Psychiatric Manifestations in Early to Middle Stages of Fragile X-Associated Tremor-Ataxia Syndrome (FXTAS).

OBJECTIVE: The purpose of the present study was to assess the psychiatric manifestations of early to middle stages of fragile X-associated tremor-ataxia syndrome (FXTAS) and their relationship with executive function and FMR1 cytosine-guanine-guanine (CGG) repeat numbers across genders. METHODS: Cross-sectional data from 100 participants (62 men, 38 women; mean±SD age=67.11±7.90 years) with FXTAS stage 1, 2, or 3 were analyzed, including demographic information, cognitive measures, psychiatric assessments (Symptom Checklist-90-Revised and Behavioral Dyscontrol Scale-II [BDS-II]), and CGG repeat number. RESULTS: Participants with FXTAS stage 3 exhibited significantly worse psychiatric outcomes compared with participants with either stage 1 or 2, with distinct gender-related differences. Men showed differences in anxiety and hostility between stage 3 and combined stages 1 and 2, whereas women exhibited differences in anxiety, depression, interpersonal sensitivity, obsessive-compulsive symptoms, and somatization, as well as in the Global Severity Index, the Positive Symptom Distress Index, and the Positive Symptom Total. Among male participants, negative correlations were observed between BDS-II total scores and obsessive-compulsive symptoms, as well as between anxiety and CGG repeat number. CONCLUSIONS: These findings suggest that even at early FXTAS stages, patients have significant cognitive and other psychiatric symptoms, with notable gender-specific differences. This study underscores the clinical and prognostic relevance of comorbid psychiatric conditions in FXTAS, highlighting the need for early intervention and targeted support for individuals with relatively mild motor deficits.

Reduction of sacsin levels in peripheral blood mononuclear cells as a diagnostic tool for spastic ataxia of Charlevoix-Saguenay.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a rare neurodegenerative disease caused by biallelic variants in the SACS gene encoding for sacsin. More than 200 pathogenic variants have been identified to date, most of which are missense. It is likely that the prevalence of autosomal recessive spastic ataxia of Charlevoix-Saguenay is underestimated due to the lack of an efficient diagnostic tool able to validate variants of uncertain significance. We have previously shown that sacsin is almost absent in fibroblasts of patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay regardless of the type of SACS variant, because sacsin carrying missense variants is cotranslationally degraded. In this work, we aimed to establish the pathogenicity of SACS variants by quantifying sacsin protein in blood samples, with relevant implications for autosomal recessive spastic ataxia of Charlevoix-Saguenay diagnosis. We developed a protocol to assess sacsin protein levels by western blot using small amounts of peripheral blood mononuclear cells, which can be propagated in culture and cryopreserved. The study involves eight patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay (including a novel case) carrying variants of different types and positions along the SACS gene and two parents who are carriers of heterozygous missense variants. We show that patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay (carrying either missense or truncating variants) almost completely lacked sacsin in peripheral blood mononuclear cells. Moreover, both carriers of a SACS missense variant showed 50% reduction in sacsin protein levels compared to controls. We also describe a patient with uniparental isodisomy carrying a homozygous nonsense variant near the 3' end of the SACS gene. This resulted in a stable sacsin protein lacking the last 202 amino acids, probably due to escape of nonsense-mediated decay of mRNA. In conclusion, we have optimized a minimally invasive diagnostic tool for autosomal recessive spastic ataxia of Charlevoix-Saguenay in blood samples based on sacsin protein level assessment. Indeed, our results provide definite evidence that sacsin carrying missense pathogenic variants undergoes cotranslational degradation. The quantitative reduction in sacsin levels in the case of missense variants of uncertain significance allows defining them as pathogenic variants, something which cannot be predicted bioinformatically with high certainty.

Bromelain decreases oxidative stress and Neuroinflammation and improves motor function in adult male rats with cerebellar Ataxia induced by 3-acetylpyridine.

