Feasibility of a randomized, sham-controlled pilot study for accelerated rTMS-treatment of the cerebellum plus physiotherapy in CANVAS patients.

BACKGROUND: Cerebellar ataxia, neuropathy and bilateral vestibular areflexia (CANVAS) is a rare neurodegenerative disease affecting the cerebellum, the peripheral nervous system and the vestibular system. Due to the lack of approved drugs, therapy comprises physiotherapy and speech therapy. Transcranial magnetic stimulation is a promising non-invasive therapeutic option to complement classical symptomatic therapies. OBJECTIVE: To test feasibility of the combination of transcranial magnetic stimulation using an accelerated protocol and standard symptomatic therapy in patients with CANVAS. METHODS: Eight patients with genetically confirmed CANVAS were assigned to either verum or sham cerebellar transcranial magnetic stimulation using an accelerated protocol. Treatment duration was limited to 5 days. Additionally, patients in both groups received symptomatic therapy (speech and physiotherapy) for the duration of the study. RESULTS: All patients completed the stimulation protocol. Adverse events were rare. Ataxia severity improved in the verum group only. CONCLUSION: The combination of transcranial magnetic stimulation and classic symptomatic therapy is feasible in a neuro-rehabilitation setting and potentially ameliorates ataxia severity.

Neuroglobin overexpression in cerebellar neurons of Harlequin mice improves mitochondrial homeostasis and reduces ataxic behavior.

Neuroglobin, a member of the globin superfamily, is abundant in the brain, retina, and cerebellum of mammals and localizes to mitochondria. The protein exhibits neuroprotective capacities by participating in electron transfer, oxygen supply, and protecting against oxidative stress. Our objective was to determine whether neuroglobin overexpression can be used to treat neurological disorders. We chose Harlequin mice, which harbor a retroviral insertion in the first intron of the apoptosis-inducing factor gene resulting in the depletion of the corresponding protein essential for mitochondrial biogenesis. Consequently, Harlequin mice display degeneration of the cerebellum and suffer from progressive blindness and ataxia. Cerebellar ataxia begins in Harlequin mice at the age of 4 months and is characterized by neuronal cell disappearance, bioenergetics failure, and motor and cognitive impairments, which aggravated with aging. Mice aged 2 months received adeno-associated viral vectors harboring the coding sequence of neuroglobin or apoptosis-inducing factor in both cerebellar hemispheres. Six months later, Harlequin mice exhibited substantial improvements in motor and cognitive skills; probably linked to the preservation of respiratory chain function, Purkinje cell numbers and connectivity. Thus, without sharing functional properties with apoptosis-inducing factor, neuroglobin was efficient in reducing ataxia in Harlequin mice.

Real-time field-programmable gate array-based closed-loop deep brain stimulation platform targeting cerebellar circuitry rescues motor deficits in a mouse model of cerebellar ataxia.

AIMS: The open-loop nature of conventional deep brain stimulation (DBS) produces continuous and excessive stimulation to patients which contributes largely to increased prevalence of adverse side effects. Cerebellar ataxia is characterized by abnormal Purkinje cells (PCs) dendritic arborization, loss of PCs and motor coordination, and muscle weakness with no effective treatment. We aim to develop a real-time field-programmable gate array (FPGA) prototype targeting the deep cerebellar nuclei (DCN) to close the loop for ataxia using conditional double knockout mice with deletion of PC-specific LIM homeobox (Lhx)1 and Lhx5, resulting in abnormal dendritic arborization and motor deficits. METHODS: We implanted multielectrode array in the DCN and muscles of ataxia mice. The beneficial effect of open-loop DCN-DBS or closed-loop DCN-DBS was compared by motor behavioral assessments, electromyography (EMG), and neural activities (neurospike and electroencephalogram) in freely moving mice. FPGA board, which performed complex real-time computation, was used for closed-loop DCN-DBS system. RESULTS: Closed-loop DCN-DBS was triggered only when symptomatic muscle EMG was detected in a real-time manner, which restored motor activities, electroencephalogram activities and neurospike properties completely in ataxia mice. Closed-loop DCN-DBS was more effective than an open-loop paradigm as it reduced the frequency of DBS. CONCLUSION: Our real-time FPGA-based DCN-DBS system could be a potential clinical strategy for alleviating cerebellar ataxia and other movement disorders.

