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Genomic instability arising from defective responses to DNA damage1 or mitotic chromosomal imbalances2 can lead to the sequestration of DNA in aberrant extranuclear structures called micronuclei (MN). Although MN are a hallmark of ageing and diseases associated with genomic instability, the catalogue of genetic players that regulate the generation of MN remains to be determined. Here we analyse 997 mouse mutant lines, revealing 145 genes whose loss significantly increases (n = 71) or decreases (n = 74) MN formation, including many genes whose orthologues are linked to human disease. We found that mice null for Dscc1, which showed the most significant increase in MN, also displayed a range of phenotypes characteristic of patients with cohesinopathy disorders. After validating the DSCC1-associated MN instability phenotype in human cells, we used genome-wide CRISPR-Cas9 screening to define synthetic lethal and synthetic rescue interactors. We found that the loss of SIRT1 can rescue phenotypes associated with DSCC1 loss in a manner paralleling restoration of protein acetylation of SMC3. Our study reveals factors involved in maintaining genomic stability and shows how this information can be used to identify mechanisms that are relevant to human disease biology1.
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Inestabilidad Genómica , Micronúcleos con Defecto Cromosómico , Animales , Humanos , Ratones , Cromosomas/genética , Daño del ADN , Inestabilidad Genómica/genética , Fenotipo , Sirtuina 1 , Mutaciones Letales SintéticasRESUMEN
We conducted a systematic review of the literature reporting phenylephrine-induced changes in blood pressure, cardiac output, cerebral blood flow and cerebral tissue oxygen saturation as measured by near-infrared spectroscopy in humans. We used the proportion change of the group mean values reported by the original studies in our analysis. Phenylephrine elevates blood pressure whilst concurrently inducing a reduction in cardiac output. Furthermore, despite increasing cerebral blood flow, it decreases cerebral tissue oxygen saturation. The extent of phenylephrine's influence on cardiac output (r = -0.54 and p = 0.09 in awake humans; r = -0.55 and p = 0.007 in anaesthetised humans), cerebral blood flow (r = 0.65 and p = 0.002 in awake humans; r = 0.80 and p = 0.003 in anaesthetised humans) and cerebral tissue oxygen saturation (r = -0.72 and p = 0.03 in awake humans; r = -0.24 and p = 0.48 in anaesthetised humans) appears closely linked to the magnitude of phenylephrine-induced blood pressure changes. When comparing the effects of phenylephrine in awake and anaesthetised humans, we found no evidence of a significant difference in cardiac output, cerebral blood flow or cerebral tissue oxygen saturation. There was also no evidence of a significant difference in effect on systemic and cerebral circulations whether phenylephrine was given by bolus or infusion. We explore the underlying mechanisms driving the phenylephrine-induced cardiac output reduction, cerebral blood flow increase and cerebral tissue oxygen saturation decrease. Individualised treatment approaches, close monitoring and consideration of potential risks and benefits remain vital to the safe and effective use of phenylephrine in acute care.
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Oxígeno , Vasoconstrictores , Humanos , Fenilefrina/farmacología , Vasoconstrictores/farmacología , Vasoconstrictores/uso terapéutico , Presión Sanguínea/fisiología , Circulación Cerebrovascular/fisiologíaRESUMEN
Giant congenital melanocytic nevi (GCMN) can be cosmetically significant and can lead to melanoma. There is no standard pharmacologic treatment for GCMN. We present the case of an 8-year-old female with kaposiform lymphangiomatosis caused by an NRAS mutation whose nevus spilus-type GCMN improved on oral selumetinib.
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OBJECTIVE: We aimed to describe characteristics of patients with ATTR variant polyneuropathy (ATTRv-PN) and ATTRv-mixed and assess the real-world use and safety profile of tafamidis meglumine 20mg. METHODS: Thirty-eight French hospitals were invited. Patient files were reviewed to identify clinical manifestations, diagnostic methods, and treatment compliance. RESULTS: Four hundred and thirteen patients (296 ATTRv-PN, 117 ATTRv-mixed) were analyzed. Patients were predominantly male (68.0%) with a mean age of 57.2±17.2 years. Interval between first symptom(s) and diagnosis was 3.4±4.3 years. First symptoms included sensory complaints (85.9%), dysautonomia (38.5%), motor deficits (26.4%), carpal tunnel syndrome (31.5%), shortness of breath (13.3%), and unexplained weight loss (16.0%). Mini-invasive accessory salivary gland or punch skin and nerve biopsies were most common, with a performance of 78.8-100%. TTR genetic sequencing, performed in all patients, revealed 31 TTR variants. Tafamidis meglumine was initiated in 156/214 (72.9%) ATTRv-PN patients at an early disease stage. Median treatment duration was 6.00 years in ATTRv-PN and 3.42 years in ATTRv-mixed patients. Tafamidis was well tolerated, with 20 adverse events likely related to study drug among the 336 patients. CONCLUSION: In France, ATTRv patients are usually identified early thanks to the national network and the help of diagnosis combining genetic testing and mini-invasive biopsies.
