197 research outputs found
Interplay between PFBC-associated SLC20A2 and XPR1 phosphate transporters requires inositol polyphosphates for control of cellular phosphate homeostasis
Solute carrier family 20 member 2 (SLC20A2) and xenotropic and polytropic retrovirus receptor 1 (XPR1) are transporters with phosphate uptake and efflux functions, respectively. Both are associated with primary familial brain calcification (PFBC), a genetic disease characterized by cerebral calcium-phosphate deposition and associated with neuropsychiatric symptoms. The association of the two transporters in the same disease suggests that they jointly regulate phosphate fluxes and cellular homeostasis, but direct evidence is missing. Here, we found that cross-talk between SLC20A2 and XPR1 regulates phosphate homeostasis and identify XPR1 as a key inositol polyphosphate (IP)-dependent regulator of this process. We found that overexpression of wildtype SLC20A2 increases phosphate uptake as expected, but also unexpectedly increases phosphate efflux, whereas PFBC-associated SLC20A2 variants did not. Conversely, SLC20A2 depletion decreased phosphate uptake only slightly, most likely compensated for by the related SLC20A1 transporter, but strongly decreased XPR1-mediated phosphate efflux. The SLC20A2-XPR1 axis maintained constant intracellular phosphate and ATP levels, which both increased in XPR1-KO cells. Elevated ATP is a hallmark of altered inositol pyrophosphate (PP-IP) synthesis, and basal ATP levels were restored after phosphate efflux rescue with wildtype XPR1, but not with XPR1 harboring a mutated PP-IP-binding pocket. Accordingly, inositol hexakisphosphate kinase 1-2 (IP6K1-2) gene inactivation or IP6K inhibitor treatment abolished XPR1-mediated phosphate efflux regulation and homeostasis. Our findings unveil an SLC20A2-XPR1 interplay that depends on IPs such as PP-IPs and controls cellular phosphate homeostasis via the efflux route, and that alteration of this interplay likely contributes to PFBC
Evaluation of treatment response in adults with relapsing MOG-Ab-associated disease
Background: Myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) are related to several acquired demyelinating syndromes in adults, but the therapeutic approach is currently unclear. We aimed to describe the response to different therapeutic strategies in adult patients with relapsing MOG-Ab-associated disease. Methods: This is a retrospective study conducted in France and Spain including 125 relapsing MOG-Ab patients aged â„ 18 years. First, we performed a survival analysis to investigate the relapse risk between treated and non-treated patients, performing a propensity score method based on the inverse probability of treatment weighting. Second, we assessed the annualised relapse rates (ARR), Expanded Disability Status Scale (EDSS) and visual acuity pre-treatment and on/end-treatment. Results: Median age at onset was 34.1 years (range 18.0-67.1), the female to male ratio was 1.2:1, and 96% were Caucasian. At 5 years, 84% (95% confidence interval [CI], 77.1-89.8) patients relapsed. At the last follow-up, 66 (52.8%) received maintenance therapy. Patients initiating immunosuppressants (azathioprine, mycophenolate mophetil [MMF], rituximab) were at lower risk of new relapse in comparison to non-treated patients (HR, 0.41; 95CI%, 0.20-0.82; p = 0.011). Mean ARR (standard deviation) was reduced from 1.05(1.20) to 0.43(0.79) with azathioprine (n = 11; p = 0.041), from 1.20(1.11) to 0.23(0.60) with MMF (n = 11; p = 0.033), and from 1.08(0.98) to 0.43(0.89) with rituximab (n = 26; p = 0.012). Other immunosuppressants (methotrexate/mitoxantrone/cyclophosphamide; n = 5), or multiple sclerosis disease-modifying drugs (MS-DMD; n = 9), were not associated with significantly reduced ARR. Higher rates of freedom of EDSS progression were observed with azathioprine, MMF or rituximab. Conclusion: In adults with relapsing MOG-Ab-associated disease, immunosuppressant therapy (azathioprine, MMF and rituximab) is associated with reduced risk of relapse and better disability outcomes. Such an effect was not found in the few patients treated with MS-DMD
Primary brain calcification: an international study reporting novel variants and associated phenotypes.
Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with a wide spectrum of motor, cognitive, and neuropsychiatric symptoms. It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1. Our study aimed at screening the coding regions of these genes in a series of 177 unrelated probands that fulfilled the diagnostic criteria for primary brain calcification regardless of their family history. Sequence variants were classified as pathogenic, likely pathogenic, or of uncertain significance (VUS), based on the ACMG-AMP recommendations. We identified 45 probands (25.4%) carrying either pathogenic or likely pathogenic variants (nâ=â34, 19.2%) or VUS (nâ=â11, 6.2%). SLC20A2 provided the highest contribution (16.9%), followed by XPR1 and PDGFB (3.4% each), and PDGFRB (1.7%). A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years). While the pathogenic and likely pathogenic variants identified in this study can be used for genetic counseling, the VUS will require additional evidence, such as recurrence in unrelated patients, in order to be classified as pathogenic
DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France
We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39â3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18â0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon
Advances and Insights into Neurological Practice 2016-17
Papers published by the European Journal of Neurology reflect the broad interest of practicing neurologists in advances in the aetiology, diagnosis and management of neurological disorders. As a general journal, the proportion of papers in the different subject areas reasonably reflects the case load of a practising neurologist. Stroke represents the largest proportion of papers published, including those on pathophysiology (1-23), acute stroke management (24-47) and the outcome of patients who have suffered stroke (48-72). This article is protected by copyright. All rights reserved
Atypical inflammatory demyelinating disorders and atypical multiple sclerosis : clinico-radiological characterization and NKp46/NCR1 function in astrocytes
Aux cĂŽtĂ©s des formes dites classiques de SclĂ©rose en plaques (SEP), un nombre important de patients prĂ©sentent des caractĂ©ristiques atypiques qui vont ĂȘtre responsable dâune pĂ©riode, parfois longue, dâerrance diagnostique. Certains de ces patients, malgrĂ© les atypies, font clairement partie du spectre de la SEP tandis-que dâautres prĂ©sentent probablement des maladies inflammatoires dĂ©myĂ©linisantes idiopathiques distinctes qui sont, Ă ce jour, toujours en attente dâindividualisation.Les objectifs principaux de ce travail de thĂšse Ă©taient de mieux caractĂ©riser ces formes atypiques de SEP et autres maladies inflammatoires dĂ©myĂ©linisantes idiopathiques.Nous avons effectuĂ© un travail rĂ©trospectif de caractĂ©risation clinique et radiologique (sur les donnĂ©es dâIRM acquises en conditions de vie rĂ©elle) afin dâaider au diagnostic et Ă mieux dĂ©finir le pronostic Ă©volutif de ces patients. Nous avons Ă©galement effectuĂ© une analyse anatomopathologique chez les patients prĂ©sentant une lĂ©sion inflammatoire nĂ©cessitant une biopsie avec pour objectif de mieux positionner ces lĂ©sions au sein du spectre de la SEP et du spectre des NeuromyĂ©lites Optiques (NMOSD). Enfin nous avons effectuĂ© une caractĂ©risation de lâexpression astrocytaire du rĂ©cepteur NKp46 au sein des lĂ©sions de SEP et des lĂ©sions inflammatoires dĂ©myĂ©linisantes atypiques.Les principaux rĂ©sultats sont :1) En lâabsence dâautre lĂ©sion cĂ©rĂ©brale Ă©vocatrice de SEP, le risque de dĂ©velopper une SEP cliniquement dĂ©finie chez un patient prĂ©sentant une lĂ©sion cĂ©rĂ©brale inflammatoire dĂ©myĂ©linisante isolĂ©e est faible.2) La SEP, notamment dans sa forme progressive, peut avoir des caractĂ©ristiques proches de celles