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Nature Jan 2023R-loops are RNA-DNA-hybrid-containing nucleic acids with important cellular roles. Deregulation of R-loop dynamics can lead to DNA damage and genome instability, which...
R-loops are RNA-DNA-hybrid-containing nucleic acids with important cellular roles. Deregulation of R-loop dynamics can lead to DNA damage and genome instability, which has been linked to the action of endonucleases such as XPG. However, the mechanisms and cellular consequences of such processing have remained unclear. Here we identify a new population of RNA-DNA hybrids in the cytoplasm that are R-loop-processing products. When nuclear R-loops were perturbed by depleting the RNA-DNA helicase senataxin (SETX) or the breast cancer gene BRCA1 (refs. ), we observed XPG- and XPF-dependent cytoplasmic hybrid formation. We identify their source as a subset of stable, overlapping nuclear hybrids with a specific nucleotide signature. Cytoplasmic hybrids bind to the pattern recognition receptors cGAS and TLR3 (ref. ), activating IRF3 and inducing apoptosis. Excised hybrids and an R-loop-induced innate immune response were also observed in SETX-mutated cells from patients with ataxia oculomotor apraxia type 2 (ref. ) and in BRCA1-mutated cancer cells. These findings establish RNA-DNA hybrids as immunogenic species that aberrantly accumulate in the cytoplasm after R-loop processing, linking R-loop accumulation to cell death through the innate immune response. Aberrant R-loop processing and subsequent innate immune activation may contribute to many diseases, such as neurodegeneration and cancer.
Topics: Humans; Apoptosis; Cytoplasm; DNA; DNA Helicases; Genes, BRCA1; Innate Immunity Recognition; Multifunctional Enzymes; Mutation; Neoplasms; Nucleic Acid Heteroduplexes; R-Loop Structures; RNA; RNA Helicases; Spinocerebellar Ataxias
PubMed: 36544021
DOI: 10.1038/s41586-022-05545-9 -
Journal of Mother and Child Mar 2022Joubert syndrome (JS; MIM PS213300) is a rare genetic autosomal recessive disease characterized by cerebellar vermis hypoplasia, a distinctive malformation of the... (Review)
Review
Joubert syndrome (JS; MIM PS213300) is a rare genetic autosomal recessive disease characterized by cerebellar vermis hypoplasia, a distinctive malformation of the cerebellum and the so-called "molar tooth sign." Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes. Such pleiotropic characteristics are typical of many disorders involving primary cilium aberrations, providing a significant overlap between JS and other ciliopathies such as nephronophthisis, Meckel syndrome, and Bardet-Biedl syndrome. This review will describe some characteristics of JS associated with changes in 35 genes, and will also address subtypes of JS, clinical diagnosis, and the future of therapeutic developments.
Topics: Humans; Cerebellum; Abnormalities, Multiple; Eye Abnormalities; Retina; Polycystic Kidney Diseases; Intellectual Disability
PubMed: 36803942
DOI: 10.34763/jmotherandchild.20222601.d-22-00034 -
CNS Neuroscience & Therapeutics Dec 2020Idiopathic normal pressure hydrocephalus (iNPH), the most common type of adult-onset hydrocephalus, is a potentially reversible neuropsychiatric entity characterized by... (Review)
Review
Idiopathic normal pressure hydrocephalus (iNPH), the most common type of adult-onset hydrocephalus, is a potentially reversible neuropsychiatric entity characterized by dilated ventricles, cognitive deficit, gait apraxia, and urinary incontinence. Despite its relatively typical imaging features and clinical symptoms, the pathogenesis and pathophysiology of iNPH remain unclear. In this review, we summarize current pathogenetic conceptions of iNPH and its pathophysiological features that lead to neurological deficits. The common consensus is that ventriculomegaly resulting from cerebrospinal fluid (CSF) dynamics could initiate a vicious cycle of neurological damages in iNPH. Pathophysiological factors including hypoperfusion, glymphatic impairment, disturbance of metabolism, astrogliosis, neuroinflammation, and blood-brain barrier disruption jointly cause white matter and gray matter lesions, and eventually lead to various iNPH symptoms. Also, we review the current treatment options and discuss the prospective treatment strategies for iNPH. CSF diversion with ventriculoperitoneal or lumboperitonealshunts remains as the standard therapy, while its complications prompt attempts to refine shunt insertion and develop new therapeutic procedures. Recent progress on advanced biomaterials and improved understanding of pathogenesis offers new avenues to treat iNPH.