Efficacy and Safety of Repetitive Transcranial Magnetic Stimulation in Cerebellar Ataxia: a Systematic Review and Meta-analysis.

Cerebellar ataxia(CA) is defined as a degenerative disease of the nervous system. Repetitive transcranial magnetic stimulation (rTMS) has been a promising treatment for neurological and psychiatric diseases. Hence, to find out whether cerebellar rTMS impacts CA as a potential therapy, we performed a systematic review and meta-analysis. Qualified studies through a systematic search were retrieved for randomized controlled trials (RCTs) using acknowledged databases. Review Manager 5.4 software was employed to synthesize the data. A total of seven studies were identified as eligible and included in the quantitative review. Comparing real and sham-rTMS interventions, the utilization of rTMS on cerebellum improved the scale for the assessment and rating of ataxia (SARA) (SMD - 0.87, 95% CI - 1.41 to - 0.34; P = 0.001; I2 = 62%), the International Cooperative Ataxia Rating Scale (ICARS) (SMD - 1.06, 95% CI - 1.47 to - 0.64; P < 0.00001; I2 = 0%) and Berg balance Scale (BBS) (SMD 0.76, 95% CI 0.33 to 1.19; P = 0.0005; I2 = 39%). The subgroup analysis demonstrated high-frequency of rTMS had a positive effect (SMD - 1.28, 95% CI - 1.82 to - 0.74; P < 0.00001; I2 = 0%). For the safety, the incidence of adverse events between the two groups was not significantly different (OR 1.73, 95% CI 0.55 to 5.46; P = 0.35; I2 = 0%). In conclusion, this meta-analysis provided limited evidence, suggesting a possible strategy that rTMS over the cerebellum could be a viable therapy for symptoms associated with CA. Besides, rTMS intervention was well-attended and did not result in unanticipated negative effects.

Consensus Paper: Latent Autoimmune Cerebellar Ataxia (LACA).

Immune-mediated cerebellar ataxias (IMCAs) have diverse etiologies. Patients with IMCAs develop cerebellar symptoms, characterized mainly by gait ataxia, showing an acute or subacute clinical course. We present a novel concept of latent autoimmune cerebellar ataxia (LACA), analogous to latent autoimmune diabetes in adults (LADA). LADA is a slowly progressive form of autoimmune diabetes where patients are often initially diagnosed with type 2 diabetes. The sole biomarker (serum anti-GAD antibody) is not always present or can fluctuate. However, the disease progresses to pancreatic beta-cell failure and insulin dependency within about 5 years. Due to the unclear autoimmune profile, clinicians often struggle to reach an early diagnosis during the period when insulin production is not severely compromised. LACA is also characterized by a slowly progressive course, lack of obvious autoimmune background, and difficulties in reaching a diagnosis in the absence of clear markers for IMCAs. The authors discuss two aspects of LACA: (1) the not manifestly evident autoimmunity and (2) the prodromal stage of IMCA's characterized by a period of partial neuronal dysfunction where non-specific symptoms may occur. In order to achieve an early intervention and prevent cell death in the cerebellum, identification of the time-window before irreversible neuronal loss is critical. LACA occurs during this time-window when possible preservation of neural plasticity exists. Efforts should be devoted to the early identification of biological, neurophysiological, neuropsychological, morphological (brain morphometry), and multimodal biomarkers allowing early diagnosis and therapeutic intervention and to avoid irreversible neuronal loss.

Comparing Cerebellar tDCS and Cerebellar tACS in Neurodegenerative Ataxias Using Wearable Sensors: A Randomized, Double-Blind, Sham-Controlled, Triple-Crossover Trial.

