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Disease Models & Mechanisms May 2024The TATA-box binding protein-associated factor 1 (TAF1) is a ubiquitously expressed protein and the largest subunit of basal transcription factor TFIID, which plays a...
The TATA-box binding protein-associated factor 1 (TAF1) is a ubiquitously expressed protein and the largest subunit of basal transcription factor TFIID, which plays a key role in initiation of RNA polymerase II-dependent transcription. TAF1 missense variants in males cause X-linked intellectual disability, a neurodevelopmental disorder, and TAF1 is dysregulated in X-linked Dystonia-Parkinsonism, a neurodegenerative disorder. However, this field has suffered from the lack of a genetic mouse model of TAF1 disease to explore mammalian mechanism and treatments. Here, we generated and validated a conditional cre-lox allele, and the first ubiquitous Taf1 knock-out mouse. We discovered that Taf1 deletion in males was embryonically lethal, which may explain why no human null-variants have been identified. In the brains of Taf1 heterozygous females, no differences were found in gross structure, overall expression, and protein localization, suggesting extreme skewed X-inactivation towards the non-mutant chromosome. Nevertheless, these female mice exhibited a significant increase in weight, weight with age, and reduced movement, suggesting a small subset of neurons has been negatively impacted by Taf1 loss. Finally, this new mouse may be a future platform for the development of TAF1 disease therapeutics.
PubMed: 38804708
DOI: 10.1242/dmm.050741 -
Neurology International May 2024(1) Background: Niemann-Pick type C1 (NP-C1) is a lysosomal storage disorder that results in the defective trafficking of cholesterol and other cellular lipids in the...
(1) Background: Niemann-Pick type C1 (NP-C1) is a lysosomal storage disorder that results in the defective trafficking of cholesterol and other cellular lipids in the endosomal-lysosomal pathway. This rare autosomal recessive disorder presents in three forms based on the age of onset. The adult form presents in patients greater than 15 years of age but is rarely seen after the age of 30. Common symptoms of the late adult-onset category of NP-C1 include progressive cognitive impairment and ataxia, with psychiatric and movement disorders presenting less frequently than in other forms of NP-C1. Dystonic movement disorders present most frequently, along with chorea, myoclonus, and parkinsonism. Herein, we present a rare case of NP-C1, diagnosed at age 35 with an initial symptom of supranuclear palsy. The goal of the presented case is to highlight the importance of the neurological examination and an inclusive differential diagnosis in patients with new-onset supranuclear palsy. (2) Methods: A single case report. (3) Results: A 46-year-old male with a past medical history of NP-C1 was admitted to the hospital for respiratory distress. He was noted to have a supranuclear gaze palsy with partially preserved voluntary saccades to the right. His mother revealed that he first had difficulty moving his eyes at the age of 34. After multiple consultations and genetic testing one year later, he was diagnosed with NP-C1. (4) Conclusions: Because NP-C1 affects many regions of the brain responsible for eye movements, neurological eye assessments can be a useful tool in diagnoses. Furthermore, eye movement abnormalities may be the initial presenting symptom of NP-C1, predisposing patients to misdiagnosis with progressive supranuclear palsy and other conditions that may mimic early-stage NP-C1. Definitive diagnosis is achieved through genetic testing. Filipin staining test was the gold standard in the past. The NP-C Suspicion Index was developed to assist in diagnoses, but its efficacy is unclear with late adult-onset NP-C1. Although no cure exists, early identification can facilitate an improved symptom management course for patients. Miglustat, a glucosylceramide synthase (GCS) inhibitor, is the approved therapy in Europe specific to NP-C1 for slowing and preventing the neurological manifestations of NP-C1. Delays between symptom onset and treatment initiation are likely to result in poorer outcomes and a progression of neurological symptoms. High doses may present tolerance concerns, especially in cases of delayed treatment and advanced neurological deficit.
PubMed: 38804481
DOI: 10.3390/neurolint16030042 -
BMC Neurology May 2024Accumulating neuroimaging evidence indicates that patients with cervical dystonia (CD) have changes in the cortico-subcortical white matter (WM) bundle. However, whether...
