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Alpha-tubulin 4A encoding gene (TUBA4A) has been associated with familial amyotrophic lateral sclerosis and frontotemporal dementia, based on identification of likely pathogenic variants in patients from distinct amyotrophic lateral sclerosis and frontotemporal dementia cohorts. By screening a multicentric French cohort of 448 unrelated probands presenting with cerebellar ataxia, we identified ultra-rare TUBA4A missense variants, all being absent from public databases and predicted pathogenic by multiple in silico tools. In addition, gene burden analyses in the 100 000 Genomes project (100KGP) showed enrichment of TUBA4A rare variants in the inherited ataxia group compared to controls [odds ratio: 57.0847 (10.2-576.7); P = 4.02 ×10-7]. Taken together, we report 12 patients presenting with spasticity and/or cerebellar ataxia and harbouring a predicted pathogenic TUBA4A missense mutation, including five confirmed de novo cases and a mutation previously reported in a large family presenting with spastic ataxia. Cultured fibroblasts from three patients harbouring distinct TUBA4A missense showed significant alterations in microtubule organization and dynamics, providing insight of TUBA4A variants pathogenicity. Our data confirm the identification of a hereditary spastic ataxia disease gene with variable age of onset, expanding the clinical spectrum of TUBA4A associated phenotypes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Digital solutions in the field of restorative neurology offer significant assistance, enabling patients to engage in rehabilitation activities remotely. This research introduces ReMoVES, an Internet of Medical Things (IoMT) system delivering telemedicine services specifically tailored for multiple sclerosis rehabilitation, within the overarching framework of the STORMS project. The ReMoVES platform facilitates the provision of a rehabilitative exercise protocol, seamlessly integrated into the Individual Rehabilitation Project, curated by a multidimensional medical team operating remotely. This manuscript delves into the second phase of the STORMS pilot feasibility study, elucidating the technology employed, the outcomes achieved, and the practical, professional, and academic implications. The STORMS initiative, as the genesis of digital telerehabilitation solutions, aims to enhance the quality of life for multiple sclerosis patients.

Introduction: Dysphagia in post COVID-19 patients could be caused by several factors, including reduced pharyngolaryngeal coordination due to SARS-CoV-2 tropism to the central and/or peripheral nervous system. To our knowledge, this is the first reported case of COVID-19-related dysphagia successfully treated with botulinum toxin type A injection., Case Description: We report the case of a patient with severe oropharyngeal dysphagia due to COVID-19 confirmed by fibre endoscopy. As a result, the patient required an enteral feeding tube. After two months of traditional swallowing therapies, there was only limited improvement. An electrophysiologic evaluation of the cricopharyngeal muscle was performed and showed a normal inhibition of the cricopharyngeal muscle, followed by a hypertonic rebound. Based on this result, we decided to perform a unilateral laryngeal injection of botulinum toxin type A. After the injection, the patient's swallowing function improved significantly, allowing him to return to oral feeding., Discussion: Newly diagnosed oropharyngeal dysphagia was found in 35.3% of hospitalised patients with COVID-19. There are several possible causes of COVID-19-associated dysphagia, including stroke, encephalitis, critical illness neuropathy, Guillain-Barré syndrome and skeletal muscle injury. In our case, since stroke was excluded by brain MRI, cranial nerve injury was a possible explanation for the difficult recovery of swallowing despite daily swallowing therapy., Conclusion: We suggest that electrophysiology is a valid tool for the diagnosis and follow-up of patients with oropharyngeal dysphagia., Learning Points: SARS-CoV-2 tropism to the central and/or peripheral nervous system can cause dysphagia in post COVID-19 patients.An electrophysiologic approach is useful for the diagnosis and follow-up of patients with oropharyngeal dysphagia.A single botulinum toxin type A injection is a valid treatment option to improve the swallowing function in patients with post COVID-19 dysphagia., Competing Interests: Conflicts of Interests: The Authors declare that there are no competing interests., (© EFIM 2023.)

