Mutational spectrum of GNAL, THAP1 and TOR1A genes in isolated dystonia: study in a population from Spain and systematic literature review

[Objective] We aimed to investigate the prevalence of TOR1A, GNAL and THAP1 variants as the cause of dystonia in a cohort of Spanish patients with isolated dystonia and in the literature.[Methods] A population of 2028 subjects (including 1053 patients with different subtypes of isolated dystonia and 975 healthy controls) from southern and central Spain was included. The genes TOR1A, THAP1 and GNAL were screened using a combination of high-resolution melting analysis and direct DNA resequencing. In addition, an extensive literature search to identify original articles (published before 10 August 2020) reporting mutations in TOR1A, THAP1 or GNAL associated to dystonia was performed.[Results] Pathogenic or likely pathogenic variants in TOR1A, THAP1 and GNAL were identified in 0.48%, 0.57% and 0.29% of our patients, respectively. Five patients carried the variation p.Glu303del in TOR1A. A very rare variant in GNAL (p.Ser238Asn) was found as a putative risk factor for dystonia. In the literature, variations in TOR1A, THAP1 and GNAL accounted for about 6%, 1.8% and 1.1% of published dystonia patients, respectively.[Conclusions] There is a different genetic contribution to dystonia of these three genes in our patients (about 1.3% of patients) and in the literature (about 3.6% of patients), probably due the high proportion of adult-onset cases in our cohort. As regards age at onset, site of dystonia onset, and final distribution, in our population there is a clear differentiation between DYT-TOR1A and DYT-GNAL, with DYT-THAP1 likely to be an intermediate phenotype.This work was supported by the Carlos III Health Institute-European Regional Development Fund (ISCIII-FEDER) [PI14/01823, PI16/01575, PI18/01898, PI19/01576], the Andalusian Regional Ministry of Economics, Innovation, Science and Employment [CVI-02526, CTS-7685], the Andalusian Regional Ministry of Health and Welfare [PI-0741-2010, PI-0471-2013, PE-0210-2018, PI-0459-2018, PE-0186-2019], and the Alicia Koplowitz and Mutua Madrileña Foundations. Pilar Gómez-Garre was supported by the "Miguel Servet" program [MSII14/00018] (from ISCIII-FEDER) and “Nicolás Monardes” program [C-0048-2017] (from the Andalusian Regional Ministry of Health). Silvia Jesús was supported by the "Juan Rodés" program [B-0007-2019] and Daniel Macías-García by the “Río Hortega” program [CM18/00142] (both from ISCIII-FEDER). María Teresa Periñán was supported by the Spanish Ministry of Education [FPU16/05061]. Cristina Tejera was supported by VPPI-US from the University of Seville.Peer reviewe

Isoreticular two-dimensional magnetic coordination polymers prepared through pre-synthetic ligand functionalization

Chemical functionalization is a powerful approach to tailor the physical and chemical properties of two-dimensional materials, increase their processability and stability, tune their functionalities and, even, create new 2D materials. This is typically achieved through post-synthetic functionalization by anchoring molecules on the surface of an exfoliated 2D crystal, but it inevitably alters the long-range structural order of the material. Here we present a pre-synthetic approach that allows the isolation of crystalline, robust, and magnetic functionalized monolayers of coordination polymers. A series of five isoreticular layered magnetic coordination polymers based on Fe(II) centres and different benzimidazole derivatives (bearing a Cl, H, CH3, Br or NH2 side group) were first prepared. On mechanical exfoliation, 2D materials are obtained that retain their long-range structural order and exhibit good mechanical and magnetic properties. This combination, together with the possibility to functionalize their surface at will, makes them good candidates to explore magnetism in the 2D limit and to fabricate mechanical resonators for selective gas sensing

