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Cells Jun 2024Defects in motile cilia, termed motile ciliopathies, result in clinical manifestations affecting the respiratory and reproductive system, as well as laterality defects...
Defects in motile cilia, termed motile ciliopathies, result in clinical manifestations affecting the respiratory and reproductive system, as well as laterality defects and hydrocephalus. We previously defined biallelic variants causing and male infertility, mirroring the findings in mice. Here, we present clinical and genomic findings in five newly identified individuals from four unrelated families affected by -related disorder. Ciliopathy panel testing and whole exome sequencing identified one previously reported and two novel variants extending the genotypic spectrum of disease. A broad spectrum of laterality defects including and heterotaxia was confirmed. Interestingly, a single affected six-year-old girl homozygous for an nonsense variant presented with a history of neonatal respiratory distress syndrome, recurrent respiratory tract infections, chronic rhinitis, and wet cough. Accordingly, immunofluorescence analysis showed the absence of MNS1 from the respiratory epithelial cells of this individual. Two other individuals with hypomorphic variants showed laterality defects and mild respiratory phenotype. This study represents the first observation of heterotaxia and respiratory disease in individuals with biallelic variants, an important extension of the phenotype associated with MNS1-related motile ciliopathy disorder.
Topics: Humans; Female; Male; Child; Alleles; Pedigree; Phenotype; Child, Preschool; Cilia; Ciliopathies
PubMed: 38920647
DOI: 10.3390/cells13121017 -
Current Neuropharmacology Jun 2024Excessive free radicals are implicated in the pathophysiology of tardive dyskinesia (TD), and Ginkgo biloba extract (EGb761) scavenges free radicals, thereby enhancing...
BACKGROUND
Excessive free radicals are implicated in the pathophysiology of tardive dyskinesia (TD), and Ginkgo biloba extract (EGb761) scavenges free radicals, thereby enhancing antioxidant enzymes such as mitochondrial manganese superoxide dismutase (MnSOD). This study examined whether EGb761 treatment would improve TD symptoms and increase MnSOD activity, particularly in TD patients with specific MnSOD Val-9Ala genotype.
METHODS
An EGb761 (240 mg/day) 12-week double-blind clinical trial with 157 TD patients was randomized. The severity of TD was measured by the Abnormal Involuntary Movement Scale (AIMS) and plasma MnSOD activity was assayed before and after 12 weeks of treatment. Further, in an expanded sample, we compared MnSOD activity in 159 TD, 227 non-TD and 280 healthy controls, as well as the allele frequencies and genotypes for the MnSOD Ala-9Val polymorphism in 352 TD, 486 non-TD and 1150 healthy controls.
RESULTS
EGb761 significantly reduced TD symptoms and increased MnSOD activity in TD patients compared to placebo (both p < 0.01). Moreover, we found an interaction between genotype and treatment response (p < 0.001). Furthermore, in the EGb761 group, patients carrying the Ala allele displayed a significantly lower AIMS total score than patients with the Val/Val genotype. In addition, MnSOD activity was significantly lower at baseline in TD patients compared with healthy controls or non-TD patients.
CONCLUSION
EGb761 treatment enhanced low MnSOD activity in TD patients and produced greater improvement in TD symptoms in patients with the Ala allele of the MnSOD Ala-9Val polymorphism.
PubMed: 38919004
DOI: 10.2174/1570159X22666240530095721 -
BMC Genomics Jun 2024Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder featured by abnormal movements, arising from the extensive neuronal loss and glial...
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder featured by abnormal movements, arising from the extensive neuronal loss and glial dysfunction in the striatum. Although the causes and pathogenetic mechanisms of HD are well established, the development of disease-modifying pharmacological therapies for HD remains a formidable challenge. Laduviglusib has demonstrated neuroprotective effects through the enhancement of mitochondrial function in the striatum of HD animal models. Ferroptosis is a nonapoptotic form of cell death that occurs as a consequence of lethal iron-dependent lipid peroxidation and mitochondrial dysfunction. However, the ferroptosis-related mechanisms underlying the neuroprotective effects of laduviglusib in the striatum of HD patients remain largely uncharted. In this study, we leveraged single-nucleus RNA sequencing data obtained from the striatum of HD patients in stages 2-4 to identify differentially expressed genes within distinct cell-type. We subsequently integrated these differentially expressed genes of HD, laduviglusib target genes and ferroptosis-related genes to predict the ferroptosis-related mechanisms underpinning the neuroprotective effects of laduviglusib in HD patients. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses unveiled that the effects of laduviglusib on direct pathway striatal projection neurons (dSPNs) is mainly associated with Th17 cell differentiation pathways. Conversely, its impact on indirect pathway striatal projection neurons (iSPNs) extends to the Neurotrophin signaling pathway, FoxO signaling pathway, and reactive oxygen species pathway. In microglia, laduviglusib appears to contribute to HD pathology via mechanisms related to Th17 cell differentiation and the FoxO signaling pathway. Further, molecular docking results indicated favorable binding of laduviglusib with PARP1 (associated with dSPNs and iSPNs), SCD (associated with astrocytes), ALOX5 (associated with microglia), and HIF1A (associated with dSPNs, iSPNs, and microglia). In addition, the KEGG results suggest that laduviglusib may enhance mitochondrial function and protect against neuronal loss by targeting ferroptosis-related signaling pathways, particularly mediated by ALOX5 in microglia. These findings provide valuable insights into the potential mechanisms through which laduviglusib exerts its effects on distinct cell-types within the HD striatum.