Cerebellar transcranial direct current stimulation (tDCS) represents a promising therapeutic approach for both motor and cognitive symptoms in neurodegenerative ataxias. Recently, transcranial alternating current stimulation (tACS) was also demonstrated to modulate cerebellar excitability by neuronal entrainment. To compare the effectiveness of cerebellar tDCS vs. cerebellar tACS in patients with neurodegenerative ataxia, we performed a double-blind, randomized, sham controlled, triple cross-over trial with cerebellar tDCS, cerebellar tACS or sham stimulation in twenty-six participants with neurodegenerative ataxia. Before entering the study, each participant underwent motor assessment with wearable sensors considering gait cadence (steps/minute), turn velocity (degrees/second) and turn duration (seconds), and a clinical evaluation with the scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS). After each intervention, participants underwent the same clinical assessment along with cerebellar inhibition (CBI) measurement, a marker of cerebellar activity. The gait cadence, turn velocity, SARA, and ICARS significantly improved after both tDCS and tACS, compared to sham stimulation (all p<0.010). Comparable effects were observed for CBI (p<0.001). Overall, tDCS significantly outperformed tACS on clinical scales and CBI (p<0.01). A significant correlation between changes of wearable sensors parameters from baseline and changes of clinical scales and CBI scores was detected. Cerebellar tDCS and cerebellar tACS are effective in ameliorating symptoms of neurodegenerative ataxias, with the former being more beneficial than the latter. Wearable sensors may serve as rater-unbiased outcome measures in future clinical trials. ClinicalTrial.gov Identifier: NCT05621200.

Ataxia-associated DNA repair genes protect the Drosophila mushroom body and locomotor function against glutamate signaling-associated damage.

The precise control of motor movements is of fundamental importance to all behaviors in the animal kingdom. Efficient motor behavior depends on dedicated neuronal circuits - such as those in the cerebellum - that are controlled by extensive genetic programs. Autosomal recessive cerebellar ataxias (ARCAs) provide a valuable entry point into how interactions between genetic programs maintain cerebellar motor circuits. We previously identified a striking enrichment of DNA repair genes in ARCAs. How dysfunction of ARCA-associated DNA repair genes leads to preferential cerebellar dysfunction and impaired motor function is however unknown. The expression of ARCA DNA repair genes is not specific to the cerebellum. Only a limited number of animal models for DNA repair ARCAs exist, and, even for these, the interconnection between DNA repair defects, cerebellar circuit dysfunction, and motor behavior is barely established. We used Drosophila melanogaster to characterize the function of ARCA-associated DNA repair genes in the mushroom body (MB), a structure in the Drosophila central brain that shares structural features with the cerebellum. Here, we demonstrate that the MB is required for efficient startle-induced and spontaneous motor behaviors. Inhibition of synaptic transmission and loss-of-function of ARCA-associated DNA repair genes in the MB affected motor behavior in several assays. These motor deficits correlated with increased levels of MB DNA damage, MB Kenyon cell apoptosis and/or alterations in MB morphology. We further show that expression of genes involved in glutamate signaling pathways are highly, specifically, and persistently elevated in the postnatal human cerebellum. Manipulation of glutamate signaling in the MB induced motor defects, Kenyon cell DNA damage and apoptosis. Importantly, pharmacological reduction of glutamate signaling in the ARCA DNA repair models rescued the identified motor deficits, suggesting a role for aberrant glutamate signaling in ARCA-DNA repair disorders. In conclusion, our data highlight the importance of ARCA-associated DNA repair genes and glutamate signaling pathways to the cerebellum, the Drosophila MB and motor behavior. We propose that glutamate signaling may confer preferential cerebellar vulnerability in ARCA-associated DNA repair disorders. Targeting glutamate signaling could provide an exciting therapeutic entry point in this large group of so far untreatable disorders.