Purpose: RPH3A encodes a protein involved in the stabilization of GluN2A subunit of N-methyl-D-aspartate (NMDA)-type glutamate receptors at the cell surface, forming a complex essential for synaptic plasticity and cognition. We investigated the effect of variants in RPH3A in patients with neurodevelopmental disorders., Methods: By using trio-based exome sequencing, GeneMatcher, and screening of 100,000 Genomes Project data, we identified 6 heterozygous variants in RPH3A. In silico and in vitro models, including rat hippocampal neuronal cultures, have been used to characterize the effect of the variants., Results: Four cases had a neurodevelopmental disorder with untreatable epileptic seizures [p.(Gln73His)dn; p.(Arg209Lys); p.(Thr450Ser)dn; p.(Gln508His)], and 2 cases [p.(Arg235Ser); p.(Asn618Ser)dn] showed high-functioning autism spectrum disorder. Using neuronal cultures, we demonstrated that p.(Thr450Ser) and p.(Asn618Ser) reduce the synaptic localization of GluN2A; p.(Thr450Ser) also increased the surface levels of GluN2A. Electrophysiological recordings showed increased GluN2A-dependent NMDA ionotropic glutamate receptor currents for both variants and alteration of postsynaptic calcium levels. Finally, expression of the Rph3A Thr450Ser variant in neurons affected dendritic spine morphology., Conclusion: Overall, we provide evidence that missense gain-of-function variants in RPH3A increase GluN2A-containing NMDA ionotropic glutamate receptors at extrasynaptic sites, altering synaptic function and leading to a clinically variable neurodevelopmental presentation ranging from untreatable epilepsy to autism spectrum disorder., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Improvements in functional genomic annotation have led to a critical mass of neurogenetic discoveries. This is exemplified in hereditary ataxia, a heterogeneous group of disorders characterised by incoordination from cerebellar dysfunction. Associated pathogenic variants in more than 300 genes have been described, leading to a detailed genetic classification partitioned by age-of-onset. Despite these advances, up to 75% of patients with ataxia remain molecularly undiagnosed even following whole genome sequencing, as exemplified in the 100 000 Genomes Project. This study aimed to understand whether we can improve our knowledge of the genetic architecture of hereditary ataxia by leveraging functional genomic annotations, and as a result, generate insights and strategies that raise the diagnostic yield. To achieve these aims, we used publicly-available multi-omics data to generate 294 genic features, capturing information relating to a gene's structure, genetic variation, tissue-specific, cell-type-specific and temporal expression, as well as protein products of a gene. We studied these features across genes typically causing childhood-onset, adult-onset or both types of disease first individually, then collectively. This led to the generation of testable hypotheses which we investigated using whole genome sequencing data from up to 2182 individuals presenting with ataxia and 6658 non-neurological probands recruited in the 100 000 Genomes Project. Using this approach, we demonstrated a high short tandem repeat (STR) density within childhood-onset genes suggesting that we may be missing pathogenic repeat expansions within this cohort. This was verified in both childhood- and adult-onset ataxia patients from the 100 000 Genomes Project who were unexpectedly found to have a trend for higher repeat sizes even at naturally-occurring STRs within known ataxia genes, implying a role for STRs in pathogenesis. Using unsupervised analysis, we found significant similarities in genomic annotation across the gene panels, which suggested adult- and childhood-onset patients should be screened using a common diagnostic gene set. We tested this within the 100 000 Genomes Project by assessing the burden of pathogenic variants among childhood-onset genes in adult-onset patients and vice versa. This demonstrated a significantly higher burden of rare, potentially pathogenic variants in conventional childhood-onset genes among individuals with adult-onset ataxia. Our analysis has implications for the current clinical practice in genetic testing for hereditary ataxia. We suggest that the diagnostic rate for hereditary ataxia could be increased by removing the age-of-onset partition, and through a modified screening for repeat expansions in naturally-occurring STRs within known ataxia-associated genes, in effect treating these regions as candidate pathogenic loci., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