The Biodiversity of the Mediterranean Sea: Estimates, Patterns, and Threats

The Mediterranean Sea is a marine biodiversity hot spot. Here we combined an extensive literature analysis with expert opinions to update publicly available estimates of major taxa in this marine ecosystem and to revise and update several species lists. We also assessed overall spatial and temporal patterns of species diversity and identified major changes and threats. Our results listed approximately 17,000 marine species occurring in the Mediterranean Sea. However, our estimates of marine diversity are still incomplete as yet—undescribed species will be added in the future. Diversity for microbes is substantially underestimated, and the deep-sea areas and portions of the southern and eastern region are still poorly known. In addition, the invasion of alien species is a crucial factor that will continue to change the biodiversity of the Mediterranean, mainly in its eastern basin that can spread rapidly northwards and westwards due to the warming of the Mediterranean Sea. Spatial patterns showed a general decrease in biodiversity from northwestern to southeastern regions following a gradient of production, with some exceptions and caution due to gaps in our knowledge of the biota along the southern and eastern rims. Biodiversity was also generally higher in coastal areas and continental shelves, and decreases with depth. Temporal trends indicated that overexploitation and habitat loss have been the main human drivers of historical changes in biodiversity. At present, habitat loss and degradation, followed by fishing impacts, pollution, climate change, eutrophication, and the establishment of alien species are the most important threats and affect the greatest number of taxonomic groups. All these impacts are expected to grow in importance in the future, especially climate change and habitat degradation. The spatial identification of hot spots highlighted the ecological importance of most of the western Mediterranean shelves (and in particular, the Strait of Gibraltar and the adjacent Alboran Sea), western African coast, the Adriatic, and the Aegean Sea, which show high concentrations of endangered, threatened, or vulnerable species. The Levantine Basin, severely impacted by the invasion of species, is endangered as well

Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/

Catástrofes en trastornos del movimiento

Resumen: Aunque el campo de los trastornos del movimiento incluye en su mayoría patologías subagudas o crónicas atendidas habitualmente en consultas externas, en ocasiones se presentan cuadros agudos cuyo reconocimiento y tratamiento urgentes son imperativos. En este artículo se revisan aquellas entidades que con frecuencia requieren un manejo neurointensivista y cuya evolución puede resultar “catastrófica”. Entre ellas se incluyen el síndrome neuroléptico maligno y otros cuadros relacionados, el estado distónico y el hemibalismo. Abstract: The field of movement disorders largely covers subacute or chronic diseases that are usually treated in outpatient clinics. However, the much less frequent acute disorders require urgent recognition and treatment. The present article reviews the entities that frequently require neurointensive management and whose development can prove “calamitous”. These include neuroleptic malignant syndrome and related conditions, status dystonicus, and hemiballism. Palabras clave: Estado distónico, Hemibalismo, Síndrome neuroléptico maligno, Trastornos del movimiento, Urgencias, Keywords: Status dystonicus, Hemiballism, Neuroleptic malignant syndrome, Movement disorders, Emergencie

Multidimensional Circadian Monitoring by Wearable Biosensors in Parkinson’s Disease

Parkinson’s disease (PD) is associated with several non-motor symptoms that may precede the diagnosis and constitute a major source of frailty in this population. The digital era in health care has open up new prospects to move forward from the qualitative and subjective scoring for PD with the use of new wearable biosensors that enable frequent quantitative, reliable, repeatable, and multidimensional measurements to be made with minimal discomfort and inconvenience for patients. A cross-sectional study was conducted to test a wrist-worn device combined with machine-learning processing to detect circadian rhythms of sleep, motor, and autonomic disruption, which can be suitable for the objective and non-invasive evaluation of PD patients. Wrist skin temperature, motor acceleration, time in movement, hand position, light exposure, and sleep rhythms were continuously measured in 12 PD patients and 12 age-matched healthy controls for seven consecutive days using an ambulatory circadian monitoring device (ACM). Our study demonstrates that a multichannel ACM device collects reliable and complementary information from motor (acceleration and time in movement) and common non-motor (sleep and skin temperature rhythms) features frequently disrupted in PD. Acceleration during the daytime (as indicative of motor impairment), time in movement during sleep (representative of fragmented sleep) and their ratio (A/T) are the best indexes to objectively characterize the most common symptoms of PD, allowing for a reliable and easy scoring method to evaluate patients. Chronodisruption score, measured by the integrative algorithm known as the circadian function index is directly linked to a low A/T score. Our work attempts to implement innovative technologies based on wearable, multisensor, objective, and easy-to-use devices, to quantify PD circadian rhythms in huge populations over extended periods of time, while controlling at the same time exposure to exogenous circadian synchronizers

Multidimensional Circadian Monitoring by Wearable Biosensors in Parkinson’s Disease

