. The key to suspecting the disease (and prompt genetic testing) is a thorough clinical examination assessing the three affected systems and noting the presence of chronic cough.

[Subacute cerebellar ataxia, an uncommon SARS-CoV-2 complication infection in older adults]. / Ataxie cérébelleuse subaiguë : une atteinte atypique par le SARS-CoV-2 chez la personne âgée.

Cerebellar ataxia can be caused by neoplasia, toxics (drugs, heavy metals, alcohol), infection, vascular lesions or auto-immune and paraneoplastic pathologies. Neuroimaging must be performed urgently in case of sudden onset and serologies as well as a lumbar puncture should be performed. Several case reports of ataxia associated with COVID-19 have been published, however the underlying pathogenic mechanisms remain unclear. This is a diagnosis of exclusion when other causes are ruled out and when the ataxia appears simultaneously to COVID-19 infection. We lack data on best management, but the prognosis appears mostly favorable with good functional recovery without any specific treatment. This paper describes the case of a patient who developed a cerebellar ataxia as the only neurological manifestation of a SARS-CoV-2 infection.

Une ataxie cérébelleuse peut être causée par un processus (para)néoplasique, auto-imun, une exposition toxique, une infection ou une lésion vasculaire. Une imagerie doit être réalisée en urgence devant toute atteinte aiguë et le bilan devrait être complété par des sérologies larges et une ponction lombaire. Plusieurs cas d'ataxie liée au Covid-19 ont été décrits, dont le mécanisme étiopathogénique reste incomplètement élucidé, le diagnostic se faisant plutôt par exclusion lorsque les symptômes apparaissent de manière concomitante à l'infection. Des données manquent sur la prise en charge mais le pronostic semble favorable, avec une bonne récupération fonctionnelle. Cet article décrit le cas d'une patiente ayant présenté une ataxie cérébelleuse comme symptôme neurologique isolé contemporain d'une infection à SARS-CoV-2.

Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia.

RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.