Bromelain is a plant-based molecule with antioxidant, antithrombotic, anticancer, and anti-inflammatory properties. Bromelain has been shown to reduce the release of inflammatory cytokines. This study aimed to determine whether bromelain can prevent ataxia in rats caused by 3-acetylpyridine (3-AP). Thirty-six albino rats were divided into the control, 3-AP, and 3-AP + Brom groups. In the 3-AP + Brom group, bromelain was injected intraperitoneally at 40 mg/kg daily for 30 days. Various techniques such as rotarod, electromyography (EMG), elevated plus maze, IHC, and Sholl analysis were used to evaluate the possible effects of bromelain on cerebellar neurons and glial cells. The results demonstrated significant improvements in most of the 3-AP + Brom, including motor coordination, neuromuscular response, anxiety, oxidative capacity, microgliosis, astrogliosis, cell death, and morphological variables compared to the 3-AP group. The mechanism of action of bromelain in restoring cerebellar ataxia needs further investigation, but it may be a candidate to help restore degeneration in animals with ataxia.

Repeat length in spinocerebellar ataxia type 4 (SCA4) predicts age at onset and disease severity.

BACKGROUND: Recently, an exonic GGC repeat expansion (RE) was identified by long-read genome sequencing in the ZFHX3 gen, causing spinocerebellar ataxia type 4 (SCA4), a dominant form of ataxia with sensory neuropathy. However, the analysis of larger cohorts of patients remained demanding, resulting in a challenge to diagnose patients and leaving the question of anticipation in SCA4 unanswered. OBJECTIVES: We aimed to develop a GGC repeat test for clinical SCA4 screening and to apply this test to screen two large German SCA pedigrees and samples of unrelated patients collected over the last 25 years. METHODS: We modulated a commercial GGC-RE kit (Bio-Techne AmplideX® Asuragen® PCR/CE FMR1 Reagents) with ZFHX3-specific primers and adapted PCR conditions. The test was applied to patients and 50 healthy controls to determine the exact repeat number. Clinical data were revised and correlated with the expanded allele sizes and an exploratory analysis of structural MRI was performed. RESULTS: Repeat size, determined by our protocol for (GGC)n RE analysis shows a strong inverse correlation between repeat length and age at onset and anticipation in subsequent generations. The phenotype also appears to be more strongly expressed in carriers of longer RE. Clinical red flags were slowed saccades, sensory neuropathy and autonomic dysfunction. CONCLUSION: Our protocol enables cost-effective and robust screening for the causative SCA4 RE within ZFHX3. Furthermore, detailed clinical data of our patients gives a more precise view on SCA4, which seems to be more common among patients with ataxia than expected.

The parkin V380L variant is a genetic modifier of Machado-Joseph disease with impact on mitophagy.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative spinocerebellar ataxia caused by a polyglutamine-coding CAG repeat expansion in the ATXN3 gene. While the CAG length correlates negatively with the age at onset, it accounts for approximately 50% of its variability only. Despite larger efforts in identifying contributing genetic factors, candidate genes with a robust and plausible impact on the molecular pathogenesis of MJD are scarce. Therefore, we analysed missense single nucleotide polymorphism variants in the PRKN gene encoding the Parkinson's disease-associated E3 ubiquitin ligase parkin, which is a well-described interaction partner of the MJD protein ataxin-3, a deubiquitinase. By performing a correlation analysis in the to-date largest MJD cohort of more than 900 individuals, we identified the V380L variant as a relevant factor, decreasing the age at onset by 3 years in homozygous carriers. Functional analysis in an MJD cell model demonstrated that parkin V380L did not modulate soluble or aggregate levels of ataxin-3 but reduced the interaction of the two proteins. Moreover, the presence of parkin V380L interfered with the execution of mitophagy-the autophagic removal of surplus or damaged mitochondria-thereby compromising cell viability. In summary, we identified the V380L variant in parkin as a genetic modifier of MJD, with negative repercussions on its molecular pathogenesis and disease age at onset.

Feasibility of differentiating gait in Parkinson's disease and spinocerebellar degeneration using a pose estimation algorithm in two-dimensional video.