BACKGROUND
Accumulating neuroimaging evidence indicates that patients with cervical dystonia (CD) have changes in the cortico-subcortical white matter (WM) bundle. However, whether these patients' WM structural networks undergo reorganization remains largely unclear. We aimed to investigate topological changes in large-scale WM structural networks in patients with CD compared to healthy controls (HCs), and explore the network changes associated with clinical manifestations.
METHODS
Diffusion tensor imaging (DTI) was conducted in 30 patients with CD and 30 HCs, and WM network construction was based on the BNA-246 atlas and deterministic tractography. Based on the graph theoretical analysis, global and local topological properties were calculated and compared between patients with CD and HCs. Then, the AAL-90 atlas was used for the reproducibility analyses. In addition, the relationship between abnormal topological properties and clinical characteristics was analyzed.
RESULTS
Compared with HCs, patients with CD showed changes in network segregation and resilience, characterized by increased local efficiency and assortativity, respectively. In addition, a significant decrease of network strength was also found in patients with CD relative to HCs. Validation analyses using the AAL-90 atlas similarly showed increased assortativity and network strength in patients with CD. No significant correlations were found between altered network properties and clinical characteristics in patients with CD.
CONCLUSION
Our findings show that reorganization of the large-scale WM structural network exists in patients with CD. However, this reorganization is attributed to dystonia-specific abnormalities or hyperkinetic movements that need further identification.
Topics: Humans; Torticollis; White Matter; Female; Male; Diffusion Tensor Imaging; Middle Aged; Adult; Nerve Net; Aged
PubMed: 38802755
DOI: 10.1186/s12883-024-03682-4 -
Cureus Apr 2024This paper examines the impact of delayed diagnosis and treatment on the prognosis of patients with leiomyosarcomas (LMS). We present a case study highlighting the...
This paper examines the impact of delayed diagnosis and treatment on the prognosis of patients with leiomyosarcomas (LMS). We present a case study highlighting the consequences of neglected LMS, focusing on vascular involvement and metastatic potential. Our findings underscore the importance of early detection and intervention in improving patient outcomes. Additionally, we discuss the challenges associated with diagnosing rare skin LMS and the implications of limited access to medical screening. Through a comprehensive analysis of the literature, we elucidate the critical role of routine surveillance in detecting these malignancies at an earlier stage, thus facilitating timely intervention and potentially curative treatment. This study underscores the urgency of raising awareness among both healthcare providers and the general population about the significance of early detection and prompt management in mitigating the adverse outcomes associated with neglected LMS.
PubMed: 38800295
DOI: 10.7759/cureus.59081 -
BioRxiv : the Preprint Server For... May 2024Dystonia is the 3 most common movement disorder. Dystonia is acquired through either injury or genetic mutations, with poorly understood molecular and cellular...
Dystonia is the 3 most common movement disorder. Dystonia is acquired through either injury or genetic mutations, with poorly understood molecular and cellular mechanisms. Eukaryotic initiation factor alpha (eIF2α) controls cell state including neuronal plasticity via protein translation control and expression of ATF4. Dysregulated eIF2α phosphorylation (eIF2α-P) occurs in dystonia patients and models including DYT1, but the consequences are unknown. We increased/decreased eIF2α-P and tested motor control and neuronal properties in a Drosophila model. Bidirectionally altering eIF2α-P produced dystonia-like abnormal posturing and dyskinetic movements in flies. These movements were also observed with expression of the risk allele. We identified cholinergic and D2-receptor neuroanatomical origins of these dyskinetic movements caused by genetic manipulations to dystonia molecular candidates eIF2α-P, ATF4, or DYT1, with evidence for decreased cholinergic release. , increased and decreased eIF2α-P increase synaptic connectivity at the NMJ with increased terminal size and bouton synaptic release sites. Long-term treatment of elevated eIF2α-P with ISRIB restored adult longevity, but not performance in a motor assay. Disrupted eIF2α-P signaling may alter neuronal connectivity, change synaptic release, and drive motor circuit changes in dystonia.