Efficacy and safety of noninvasive brain stimulation for patients with cerebellar ataxia: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: With the development of noninvasive brain stimulation (NIBS) techniques, many researchers have turned their attention to NIBS as a promising treatment for cerebellar ataxia. Therefore, we conducted a systematic review and meta-analysis to investigate the efficacy and safety of NIBS in treating patients with cerebellar ataxia. METHODS: Databases, including PubMed, Embase, Web of Science, Medline, and Cochrane Library, were retrieved for relevant randomized controlled trials (RCTs). Two researchers conducted literature screening, data extraction, literature quality assessment, and heterogeneity analysis between RCTs. According to the magnitude of heterogeneity I2, an appropriate data analysis model was selected for meta-analysis. RESULTS: A total of 14 RCTs including 406 patients with cerebellar ataxia met the inclusion criteria. The included RCTs had an overall low-risk bias and an intermediate level of evidence recommendation for key outcome indicators, such as the scale for the assessment and rating of ataxia (SARA) and international cooperative ataxia rating scale (ICARS). The results of meta-analysis showed that cerebellar NIBS, including transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), was effective in reducing the SARA scores (MD = - 3.45, 95%CI = [- 4.85, - 2.50], P < 0.05) and ICARS scores (MD = - 10.87, 95%CI = [- 14.46, - 7.28], P < 0.05) in patients with cerebellar ataxia compared to controls. Subgroup analysis showed that the efficacy of tDCS and rTMS was statistically different in patients with cerebellar ataxia as assessed by the SARA scores, but not by the ICARS scores. There was statistically significant difference in the efficacy of NIBS for the treatment of cerebellar ataxia caused by different etiologies. As for safety, 8 of 14 included studies documented the adverse effects of NIBS, and only two studies reported the mild adverse events of NIBS. CONCLUSIONS: Cerebellar NIBS was safe and effective in improving the motor coordination of patients with cerebellar ataxia, and tDCS was better than rTMS in the treatment of cerebellar ataxia. In addition, the efficacy of NIBS was different in the treatment of different types of cerebellar ataxia.

Autosomal dominant cerebellar ataxias: new genes and progress towards treatments.

Dominantly inherited spinocerebellar ataxias (SCAs) are associated with phenotypes that range from pure cerebellar to multisystemic. The list of implicated genes has lengthened in the past 5 years with the inclusion of SCA37/DAB1, SCA45/FAT2, SCA46/PLD3, SCA47/PUM1, SCA48/STUB1, SCA50/NPTX1, SCA25/PNPT1, SCA49/SAM9DL, and SCA27B/FGF14. In some patients, co-occurrence of multiple potentially pathogenic variants can explain variable penetrance or more severe phenotypes. Given this extreme clinical and genetic heterogeneity, genome sequencing should become the diagnostic tool of choice but is still not available in many clinical settings. Treatments tested in phase 2 and phase 3 studies, such as riluzole and transcranial direct current stimulation of the cerebellum and spinal cord, have given conflicting results. To enable early intervention, preataxic carriers of pathogenic variants should be assessed with biomarkers, such as neurofilament light chain and brain MRI; these biomarkers could also be used as outcome measures, given that clinical outcomes are not useful in the preataxic phase. The development of bioassays measuring the concentration of the mutant protein (eg, ataxin-3) might facilitate monitoring of target engagement by gene therapies.

Effects of non-invasive brain stimulation for degenerative cerebellar ataxia: a protocol for a systematic review and meta-analysis.

INTRODUCTION: To date, the medical and rehabilitation needs of people with degenerative cerebellar ataxia (DCA) are not fully met because no curative treatment has yet been established. Movement disorders such as cerebellar ataxia and balance and gait disturbance are common symptoms of DCA. Recently, non-invasive brain stimulation (NIBS) techniques, including repetitive transcranial magnetic stimulation and transcranial electrical stimulation, have been reported as possible intervention methods to improve cerebellar ataxia. However, evidence of the effects of NIBS on cerebellar ataxia, gait ability, and activity of daily living is insufficient. This study will aim to systematically evaluate the clinical effects of NIBS on patients with DCA. METHODS AND ANALYSIS: We will conduct a preregistered systematic review and meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We will include randomised controlled trials to assess the effects of NIBS on patients with DCA. The primary clinical outcome will be cerebellar ataxia, as measured by the Scale for Assessment and Rating of Ataxia and the International Cooperative Ataxia Rating Scale. The secondary outcomes will include gait speed, functional ambulatory capacity and functional independence measure, as well as any other reported outcomes that the reviewer considers important. The following databases will be searched: PubMed, Cochrane Central Register of Controlled Trials, CINAHL and PEDro. We will assess the strength of the evidence included in the studies and estimate the effects of NIBS. ETHICS AND DISSEMINATION: Because of the nature of systematic reviews, no ethical issues are anticipated. This systematic review will provide evidence on the effects of NIBS in patients with DCA. The findings of this review are expected to contribute to clinical decision-making towards selecting NIBS techniques for treatment and generating new clinical questions to be addressed. PROSPERO REGISTRATION NUMBER: CRD42023379192.