BACKGROUND: Although pose estimation algorithms have been used to analyze videos of patients with Parkinson's disease (PD) to assess symptoms, their feasibility for differentiating PD from other neurological disorders that cause gait disturbances has not been evaluated yet. We aimed to determine whether it was possible to differentiate between PD and spinocerebellar degeneration (SCD) by analyzing video recordings of patient gait using a pose estimation algorithm. METHODS: We videotaped 82 patients with PD and 61 patients with SCD performing the timed up-and-go test. A pose estimation algorithm was used to extract the coordinates of 25 key points of the participants from these videos. A transformer-based deep neural network (DNN) model was trained to predict PD or SCD using the extracted coordinate data. We employed a leave-one-participant-out cross-validation method to evaluate the predictive performance of the trained model using accuracy, sensitivity, and specificity. As there were significant differences in age, weight, and body mass index between the PD and SCD groups, propensity score matching was used to perform the same experiment in a population that did not differ in these clinical characteristics. RESULTS: The accuracy, sensitivity, and specificity of the trained model were 0.86, 0.94, and 0.75 for all participants and 0.83, 0.88, and 0.78 for the participants extracted by propensity score matching. CONCLUSION: The differentiation of PD and SCD using key point coordinates extracted from gait videos and the DNN model was feasible and could be used as a collaborative tool in clinical practice and telemedicine.

Neurologic Deficits Following Oral Misuse of the Nasal Decongestant Propylhexedrine.

INTRODUCTION: Propylhexedrine is an over-the-counter nasal decongestant used recreationally for amphetamine-like effects. Prior reports have associated intravenous misuse with brainstem dysfunction and diplopia. This is a case of propylhexedrine ingestion resulting in neurological impairment with associated MRI findings. CASE REPORT: A 21-year-old man presented with neurologic symptoms after ingesting propylhexedrine extracted from a 250 mg nasal inhaler into a lemon juice solution following recommendations from an online forum. He also followed recommendations to simultaneously ingest 1 g L-arginine to theoretically mitigate the risk of vasoconstriction. He developed flushing and euphoria before falling asleep. He awoke 12 h later with dizziness, intractable vomiting, diplopia, ataxia, dysmetria, and spontaneous horizontal nystagmus. Magnetic resonance imaging (MRI) revealed T2 enhancement concerning for vasogenic edema of the right posterior limbs of the internal capsule extending into the midbrain, cerebellar peduncles, and cerebellar white matter. Workup for primary vascular or autoimmune etiologies was unrevealing. Expanded drug testing was positive for mitragynine and THC. Blood analyzed via liquid chromatography quadrupole time-of-flight mass spectrometry was positive for propylhexedrine. On hospital day 6, the patient was discharged to physical rehabilitation with unresolved dysmetria and ataxia. DISCUSSION: Recreational oral misuse of propylhexedrine may be associated with neurologic injury. MRI findings in this case demonstrated vasogenic edema suggesting vasospasm as a possible etiology. Serum testing confirmed the presence of propylhexedrine. Although testing was also positive for mitragynine and THC, these have not been associated with similar neurologic deficits or MRI findings.

Comprehensive Physiotherapy Rehabilitation in a Patient With Cerebellar Ataxia and Dysphagia: A Case Report Investigating Symptomatology, Management, and Outcomes.