Topics: Ferroptosis; Huntington Disease; Humans; Corpus Striatum; Neuroprotective Agents
PubMed: 38918688
DOI: 10.1186/s12864-024-10534-5 -
Journal of Cardiovascular Medicine... Jun 2024The role of epicardial adipose tissue (EAT) in cardiovascular health has undergone a paradigm shift in recent years, evolving from a passive reservoir into a dynamic...
INTRODUCTION
The role of epicardial adipose tissue (EAT) in cardiovascular health has undergone a paradigm shift in recent years, evolving from a passive reservoir into a dynamic contributor to cardiovascular risk. This case critically examines the multifaceted functions of EAT, explores its implications for cardiovascular risk, and discusses the potential benefits of the GLP-1 receptor agonist Liraglutide in mitigating its effects.
CASE PRESENTATION
We present the case of a 62-year-old male patient who is obese, hypertensive, and has a history of chronic coronary syndrome. He was admitted to the emergency room with complaints of palpitations and shortness of breath. The 12-lead ECG revealed atrial fibrillation with a rapid ventricular response and evidence of a new-onset left bundle branch block. The transthoracic echocardiogram showed heart-rate-dependent regional dyskinesias, while both echocardiographic and computed tomographic scan findings indicated the presence of thick EAT. A coronary angiogram showed intrastent restenosis in the left anterior descending artery, which was treated with percutaneous revascularization. To address residual cardiovascular risk, the patient was initiated on Liraglutide during hospitalization. The follow-up revealed reduced low-density lipoprotein-cholesterol and high-sensitivity C-reactive protein levels, along with a decrease in EAT thickness and BMI, accompanied by improved echocardiographic parameters.
DISCUSSION
Targeted interventions aimed at reducing EAT are imperative given its active role in cardiovascular risk. GLP-1 receptor agonists, such as Liraglutide, hold promise in mitigating the effects of EAT and represent a potential avenue for therapeutic exploration in addressing residual cardiovascular risk.
PubMed: 38916237
DOI: 10.2459/JCM.0000000000001652 -
Pediatric Neurology Jun 2024Since the initial description of glucose transporter-1 deficiency syndrome (Glut1-DS) the phenotype of the condition has expanded, even leading to the recognition of...
BACKGROUND
Since the initial description of glucose transporter-1 deficiency syndrome (Glut1-DS) the phenotype of the condition has expanded, even leading to the recognition of atypical manifestations. We report on eight patients with Glut1-DS who experienced at least one episode of acute focal neurological deficits.
METHODS
We conducted a retrospective analysis, collecting clinical, electrophysiological, neuroradiological, and genetic information. We focused in particular on three well-documented cases.
RESULTS
Among 42 patients with Glut1-DS, eight individuals aged between six and 38 years presented with an acute onset of neurological disturbances: dysarthria/aphasia, oral dyskinesia, swallowing difficulties, paresthesia, facial palsy, hemi/monoplegia, vomiting, headache, and behavioral disturbances. When performed, magnetic resonance imaging (MRI) revealed signs of venous congestion and hypoperfusion and electroencephalography showed focal contralateral slowing. Deficits were transient in all patients but one. Four patients (50%) were on a ketogenic diet (KD), and two of these patients had lower than usual ketonemia levels during the episode. In two patients, MRI demonstrated the presence of an ischemic brain lesion.
CONCLUSIONS
In Glut1-DS, stroke-like episodes are a recurrent manifestation, particularly during early adulthood, and they were reported in 19% of the patients in our cohort. Stroke mimics should be considered a key feature of Glut1-DS, as other paroxysmal disorders. It remains to be established whether a KD can prevent the recurrence of episodes and, if so, at what level of ketosis. Further observations are needed to confirm the correlation between Glut1-DS and ischemic stroke.