By blocking the release of neurotransmitters, botulinum toxin A (BoNT-A) is an effective treatment for muscle over-activity and pain in stroke patients. BoNT-A has also been reported to increase passive range of motion (p-ROM), the decrease of which is mainly due to muscle shortening (i.e., muscle contracture). Although the mechanism of action of BoNT-A on p-ROM is far from understood, pain relief may be hypothesized to play a role. To test this hypothesis, a retrospective investigation of p-ROM and pain was conducted in post-stroke patients treated with BoNT-A for upper limb hypertonia. Among 70 stroke patients enrolled in the study, muscle tone (Modified Ashworth Scale), pathological postures, p-ROM, and pain during p-ROM assessment (Numeric Rating Scale, NRS) were investigated in elbow flexors (48 patients) and in finger flexors (64 patients), just before and 3-6 weeks after BoNT-A treatment. Before BoNT-A treatment, pathological postures of elbow flexion were found in all patients but one. A decreased elbow p-ROM was found in 18 patients (38%). Patients with decreased p-ROM had higher pain-NRS scores (5.08 ± 1.96, with a pain score ≥8 in 11% of cases) than patients with normal p-ROM (0.57 ± 1.36) ( p < 0.001). Similarly, pathological postures of finger flexion were found in all patients but two. A decreased finger p-ROM was found in 14 patients (22%). Pain was more intense in the 14 patients with decreased p-ROM (8.43 ± 1.74, with a pain score ≥ 8 in 86% of cases) than in the 50 patients with normal p-ROM (0.98 ± 1.89) ( p < 0.001). After BoNT-A treatment, muscle tone, pathological postures, and pain decreased in both elbow and finger flexors. In contrast, p-ROM increased only in finger flexors. The study discusses that pain plays a pivotal role in the increase in p-ROM observed after BoNT-A treatment.

Purpose: Biallelic variants in UCHL1 have been associated with a progressive early-onset neurodegenerative disorder, autosomal recessive spastic paraplegia type 79. In this study, we investigated heterozygous UCHL1 variants on the basis of results from cohort-based burden analyses., Methods: Gene-burden analyses were performed on exome and genome data of independent cohorts of patients with hereditary ataxia and spastic paraplegia from Germany and the United Kingdom in a total of 3169 patients and 33,141 controls. Clinical data of affected individuals and additional independent families were collected and evaluated. Patients' fibroblasts were used to perform mass spectrometry-based proteomics., Results: UCHL1 was prioritized in both independent cohorts as a candidate gene for an autosomal dominant disorder. We identified a total of 34 cases from 18 unrelated families, carrying 13 heterozygous loss-of-function variants (15 families) and an inframe insertion (3 families). Affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17). The mass spectrometry-based proteomics showed approximately 50% reduction of UCHL1 expression in patients' fibroblasts., Conclusion: Our bioinformatic analysis, in-depth clinical and genetic workup, and functional studies established haploinsufficiency of UCHL1 as a novel disease mechanism in spastic ataxia., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved.)