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Neuropatías Amiloides Familiares , Benzoxazoles , Humanos , Masculino , Francia/epidemiología , Femenino , Persona de Mediana Edad , Anciano , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/epidemiología , Estudios Transversales , Adulto , Benzoxazoles/uso terapéutico , Benzoxazoles/efectos adversos , Anciano de 80 o más Años , Prealbúmina/genéticaRESUMEN
This corrects the article DOI: 10.1103/PhysRevLett.126.171801.
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OBJECTIVES: Vaccine hesitancy is a public health challenge highlighted during the COVID-19 pandemic. This study sought to determine the prevalence and explanatory factors leading to COVID-19 vaccine hesitancy in the Jamaican population to inform vaccination strategies. STUDY DESIGN: This was an exploratory cross-sectional study. METHODS: An exploratory survey was distributed electronically between September and October 2021 to gather information on COVID-19 vaccination behaviour and beliefs among the Jamaican population. Data were expressed as frequencies and analysed using Chi-squared followed by multivariate logistic regressions. Significant analyses were determined at P < 0.05. RESULTS: Of the 678 eligible responses, most were females (71.5%, n = 485), between ages 18-45 years (68.2%, n = 462), had tertiary education (83.4%, n = 564) and were employed (73.4%, n = 498), with 10.6% (n = 44) being healthcare workers. COVID-19 vaccine hesitancy was present in 29.8% (n = 202) of the survey population, mainly because of safety and efficacy concerns and a general lack of reliable information about the vaccines. The likelihood of hesitancy increased amongst respondents under 36 years (odds ratio [OR] 6.8, 95% confidence interval [CI] 3.6, 12.9), those who delayed initial acceptance of vaccines (OR 2.7, 95% CI 2.3, 3.1); parents for their children and with long waits at vaccination centres. Likelihood of hesitancy decreased for respondents over 36 years (OR 3.7, 95% CI 1.8, 7.8) and with vaccine support from pastors/religious leaders (OR 1.6, 95% CI 1.1, 2.4). CONCLUSIONS: Vaccine hesitancy was more prevalent in younger respondents who were never exposed to the effects of vaccine-preventable diseases. Religious leaders had more influence than healthcare workers to increase vaccine uptake.
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Vacunas contra la COVID-19 , COVID-19 , Niño , Femenino , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Masculino , Vacunas contra la COVID-19/uso terapéutico , COVID-19/epidemiología , COVID-19/prevención & control , Prevalencia , Estudios Transversales , Países en Desarrollo , Pandemias , VacunaciónRESUMEN
Hereditary transthyretin amyloidosis (ATTRv) is a rare, lethal, autosomal dominant adult-onset genetic gain-of function (GOF) disorder provoked by mutations in the TTR gene. Until recently, therapeutic options were limited and consisted mainly in liver transplantation and TTR-stabilizers. In the last few years, ATTRv has been at the center of major therapeutic breakthroughs, including development of effective small interfering RNA (siRNA) and antisense oligonucleotide (ASO) treatments targeting liver TTR mRNA. Both siRNA (patisiran) and ASO (inotersen) treatments are now commercially available and have dramatically improved ATTRv neurological outcome. Ongoing clinical trials currently evaluate another siRNA, vutrisiran and a novel ASO formulation, eplontersen. A CRISPR-Cas9-based TTR gene editing treatment is also currently evaluated, with encouraging preliminary results. These recent therapeutic developments demonstrate the shifting paradigm of ATTRv, a previously untreatable and lethal disorder and provide a proof-of-concept for developing siRNA, ASO and CRISPR-Cas9 treatments for other GOF genetic disorders.