PubMed: 38914025
DOI: 10.1016/j.pediatrneurol.2024.05.024 -
The Journal of Cell Biology Aug 2024The double-stranded RNA-binding protein Staufen1 (STAU1) regulates a variety of physiological and pathological events via mediating RNA metabolism. STAU1 overabundance...
The double-stranded RNA-binding protein Staufen1 (STAU1) regulates a variety of physiological and pathological events via mediating RNA metabolism. STAU1 overabundance was observed in tissues from mouse models and fibroblasts from patients with neurodegenerative diseases, accompanied by enhanced mTOR signaling and impaired autophagic flux, while the underlying mechanism remains elusive. Here, we find that endogenous STAU1 forms dynamic cytoplasmic condensate in normal and tumor cell lines, as well as in mouse Huntington's disease knockin striatal cells. STAU1 condensate recruits target mRNA MTOR at its 5'UTR and promotes its translation both in vitro and in vivo, and thus enhanced formation of STAU1 condensate leads to mTOR hyperactivation and autophagy-lysosome dysfunction. Interference of STAU1 condensate normalizes mTOR levels, ameliorates autophagy-lysosome function, and reduces aggregation of pathological proteins in cellular models of neurodegenerative diseases. These findings highlight the importance of balanced phase separation in physiological processes, suggesting that modulating STAU1 condensate may be a strategy to mitigate the progression of neurodegenerative diseases with STAU1 overabundance.
Topics: RNA-Binding Proteins; TOR Serine-Threonine Kinases; Animals; Humans; Autophagy; Mice; Protein Biosynthesis; Cytoskeletal Proteins; Neurodegenerative Diseases; Lysosomes; Signal Transduction; Huntington Disease
PubMed: 38913026
DOI: 10.1083/jcb.202311127 -
Tremor and Other Hyperkinetic Movements... 2024Spinocerebellar ataxia (SCA) denotes an expanding list of autosomal dominant cerebellar ataxias. Although tremor is an important aspect of the clinical spectrum of the... (Review)
Review
BACKGROUND
Spinocerebellar ataxia (SCA) denotes an expanding list of autosomal dominant cerebellar ataxias. Although tremor is an important aspect of the clinical spectrum of the SCAs, its prevalence, phenomenology, and pathophysiology are unknown.
OBJECTIVES
This review aims to describe the various types of tremors seen in the different SCAs, with a discussion on the pathophysiology of the tremors, and the possible treatment modalities.
METHODS
The authors conducted a literature search on PubMed using search terms including tremor and the various SCAs. Relevant articles were included in the review after excluding duplicate publications.
RESULTS
While action (postural and intention) tremors are most frequently associated with SCA, rest and other rare tremors have also been documented. The prevalence and types of tremors vary among the different SCAs. SCA12, common in certain ethnic populations, presents a unique situation, where the tremor is typically the principal manifestation. Clinical manifestations of SCAs may be confused with essential tremor or Parkinson's disease. The pathophysiology of tremors in SCAs predominantly involves the cerebellum and its networks, especially the cerebello-thalamo-cortical circuit. Additionally, connections with the basal ganglia, and striatal dopaminergic dysfunction may have a role. Medical management of tremor is usually guided by the phenomenology and associated clinical features. Deep brain stimulation surgery may be helpful in treatment-resistant tremors.
CONCLUSIONS
Tremor is an elemental component of SCAs, with diverse phenomenology, and emphasizes the role of the cerebellum in tremor. Further studies will be useful to delineate the clinical, pathophysiological, and therapeutic aspects of tremor in SCAs.
Topics: Humans; Tremor; Spinocerebellar Ataxias; Deep Brain Stimulation
PubMed: 38911333
DOI: 10.5334/tohm.911 -
Combinatorial Chemistry & High... Jun 2024Variants in the PRRT2 gene are associated with paroxysmal kinesigenic dyskinesia and other episodic disorders. With the employment of variant screening in patients with...
BACKGROUND
Variants in the PRRT2 gene are associated with paroxysmal kinesigenic dyskinesia and other episodic disorders. With the employment of variant screening in patients with episodic dyskinesia, many PRRT2 variants have been discovered. Bioinformatics tools are becoming increasingly important for predicting the functional significance of variants. This study aimed to evaluate the performance of six in silico tools for PRRT2 missense variants.
METHODS
Pathogenic PRRT2 variants were retrieved from the Human Gene Mutation Database (HGMD) and literature from the PubMed database. The benign set of non-deleterious variants was retrieved from the Genome Aggregation Database (gnomAD). The overall accuracy, sensitivity, specificity, positive predictive values, and negative predictive values of SIFT, PolyPhen2, MutationTaster, CADD, Fathmm, and Provean were analyzed. The MCC score and ROC curve were calculated. The GraphPad Prism 8.0 software was used to plot ROC curves for the six bioinformatics software.