Cerebellar ataxia-neuropathy-vestibular areflexia-syndrome.

CANVAS including its clinical components of cerebellar ataxia, sensory neuropathy and vestibular areflexia is presented in this review. An intronic biallelic pentanucleotide expansion in RFC1 is the genetic cause of CANVAS. Several patients diagnosed with isolated "idiopathic" neurological or otological conditions might have a CANVAS spectrum disorder. The number of CANVAS patients may well increase considerably in the near future, making it important to consider the diagnostic set-up and infrastructure for counselling, treatment and follow-up in the Danish healthcare system.

The Therapeutic Potential of Non-Invasive and Invasive Cerebellar Stimulation Techniques in Hereditary Ataxias.

The degenerative ataxias comprise a heterogeneous group of inherited and acquired disorders that are characterized by a progressive cerebellar syndrome, frequently in combination with one or more extracerebellar signs. Specific disease-modifying interventions are currently not available for many of these rare conditions, which underscores the necessity of finding effective symptomatic therapies. During the past five to ten years, an increasing number of randomized controlled trials have been conducted examining the potential of different non-invasive brain stimulation techniques to induce symptomatic improvement. In addition, a few smaller studies have explored deep brain stimulation (DBS) of the dentate nucleus as an invasive means to directly modulate cerebellar output, thereby aiming to alleviate ataxia severity. In this paper, we comprehensively review the clinical and neurophysiological effects of transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and dentate nucleus DBS in patients with hereditary ataxias, as well as the presumed underlying mechanisms at the cellular and network level and perspectives for future research.

Gene Suppression Therapies in Hereditary Cerebellar Ataxias: A Systematic Review of Animal Studies.

INTRODUCTION: Hereditary cerebellar ataxias (HCAs) are a heterogenous group of neurodegenerative disorders associated with severe disability. Treatment options are limited and overall restricted to symptomatic approaches, leading to poor prognoses. In recent years, there has been extensive research on gene suppression therapies (GSTs) as a new hope for disease-modifying strategies. In this article, we aim to perform a review of in vivo studies investigating the efficacy and safety profile of GSTs in HCAs. METHODS: A structured PubMed® search on GSTs in HCAs from January 1993 up to October 2020 was performed. Inclusion and exclusion criteria were defined, and the selection process was conducted accordingly. The screening process was independently carried out by two authors and was initially based on title and abstract, followed by full-text reading. The risk-of-bias assessment was performed with SYRCLE's tool. A data extraction sheet was created to collect relevant information from each selected article. RESULTS: The initial search yielded 262 papers, of which 239 were excluded. An additional article was obtained following reference scrutiny, resulting in a total of 24 articles for final analysis. Most studies were not clear on the tools used to assess bias. In SCA1, SCA2, MJD/SCA3 and SCA7, RNA interference (iRNA) and antisense oligonucleotide (ASO) therapies proved to be well tolerated and effective in suppressing mutant proteins, improving neuropathological features and the motor phenotype. In SCA6, the phenotype was improved, but no investigation of adverse effects was performed. In FRDA, only the suppression efficacy of the electroporation of the clustered regularly interspaced short palindromic repeats associated with Cas9 enzyme system (CRISPR-Cas9) system was tested and confirmed. CONCLUSION: The literature reviewed suggests that GSTs are well tolerated and effective in suppressing the targeted proteins, improving neuropathological features and the motor phenotype in vivo. Nonetheless, there is no guarantee that these results are free of bias. Moreover, further investigation is still needed to clarify the GST effect on HCAs such as FRDA, SCA6 and SCA2.

