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Ugeskrift For Laeger Sep 2023In this case report, we present a case of a 62-year-old woman with unsteadiness due to CANVAS. In addition to sensory, cerebellar, and vestibular affection she had...
In this case report, we present a case of a 62-year-old woman with unsteadiness due to CANVAS. In addition to sensory, cerebellar, and vestibular affection she had unusual features in the form of chorea and facial dystonia. Moreover, she had cervical dystonia which, to the best of our knowledge, has not previously been reported in CANVAS.
Topics: Female; Humans; Middle Aged; Chorea; Ataxia; Torticollis
PubMed: 37767867
DOI: No ID Found -
Cell Reports. Medicine Oct 2023Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist 3,4-dihydroxy-L-phenylalanine (L-DOPA) to treat...
Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist 3,4-dihydroxy-L-phenylalanine (L-DOPA) to treat Parkinson's disease (L-DOPA-induced dyskinesia [LID]) or dopamine antagonists to treat schizophrenia (tardive dyskinesia [TD]). However, it remains unknown why distinct types of medications for distinct neuropsychiatric disorders induce similar involuntary movements. Here, we search for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identify the enlarged axon terminals of striatal medium spiny neurons in LID and TD model mice. Striatal overexpression of the vesicular gamma-aminobutyric acid transporter (VGAT) is necessary and sufficient for modeling these structural changes; VGAT levels gate the functional and behavioral alterations in dyskinesia models. Our findings indicate that lowered type 2 dopamine receptor signaling with repetitive dopamine fluctuations is a common cause of VGAT overexpression and late-onset dyskinesia formation and that reducing dopamine fluctuation rescues dyskinesia pathology via VGAT downregulation.
Topics: Mice; Animals; Dopamine Agonists; Levodopa; Dopamine; Antiparkinson Agents; Parkinsonian Disorders; Dyskinesia, Drug-Induced; Oxidopamine; gamma-Aminobutyric Acid
PubMed: 37774703
DOI: 10.1016/j.xcrm.2023.101208 -
Neurology India 2023
Topics: Humans; Chorea; Dyskinesias; Hyperglycemic Hyperosmolar Nonketotic Coma
PubMed: 37635540
DOI: 10.4103/0028-3886.383864 -
Brain : a Journal of Neurology Nov 2023Cortical cell loss is a core feature of Huntington's disease (HD), beginning many years before clinical motor diagnosis, during the premanifest stage. However, it is...
Cortical cell loss is a core feature of Huntington's disease (HD), beginning many years before clinical motor diagnosis, during the premanifest stage. However, it is unclear how genetic topography relates to cortical cell loss. Here, we explore the biological processes and cell types underlying this relationship and validate these using cell-specific post-mortem data. Eighty premanifest participants on average 15 years from disease onset and 71 controls were included. Using volumetric and diffusion MRI we extracted HD-specific whole brain maps where lower grey matter volume and higher grey matter mean diffusivity, relative to controls, were used as proxies of cortical cell loss. These maps were combined with gene expression data from the Allen Human Brain Atlas (AHBA) to investigate the biological processes relating genetic topography and cortical cell loss. Cortical cell loss was positively correlated with the expression of developmental genes (i.e. higher expression correlated with greater atrophy and increased diffusivity) and negatively correlated with the expression of synaptic and metabolic genes that have been implicated in neurodegeneration. These findings were consistent for diffusion MRI and volumetric HD-specific brain maps. As wild-type huntingtin is known to play a role in neurodevelopment, we explored the association between wild-type huntingtin (HTT) expression and developmental gene expression across the AHBA. Co-expression network analyses in 134 human brains free of neurodegenerative disorders were also performed. HTT expression was correlated with the expression of genes involved in neurodevelopment while co-expression network analyses also revealed that HTT expression was associated with developmental biological processes. Expression weighted cell-type enrichment (EWCE) analyses were used to explore which specific cell types were associated with HD cortical cell loss and these associations were validated using cell specific single nucleus RNAseq (snRNAseq) data from post-mortem HD brains. The developmental transcriptomic profile of cortical cell loss in preHD was enriched in astrocytes and endothelial cells, while the neurodegenerative transcriptomic profile was enriched for neuronal and microglial cells. Astrocyte-specific genes differentially expressed in HD post-mortem brains relative to controls using snRNAseq were enriched in the developmental transcriptomic profile, while neuronal and microglial-specific genes were enriched in the neurodegenerative transcriptomic profile. Our findings suggest that cortical cell loss in preHD may arise from dual pathological processes, emerging as a consequence of neurodevelopmental changes, at the beginning of life, followed by neurodegeneration in adulthood, targeting areas with reduced expression of synaptic and metabolic genes. These events result in age-related cell death across multiple brain cell types.