Parkinson's disease (PD) is associated with several non-motor symptoms that may precede the diagnosis and constitute a major source of frailty in this population. The digital era in health care has open up new prospects to move forward from the qualitative and subjective scoring for PD with the use of new wearable biosensors that enable frequent quantitative, reliable, repeatable, and multidimensional measurements to be made with minimal discomfort and inconvenience for patients. A cross-sectional study was conducted to test a wrist-worn device combined with machine-learning processing to detect circadian rhythms of sleep, motor, and autonomic disruption, which can be suitable for the objective and non-invasive evaluation of PD patients. Wrist skin temperature, motor acceleration, time in movement, hand position, light exposure, and sleep rhythms were continuously measured in 12 PD patients and 12 age-matched healthy controls for seven consecutive days using an ambulatory circadian monitoring device (ACM). Our study demonstrates that a multichannel ACM device collects reliable and complementary information from motor (acceleration and time in movement) and common non-motor (sleep and skin temperature rhythms) features frequently disrupted in PD. Acceleration during the daytime (as indicative of motor impairment), time in movement during sleep (representative of fragmented sleep) and their ratio (A/T) are the best indexes to objectively characterize the most common symptoms of PD, allowing for a reliable and easy scoring method to evaluate patients. Chronodisruption score, measured by the integrative algorithm known as the circadian function index is directly linked to a low A/T score. Our work attempts to implement innovative technologies based on wearable, multisensor, objective, and easy-to-use devices, to quantify PD circadian rhythms in huge populations over extended periods of time, while controlling at the same time exposure to exogenous circadian synchronizers

Stroke-related mortality in a tertiary care hospital in Andalusia: Analysis and reflections

Objectives: Stroke is a very common cause of death, especially in southern Spain. The present study analyses in-hospital mortality associated with stroke in an Andalusian tertiary care hospital. Methods: We gathered the files of all patients who had died at Hospital Universitario Virgen de las Nieves in Granada in 2013 and whose death certificates indicated stroke as the cause of death. We also gathered stroke patients discharge data and compared them to that of patients with acute coronary syndrome (ACS). Results: A total of 825 patients had a diagnosis of stroke (96 deaths, 11.6%); of these, 562 had ischaemic stroke (IS) (44 deaths, 7.8%) and 263 haemorrhagic stroke (HS) (52 deaths, 19.7%). Patients with HS therefore showed greater mortality rate (odds ratio, OR 2.9). Patients in this group died after a shorter time in hospital (median, 4 vs. 7 days; mean, 6 days). However, patients with IS were older and presented with more comorbidities. On the other hand, 617 patients had a diagnosis of ACS (36 deaths, 5.8%). The mortality odds ratio was 2.1 (stroke/SCA). Around 23% of the patients who died from stroke were taking anticoagulants. 60% of the deceased patients with IS and 20% of those with HS had atrial fibrillation (AF); 35% of the patients with IS and AF were taking anticoagulants. Conclusions: Stroke is associated with higher admission and in-hospital mortality rates than SCA. Likewise, patients with HS showed higher mortality rates than those with IS. Patients with fatal stroke usually had a history of long-term treatment with anticoagulants; two-thirds of the patients with fatal IS and AF were not receiving anticoagulants. According to our results, optimising prevention in patients with AF may have a positive impact on stroke-related in-hospital mortality. Resumen: Objetivos: El ictus constituye una causa muy frecuente de muerte, especialmente en el sur de España; se analiza la mortalidad intrahospitalaria asociada a ictus en un hospital andaluz de tercer nivel. Métodos: Registro de pacientes con ictus como diagnóstico en su informe de defunción en el Hospital Virgen de las Nieves de Granada durante 2013. Se utilizan además datos globales sobre altas en ictus y se comparan con iguales variables en síndrome coronario agudo (SCA). Resultados: Altas con diagnóstico de ictus 825 (96 defunciones, 11,6%); 562 isquémicos (44 fallecidos, 7,8%); 263 hemorrágicos (52 muertes, 19,7%). Los hemorrágicos, por tanto, tuvieron mayor mortalidad (OR = 2,9) y más precoz durante el ingreso (mediana 4 vs. 7 días, global 6 días), aunque los isquémicos fueron más ancianos y más pluripatológicos. Altas con SCA 617 (36 fallecidos, 5,8%); OR de mortalidad en ictus/SCA = 2,1. Un 23% de los fallecidos con ictus estaban anticoagulados cuando lo presentaron. El 60% de los ictus isquémicos y el 20% de los ictus hemorrágicos fallecidos tenían fibrilación auricular; solo el 35% de los pacientes con ictus isquémico y fibrilación auricular estaban anticoagulados. Conclusiones: El ictus supera al SCA en ingresos y mortalidad intrahospitalaria. El ictus hemorrágico supera al isquémico en mortalidad asociada. La anticoagulación crónica es frecuente en pacientes con ictus fatal; 2 tercios de los pacientes con ictus isquémico mortal y fibrilación auricular no estaban anticoagulados. Según nuestros resultados, optimizar la prevención en pacientes con fibrilación auricular podría impactar favorablemente sobre la mortalidad intrahospitalaria asociada al ictus. Keywords: Stroke, In-hospital mortality, Ischaemic stroke, Haemorrhagic stroke, Acute coronary syndrome, Oral anticoagulants, Palabras clave: Ictus, Mortalidad intrahospitalaria, Ictus isquémico, Ictus hemorrágico, Síndrome coronario agudo, Anticoagulación ora