Forebrain dopamine-sensitive (dopaminoceptive) neurons play a key role in movement, action selection, motivation, and working memory. Their activity is altered in Parkinson's disease, addiction, schizophrenia, and other conditions, and drugs that stimulate or antagonize dopamine receptors have major therapeutic applications. Yet, similarities and differences between the various neuronal populations sensitive to dopamine have not been systematically explored. To characterize them, we compared translating mRNAs in the dorsal striatum and nucleus accumbens neurons expressing D1 or D2 dopamine receptor and prefrontal cortex neurons expressing D1 receptor. We identified genome-wide cortico-striatal, striatal D1/D2 and dorso/ventral differences in the translating mRNA and isoform landscapes, which characterize dopaminoceptive neuronal populations. Expression patterns and network analyses identified novel transcription factors with presumptive roles in these differences. Prostaglandin E2 (PGE2) was a candidate upstream regulator in the dorsal striatum. We pharmacologically explored this hypothesis and showed that misoprostol, a PGE2 receptor agonist, decreased the excitability of D2 striatal projection neurons in slices, and diminished their activity in vivo during novel environment exploration. We found that misoprostol also modulates mouse behavior including by facilitating reversal learning. Our study provides powerful resources for characterizing dopamine target neurons, new information about striatal gene expression patterns and regulation. It also reveals the unforeseen role of PGE2 in the striatum as a potential neuromodulator and an attractive therapeutic target., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Digital medical solutions can be very helpful in restorative neurology, as they allow the patients to practice their rehabilitation activities remotely. This work discloses ReMoVES, an IoMT system providing telemedicine services, in the context of Multiple Sclerosis rehabilitation, within the frame of the project STORMS. A rehabilitative protocol of exercises can be provided as ReMoVES services and integrated into the Individual Rehabilitation Project as designed by a remote multidimensional medical team. In the present manuscript, the first phase of the study is described, including the definition of the needs to be addressed, the employed technology, the design and the development of the exergames, and the possible practical/professional and academic consequences. The STORMS project has been implemented with the aim to act as a starting point for the development of digital telerehabilitation solutions that support Multiple Sclerosis patients, improving their living conditions. This paper introduces a study protocol and it addresses pre-clinical research needs, where system issues can be studied and better understood how they might be addressed. It also includes tools to favor remote patient monitoring and to support the clinical staff.

Cerebellar ataxias are a large family of movement disorders that generally follow a stroke. The clinical picture is very complicated and normal activities become difficult for ataxic patients. For instance, dynamic ataxia involves both walk and upper-limbs movement, thus affecting the possibility to fulfill daily life tasks. Rehabilitation treatments and strategies for cerebellar ataxia are nowadays controversial, since different opinions on the several approaches are spread among the clinical community. The purpose of the present work is not to shed some light on such disagreements. Indeed, here a solution for delivering rehabilitation activities in the form of videogame is presented. Data related to patient's performance are collected and analyzed in order to provide the clinical staff with objective indicators that properly describe the activity. Such information can also be used to discuss the effectiveness and the incidence of some strategy adopted for fulfilling some task. The experimental phase is conducted on two case-studies with regards to the upper-limb rehabilitation. The adoption of the strategy of weighting the limb when performing the movement is discussed. The indicators computed in both sessions with and without strategy are compared, also referring to the practice of some healthy subjects. The present work introduces the preliminary phase of a wider study and foretells its future development conducted on a larger population.

Animal models have long been used to study gene function and the impact of genetic mutations on phenotype. Through the research efforts of thousands of research groups, systematic curation of published literature and high-throughput phenotyping screens, the collective body of knowledge for the mouse now covers the majority of protein-coding genes. We here collected data for over 53 000 mouse models with mutations in over 15 000 genomic markers and characterized by more than 254 000 annotations using more than 9000 distinct ontology terms. We investigated dimensional reduction and embedding techniques as means to facilitate access to this diverse and high-dimensional information. Our analyses provide the first visual maps of the landscape of mouse phenotypic diversity. We also summarize some of the difficulties in producing and interpreting embeddings of sparse phenotypic data. In particular, we show that data preprocessing, filtering and encoding have as much impact on the final embeddings as the process of dimensional reduction. Nonetheless, techniques developed in the context of dimensional reduction create opportunities for explorative analysis of this large pool of public data, including for searching for mouse models suited to study human diseases., Availability and Implementation: Source code for analysis scripts is available on GitHub at https://github.com/tkonopka/mouse-embeddings. The data underlying this article are available in Zenodo at https://doi.org/10.5281/zenodo.4916171., Contact: t.konopka@qmul.ac.uk., Supplementary Information: Supplementary data are available at Bioinformatics Advances online., (© The Author(s) 2021. Published by Oxford University Press.)