Topics: Animals; Blood-Brain Barrier; Glymphatic System; Humans; Hydrocephalus, Normal Pressure; Retrospective Studies
PubMed: 33242372
DOI: 10.1111/cns.13526 -
Journal of Neurology, Neurosurgery, and... Jun 2022Corticobasal syndrome (CBS) is a clinical syndrome characterised by progressive asymmetric limb rigidity and apraxia with dystonia, myoclonus, cortical sensory loss and... (Review)
Review
Corticobasal syndrome (CBS) is a clinical syndrome characterised by progressive asymmetric limb rigidity and apraxia with dystonia, myoclonus, cortical sensory loss and alien limb phenomenon. Corticobasal degeneration (CBD) is one of the most common underlying pathologies of CBS, but other disorders, such as progressive supranuclear palsy (PSP), Alzheimer's disease (AD) and frontotemporal lobar degeneration with TDP-43 inclusions, are also associated with this syndrome.In this review, we describe common and rare neuropathological findings in CBS, including tauopathies, synucleinopathies, TDP-43 proteinopathies, fused in sarcoma proteinopathy, prion disease (Creutzfeldt-Jakob disease) and cerebrovascular disease, based on a narrative review of the literature and clinicopathological studies from two brain banks. Genetic mutations associated with CBS, including and , are also reviewed. Clinicopathological studies on neurodegenerative disorders associated with CBS have shown that regardless of the underlying pathology, frontoparietal, as well as motor and premotor pathology is associated with CBS. Clinical features that can predict the underlying pathology of CBS remain unclear. Using AD-related biomarkers (ie, amyloid and tau positron emission tomography (PET) and fluid biomarkers), CBS caused by AD often can be differentiated from other causes of CBS. Tau PET may help distinguish AD from other tauopathies and non-tauopathies, but it remains challenging to differentiate non-AD tauopathies, especially PSP and CBD. Although the current clinical diagnostic criteria for CBS have suboptimal sensitivity and specificity, emerging biomarkers hold promise for future improvements in the diagnosis of underlying pathology in patients with CBS.
PubMed: 35697501
DOI: 10.1136/jnnp-2021-328586 -
Neuropsychiatric Disease and Treatment 2022The aim of this paper is to provide information regarding diversity in speech and language profiles of individuals with Autism Spectrum Disorders (ASD) and try to... (Review)
Review
The aim of this paper is to provide information regarding diversity in speech and language profiles of individuals with Autism Spectrum Disorders (ASD) and try to classify these profiles according to the combination of the communication difficulties. Research findings confirm the existence of heterogeneity of communication challenges in ASD across the lifespan. A lot of children with ASD experience communication challenges and strengths across all language sub-systems including pragmatics, grammar, semantics, syntax, phonology, and morphology in both oral and written language, while some children with autism demonstrate exceptional language abilities incl. linguistic creativity. Communication issues vary on a continuum of severity so that some children may be verbal, whereas others remain non-verbal or minimally-verbal. The diversity of profiles in speech and language development stem from either the presence of comorbid factors, as a core symptom of autistic behavior without comorbidity or both, with the development of complex clinical symptoms. Difficulties with the semantic aspect of language affect the individual's skills in abstract thinking, multiple meanings of words, concept categorization, and so on. Finally, the coexistence of ASD with other communication difficulties such as a Language Disorder, Apraxia of Speech, Speech Sound Disorders or/and other neurodevelopmental disorders raises the need for examining more carefully the emergence of new clinical profiles and clinical markers useful in performing differential diagnosis and different intervention.