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Neuropatías Amiloides Familiares , Adulto , Humanos , Neuropatías Amiloides Familiares/terapia , Neuropatías Amiloides Familiares/tratamiento farmacológico , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/uso terapéutico , Hígado , Mutación , Prealbúmina/genética , Prealbúmina/uso terapéuticoRESUMEN
The Cryogenic Underground Observatory for Rare Events (CUORE) at Laboratori Nazionali del Gran Sasso of INFN in Italy is an experiment searching for neutrinoless double beta (0νßß) decay. Its main goal is to investigate this decay in ^{130}Te, but its ton-scale mass and low background make CUORE sensitive to other rare processes as well. In this Letter, we present our first results on the search for 0νßß decay of ^{128}Te, the Te isotope with the second highest natural isotopic abundance. We find no evidence for this decay, and using a Bayesian analysis we set a lower limit on the ^{128}Te 0νßß decay half-life of T_{1/2}>3.6×10^{24} yr (90% CI). This represents the most stringent limit on the half-life of this isotope, improving by over a factor of 30 the previous direct search results, and exceeding those from geochemical experiments for the first time.
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Granisetrón , Semivida , Teorema de BayesRESUMEN
PURPOSE: Ataxia-Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear. METHODS: From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set. RESULTS: LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56-4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6-5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case-control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018). CONCLUSION: This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.
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Ataxia Telangiectasia , Melanoma , Proteínas de la Ataxia Telangiectasia Mutada/genética , Australia , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Melanoma/genéticaRESUMEN
We measured two-neutrino double beta decay of ^{130}Te using an exposure of 300.7 kg yr accumulated with the CUORE detector. Using a Bayesian analysis to fit simulated spectra to experimental data, it was possible to disentangle all the major background sources and precisely measure the two-neutrino contribution. The half-life is in agreement with past measurements with a strongly reduced uncertainty: T_{1/2}^{2ν}=7.71_{-0.06}^{+0.08}(stat)_{-0.15}^{+0.12}(syst)×10^{20} yr. This measurement is the most precise determination of the ^{130}Te 2νßß decay half-life to date.
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We report new results from the search for neutrinoless double-beta decay in ^{130} Te with the CUORE detector. This search benefits from a fourfold increase in exposure, lower trigger thresholds, and analysis improvements relative to our previous results. We observe a background of (1.38±0.07)×10^{-2} counts/(keV kg yr)) in the 0νßß decay region of interest and, with a total exposure of 372.5 kg yr, we attain a median exclusion sensitivity of 1.7×10^{25} yr. We find no evidence for 0νßß decay and set a 90% credibility interval Bayesian lower limit of 3.2×10^{25} yr on the ^{130} Te half-life for this process. In the hypothesis that 0νßß decay is mediated by light Majorana neutrinos, this results in an upper limit on the effective Majorana mass of 75-350 meV, depending on the nuclear matrix elements used.
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BACKGROUND AND PURPOSE: Whether the Lewis-Sumner syndrome (L-SS) is a distinct entity from other types of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP-ot) remains controversial. METHOD: The clinical/electrophysiological characteristics and long-term outcomes of 45 L-SS and 35 CIDP-ot patients were retrospectively compared. RESULTS: The CIDP-ot group was composed of 11 patients with a typical CIDP, 17 with a pure sensory form, four with a distal form and three with a pure motor form. In the L-SS group, asymmetric (P < 0.001) and monomelic involvement (P = 0.04) of the upper limbs (P < 0.001) was significantly more frequent; paucisymptomatic forms (Overall Neuropathy Limitations Scale ≤ 1) were less frequent (P < 0.001); electroneuromyography showed that conduction block in intermediate nerve segments was the main demyelinating feature, with frequent F-wave abnormalities on nerves without conduction block (44%). Long-term prognosis was globally poorer in the L-SS group with more frequent aggravation during treatment (P = 0.02), less frequent treatment withdrawal (P = 0.03) and longer time to achieve successful withdrawal (39 vs. 15 months). CONCLUSIONS: Our study suggests that L-SS patients have a less favourable therapeutic response rate and long-term outcomes. Rapid differentiation of L-SS from other forms of CIDP is important in order to anticipate a more complicated disease course management, with from one side the inefficacy or even harmfulness of corticosteroids and from the other side a difficult weaning procedure. A prospective study is necessary to confirm these results.
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Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/fisiopatología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/terapia , Adulto , Anciano , Enfermedades Desmielinizantes/patología , Evaluación de la Discapacidad , Electrodiagnóstico , Fenómenos Electrofisiológicos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Conducción Nerviosa , Pronóstico , Estudios Retrospectivos , Síndrome , Centros de Atención Terciaria , Resultado del TratamientoRESUMEN
The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.