Topics: Humans; Huntington Disease; Endothelial Cells; Brain; Gray Matter; Atrophy; Magnetic Resonance Imaging
PubMed: 37587097
DOI: 10.1093/brain/awad275 -
Epileptic Disorders : International... Oct 2023Progressive Myoclonus Epilepsy (PME) is a rare epilepsy syndrome characterized by the development of progressively worsening myoclonus, ataxia, and seizures. A molecular... (Review)
Review
Progressive Myoclonus Epilepsy (PME) is a rare epilepsy syndrome characterized by the development of progressively worsening myoclonus, ataxia, and seizures. A molecular diagnosis can now be established in approximately 80% of individuals with PME. Almost fifty genetic causes of PME have now been established, although some remain extremely rare. Herein, we provide a review of clinical phenotypes and genotypes of the more commonly encountered PMEs. Using an illustrative case example, we describe appropriate clinical investigation and therapeutic strategies to guide the management of this often relentlessly progressive and devastating epilepsy syndrome. This manuscript in the Genetic Literacy series maps to Learning Objective 1.2 of the ILAE Curriculum for Epileptology (Epileptic Disord. 2019;21:129).
Topics: Humans; Literacy; Myoclonic Epilepsies, Progressive; Unverricht-Lundborg Syndrome; Myoclonus; Ataxia
PubMed: 37616028
DOI: 10.1002/epd2.20152 -
Cerebellum (London, England) Jun 2024We describe a male patient presenting with cerebellar ataxia and behavioural frontotemporal dementia in whom imaging showed cerebellar atrophy. He had significantly low...
We describe a male patient presenting with cerebellar ataxia and behavioural frontotemporal dementia in whom imaging showed cerebellar atrophy. He had significantly low N-acetyl aspartate to creatine (NAA/Cr) area ratio on MR spectroscopy of the cerebellum, primarily affecting the vermis. CT body scan showed extensive abnormal tissue within the mesentery, the retroperitoneum and perinephric areas. PET-CT showed increased tracer uptake within the wall of the aorta suggestive of an aortitis and within the perinephric tissue bilaterally. Biopsy of the perinephric tissue confirmed IgG4 disease. Treatment with steroids and mycophenolate improved his clinical state, but he developed symptoms attributed to pericardiac effusion that necessitated treatment initially with drainage and subsequently with pericardial window. After a course of rituximab, he had an episode of sepsis that did not respond to appropriate treatment and died as a result. Both the imaging findings and neurological presentation with cerebellar ataxia and behavioural frontotemporal dementia are novel in the context of IgG4 disease.
Topics: Humans; Male; Cerebellar Ataxia; Immunoglobulin G4-Related Disease; Middle Aged; Frontotemporal Dementia
PubMed: 37558930
DOI: 10.1007/s12311-023-01592-8 -
Child's Nervous System : ChNS :... Oct 2023Non-spastic movement disorders in children are common, although true epidemiologic data is difficult to ascertain. Children are more likely than adults to have... (Review)
Review
BACKGROUND
Non-spastic movement disorders in children are common, although true epidemiologic data is difficult to ascertain. Children are more likely than adults to have hyperkinetic movement disorders defined as tics, dystonia, chorea/athetosis, or tremor. These conditions manifest from acquired or heredodegenerative etiologies and often severely limit function despite medical and surgical management paradigms. Neurosurgical management for these conditions is highlighted.
METHODS
We performed a focused review of the literature by searching PubMed on 16 May 2023 using key terms related to our review. No temporal filter was applied, but only English articles were considered. We searched for the terms (("Pallidotomy"[Mesh]) OR "Rhizotomy"[Mesh]) OR "Deep Brain Stimulation"[Mesh], dystonia, children, adolescent, pediatric, globus pallidus, in combination. All articles were reviewed for inclusion in the final reference list.
RESULTS
Our search terms returned 37 articles from 2004 to 2023. Articles covering deep brain stimulation were the most common (n = 34) followed by pallidotomy (n = 3); there were no articles on rhizotomy.
DISCUSSION
Non-spastic movement disorders are common in children and difficult to treat. Most of these patients are referred to neurosurgery for the management of dystonia, with modern neurosurgical management including pallidotomy, rhizotomy, and deep brain stimulation. Historically, pallidotomy has been effective and may still be preferred in subpopulations presenting either in status dystonicus or with high risk for hardware complications. Superiority of DBS over pallidotomy for secondary dystonia has not been determined. Rhizotomy is an underutilized surgical tool and more study characterizing efficacy and risk profile is indicated.