Electronic consultation (e-consultation) between primary care and the neurology department: One-year experience in a healthcare area in Andalusia, Spain

Introduction: The COVID-19 pandemic has prompted the implementation of telemedicine programmes to facilitate healthcare. In November 2020 we initiated an e-consultation programme between primary care and the neurology department, with asynchronous response, through a platform integrated into the corporate computer system of the Andalusian Public Health System. We present the results of the first year of operation. Methods: We present a descriptive study of the e-consultations received in 2021 from a health area of approximately 300,000 inhabitants aged ≥14 years. The reasons for consultation were pre-established: “primary headache” (PH), “new-onset cognitive impairment” (CI), “complications of dementia” (DEM), and “epilepsy” (EPI). We defined inclusion criteria and the clinical information/tests that had to be provided. General practitioners could choose between e-consultation or face-to-face referral. Results: A total of 1,806 e-consultations were received (approximately 6/1,000 population/year). By reasons for consultation: CI 34.3%, PH 32%, DEM 14.4%, EPI 11.7%, unspecified 7.6%. Responses were sent after an average of 2.25 days and were classified as: “refer for in-person consultation” (47.12%), “resolved” (39.98%), “criteria not met” (12.57%), or “follow-up by e-consultation” (0.33%). As expected, a high proportion of face-to-face referrals were required for CI (73.46%); the main value of the system for these patients was to prioritise appointments and select the most appropriate form of care. For the rest of the reasons for consultation, the proportion of “resolved” e-consultations reached 52.61%. Conclusions: Asynchronous e-consultation between primary care and the neurology department is a useful tool in the indicated conditions, offering a rapid, “one-stop” response to a significant proportion of clinical or therapeutic uncertainties, as well as optimising face-to-face appointments. Resumen: Introducción: La pandemia por Covid-19 ha impulsado la implantación de programas de telemedicina para facilitar la asistencia sanitaria. En noviembre de 2020 iniciamos un programa de e-interconsulta entre Atención Primaria (AP) y Neurología, de respuesta asíncrona, a través de una plataforma integrada en la estación clínica corporativa del Sistema Sanitario Público de Andalucía. Presentamos los resultados de su primer año de funcionamiento. Métodos: Estudio descriptivo de las e-interconsultas recibidas durante 2021 desde un área sanitaria de aproximadamente 300.000 habitantes ≥14 años. Se establecieron como motivos de consulta: “Cefalea primaria” (CEF), “Deterioro cognitivo de novo” (DC), “Complicaciones de la demencia” (DEM) y “Epilepsia” (EPI), definiéndose unos criterios preestablecidos y la información clínica/pruebas que se debían aportar. Los médicos/as de familia podían elegir entre e-interconsultar o derivar directamente para cita presencial. Resultados: Se recibieron 1.806 e-interconsultas (≈6/1.000 hab./año). Por motivos de consulta: DC 34′3%, CEF 32%, DEM 14′4%, EPI 11′7%, no especificado 7′6%. Las respuestas se demoraron una media de 2′25 días y se clasificaron en: “precisa cita presencial” (47′12%), “alta” (39´98%), “no cumple criterios” (12′57%) o “seguimiento por e-interconsulta” (0′33%). Como era previsible, para el DC una alta proporción precisó cita presencial (73′46%); su mayor utilidad fue priorizar las citas y modalidad de asistencia. Para el resto de motivos, la proporción de “alta” alcanzó el 52′61%. Conclusiones: La e-interconsulta asíncrona entre AP y Neurología es una herramienta útil en las condiciones indicadas, permitiendo resolver en un “acto único” y con escasa demora una significativa proporción de dudas clínicas o terapéuticas, así como optimizar las citas presenciales