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Enfermedad , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Guías como Asunto , Reacciones Falso Positivas , Genes/genética , Humanos , Difusión de la Información , Edición , Reproducibilidad de los Resultados , Proyectos de Investigación , Investigación Biomédica Traslacional/normasRESUMEN
Sugammadex is a novel reversal agent for aminosteroid neuromuscular blocking drugs, especially rocuronium. Given its renal excretion, sugammadex is not recommended for patients with end-stage renal disease; however, reports exist of its use in this group of patients. This two-institutional retrospective observational study aimed to review the safety profile and effectiveness of sugammadex in surgical patients with end-stage renal disease who required pre-operative renal replacement therapy. Adult surgical patients with end-stage renal disease requiring pre-operative renal replacement therapy, who received sugammadex between April 2016 and January 2019, were studied. The primary outcome was the incidence of postoperative tracheal re-intubation within 48 h. The secondary outcome was the incidence of deferred tracheal extubation in the operating theatre. One hundred and fifty-eight patients were identified from 125,653 surgical patients: 48 patients (30%) underwent renal transplantation and 110 (70%) underwent non-renal transplantation procedures. There were 22 instances (14%) of deferred tracheal extubation due to surgical and/or pre-existing medical conditions. Out of the 136 patients who had the tracheal tube removed at the end of the procedure, three patients had their trachea re-intubated within 48 h: two patients developed pulmonary oedema resulting from volume overload; and one patient had worsening sepsis. No incidence of recurrence of neuromuscular blockade was observed. Of note, 24 (18%) patients were found to have incomplete neuromuscular blockade reversal with neostigmine but administration of sugammadex led to successful tracheal extubation. In conclusion, sugammadex appears to be safe and effective in adult patients with end-stage renal disease receiving pre-operative renal replacement therapy.
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Fallo Renal Crónico/complicaciones , Sugammadex/efectos adversos , Sugammadex/uso terapéutico , Adulto , Anciano , Extubación Traqueal , Femenino , Humanos , Incidencia , Intubación Intratraqueal , Fallo Renal Crónico/fisiopatología , Trasplante de Riñón/métodos , Masculino , Persona de Mediana Edad , Bloqueo Neuromuscular , Complicaciones Posoperatorias/epidemiología , Cuidados Preoperatorios , Terapia de Reemplazo Renal , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: There is growing evidence to suggest that children with neurodevelopmental disorders may evidence differences in their sensory processing. The aim of this study was to compare sensory processing patterns in three genetic syndromes associated with sensory difference. METHODS: Sensory processing in Angelman syndrome (n = 91), Cornelia de Lange syndrome (n = 28) and Fragile X syndrome (n = 40) was examined using the informant report measure the Sensory Experiences Questionnaire (SEQ). RESULTS: All three groups were associated with a heightened prevalence of unusual sensory processing in comparison with normative data, evidenced in over 80% of all participants. Cross-syndrome comparisons highlighted syndrome-specific sensory processing profiles, with heightened hypo responsivity in Cornelia de Lange syndrome and sensory seeking in Angelman syndrome. CONCLUSIONS: The results have important implications for the understanding of sensory processing in genetic syndromes and the development of tailored behavioural interventions.
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Síndrome de Angelman/fisiopatología , Síndrome de Cornelia de Lange/fisiopatología , Síndrome del Cromosoma X Frágil/fisiopatología , Trastornos de la Sensación/fisiopatología , Adolescente , Síndrome de Angelman/complicaciones , Niño , Preescolar , Síndrome de Cornelia de Lange/complicaciones , Femenino , Síndrome del Cromosoma X Frágil/complicaciones , Humanos , Masculino , Trastornos de la Sensación/etiologíaRESUMEN
In France, the epidemic phase of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in February 2020 and resulted in the implementation of emergency measures and a degradation in the organization of neuromuscular reference centers. In this special context, the French Rare Health Care for Neuromuscular Diseases Network (FILNEMUS) has established guidance in an attempt to homogenize the management of neuromuscular (NM) patients within the French territory. Hospitalization should be reserved for emergencies, the conduct of treatments that cannot be postponed, check-ups for which the diagnostic delay may result in a loss of survival chance, and cardiorespiratory assessments for which the delay could be detrimental to the patient. A national strategy was adopted during a period of 1 to 2months concerning treatments usually administered in hospitalization. NM patients treated with steroid/immunosuppressants for a dysimmune pathology should continue all of their treatments in the absence of any manifestations suggestive of COVID-19. A frequently asked questions (FAQ) sheet has been compiled and updated on the FILNEMUS website. Various support systems for self-rehabilitation and guided exercises have been also provided on the website. In the context of NM diseases, particular attention must be paid to two experimental COVID-19 treatments, hydroxycholoroquine and azithromycin: risk of exacerbation of myasthenia gravis and QT prolongation in patients with pre-existing cardiac involvement. The unfavorable emergency context related to COVID-19 may specially affect the potential for intensive care admission (ICU) for people with NMD. In order to preserve the fairest medical decision, a multidisciplinary working group has listed the neuromuscular diseases with a good prognosis, usually eligible for resuscitation admission in ICU and, for other NM conditions, the positive criteria suggesting a good prognosis. Adaptation of the use of noninvasive ventilation (NIV) make it possible to limit nebulization and continue using NIV in ventilator-dependent patients.