A cerebellar infarct occurs when blood flow to the cerebellum, located in the posterior cranial fossa, is disrupted. This diminished blood supply leads to decreased oxygen delivery, resulting in motor and balance control impairments. One prevalent sign of neurodegenerative diseases is dysphagia, which is typically linked to a higher death rate. No systematic and uniform assessment of dysphagia is used in the clinical care environment of individuals with ataxia. Its effect on the quality of life associated with health in patients is little understood. Therefore, this case report works to address dysphagia in cerebellar ataxia. This case report examines the physiotherapy management of a 41-year-old male who had cerebellar ataxia secondary to an infarct in the bilateral cerebellar hemisphere and vermis. The rehabilitation period lasted for six weeks. On examination, the patient had difficulty swallowing and showed symptoms of cerebellar dysfunctions, such as nystagmus, dyssynergia, dysmetria, and dysdiadochokinesia. Neuro-physiotherapy interventions, like conventional physiotherapy, trunk, and pelvis proprioceptive neuromuscular facilitation (PNF), Kinesio taping for dysphagia, interventions to treat gait, balance training interventions, and Frenkel's exercises were commenced. The outcome measures were evaluated using standardized outcome measures like the Swallowing Quality of Life Scale (SWAL-QOL), Severity of Ataxia Scale (SARA), Trunk Impairment Scale (TIS), Berg Balance Scale (BBS), Barthel Index, and World Health Organization Quality of Life (WHO-QOL). We conclude that a properly structured physiotherapy program subsequently improved the symptoms of patients. Furthermore, it enhanced functional independence, which subsequently improved the patient's quality of life.

Clinical and genetic spectrum of Ataxia Telangiectasia Tunisian patients: Bioinformatic analysis unveil mechanisms of ATM variants pathogenicity.

Ataxia Telangiectasia (AT) is a rare multisystemic neurodegenerative disease caused by biallelic mutations in the ATM gene. Few clinical studies on AT disease have been conducted in Tunisia, however, the mutational landscape is still undefined. Our aim is to determine the clinical and genetic spectrum of AT Tunisian patients and to explore the potential underlying mechanism of variant pathogenicity. Sanger sequencing was performed for nine AT patients. A comprehensive computational analysis was conducted to evaluate the possible pathogenic effect of ATM identified variants. Genetic screening of ATM gene has identified nine different variants from which six have not been previously reported. In silico analysis have predicted a pathogenic effect of identified mutations. This was corroborated by a structural bioinformatics study based on molecular modeling and docking for novel missense mutations. Our findings suggest a profound impact of identified mutations not only on the ATM protein stability, but also on the ATM-ligand interactions. Our study characterizes the mutational landscape of AT Tunisian patients which will allow to set up genetic counseling and prenatal diagnosis for families at risk and expand the spectrum of ATM variants worldwide. Furthermore, understanding the mechanism that underpin variant pathogenicity could provide further insights into disease pathogenesis.

Targeting the ATM pathway in cancer: Opportunities, challenges and personalized therapeutic strategies.

Ataxia telangiectasia mutated (ATM) kinase plays a pivotal role in orchestrating the DNA damage response, maintaining genomic stability, and regulating various cellular processes. This review provides a comprehensive analysis of ATM's structure, activation mechanisms, and various functions in cancer development, progression, and treatment. I discuss ATM's dual nature as both a tumor suppressor and potential promoter of cancer cell survival in certain contexts. The article explores the complex signaling pathways mediated by ATM, its interactions with other DNA repair mechanisms, and its influence on cell cycle checkpoints, apoptosis, and metabolism. I examine the clinical implications of ATM alterations, including their impact on cancer predisposition, prognosis, and treatment response. The review highlights recent advances in ATM-targeted therapies, discussing ongoing clinical trials of ATM inhibitors and their potential in combination with other treatment modalities. I also address the challenges in developing effective biomarkers for ATM activity and patient selection strategies for personalized cancer therapy. Finally, I outline future research directions, emphasizing the need for refined biomarker development, optimized combination therapies, and strategies to overcome potential resistance mechanisms. This comprehensive overview underscores the critical importance of ATM in cancer biology and its emerging potential as a therapeutic target in precision oncology.

Maculopathy and adult-onset ataxia in patients with biallelic MFSD8 variants.