PubMed: 38798458
DOI: 10.1101/2024.05.14.594240 -
International Journal of Molecular... May 2024The gene encodes an orphan transcription factor of the steroid-thyroid hormone-retinoid receptor superfamily. This review focuses on the clinical findings associated... (Review)
Review
The gene encodes an orphan transcription factor of the steroid-thyroid hormone-retinoid receptor superfamily. This review focuses on the clinical findings associated with the pathogenic variants so far reported, including three unreported cases. Also, its role in neurodegenerative diseases, such as Parkinson's or Alzheimer's disease, is examined, as well as a brief exploration on recent proposals to develop novel therapies for these neurological diseases based on small molecules that could modulate transcriptional activity. The main characteristic shared by all patients is mild to severe developmental delay/intellectual disability. Moderate to severe disorder of the expressive and receptive language is present in at least 42%, while neuro-psychiatric issues were reported in 53% of patients. Movement disorders, including dystonia, chorea or ataxia, are described in 37% patients, although probably underestimated because of its frequent onset in late adolescence-young adulthood. Finally, epilepsy was surprisingly present in 42% of patients, being drug-resistant in three of them. The age at onset varied widely, from five months to twenty-six years, as did the classification of epilepsy, which ranged from focal epilepsy to infantile spasms or Lennox-Gastaut syndrome. Accordingly, we propose that should be considered as a first-tier target gene for the genetic diagnosis of developmental and epileptic encephalopathy.
Topics: Humans; Epilepsy; Nuclear Receptor Subfamily 4, Group A, Member 2; Developmental Disabilities; Intellectual Disability
PubMed: 38791237
DOI: 10.3390/ijms25105198 -
International Journal of Molecular... May 2024Movement disorders such as bradykinesia, tremor, dystonia, chorea, and myoclonus most often arise in several neurodegenerative diseases with basal ganglia and white...
Movement disorders such as bradykinesia, tremor, dystonia, chorea, and myoclonus most often arise in several neurodegenerative diseases with basal ganglia and white matter involvement. While the pathophysiology of these disorders remains incompletely understood, dysfunction of the basal ganglia and related brain regions is often implicated. The gene, part of the family, has emerged as a crucial player in neurological pathology, implicated in diverse phenotypes ranging from movement disorders to Leigh syndrome. We present a clinical case of -associated disease with two variants in the gene in an adult female. This case contributes to our evolving understanding of -related diseases and underscores the importance of genetic screening in diagnosing and managing such conditions.
Topics: Humans; Female; Spinocerebellar Ataxias; Vesicular Transport Proteins; Adult; Phenotype; Mutation; Genes, Recessive; Pedigree; Proteins
PubMed: 38791166
DOI: 10.3390/ijms25105127 -
BMC Neurology May 2024The thalamus has a central role in the pathophysiology of idiopathic cervical dystonia (iCD); however, the nature of alterations occurring within this structure remain...
BACKGROUND
The thalamus has a central role in the pathophysiology of idiopathic cervical dystonia (iCD); however, the nature of alterations occurring within this structure remain largely elusive. Using a structural magnetic resonance imaging (MRI) approach, we examined whether abnormalities differ across thalamic subregions/nuclei in patients with iCD.
METHODS
Structural MRI data were collected from 37 patients with iCD and 37 healthy controls (HCs). Automatic parcellation of 25 thalamic nuclei in each hemisphere was performed based on the FreeSurfer program. Differences in thalamic nuclei volumes between groups and their relationships with clinical information were analysed in patients with iCD.
RESULTS
Compared to HCs, a significant reduction in thalamic nuclei volume primarily in central medial, centromedian, lateral geniculate, medial geniculate, medial ventral, paracentral, parafascicular, paratenial, and ventromedial nuclei was found in patients with iCD (P < 0.05, false discovery rate corrected). However, no statistically significant correlations were observed between altered thalamic nuclei volumes and clinical characteristics in iCD group.