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Betacoronavirus , Infecciones por Coronavirus/epidemiología , Enfermedades Neuromusculares/terapia , Pandemias , Neumonía Viral/epidemiología , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antibacterianos/uso terapéutico , Antimaláricos/uso terapéutico , Azitromicina/uso terapéutico , COVID-19 , Capacidad Cardiovascular , Infecciones por Coronavirus/tratamiento farmacológico , Tratamiento de Urgencia , Francia/epidemiología , Enfermedad del Almacenamiento de Glucógeno Tipo II/terapia , Hospitalización , Humanos , Hidroxicloroquina/uso terapéutico , Enfermedades del Sistema Inmune/terapia , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunosupresores/uso terapéutico , Atrofia Muscular Espinal/tratamiento farmacológico , Oligonucleótidos/uso terapéutico , Modalidades de Fisioterapia , Neumonía Viral/tratamiento farmacológico , Pronóstico , ARN Interferente Pequeño/uso terapéutico , SARS-CoV-2 , Esteroides/uso terapéutico , Privación de Tratamiento , alfa-Glucosidasas/uso terapéuticoRESUMEN
Disrupted in schizophrenia 1 (DISC1) is a multi-functional scaffolding protein that has been associated with neuropsychiatric disease. The role of DISC1 is to assemble protein complexes that promote neural development and signaling, hence tight control of the concentration of cellular DISC1 in neurons is vital to brain function. Using structural and biochemical techniques, we show for we believe the first time that not only is DISC1 turnover elicited by the ubiquitin proteasome system (UPS) but that it is orchestrated by the F-Box protein, FBXW7. We present the structure of FBXW7 bound to the DISC1 phosphodegron motif and exploit this information to prove that disruption of the FBXW7-DISC1 complex results in a stabilization of DISC1. This action can counteract DISC1 deficiencies observed in neural progenitor cells derived from induced pluripotent stem cells from schizophrenia patients with a DISC1 frameshift mutation. Thus manipulation of DISC1 levels via the UPS may provide a novel method to explore DISC1 function.
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Proteína 7 que Contiene Repeticiones F-Box-WD/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina/metabolismo , Células Cultivadas , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Células HEK293 , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Modelos Moleculares , Proteínas del Tejido Nervioso/genética , Células-Madre Neurales/metabolismo , Neurogénesis , Neuronas/metabolismo , Complejo de la Endopetidasa Proteasomal/genética , Unión Proteica , Esquizofrenia/metabolismo , Transducción de Señal , Ubiquitina/genética , UbiquitinaciónRESUMEN
BACKGROUND: Germline mutations in telomere-related genes such as POT1 and TERT predispose individuals to familial melanoma. OBJECTIVES: To evaluate the prevalence of germline mutations in POT1 and TERT in a large cohort of Spanish melanoma-prone families (at least two affected first- or second-degree relatives). METHODS: Overall, 228 CDKN2A wild-type melanoma-prone families were included in the study. Screening of POT1 was performed in one affected person from each family and TERT was sequenced in one affected patient from 202 families (26 families were excluded owing to DNA exhaustion/degradation). TERT promoter sequencing was extended to an additional 30 families with CDKN2A mutation and 70 patients with sporadic multiple primary melanoma (MPM) with a family history of other cancers. RESULTS: We identified four families with potentially pathogenic POT1 germline mutations: a missense variant c.233T>C (p.Ile78Thr); a nonsense variant c.1030G>T (p.Glu344*); and two other variants, c.255G>A (r.125_255del) and c.1792G>A (r.1791_1792insAGTA, p.Asp598Serfs*22), which we confirmed disrupted POT1 mRNA splicing. A TERT promoter variant of unknown significance (c.-125C>A) was detected in a patient with MPM, but no germline mutations were detected in TERT promoter in cases of familial melanoma. CONCLUSIONS: Overall, 1·7% of our CDKN2A/CDK4-wild type Spanish melanoma-prone families carry probably damaging mutations in POT1. The frequency of TERT promoter germline mutations in families with melanoma in our population is extremely rare.