RESULTS
A total of 45 missense variants with confirmed pathogenicity were used as a positive set, and 222 missense variants were used as a negative set. The top three tools in accuracy are Fathmm, Provean, and MutationTaster. The top three predictors in sensitivity are SIFT, PolyPhen2, and CADD. Regarding specificity, the top three tools were Provean, Fathmm, and MutationTaster. In terms of the MCC and F-score, the highest degree was observed in Fathmm. Fathmm also had the highest AUC score. The cutoff values of Fathmm, CADD, PolyPhen2, and Provean were between the median prediction scores of the positive and negative sets. In contrast, the cutoff value of SIFT was below the median prediction score of the positive and negative sets. Fathmm had the highest accuracy.
CONCLUSION
The prediction performance of six in silico tools differed among the parameters. Fathmm had the best prediction performance, with the highest accuracy and MCC/F-score for PRRT2 missense variants.
PubMed: 38910474
DOI: 10.2174/0113862073308898240607090256 -
Rural and Remote Health Jun 2024Physical activity and lifestyle programs are scarce for people with hereditary ataxias and neurodegenerative diseases. Aboriginal families in the Top End of Australia...
INTRODUCTION
Physical activity and lifestyle programs are scarce for people with hereditary ataxias and neurodegenerative diseases. Aboriginal families in the Top End of Australia who have lived with Machado-Joseph disease (MJD) for generations co-designed a physical activity and lifestyle program called the Staying Strong Toolbox. The aim of the present study was to explore feasibility and impact of the program on walking and moving around.
METHODS
A mixed-methods, multiple case study design was used to pilot the Staying Strong Toolbox. Eight individuals with MJD participated in the program for 4 weeks. Participants tailored their own program using the Toolbox workbook. Families, support workers and researchers facilitated each individual's program. Feasibility was determined through program participation, adherence, coinciding or serious adverse events, participant acceptability and cost. Impact was determined through measures of mobility, ataxia, steps, quality of life, wellbeing and goal attainment, assessed before and after the program.
RESULTS
All participants completed the program, averaging five activity sessions per week, 66 minutes per session, of walking (63.5%), strengthening/balance-based activities (16%), cycling (11.4%) and activities of daily living, cultural and lifestyle activities (10.5%). Seven participants were assessed on all measures on three occasions (baseline, pre-program and post-program), while one participant could not complete post-program measures due to ceremonial responsibilities. All had significant improvements in mobility, steps taken and ataxia severity (p<0.05) after the program. Quality of life and wellbeing were maintained.
CONCLUSION
The program helped participants remain 'strong on the inside and outside'. Participants recommended implementation in 4-week blocks and for the program to be shared internationally. The Staying Strong Toolbox program was feasible for families with MJD. The program had a positive impact on walking and moving around, with participants feeling stronger on the outside (physically) and inside (emotionally, spiritually, psychosocially). The program could be adapted for use by other families with MJD.
Topics: Humans; Machado-Joseph Disease; Male; Female; Native Hawaiian or Other Pacific Islander; Adult; Exercise; Australia; Middle Aged; Life Style; Feasibility Studies; Quality of Life; Walking; Activities of Daily Living
PubMed: 38909987
DOI: 10.22605/RRH8376 -
Medicina 2024Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is a late onset neurodegenerative disorder. Its genetic basis has recently been identified in...
Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is a late onset neurodegenerative disorder. Its genetic basis has recently been identified in the gene encoding a subunit of the Replication Factor C (RFC1). We present the case of a 62-year-old woman who experienced a history of a biphasic presentation of imbalance and gait disorders, with rapid onset of symptoms followed by slow and progressive neurological deterioration. The diagnostic process was challenging, and numerous tests were conducted to rule out acquired and genetic causes of ataxia, leading to a diagnosis of late-onset idiopathic cerebellar ataxia. Subsequently, vestibular function tests identified severe bilateral vestibulopathy. This led to considering CANVAS among the diagnoses, which was ultimately confirmed through genetic testing (biallelic expansion of the pentanucleotide AAGGG in the RFC1 gene). This case highlights the importance of this new described genetic disease and its subacute presentation variant, emphasizing the relevance of objective vestibular function tests in idiopathic ataxias to achieve proper diagnosis and eventual genetic counseling for offspring.
Topics: Humans; Female; Middle Aged; Cerebellar Ataxia; Bilateral Vestibulopathy; Syndrome; Replication Protein C; Vestibular Function Tests
PubMed: 38907973
DOI: No ID Found