Background: Autoimmune encephalitis (AE) is a rare inflammatory disorder characterized by important psychiatric and neurologic symptoms. The literature documents high rates of neuropsychological dysfunction in N-methyl D-aspartate-receptor (NMDAr) encephalitis but papers don't consider specifically calculation disturbances between the long-term deficits, although deficits in executive control and episodic memory were less likely to resolve., Case Report: Here we present a severe case of NMDAr encephalitis in a young patient without a relevant past medical history. Upon first examination he presented psycho-motor slowdown, speech disorders, severe cognitive deficits in all areas: concentration, attention, memory, language, dual task functions, increased latency in responses, severe dyscalculia. Upon first evaluation, the young patient underwent a battery of neuropsychological tests and he showed a dysexecutive syndrome with performances significantly low for age and education. Our patient hence underwent 1 month of intensive cognitive rehabilitation. After the rehabilitation treatment, he presented an amelioration in all domains except calculations., Conclusions: In our patient the calculation disorder has proved to be the most relevant problem and the most difficult to treat. Clinicians should consider a careful approach to determine the prognosis of this syndrome because of the wide range of deficits, the need of prolonged treatment and the rate of long-term sequelae., (© 2021. The Author(s).)

Visuospatial neglect (VN) frequently occurs in Posterior Cortical Atrophy (PCA) and requires specific rehabilitation. In this single-case study, we investigated the efficacy of a computer-assisted cognitive training (CCT) alone or coupled with multiple sessions of anodal transcranial direct-current stimulation (A-tDCS) over the right posterior parietal cortex in improving left VN symptoms in a patient with PCA. The digital ReMoVES platform was used for both VN assessment and training. We found a significant improvement after CCT combined with A-tDCS within the limits of a single-case, our results suggest, for the first time, the usefulness of this combined approach in a neurodegenerative disorder.

Background: Although many studies have demonstrated the effectiveness of transcranial direct current stimulation (tDCS) in improving speech recovery in post-stroke aphasia, as far as we know patients affected by thalamic aphasia have never been investigated., Patient and Method: A 65-year-old man with severe non-fluent aphasia due to a left thalamic haemorrhagic stroke underwent intensive daily speech therapy combined with tDCS., Results: The patient showed progressive improvement with almost complete recovery of his speech disorder, behavioural disinhibition and apathy., Conclusions: Our findings suggest that tDCS with concurrent speech therapy can be useful in patients with subcortical stroke lesions., Learning Points: The thalamus has a central role in the development of the higher functions, such as memory, regulation of behaviour and emotions, and language elaboration.Transcranial direct current stimulation (tDCS) applied to the cerebral cortex is a promising tool for improving language recovery in patients with post-stroke aphasia.Combined treatment with tDCS and speech and language therapy (SLT) was effective in a patient with subacute thalamic aphasia, who showed improvement in all aspects of linguistic and behavioural communication., Competing Interests: Conflicts of Interests: The Authors declare that there are no competing interests., (© EFIM 2020.)