PubMed: 36268264
DOI: 10.2147/NDT.S331987 -
Movement Disorders Clinical Practice Apr 2022Oculomotor assessment is an essential element of the neurological clinical examination and is particularly important when evaluating patients with movements disorders.... (Review)
Review
Oculomotor assessment is an essential element of the neurological clinical examination and is particularly important when evaluating patients with movements disorders. Most of the brain is involved in oculomotor control, and thus many neurological conditions present with oculomotor abnormalities. Each of the different classes of eye movements and their features can provide important information that can facilitate differential diagnosis. This educational review presents a clinical approach to eye movement abnormalities that are commonly seen in parkinsonism, ataxia, dystonia, myoclonus, tremor, and chorea. In parkinsonism, subtle signs such as prominent square wave jerks, impaired vertical optokinetic nystagmus, and/or the "round the houses" sign suggest early progressive supranuclear gaze palsy before vertical gaze is restricted. In ataxia, nystagmus is common, but other findings such as oculomotor apraxia, supranuclear gaze palsy, impaired fixation, or saccadic pursuit can contribute to diagnoses such as ataxia with oculomotor apraxia, Niemann-Pick type C, or ataxia telangiectasia. Opsoclonus myoclonus and oculopalatal myoclonus present with characteristic phenomenology and are usually easy to identify. The oculomotor exam is usually unremarkable in isolated dystonia, but oculogyric crisis is a medical emergency and should be recognized and treated in a timely manner. Gaze impersistence in a patient with chorea suggests Huntington's disease, but in a patient with dystonia or tremor, Wilson's disease is more likely. Finally, functional eye movements can reinforce the clinical impression of a functional movement disorder.
PubMed: 35402641
DOI: 10.1002/mdc3.13413 -
Frontiers in Psychology 2019Speech Sound Disorders (SSDs) is a generic term used to describe a range of difficulties producing speech sounds in children (McLeod and Baker, 2017). The foundations of... (Review)
Review
Speech Sound Disorders (SSDs) is a generic term used to describe a range of difficulties producing speech sounds in children (McLeod and Baker, 2017). The foundations of clinical assessment, classification and intervention for children with SSD have been heavily influenced by psycholinguistic theory and procedures, which largely posit a firm boundary between phonological processes and phonetics/articulation (Shriberg, 2010). Thus, in many current SSD classification systems the complex relationships between the etiology (distal), processing deficits (proximal) and the behavioral levels (speech symptoms) is under-specified (Terband et al., 2019a). It is critical to understand the complex interactions between these levels as they have implications for differential diagnosis and treatment planning (Terband et al., 2019a). There have been some theoretical attempts made towards understanding these interactions (e.g., McAllister Byun and Tessier, 2016) and characterizing speech patterns in children either solely as the product of speech motor performance limitations or purely as a consequence of phonological/grammatical competence has been challenged (Inkelas and Rose, 2007; McAllister Byun, 2012). In the present paper, we intend to reconcile the phonetic-phonology dichotomy and discuss the interconnectedness between these levels and the nature of SSDs using an alternative perspective based on the notion of an articulatory "gesture" within the broader concepts of the Articulatory Phonology model (AP; Browman and Goldstein, 1992). The articulatory "gesture" serves as a unit of phonological contrast and characterization of the resulting articulatory movements (Browman and Goldstein, 1992; van Lieshout and Goldstein, 2008). We present evidence supporting the notion of articulatory gestures at the level of speech production and as reflected in control processes in the brain and discuss how an articulatory "gesture"-based approach can account for articulatory behaviors in typical and disordered speech production (van Lieshout, 2004; Pouplier and van Lieshout, 2016). Specifically, we discuss how the AP model can provide an explanatory framework for understanding SSDs in children. Although other theories may be able to provide alternate explanations for some of the issues we will discuss, the AP framework in our view generates a unique scope that covers linguistic (phonology) and motor processes in a unified manner.
PubMed: 32047453
DOI: 10.3389/fpsyg.2019.02998 -
CoDAS 2019Apraxia of speech is defined as the inability to sequence the movements required for accurate articulatory production, traditionally involving a deficit in speech motor...
Apraxia of speech is defined as the inability to sequence the movements required for accurate articulatory production, traditionally involving a deficit in speech motor programming. Language clinicians often confront about speech inconsistency clinical cases, which raise questions concerning the differential diagnosis between apraxia and language disorders. Such problem often results in the difficulty to establish an adequate treatment decision. In this work, we discuss a clinical report in which both diagnosis and treatment raise questions about the apraxic speech condition in childhood. We start from the recognition that, in apraxia, it seems imperative to consider that the body to be considered is the one that surpasses its organic functions and structure. Clinical consequences are drawn from the premise that the human body is one whose ear can listen, and mouth can speak, i.e., the organic structure is a material realm open to the incidence of language and its "music", which creates the speaking body.
Topics: Apraxias; Child, Preschool; Diagnosis, Differential; Female; Humans; Language Development Disorders; Language Therapy; Speech Disorders; Speech Production Measurement
PubMed: 31691745
DOI: 10.1590/2317-1782/20192018121