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Predisposición Genética a la Enfermedad , Melanoma/genética , Regiones Promotoras Genéticas/genética , Neoplasias Cutáneas/genética , Telomerasa/genética , Proteínas de Unión a Telómeros/genética , Adulto , Anciano , Codón sin Sentido , Estudios de Cohortes , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Mutación de Línea Germinal , Humanos , Masculino , Anamnesis , Melanoma/epidemiología , Persona de Mediana Edad , Mutación , Mutación Missense , Linaje , Complejo Shelterina , Neoplasias Cutáneas/epidemiología , España/epidemiología , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND AND PURPOSE: The usefulness of plexus magnetic resonance imaging (MRI) in the diagnosis of chronic inflammatory demyelinating polyradiculopathy (CIDP) without definite European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria is currently unclear. METHODS: Data from consecutive patients with clinical manifestations suggesting CIDP, with or without (CIDP-D and CIDP-ND, respectively) definite EFNS/PNS electrodiagnostic criteria, and referred for plexus MRI in our imaging centre were retrospectively analysed. An expert committee of neurologists compared the level of suspicion of CIDP in CIDP-ND patients to the blinded/unblinded MRI findings. Plexus MRI was reviewed by a neuroradiologist blinded to the final diagnosis. RESULTS: In all, 38 patients were assessed with suspected CIDP-ND [7/38 (18%) probable; 13/38 (34%) possible; 18/38 (47%), no EFNS/PNS electrodiagnostic criteria], plus 10 with CIDP-D. Thirty-six of the 38 (95%) fulfilled clinical criteria of CIDP variants, including pure sensory neuropathy in 22/36 (61%). Plexus MRI showed abnormalities in 22/38 (58%) patients including increased nerve signal intensity on T2-weighted images in 22/22 (100%), nerve enlargement in 20/22 (91%) and contrast enhancement in 8/22 (36%). Plexus MRI enabled the expert committee's final diagnosis to be adjusted in 7/38 (18%) patients, and in conjunction with nerve conduction studies was a supportive criterion to classify 7/24 (29%) patients as definite CIDP. MRI abnormalities were more asymmetrical (P = 0.03) and less diffuse (P = 0.1) in CIDP-ND than in CIDP-D. CONCLUSIONS: Our observations suggest that plexus MRI makes a valuable contribution to the diagnosis of CIDP-ND patients. Further studies are needed to investigate inter-rater reliability of clinical and imaging criteria of CIDP in these patients, and the impact on outcomes.
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Nervios Periféricos/diagnóstico por imagen , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Adulto , Anciano , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Conducción Nerviosa/fisiología , Nervios Periféricos/fisiopatología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico por imagen , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/fisiopatología , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
BACKGROUND AND PURPOSE: The aim is to describe an uncommon phenotype of hereditary ATTR neuropathy with upper limb onset. METHODS: The French TTR Familial Amyloid Polyneuropathy database was used for a retrospective evaluation of 32 consecutive patients with upper limb onset of the neuropathy (study group) and they were compared to 31 Portuguese early-onset patients and 99 late-onset patients without upper limb onset. RESULTS: Initial upper limb symptoms were mostly sensory. Lower limb symptoms began 2.3 ± 3 years after upper limb symptoms. Twenty-four (75%) patients were initially misdiagnosed, with 15 different diagnoses. More patients in the study group had a Neuropathy Impairment Score upper limb/lower limb ratio > 1 compared to the late-onset patient group. The study group had significantly more pronounced axonal loss in the median and ulnar motor nerves and the ulnar sensory and sural nerves. On radial nerve biopsies (n = 11), epineurial vessels were abnormal in six cases, including amyloid deposits in vessel walls (3/11), with vessel occlusion in two cases. CONCLUSION: Upper limb onset of hereditary ATTR neuropathy is not rare in non-endemic areas. It is important to propose early TTR sequencing of patients with idiopathic upper limb neuropathies, as specific management and treatment are required.