Molecular characterisation of congenital myasthenic syndromes in Southern Brazil

Objective To perform genetic testing of patients with congenital myasthenic syndromes (CMS) from the Southern Brazilian state of Parana. Patients and methods Twenty-five CMS patients from 18 independent families were included in the study. Known CMS genes were sequenced and restriction digest for the mutation RAPSN p.N88K was performed in all patients. Results We identified recessive mutations of CHRNE in ten families, mutations in DOK7 in three families and mutations in COLQ, CHRNA1 and CHRNB1 in one family each. The mutation CHRNE c. 70insG was found in six families. We have repeatedly identified this mutation in patients from Spain and Portugal and haplotype studies indicate that CHRNE c. 70insG derives from a common ancestor. Conclusions Recessive mutations in CHRNE are the major cause of CMS in Southern Brazil with a common mutation introduced by Hispanic settlers. The second most common cause is mutations in DOK7. The minimum prevalence of CMS in Parana is 0.18/100 000

Molecular characterisation of congenital myasthenic syndromes in Southern Brazil

Objective To perform genetic testing of patients with congenital myasthenic syndromes (CMS) from the Southern Brazilian state of Parana. Patients and methods Twenty-five CMS patients from 18 independent families were included in the study. Known CMS genes were sequenced and restriction digest for the mutation RAPSN p.N88K was performed in all patients. Results We identified recessive mutations of CHRNE in ten families, mutations in DOK7 in three families and mutations in COLQ, CHRNA1 and CHRNB1 in one family each. The mutation CHRNE c. 70insG was found in six families. We have repeatedly identified this mutation in patients from Spain and Portugal and haplotype studies indicate that CHRNE c. 70insG derives from a common ancestor. Conclusions Recessive mutations in CHRNE are the major cause of CMS in Southern Brazil with a common mutation introduced by Hispanic settlers. The second most common cause is mutations in DOK7. The minimum prevalence of CMS in Parana is 0.18/100 000

Novel homozygous RARS2 mutation in two siblings without pontocerebellar hypoplasia - further expansion of the phenotypic spectrum.

BACKGROUND: Pontocerebellar hypoplasia type 6 (PCH6) is a mitochondrial disease caused by mutations in the RARS2 gene. RARS2 encodes mitochondrial arginyl transfer RNA synthetase, an enzyme involved in mitochondrial protein translation. A total of 27 patients from 14 families have been reported so far. Characteristic clinical features comprise neonatal lactic acidosis, severe encephalopathy, intractable seizures, feeding problems and profound developmental delay. Most patients show typical neuroradiologic abnormalities including cerebellar hypoplasia and progressive pontocerebellar atrophy. METHODS: We describe the clinical, biochemical and molecular features of 2 siblings with a novel homozygous mutation in RARS2. Both patients presented neonatally with lactic acidosis. While the older sibling had severe neurological symptoms with microcephaly, seizures and developmental delay, the younger patient was still neurologically asymptomatic at the age of 2 months. RESULTS: MRI studies in both children lacked pontocerebellar involvement. The expression of the OXPHOS complex proteins was decreased in both patients, whereas oxygen consumption was increased. CONCLUSIONS: Characteristic neuroradiological abnormalities of PCH6 such as vermis and cerebellar hypoplasia and progressive pontocerebellar atrophy may be missing in patients with RARS2 mutations. RARS2 testing should therefore also be performed in patients without pontocerebellar hypoplasia but otherwise typical clinical symptoms