Objective: Moderate to severe spasticity is commonly reported in Multiple Sclerosis (MS) and its management is still a challenge. Cannabinoids were recently suggested as add-on therapy for the treatment of spasticity and chronic pain in MS but there is no conclusive scientific evidence on their safety, especially on cognition and over long periods. The aim of this prospective pilot study was to assess the long-term effects of a tetrahydrocannabinol-cannabidiol (THC/CBD) oromucosal spray (Sativex®) on cognition, mood and anxiety., Patients and Methods: An extensive and specific battery of neuropsychological tests (Symbol Digit Modalities Test-SDMT, California Verbal Learning Test-CVLT, Brief Visuospatial Memory Test-BVMT; PASAT-3 and 2; Free and Cued Selective Remind Test-FCSRT, Index of Sensitivity of Cueing-ISC) was applied to longitudinally investigate different domains of cognition in 20 consecutive MS patients receiving Sativex for spasticity. The primary endpoint was to assess any variation in cognitive performance. Secondary outcomes regarding mood and anxiety were investigated by means of Beck Depression Inventory (BDI) and Hamilton Anxiety Rating Scale (HAM-A). Any change in patients' spasticity was evaluated using the 0-10 Numerical Rating Scale (NRS)., Results: Twenty per protocol patients were followed up and evaluated at baseline, 6 and 12 months. Domains involving processing speed and auditory verbal memory significantly improved within the first 6 months of therapy (SDMT: p < 0.001; CVLT: p = 0.0001). Mood and anxiety did not show any significant variation. Additionally, the NRS score significantly improved since the beginning (p < 0.0001)., Conclusions: These results are encouraging in supporting possible long-term benefits of Sativex on cognition and a wider role than symptom alleviator. Further studies on larger groups of patients would be necessary in order to test this intriguing possibility., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Mutations in the SNX14 gene cause spinocerebellar ataxia, autosomal recessive 20 (SCAR20) in both humans and dogs. Studies implicating the phenotypic consequences of SNX14 mutations to be consequences of subcellular disruption to autophagy and lipid metabolism have been limited to in vitro investigation of patient-derived dermal fibroblasts, laboratory engineered cell lines and developmental analysis of zebrafish morphants. SNX14 homologues Snz (Drosophila) and Mdm1 (yeast) have also been conducted, demonstrated an important biochemical role during lipid biogenesis. In this study we report the effect of loss of SNX14 in mice, which resulted in embryonic lethality around mid-gestation due to placental pathology that involves severe disruption to syncytiotrophoblast cell differentiation. In contrast to other vertebrates, zebrafish carrying a homozygous, maternal zygotic snx14 genetic loss-of-function mutation were both viable and anatomically normal. Whilst no obvious behavioural effects were observed, elevated levels of neutral lipids and phospholipids resemble previously reported effects on lipid homeostasis in other species. The biochemical role of SNX14 therefore appears largely conserved through evolution while the consequences of loss of function varies between species. Mouse and zebrafish models therefore provide valuable insights into the functional importance of SNX14 with distinct opportunities for investigating its cellular and metabolic function in vivo.

Digital solutions for unilateral spatial neglect (USN) assessment and treatment are nowadays of great interest, because of both the possibility of combining them with other rehabilitation practices, and the easy-to-understand data and indicators they collect. The ReMoVES platform, developed in DITEN laboratories, is conceived in the Assistive Technologies framework and provides motor and cognitive exergames and activities to be performed in conjunction with traditional rehabilitation. In this work, two case-studies, related to the USN rehabilitation, are presented. The combination of cognitive therapy, delivered by the ReMoVES platform, and transcranial direct-current stimulation (tDCS) technique was used as rehabilitation treatment for both the patients. Data collected at the beginning or at the end of the rehabilitation process, or also during the treatment sessions, are shown and discussed in this paper. This work is a preliminary part of a wider one, that will be conducted involving many different rehabilitation centers, aimed at proving the validity of such an approach to USN treatments.

Transcranial direct-current stimulation (tDCS) has been suggested to improve language function in patients with post-stroke aphasia. Most studies on aphasic patients, however, were conducted with a very limited follow-up period, if any. In this pilot, single-blind study on chronic post-stroke aphasic patients, we aimed to verify whether or not tDCS is able to extend its beneficial effects for a longer period of time (21 weeks after the end of stimulation). Three aphasic patients underwent anodal tDCS (A-tDCS, 20 min, 1.5 mA) and sham stimulation (S-tDCS) over the left frontal (perilesional) region, coupled with a simultaneous naming training (on-line tDCS). Ten consecutive sessions (5 days per week for 2 weeks) were implemented. In the first five sessions, we used a list of 40 figures, while in the subsequent five sessions we utilized a second set of 40 figures differing in word difficulty. At the end of the stimulation period, we found a significant beneficial effect of A-tDCS (as compared to baseline and S-tDCS) in all our subjects, regardless of word difficulty, although with some inter-individual differences. In the follow-up period, the percentage of correct responses persisted significantly better until the 16th week, when an initial decline in naming performance was observed. Up to the 21st week, the number of correct responses, though no longer significant, was still above the baseline level. These results in a small group of aphasic patients suggest a long-term beneficial effect of on-line A-tDCS.