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Genes Jun 2024Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG expansion on the huntingtin () gene and is characterized by progressive... (Review)
Review
Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG expansion on the huntingtin () gene and is characterized by progressive motor, cognitive, and neuropsychiatric decline. Recently, new genetic factors besides CAG repeats have been implicated in the disease pathogenesis. Most genetic modifiers are involved in DNA repair pathways and, as the cause of the loss of CAA interruption in the gene, they exert their main influence through somatic expansion. However, this mechanism might not be the only driver of HD pathogenesis, and future studies are warranted in this field. The aim of the present review is to dissect the many faces of genetics in HD pathogenesis, from cis- and trans-acting genetic modifiers to RNA toxicity, mitochondrial DNA mutations, and epigenetics factors. Exploring genetic modifiers of HD onset and progression appears crucial to elucidate not only disease pathogenesis, but also to improve disease prediction and prevention, develop biomarkers of disease progression and response to therapies, and recognize new therapeutic opportunities. Since the same genetic mechanisms are also described in other repeat expansion diseases, their implications might encompass the whole spectrum of these disorders.
Topics: Huntington Disease; Humans; Huntingtin Protein; Trinucleotide Repeat Expansion; Animals; Epigenesis, Genetic; DNA, Mitochondrial
PubMed: 38927742
DOI: 10.3390/genes15060807 -
BMC Geriatrics Jun 202440-60% of persons living with dementia (PLWD) experience agitation and/or aggression symptoms. There is a need to understand the best method to detect agitation and/or...
OBJECTIVE
40-60% of persons living with dementia (PLWD) experience agitation and/or aggression symptoms. There is a need to understand the best method to detect agitation and/or aggression in PLWD. We aimed to identify agitation and/or aggression tools that are validated against a reference standard within the context of PLWD.
METHODS
Our study was registered on PROSPERO (CRD42020156708). We searched MEDLINE, Embase, and PsycINFO up to April 22, 2024. There were no language or date restrictions. Studies were included if they used any tools or questionnaires for detecting either agitation or aggression compared to a reference standard among PLWD, or any studies that compared two or more agitation and/or aggression tools in the population. All screening and data extraction were done in duplicates. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Data extraction was completed in duplicates by two independent authors. We extracted demographic information, prevalence of agitation and/or aggression, and diagnostic accuracy measures. We also reported studies comparing the correlation between two or more agitation and/or aggression tools.
RESULTS
6961 articles were screened across databases. Six articles reporting diagnostic accuracy measures compared to a reference standard and 30 articles reporting correlation measurements between tools were included. The agitation domain of the Spanish NPI demonstrated the highest sensitivity (100%) against the agitation subsection of the Spanish CAMDEX. Single-study evidence was found for the diagnostic accuracy of commonly used agitation scales (BEHAVE-AD, NPI and CMAI).
CONCLUSIONS
The agitation domain of the Spanish NPI, the NBRS, and the PAS demonstrated high sensitivities, and may be reasonable for clinical implementation. However, a limitation to this finding is that despite an extensive search, few studies with diagnostic accuracy measurements were identified. Ultimately, more research is needed to understand the diagnostic accuracy of agitation and/or aggression detection tools among PLWD.
Topics: Humans; Aggression; Psychomotor Agitation; Dementia
PubMed: 38926638
DOI: 10.1186/s12877-024-05143-6 -
Clinical and Translational Medicine Jul 2024
Topics: Huntington Disease; Humans; Cholesterol; Brain
PubMed: 38924677
DOI: 10.1002/ctm2.1746 -
Toxins Jun 2024Deep Brain Stimulation (DBS) is a recognized treatment for different dystonia subtypes and has been approved by the Food and Drug Administration (FDA) since 2003. The...
Deep Brain Stimulation (DBS) is a recognized treatment for different dystonia subtypes and has been approved by the Food and Drug Administration (FDA) since 2003. The European Federation of Neurological Societies (EFNS) and the International Parkinson and Movement Disorders Society (MDS) recommend DBS for dystonia after failure of botulinum toxin (BoNT) and other oral medications for dystonia treatment. In addition, several long-term studies have demonstrated the continuous efficacy of DBS on motor and quality of life (QoL) scores. However, there are only a few reports comparing the overall impact of surgical treatment in BoNT protocols (e.g., dosage and number of selected muscles before and after surgery). This retrospective multicenter chart-review study analyzed botulinum toxin total dosage and dosage per muscle in 23 dystonic patients before and after DBS surgery. The study's primary outcome was to analyze whether there was a reduction in BoNT dosage after DBS surgery. The mean BoNT dosages difference between baseline and post-surgery was 293.4 units for 6 months, 292.6 units for 12 months, and 295.2 units at the last visit. The median total dose of BoNT in the preoperative period was 800 units (N = 23). At the last visit, the median was 700 units ( = 0.05). This represents a 12.5% reduction in BoNT median dosage. In conclusion, despite the limitations of this retrospective study, there was a significant reduction in BoNT doses after DBS surgery in patients with generalized dystonia.
Topics: Humans; Deep Brain Stimulation; Retrospective Studies; Male; Female; Dystonia; Middle Aged; Adult; Botulinum Toxins; Aged; Treatment Outcome; Quality of Life
PubMed: 38922176
DOI: 10.3390/toxins16060282 -
Cells Jun 2024gene loss-of-function mutation leads to Primary Ciliary Dyskinesia (PCD), a disease caused by motile cilia dysfunction. Previously, we demonstrated that knockout of the...
gene loss-of-function mutation leads to Primary Ciliary Dyskinesia (PCD), a disease caused by motile cilia dysfunction. Previously, we demonstrated that knockout of the gene in mice replicates several features of PCD, such as hydrocephalus, defects in left-right body symmetry, and male infertility, with a complete absence of sperm in the reproductive tract. The majority of knockout animals die before sexual maturation due to severe hydrocephalus and failure to thrive, which precludes fertility studies. Here, we performed the expression analysis of the gene during gonad development and in adult testes. We showed that starts its expression during the first wave of spermatogenesis, specifically at the meiotic stage, and that its expression is restricted to the germ cells in the adult testes, suggesting that plays a role in spermatozoa formation. Subsequently, we conditionally deleted the gene in adult males and demonstrated that even partial ablation of the gene leads to asthenoteratozoospermia with multiple morphological abnormalities of sperm flagella (MMAF) in mice. The analysis of the seminiferous tubules in -deficient mice revealed defects in spermatogenesis with accumulation of seminiferous tubules at the spermiogenesis and spermiation phases. Furthermore, analysis of fertility in heterozygous knockout mice revealed a reduction in sperm count and motility as well as abnormal sperm morphology. Additionally, males exhibited a shorter fertile lifespan. Overall, these results suggest the important role of and gene dosage in male fertility. These findings may have an impact on the genetic and fertility counseling practice of PCD patients carrying loss-of-function mutations.
Topics: Animals; Male; Spermatogenesis; Fertility; Mice; Spermatozoa; Mice, Knockout; Testis; Infertility, Male; Mice, Inbred C57BL
PubMed: 38920681
DOI: 10.3390/cells13121053 -
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 -
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 -
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 -
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