BACKGROUND: Biallelic variants in the major facilitator superfamily domain containing 8 gene (MFSD8) are associated with distinct clinical presentations that range from typical late-infantile neuronal ceroid lipofuscinosis type 7 (CLN7 disease) to isolated adult-onset retinal dystrophy. Classic late-infantile CLN7 disease is a severe, rare neurological disorder with an age of onset typically between 2 and 6 years, presenting with seizures and/or cognitive regression. Its clinical course is progressive, leading to premature death, and often includes visual loss due to severe retinal dystrophy. In rare cases, pathogenic variants in MFSD8 can be associated with isolated non-syndromic macular dystrophy with variable age at onset, in which the disease process predominantly or exclusively affects the cones of the macula and where there are no neurological or neuropsychiatric manifestations. METHODS: Here we present longitudinal studies on four adult-onset patients who were biallelic for four MFSD8 variants. RESULTS: Two unrelated patients who presented with adult-onset ataxia and had macular dystrophy on examination were homozygous for a novel variant in MFSD8 NM_152778.4: c.935T>C p.(Ile312Thr). Two other patients presented in adulthood with visual symptoms, and one of these developed mild to moderate cerebellar ataxia years after the onset of visual symptoms. CONCLUSIONS: Our observations expand the knowledge on biallelic pathogenic MFSD8 variants and confirm that these are associated with a spectrum of more heterogeneous clinical phenotypes. In MFSD8-related disease, adult-onset recessive ataxia can be the presenting manifestation or may occur in combination with retinal dystrophy.

Insulin sensitivity and insulin secretion in adults with Friedreich's Ataxia: the role of skeletal muscle.

INTRODUCTION: Friedreich's Ataxia (FRDA) is a multi-system disorder caused by frataxin deficiency. FRDA-related diabetes mellitus (DM) is common. Frataxin supports skeletal muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity, a mediator of insulin sensitivity. Our objective was to test the association between skeletal muscle health and insulin sensitivity and secretion in adults with FRDA without DM. METHODS: Case-control study (NCT02920671). Glucose and insulin metabolism (stable-isotope oral glucose tolerance tests), body composition (dual-energy x-ray absorptiometry), physical activity (self-report), and skeletal muscle OXPHOS capacity (creatine chemical exchange saturation transfer MRI) were assessed. RESULTS: Participants included 11 individuals with FRDA (4 female), median age 27y (IQR 23, 39), BMI 26.9kg/m2 (24.1, 29.4), and 24 controls (11 female), 29y (26, 39), 24.4kg/m2 (21.8, 27.0). Fasting glucose was higher in FRDA (91 vs. 83mg/dL (5.0 vs. 4.6mmol/L), p<0.05). Individuals with FRDA had lower insulin sensitivity (WBISI 2.8 vs. 5.3, p<0.01), higher post-prandial insulin secretion (insulin secretory rate iAUC 30-180 minutes, 24,652 vs. 17,858, p<0.05), and more suppressed post-prandial endogenous glucose production (-0.9% vs. 26.9% of fasting EGP, p<0.05). In regression analyses, lower OXPHOS and inactivity explained some of the difference in insulin sensitivity. More visceral fat contributed to lower insulin sensitivity independent of FRDA. Insulin secretion accounting for sensitivity (disposition index) was not different. CONCLUSIONS: Lower mitochondrial OXPHOS capacity, inactivity, and visceral adiposity contribute to lower insulin sensitivity in FRDA. Higher insulin secretion appears compensatory, and when inadequate, could herald DM. Further studies are needed to determine if muscle- or adipose-focused interventions could delay FRDA-related DM.

Natural history of non-polyglutamine CACNA1A disease in Austria.

BACKGROUND AND OBJECTIVES: Non-polyglutamine CACNA1A variants underlie an extremely variable phenotypic spectrum encompassing developmental delay, hemiplegic migraine, epilepsy, psychiatric symptoms, episodic and chronic cerebellar signs. We provide our experience with the long-term follow-up of CACNA1A patients and their response to interval therapy. METHODS: Patients with genetically confirmed non-polyglutamine CACNA1A disease were prospectively followed at the Center for Rare Movement Disorders of the Medical University of Innsbruck from 2004 to 2024. RESULTS: We recruited 41 subjects with non-polyglutamine CACNA1A disease, of which 38 (93%) familial cases. The mean age at the first examination was 35 ± 22 years. Disease onset was in the childhood/adolescence in 31/41 patients (76%). Developmental delay and episodic symptoms were the first disease manifestation in 9/41 (22%) and 32/41 (78%) patients respectively. Chronic neurological signs encompassed a cerebellar syndrome in 35/41 (85%), which showed almost no progression during the observation period, as well as cognitive deficits in 9/20 (45%, MOCA test score < 26), psychiatric and behavioral symptoms in 11/41(27%). Seizures occurred in two patients concomitant to severe hemiplegic migraine. At the last visit, 27/41 patients (66%) required an interval prophylaxis (including acetazolamide, flunarizine, 4-aminopyridine, topiramate), which was efficacious in reducing the frequency and severity of episodic symptoms in all cases. In one patient in his 70ies with progressively therapy resistant hemiplegic migraine, treatment with the anti-CGRP antibody galcanezumab successfully reduced the frequency of migraine days from 4 to 1/month. CONCLUSIONS: Non-polyglutamine CACNA1A disease show an evolving age-dependent presentation. Interval prophylaxis is effective in reducing the burden of episodic symptoms.