Congental myasthenic syndromes - diagnostics and treatment

Kongenitalni mijastenički sindromi (KMS) predstavljaju poremećaje granice sigurnosti neuralne transmisije na presinaptičkoj, sinaptičkoj i postinaptičkoj razini. Dijagnoza kongenitalnog mijasteničkog sindroma postavlja se na temelju kliničke slike koja uključuje mišićnu slabost uzrokovanu zamorom što se pojavljuje od ranog djetinjstva, oftalmoparezu, respiratornu insuficijenciju, poremećaj funkcije mišića inerviranih kranijalnim živcima te pad amplitude mišićnog potencijala pri repetitivnoj stimulaciji (dekrementalni odgovor) i odsutnost protutijela na acetilkolinske receptore (AchR) i mišićno specifičnu tirozinsku kinazu (MuSK). Neki kongenitalni mijastenički sindromi manifestiraju se kasnije, a mišićna slabost i dekrementalni odgovor pojavljuju se intermintentno sa selektivnom raspodjelom u određenim mišićnim skupinama. Molekularno genetska analiza je vrlo značajna u dijagnostici kongenitalnog mijasteničkog sindroma. Presinaptički kongenitalni mijastenički sindrom vezan je za recesivne mutacije gena CHAT (kolinacetiltransferaza). Sinaptički oblik uzrokovan je mutacijom podjedinice kolagenskog repa acetilkolinesteraze (AchE). Većina kongenitalnih mijasteničkih sindroma su postsinaptički, uzrokovani mutacijama gena AchR podjedinica. Najčešće su mutacije gena CHRNE za ε-podjedinicu. Općenito, besmislene ili mutacije s pomakom okvira čitanja uzrokuju kongenitalni mijastenički sindrom zbog smanjene ili odsutne ekpresije proteina i nasljeđuju se autosomno recesivno. Mutacije gena rapsina (RAPSN) uzrokuju primarni nedostatak AchR-a na završnoj ploči. U terapiji kongenitalnog mijasteničkog sindroma ponajprije se primjenjuju inhibitori AchE. Prikazujemo djecu s kongenitalnim presinaptičkim i postinaptičkim poremećajima koji su udruženi sa značajnom varijabilnošću kliničke ekspresije u okviru kongenitalnog mijasteničkog sindroma.Congenital myasthenic syndromes (CMS) are genetically determined disorders affecting safety margins of neural transmission at presynaptic, postsynaptic and synaptic level. Diagnosis of CMS is made based on clinical symptoms including fatigable muscle weakness since infancy or childhood, decremental EMG response and negative antibodies to acetylcholine receptors (AchR) and muscle specific tyrosine kinase (MuSK). In some CMS the onset is delayed, weakness and EMG abnormalities appear intermittently in restricted distribution. Molecular genetic analysis has an important role in diagnosis of CMS. Presynaptic CMS are associated with recessive CHAT (cholinacyltransferase) gene mutations. The synaptic disorder is caused by mutation of the collagenic tail subunit of the AchE gene. However most CMS are postsynaptic, mostly caused by CHRNE gene mutations of AchR ε-subunit. In general, nonsense or frame shifting mutations cause CMS by decreased or absent protein expression and are inherited in autosomal recessive traits. Rapsyn gene (RAPSN) mutations cause primary endplate AchR deficiency. AchE inhibitors are the drugs of first choice in the treatment of CMS. We present children with presynaptic and with postsynaptic defects manifesting remarkable clinical heterogeneity

AChR deficiency due to ε-subunit mutations: two common mutations in the Netherlands

Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of hereditary disorders affecting neuromuscular transmission. We have identified mutations within the acetylcholine receptor (AChR) ε-subunit gene underlying congenital myasthenic syndromes in nine patients (seven kinships) of Dutch origin. Previously reported mutations ε1369delG and εR311Q were found to be common; ε1369delG was present on at least one allele in seven of the nine patients, and εR311Q in six. Phenotypes ranged from relatively mild ptosis and external ophthalmoplegia to generalized myasthenia. The common occurrence of εR311Q and ε1369delG suggests a possible founder for each of these mutations originating in North Western Europe, possibly in Holland. Knowledge of the ethnic or geographic origin within Europe of AChR deficiency patients can help in targeting genetic screening and it may be possible to provide a rapid genetic diagnosis for patients of Dutch origin by screening first for εR311Q and ε1369delG

Differential cross-sections for events with missing transverse momentum and jets measured with the ATLAS detector in 13 TeV proton-proton collisions

Measurements of inclusive, differential cross-sections for the production of events with missing transverse momentum in association with jets in proton-proton collisions at s = 13 TeV are presented. The measurements are made with the ATLAS detector using an integrated luminosity of 140 fb−1 and include measurements of dijet distributions in a region in which vector-boson fusion processes are enhanced. They are unfolded to correct for detector resolution and efficiency within the fiducial acceptance, and are designed to allow robust comparisons with a wide range of theoretical predictions. A measurement of differential cross sections for the Z → νν process is made. The measurements are generally well-described by Standard Model predictions except for the dijet invariant mass distribution. Auxiliary measurements of the hadronic system recoiling against isolated leptons, and photons, are also made in the same phase space. Ratios between the measured distributions are then derived, to take advantage of cancellations in modelling effects and some of the major systematic uncertainties. These measurements are sensitive to new phenomena, and provide a mechanism to easily set constraints on phenomenological models. To illustrate the robustness of the approach, these ratios are compared with two common Dark Matter models, where the constraints derived from the measurement are comparable to those set by dedicated detector-level searches