Toward a cerebello-thalamo-cortical computational model of spinocerebellar ataxia.

Computational neural network modelling is an emerging approach for optimization of drug treatment of neurological disorders and fine-tuning of rehabilitation strategies. In the current study, we constructed a cerebello-thalamo-cortical computational neural network model to simulate a mouse model of cerebellar ataxia (pcd5J mice) by manipulating cerebellar bursts through reduction of GABAergic inhibitory input. Cerebellar output neurons were projected to the thalamus and bidirectionally connected with the cortical network. Our results showed that reduction of inhibitory input in the cerebellum orchestrated the cortical local field potential (LFP) dynamics to generate specific motor outputs of oscillations of the theta, alpha, and beta bands in the computational model as well as in mouse motor cortical neurons. The therapeutic potential of deep brain stimulation (DBS) was tested in the computational model by increasing the sensory input to restore cortical output. Ataxia mice showed normalization of the motor cortex LFP after cerebellum DBS. We provide a novel approach to computational modelling to investigate the effect of DBS by mimicking cerebellar ataxia involving degeneration of Purkinje cells. Simulated neural activity coincides with findings from neural recordings of ataxia mice. Our computational model could thus represent cerebellar pathologies and provide insight into how to improve disease symptoms by restoring neuronal electrophysiological properties using DBS.

Effect of disturbance stimulation using a split-belt treadmill on a patient with cerebellar ataxia: a case report.

PURPOSE: We present the case of a patient with cerebellar ataxia who was treated with walking practice using a split-belt treadmill with disturbance stimulation. The treatment effects were evaluated for improvements in standing postural balance and walking ability. CASE PRESENTATION: The patient was a 60-year-old Japanese male who developed ataxia after cerebellar hemorrhage. Assessment was performed using the Scale for the Assessment and Rating of Ataxia, Berg Balance Scale, and Timed Up-and-Go tests. A 10 m walking speed and walking rate were also assessed longitudinally. The obtained values were fit into a linear equation (y = ax + b), and the slope was calculated. This slope was then used as the predicted value for each period relative to the pre-intervention value. After removing the trend of the value for each period relative to the pre-intervention value, the amount of pre- to post-intervention change for each period was calculated to verify the intervention effect. Furthermore, to verify the changes in gait over time, a three-dimensional motion analyzer was used to analyze the pre- and post-intervention gait five times, and the results were kinematically compared. RESULTS: No significant pre- to post-intervention changes were observed in the Scale for the Assessment and Rating of Ataxia scores. Conversely, the Berg Balance Scale score, walking rate, and 10 m walking speed increased, and the Timed Up-and-Go score decreased in the B1 period, indicating a marked improvement from the predicted results based on the linear equation. For changes in gait determined using three-dimensional motion analysis, an increase in stride length was observed in each period. CONCLUSION: The present case findings suggest that walking practice with disturbance stimulation using a split-belt treadmill does not improve inter-limb coordination, but contributes to improving standing posture balance, 10 m walking speed, and walking rate.

CACNA1A-Related Channelopathies: Clinical Manifestations and Treatment Options.

In the last decade, variants in the Ca2+ channel gene CACNA1A emerged as a frequent aetiology of rare neurological phenotypes sharing a common denominator of variable paroxysmal manifestations and chronic cerebellar dysfunction. The spectrum of paroxysmal manifestations encompasses migraine with hemiplegic aura, episodic ataxia, epilepsy and paroxysmal non-epileptic movement disorders. Additional chronic neurological symptoms range from severe developmental phenotypes in early-onset cases to neurobehavioural disorders and chronic cerebellar ataxia in older children and adults.In the present review we systematically approach the clinical manifestations of CACNA1A variants, delineate genotype-phenotype correlations and elaborate on the emerging concept of an age-dependent phenotypic spectrum in CACNA1A disease. We furthermore reflect on different therapy options available for paroxysmal symptoms in CACNA1A and address open issues to prioritize in the future clinical research.

ATP1A3-related phenotypes in Chinese children: AHC, CAPOS, and RECA.