Glial cell activation precedes neurodegeneration in the cerebellar cortex of the YG8-800 murine model of Friedreich ataxia.

Friedreich ataxia is a hereditary neurodegenerative disorder resulting from reduced levels of the protein frataxin due to an expanded GAA repeat in the FXN gene. This deficiency causes progressive degeneration of specific neuronal populations in the cerebellum and the consequent loss of movement coordination and equilibrium, which are some of the main symptoms observed in affected individuals. Like in other neurodegenerative diseases, previous studies suggest that glial cells could be involved in the neurodegenerative process and disease progression in patients with Friedreich ataxia. In this work, we followed and characterized the progression of changes in the cerebellar cortex in the latest version of Friedreich ataxia humanized mouse model, YG8-800 (Fxnnull:YG8s(GAA)>800), which carries a human FXN transgene containing >800 GAA repeats. Comparative analyses of behavioral, histopathological, and biochemical parameters were conducted between the control strain Y47R and YG8-800 mice at different time points. Our findings revealed that YG8-800 mice exhibit an ataxic phenotype characterized by poor motor coordination, decreased body weight, cerebellar atrophy, neuronal loss, and changes in synaptic proteins. Additionally, early activation of glial cells, predominantly astrocytes and microglia, was observed preceding neuronal degeneration, as was increased expression of key proinflammatory cytokines and downregulation of neurotrophic factors. Together, our results show that the YG8-800 mouse model exhibits a stronger phenotype than previous experimental murine models, reliably recapitulating some of the features observed in humans. Accordingly, this humanized model could represent a valuable tool for studying Friedreich ataxia molecular disease mechanisms and for preclinical evaluation of possible therapies.

Cerebellitis following COVID-19 infection: A case-based systematic review and pooled analysis.

Background: The COVID-19 pandemic has been linked to neurological complications, including Cerebellitis. This study aims to investigate the clinical features, and consequences of Cerebellitis following COVID-19 infection, informing medical management strategies. Methods: A systematic search was conducted through PubMed, Web of Science, Embase, ProQuest, and Cochrane databases from January 2018 to September 12, 2023, on cases post-COVID-19. Demographics, clinical characteristics, and diagnostic techniques were analyzed using descriptive statistics. Chi-Square tests assessed associations between diagnoses and treatments, with visualizations including heatmaps and scatter plots. Results: After the final Screening, the analysis of 18 cases revealed Cerebellitis post-COVID-19 spanned 9 countries, predominantly from the USA (27.8 %), with a mean patient age of 40.1 years (±24.6). Males comprised 94.4 % of cases. Common underlying conditions included hypertension (22.2 %) and diabetes (11.1 %). Neurological symptoms presented on average 15.15 ± 12.7 days post-COVID-19 infection. A moderate negative correlation (r = -0.358) was observed between age and symptom onset. Blood and CSF biomarkers showed weak correlations with symptom onset intervals. Treatment efficacy varied, with most cases achieving symptom-free outcomes. The Chi-Square test for diagnosis-treatment associations yielded a p-value of 0.089, and for follow-up outcomes, a p-value of 0.283, indicating no significant statistical associations. Conclusion: This systematic review highlights increased reports of Cerebellitis in males in their fourth decade of life, with the highest comorbidities being vascular diseases. Marker assessments show a decrease in CSF protein in half of patients, along with complete recovery following combination treatment with antivirals and steroids in acute Cerebellitis.