CONCLUSION
This study highlights the neurobiological mechanisms of iCD related to thalamic volume changes.
Topics: Humans; Male; Female; Middle Aged; Torticollis; Magnetic Resonance Imaging; Thalamus; Adult; Aged; Thalamic Nuclei
PubMed: 38789945
DOI: 10.1186/s12883-024-03680-6 -
Neuropharmacology Sep 2024Neuromodulation such as deep brain stimulation (DBS) is advancing as a clinical intervention in several neurological and neuropsychiatric disorders, including... (Review)
Review
Concerning neuromodulation as treatment of neurological and neuropsychiatric disorder: Insights gained from selective targeting of the subthalamic nucleus, para-subthalamic nucleus and zona incerta in rodents.
Neuromodulation such as deep brain stimulation (DBS) is advancing as a clinical intervention in several neurological and neuropsychiatric disorders, including Parkinson's disease, dystonia, tremor, and obsessive-compulsive disorder (OCD) for which DBS is already applied to alleviate severely afflicted individuals of symptoms. Tourette syndrome and drug addiction are two additional disorders for which DBS is in trial or proposed as treatment. However, some major remaining obstacles prevent this intervention from reaching its full therapeutic potential. Side-effects have been reported, and not all DBS-treated individuals are relieved of their symptoms. One major target area for DBS electrodes is the subthalamic nucleus (STN) which plays important roles in motor, affective and associative functions, with impact on for example movement, motivation, impulsivity, compulsivity, as well as both reward and aversion. The multifunctionality of the STN is complex. Decoding the anatomical-functional organization of the STN could enhance strategic targeting in human patients. The STN is located in close proximity to zona incerta (ZI) and the para-subthalamic nucleus (pSTN). Together, the STN, pSTN and ZI form a highly heterogeneous and clinically important brain area. Rodent-based experimental studies, including opto- and chemogenetics as well as viral-genetic tract tracings, provide unique insight into complex neuronal circuitries and their impact on behavior with high spatial and temporal precision. This research field has advanced tremendously over the past few years. Here, we provide an inclusive review of current literature in the pre-clinical research fields centered around STN, pSTN and ZI in laboratory mice and rats; the three highly heterogeneous and enigmatic structures brought together in the context of relevance for treatment strategies. Specific emphasis is placed on methods of manipulation and behavioral impact.
Topics: Subthalamic Nucleus; Animals; Deep Brain Stimulation; Zona Incerta; Mental Disorders; Humans; Nervous System Diseases; Rodentia
PubMed: 38789078
DOI: 10.1016/j.neuropharm.2024.110003 -
Diseases (Basel, Switzerland) May 2024Calcium channels are specialized ion channels exhibiting selective permeability to calcium ions. Calcium channels, comprising voltage-dependent and ligand-gated types,... (Review)
Review
Calcium channels are specialized ion channels exhibiting selective permeability to calcium ions. Calcium channels, comprising voltage-dependent and ligand-gated types, are pivotal in neuronal function, with their dysregulation is implicated in various neurological disorders. This review delves into the significance of the genes, including , , , , , and , in the pathogenesis of conditions such as migraine, epilepsy, cerebellar ataxia, dystonia, and cerebellar atrophy. Specifically, variants in have been linked to familial hemiplegic migraine and epileptic seizures, underscoring its importance in neurological disease etiology. Furthermore, different genetic variants of have been associated with migraine susceptibility, further highlighting the role of genes in migraine pathology. The complex relationship between gene variants and neurological phenotypes, including focal seizures and ataxia, presents a variety of clinical manifestations of impaired calcium channel function. The aim of this article was to explore the role of genes in various neurological disorders, elucidating their significance in conditions such as migraine, epilepsy, and cerebellar ataxias. Further exploration of gene variants and their interactions with molecular factors, such as microRNAs, holds promise for advancing our understanding of genetic neurological disorders.
PubMed: 38785745
DOI: 10.3390/diseases12050090