Search for new phenomena with top-quark pairs and large missing transverse momentum using 140 fb − 1 of pp collision data at s = 13 TeV with the ATLAS detector

A search is conducted for new phenomena in events with a top quark pair and large missing transverse momentum, where the top quark pair is reconstructed in final states with one isolated electron or muon and multiple jets. The search is performed using the Large Hadron Collider proton-proton collision data sample at a centre-of-mass energy of s = 13 TeV recorded by the ATLAS detector that corresponds to an integrated luminosity of 140 fb−1. An analysis based on neural network classifiers is optimised to search for directly produced pairs of supersymmetric partners of the top quark (stop), and to search for spin-0 mediators, produced in association with a pair of top quarks, that decay into dark-matter particles. In the stop search, the analysis is designed to target models in which the mass difference between the stop and the neutralino from the stop decay is close to the top quark mass. This new search is combined with previously published searches in final states with different lepton multiplicities. No significant excess above the Standard Model background is observed, and limits at 95% confidence level are set. Models with neutralinos with masses up to 570 GeV are excluded, while for small neutralino masses models are excluded for stop masses up to 1230 GeV. Scalar (pseudoscalar) dark matter mediator masses as large as 350 (370) GeV are excluded when the coupling strengths of the mediator to Standard Model and dark-matter particles are both set to one. At lower mediator masses, models with production cross-sections as small as 0.15 (0.16) times the nominal predictions are excluded. Results of this search are also used to set constraints on effective four-fermion contact interactions between top quarks and neutrinos

Combination of searches for heavy spin-1 resonances using 139 fb − 1 of proton-proton collision data at s = 13 TeV with the ATLAS detector

A combination of searches for new heavy spin-1 resonances decaying into different pairings of W, Z, or Higgs bosons, as well as directly into leptons or quarks, is presented. The data sample used corresponds to 139 fb−1 of proton-proton collisions at s = 13 TeV collected during 2015–2018 with the ATLAS detector at the CERN Large Hadron Collider. Analyses selecting quark pairs (qq, bb, tt¯, and tb) or third-generation leptons (τν and ττ) are included in this kind of combination for the first time. A simplified model predicting a spin-1 heavy vector-boson triplet is used. Cross-section limits are set at the 95% confidence level and are compared with predictions for the benchmark model. These limits are also expressed in terms of constraints on couplings of the heavy vector-boson triplet to quarks, leptons, and the Higgs boson. The complementarity of the various analyses increases the sensitivity to new physics, and the resulting constraints are stronger than those from any individual analysis considered. The data exclude a heavy vector-boson triplet with mass below 5.8 TeV in a weakly coupled scenario, below 4.4 TeV in a strongly coupled scenario, and up to 1.5 TeV in the case of production via vector-boson fusion

Measurements of electroweak W ± Z boson pair production in association with two jets in pp collisions at s = 13 TeV with the ATLAS detector

Measurements of integrated and differential cross-sections for electroweak W±Z production in association with two jets (W±Zjj) in proton-proton collisions are presented. The data collected by the ATLAS detector at the Large Hadron Collider from 2015 to 2018 at a centre-of-mass energy of s = 13 TeV are used, corresponding to an integrated luminosity of 140 fb−1. The W±Zjj candidate events are reconstructed using leptonic decay modes of the gauge bosons. Events containing three identified leptons, either electrons or muons, and two jets are selected. Processes involving pure electroweak W±Zjj production at Born level are separated from W±Zjj production involving a strong coupling. The measured integrated fiducial cross-section of electroweak W±Zjj production per lepton flavour is σWZjj−EW→ℓ′νlljj = 0.368 ± 0.037 (stat.) ± 0.059 (syst.) ± 0.003 (lumi.) fb, where ℓ and ℓ′ are either an electron or a muon. Respective cross-sections of electroweak and strong W±Zjj production are measured separately for events with exactly two jets or with more than two jets, and in three bins of the invariant mass of the two jets. The inclusive W±Zjj production cross-section, without separating electroweak and strong production, is also measured to be σWZjj→ℓ′νlljj = 1.462 ± 0.063 (stat.) ± 0.118 (syst.) ± 0.012 (lumi.) fb, per lepton flavour. The inclusive W±Zjj production cross-section is measured differentially for several kinematic observables. Finally, the measurements are used to constrain anomalous quartic gauge couplings by extracting 95% confidence level intervals on dimension-8 operators