Oculomotor and Vestibular Deficits in Friedreich Ataxia - Systematic Review and Meta-Analysis of Quantitative Measurements.

Disease-specific oculomotor assessments play a crucial role in the early diagnosis of hereditary cerebellar ataxias. Whereas several studies have reported on quantitative oculomotor and vestibular measurements in Friedreich's Ataxia (FRDA), the value of specific oculomotor paradigms remains unclear. We aimed to address this knowledge gap through a systematic literature review and providing disease-specific recommendations for a tailored set of eye-movement recordings in FRDA. MEDLINE and Embase were searched for studies reporting on quantitative oculomotor and/or vestibular measurements in FRDA-patients. Data on oculomotor and vestibular parameters were extracted and correlations with a range of clinical parameters were sought. Included studies (n = 17) reported on 185 patients. Abnormalities observed included the presence of saccadic intrusions (143/161) such as square-wave jerks (SWJ, 90/109) and ocular flutter (21/43), impaired eccentric gaze-holding (40/104), abnormal pursuit (81/93) and angular vestibulo-ocular reflex (aVOR) deficits (39/48). For visually-guided saccades (VGS), we frequently observed increases in saccade latency (27/38) and dysmetric saccades (71/93), whereas saccade velocity was more often preserved (37/43). Augmented anti-saccade (AS) latency, downbeat nystagmus and frequent macro-SWJ correlated with disease duration. Increased AS-latency and VGS-latency, frequent macro-SWJ, reduced aVOR-gain and augmented aVOR peak-latency correlated with disease severity. A broad range of oculomotor and vestibular deficits are documented in the literature. Impairments in pursuit, saccades and aVOR-responses are most commonly reported, and as such, should be prioritized as disease markers. Quantitative oculomotor testing in FRDA may facilitate early diagnosis and prove valuable in monitoring disease progression and treatment response.

Whole genome joint analysis reveals ATM:C.1564_1565del variant segregating with Ataxia-Telangiectasia and breast cancer.

ATM gene is implicated in the development of breast cancer in the heterozygous state, and Ataxia-telangiectasia (A-T) in a homozygous or compound heterozygous state. Ataxia-telangiectasia (A-T) is a rare cerebellar ataxia syndrome presenting with progressive neurologic impairment, telangiectasia, and an increased risk of leukemia and lymphoma. Although the role of ATM, separately, in association with A-T and breast cancer is well documented, there is a limited number of studies investigating ATM variants when segregating with both phenotypes in the same family. Here, using joint analysis and whole genome sequencing, we investigated ATM c.1564_1565del in a family with one homozygous member presenting with A-T (OMIM # 208900) and three heterozygous members, of whom one had breast cancer (OMIM #114480). To our knowledge, this is the first study of ATM c.1564_1565del segregation with both A-T and breast cancer phenotypes within the same kindred. This study highlights the need for a comprehensive genomic approach in the appropriate cancer risk management of heterozygote carriers of ATM in families with A-T.

Early inhibition of the ATM/p53 pathway reduces the susceptibility to atrial fibrillation and atrial remodeling following acute myocardial infarction.