The aim of this research is to study the phenotype, genotype, treatment strategies, and short-term prognosis of Chinese children with ATP1A3 (Na+/K+-ATPase alpha 3 gene)-related disorders in Southwest China. Patients with pathogenic ATP1A3 variants identified using next-generation sequencing were registered at the Children's Hospital of Chongqing Medical University from December 2015 to May 2019. We followed them as a cohort and analyzed their clinical data. Eleven patients were identified with de novo pathogenic ATP1A3 heterozygous variants. One (c.2542 + 1G > T, splicing) has not been reported. Eight patients with alternating hemiplegia of childhood (AHC), one with cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), and two with relapsing encephalopathy with cerebellar ataxia (RECA) were included. The initial manifestations of AHC included hemiplegia, oculomotor abnormalities, and seizures, and the most common trigger was an upper respiratory tract infection without fever. All patients had paroxysmal hemiplegic attacks during their disease course. The brain MRI showed no abnormalities. Six out of eight AHC cases reached a stable disease state after treatment. The initial symptom of the patient with CAPOS was ataxia followed by developmental regression, seizures, deafness, visual impairment, and dysarthria, and the brain MRI indicated mild cerebellar atrophy. No fluctuation was noted after using Acetazolamide. The initial manifestations of the two RECA cases were dystonia and encephalopathy, respectively. One manifested a rapid-onset course of dystonia triggered by a fever followed by dysarthria and action tremors, and independent walking was impossible. The brain MRI image was normal. The other one presented with disturbance of consciousness, seizures, sleep disturbance, tremor, and dyskinesias. The EEG revealed a slow background (δ activity), and the brain MRI result was normal. No response to Flunarizine was noted for them, and it took 61 and 60 months for them to reach a stable disease state, respectively. CONCLUSION: Pathogenic ATP1A3 variants play an essential role in the pathogenesis of Sodium-Potassium pump disorders, and AHC is the most common phenotype. The treatment strategies and prognosis depend on the phenotype categories caused by different variation sites and types. The correlation between the genotype and phenotype requires further exploration. WHAT IS KNOWN: • Pathogenic heterozygous ATP1A3 variants cause a spectrum of neurological phenotypes, and ATP1A3-disorders are viewed as a phenotypic continuum presenting with atypical and overlapping features. • The genotype-phenotype correlation of ATP1A3-disorders remains unclear. WHAT IS NEW: • In this study, the genotypes and phenotypes of ATP1A3-related disorders from Southwest of China were described. The splice-site variation c.2542+1G>T was detected for the first time in ATP1A3-related disorders. • The prognosis of twins with AHC p. Gly947Arg was more serious than AHC cases with other variants, which was inconsistent with previous reports. The phenomenon indicated the diversity of the correlation between the genotype and phenotype.

Treatment and Management of Autosomal Recessive Cerebellar Ataxias: Current Advances and Future Perspectives.

The autosomal recessive cerebellar ataxias (ARCAs) compose a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by prominent cerebellar ataxia, dysmetria, dysarthria, and nystagmus that are inherited in an autosomal recessive fashion. The diagnosis of ARCAs is challenging because of their low prevalence, poor medical recognition, and heterogeneous clinical presentation with many overlapping features between entities. There currently exist no disease-modifying therapies for most ARCAs, and treatment is mainly symptomatic, aimed at prolonging independence and maintaining the quality of life. As knowledge of the common pathogenic pathways underlying several ARCAs grows, so do these pathways to target with new drugs. Chelation or enzyme replacement therapies are available for some specific ataxias caused by amenable metabolic alterations. A large number of drug trials are ongoing and aim to identify new therapeutic approaches to expand the options in our repertoire. Improved protocols of motor rehabilitation and noninvasive cerebellar stimulation have been shown to delay disease progression and maintain quality of life. Furthermore, recent progress in gene and molecular targeting therapies is rapidly expanding and holds promise for repairing defective genes. Neurotransplantation of grafted stem cells, which is still at the experimental preclinical stage, has opened new therapeutic strategies aimed at delaying cell degeneration and facilitating compensatory functions. This article is an overview of the current management and treatment strategies with an emphasis on promising perspectives for patients with ARCAs.