Topics: Adult; Adolescent; Humans; Child; Dystonia; Movement Disorders; Tremor; Dystonic Disorders; Neurosurgical Procedures; Globus Pallidus; Deep Brain Stimulation; Treatment Outcome
PubMed: 37522933
DOI: 10.1007/s00381-023-06100-1 -
International Journal of Molecular... Mar 2024Huntington's disease (HD) arises from the abnormal expansion of CAG repeats in the huntingtin gene (), resulting in the production of the mutant huntingtin protein... (Review)
Review
Huntington's disease (HD) arises from the abnormal expansion of CAG repeats in the huntingtin gene (), resulting in the production of the mutant huntingtin protein (mHTT) with a polyglutamine stretch in its N-terminus. The pathogenic mechanisms underlying HD are complex and not yet fully elucidated. However, mHTT forms aggregates and accumulates abnormally in neuronal nuclei and processes, leading to disruptions in multiple cellular functions. Although there is currently no effective curative treatment for HD, significant progress has been made in developing various therapeutic strategies to treat HD. In addition to drugs targeting the neuronal toxicity of mHTT, gene therapy approaches that aim to reduce the expression of the mutant gene hold great promise for effective HD therapy. This review provides an overview of current HD treatments, discusses different therapeutic strategies, and aims to facilitate future therapeutic advancements in the field.
Topics: Humans; Huntington Disease; Genetic Therapy; Mutant Proteins
PubMed: 38612657
DOI: 10.3390/ijms25073845 -
Cell Reports Aug 2023Neuroblastoma is a lethal childhood solid tumor of developing peripheral nerves. Two percent of children with neuroblastoma develop opsoclonus myoclonus ataxia syndrome...
Neuroblastoma is a lethal childhood solid tumor of developing peripheral nerves. Two percent of children with neuroblastoma develop opsoclonus myoclonus ataxia syndrome (OMAS), a paraneoplastic disease characterized by cerebellar and brainstem-directed autoimmunity but typically with outstanding cancer-related outcomes. We compared tumor transcriptomes and tumor-infiltrating T and B cell repertoires from 38 OMAS subjects with neuroblastoma to 26 non-OMAS-associated neuroblastomas. We found greater B and T cell infiltration in OMAS-associated tumors compared to controls and showed that both were polyclonal expansions. Tertiary lymphoid structures (TLSs) were enriched in OMAS-associated tumors. We identified significant enrichment of the major histocompatibility complex (MHC) class II allele HLA-DOB01:01 in OMAS patients. OMAS severity scores were associated with the expression of several candidate autoimmune genes. We propose a model in which polyclonal auto-reactive B lymphocytes act as antigen-presenting cells and drive TLS formation, thereby supporting both sustained polyclonal T cell-mediated anti-tumor immunity and paraneoplastic OMAS neuropathology.
Topics: Child; Humans; Autoimmunity; Neuroblastoma; Opsoclonus-Myoclonus Syndrome; Autoantibodies; Genes, MHC Class II; Ataxia
PubMed: 37537844
DOI: 10.1016/j.celrep.2023.112879 -
Current Opinion in Neurology Aug 2023The aim of this review is to showcase the recent developments in the field of diagnosis and treatment of adult-onset focal dystonia. (Review)
Review
PURPOSE OF REVIEW
The aim of this review is to showcase the recent developments in the field of diagnosis and treatment of adult-onset focal dystonia.
RECENT FINDINGS
Accurate phenotyping of focal dystonia is essential in the process of finding an underlying cause, including acquired, genetic, and idiopathic causes. Motor symptoms as well as the associated nonmotor symptoms and their detrimental impact on quality of life have received increased interest over the last years. The diagnostic process is complicated by the steadily increasing numbers of newly discovered genes associated with dystonia. Recent efforts have been aimed at further developing recommendations and algorithms to aid in diagnosis and in navigating the use of diagnostic tools. In terms of treatment, research on DBS is advancing towards a better understanding of the most effective stimulation locations within the globus pallidus. Moreover, with the introduction of the LFP-recording devices, the search continues for an accurate electrophysiological biomarker for dystonia.
SUMMARY
Accurate phenotyping and (sub)classification of patients with dystonia is important for improving diagnosis, subsequent treatment effect and population-based study outcomes in research. Medical practitioners should be attentive to the presence of nonmotor symptoms in dystonia.
Topics: Humans; Adult; Dystonia; Quality of Life; Deep Brain Stimulation; Treatment Outcome; Dystonic Disorders; Globus Pallidus
PubMed: 37381892
DOI: 10.1097/WCO.0000000000001165