Atrial fibrillation (AF) emerges as a critical complication following acute myocardial infarction (AMI) and is associated with a significant increased risk of heart failure, stroke and mortality. Ataxia telangiectasia mutated (ATM), a key player in DNA damage repair (DDR), has been implicated in multiple cardiovascular conditions, however, its involvement in the development of AF following AMI remains unexplored. This study seeks to clarify the contribution of the ATM/p53 pathway in the onset of AF post-AMI and to investigate the underlying mechanisms. The rat model of AMI was established by ligating left anterior descending coronary artery in the presence or absence of Ku55933 (an ATM kinase inhibitor, 5 mg/kg/d) treatment. Rats receiving Ku55933 were further divided into the early administration group (administered on days 1, 2, 4, and 7 post-AMI) and the late administration group (administered on days 8, 9, 11 and 14 post-AMI). RNA-sequencing was performed 14 days post-operation. In vitro, H2O2-challenged HL-1 atrial muscle cells were utilized to evaluate the potential effects of different ATM inhibition schemes, including earlier, middle, and late periods of intervention. Fourteen days post-AMI injury, the animals exhibited significantly increased AF inducibility, exacerbated atrial electrical/structural remodeling, reduced ventricular function and exacerbated atrial DNA damage, as evidenced by enhanced ATM/p53 signaling as well as γH2AX level. These effects were partially consistent with the enrichment results of bioinformatics analysis. Notably, the deleterious effects were ameliorated by early, but not late, administration of Ku55933. Mechanistically, inhibition of ATM signaling successfully suppressed atrial NLRP3 inflammasome-mediated pyroptotic pathway. Additionally, the results were validated in the in vitro experiments demonstrating that early inhibition of Ku55933 not only attenuated cellular ATM/p53 signaling, but also mitigated inflammatory response by reducing NLRP3 activation. Collectively, hyperactivation of ATM/p53 contributed to the pathogenesis of AF following AMI. Early intervention with ATM inhibitors substantially mitigated AF susceptibility and atrial electrical/structural remodeling, highlighting a novel therapeutic avenue against cardiac arrhythmia following AMI.

Cerebellar nuclei cells produce distinct pathogenic spike signatures in mouse models of ataxia, dystonia, and tremor.

The cerebellum contributes to a diverse array of motor conditions, including ataxia, dystonia, and tremor. The neural substrates that encode this diversity are unclear. Here, we tested whether the neural spike activity of cerebellar output neurons is distinct between movement disorders with different impairments, generalizable across movement disorders with similar impairments, and capable of causing distinct movement impairments. Using in vivo awake recordings as input data, we trained a supervised classifier model to differentiate the spike parameters between mouse models for ataxia, dystonia, and tremor. The classifier model correctly assigned mouse phenotypes based on single-neuron signatures. Spike signatures were shared across etiologically distinct but phenotypically similar disease models. Mimicking these pathophysiological spike signatures with optogenetics induced the predicted motor impairments in otherwise healthy mice. These data show that distinct spike signatures promote the behavioral presentation of cerebellar diseases.

Intentional movement is fundamental to achieving many goals, whether they are as complicated as driving a car or as routine as feeding ourselves with a spoon. The cerebellum is a key brain area for coordinating such movement. Damage to this region can cause various movement disorders: ataxia (uncoordinated movement); dystonia (uncontrolled muscle contractions); and tremor (involuntary and rhythmic shaking). While abnormal electrical activity in the brain associated with movement disorders has been recorded for decades, previous studies often explored one movement disorder at a time. Therefore, it remained unclear whether the underlying brain activity is similar across movement disorders. Van der Heijden and Brown et al. analyzed recordings of neuron activity in the cerebellum of mice with movement disorders to create an activity profile for each disorder. The researchers then used machine learning to generate a classifier that could separate profiles associated with manifestations of ataxia, dystonia, and tremor based on unique features of their neural activity. The ability of the model to separate the three types of movement disorders indicates that abnormal movements can be distinguished based on neural activity patterns. When additional manifestations of these abnormal movements were considered, multiple mouse models of dystonia and tremor tended to show similar profiles. Ataxia models had several different types of neural activity that were all distinct from the dystonia and tremor profiles. After identifying the activity associated with each movement disorder, Van der Heijden and Brown et al. induced the same activity in the cerebella of healthy mice, which then caused the corresponding abnormal movements. These findings lay an important groundwork for the development of treatments for neurological disorders involving ataxia, dystonia, and tremor. They identify the cerebellum, and specific patterns of activity within it, as potential therapeutic targets. While the different activity profiles of ataxia may require more consideration, the neural activity associated with dystonia and tremor appears to be generalizable across multiple manifestations, suggesting potential treatments could be broadly applicable for these disorders.