rencontrĂ©es dans le cadre des lĂ©ucoencĂ©phalopathies hĂ©rĂ©ditaires. Dans ces situations, lâanalyse des lĂ©sions de la substance grise, de la topographie des lĂ©sions de la substance blanche et le caractĂšre nodulaire (>3mm mais non diffus) sont en faveur du diagnostic de SEP.3) Les lĂ©sions inflammatoires dĂ©myĂ©linisantes du systĂšme nerveux central sont extrĂȘmement hĂ©tĂ©rogĂšnes en IRM. NĂ©anmoins, certaines caractĂ©ristiques leurs sont communes : liserĂ© pĂ©riphĂ©rique en hypersignal en diffusion, prise de contraste pĂ©riphĂ©rique ouverte, respect de la substance grise. Lâanalyse anatomopathologique sur tissus provenant de biopsies rĂ©alisĂ©es pour incertitude diagnostique dĂ©montre une prĂ©servation quasi systĂ©matique du marquage AQP4.4) Lâexpression astrocytaire de NKp46, rĂ©cepteur classiquement dĂ©crit comme spĂ©cifique des lymphocytes NK, est commune Ă de nombreuses conditions neuroinflammatoires et neurodĂ©gĂ©nĂ©ratives y compris la SEP, les NMOSD et les autres maladies inflammatoires dĂ©myĂ©linisantes. Nous nâavons, Ă ce jour, pas pu dĂ©terminer lâimplication du rĂ©cepteur NKp46 dans la rĂ©ponse astrocytaire en conditions inflammatoires.En conclusion, lâĂ©tude de notre cohorte rĂ©trospective multicentrique a permis de mieux prĂ©ciser les caractĂ©ristiques clinique (y compris de suivi), anatomopathologiques et IRM de patients prĂ©sentant des formes atypiques de SEP et de maladies inflammatoires dĂ©myĂ©linisantes.Lâidentification de sous-types de SEP caractĂ©risĂ©s par une atteinte extrĂȘmement sĂ©vĂšre tant sur le plan clinique que radiologique nous semble pouvoir ĂȘtre un modĂšle dâĂ©tude intĂ©ressant dans la recherche de biomarqueurs dâimagerie et biologiques de la maladie.Beside classical multiple sclerosis (MS), a significant proportion of patients can present some atypical clinical or radiological characteristics that will lead to diagnostic uncertainties. On one side, some of these patients belong to MS spectrum whereas some other probably have yet unidentified inflammatory demyelinating disorders.Our objectives were to describe those patients with atypical MS and atypical idiopathic inflammatory demyelinating disorders.We retrospectively gathered clinical and radiological (in a real-life setting) data from patient to better delineate diagnostic clues and to better assess prognosis of these patients. Moreover, a neuropathological analysis of patientsâ tissue collected for diagnostic uncertainties was performed to assess AQP4 staining in patients with acute atypical inflammatory demyelinating disease. Finally, we characterized the expression of the activating receptor NKp46 within astrocytes in MS and other inflammatory neurological diseases.Our main results were the following:1) in the absence of any other lesion suggestive of MS, the overall risk of MS diagnosis and typical MS relapse is low.2) MS, notably primary progressive or bout-onset MS, can share MRI characteristics with inherited leukoencephalopathies and leukodystrophies. In this context, a thorough analysis of deep and cortical gray matter, topography of white matter lesions and size (typically nodular > 3mm but not confluent) strongly argues in favor of MS.3) In spite of a marked heterogeneity of central nervous system inflammatory demyelinating lesions, some characteristics such as a peripheral B1000 hyperintensity with open rim gadolinium enhancement (with or without central enhancement) and gray matter sparing are common to all of these conditions. Moreover, neuropathological analysis of these lesions suggests a systematic normal/increased AQP4 staining.4) NKp46 astrocytic expression, a classical NK cells marker is common to several neuroinflammatory diseases including MS, NMOSD and other inflammatory demyelinating disorders. To date, we were not able to ascertain NKp46 involvement in the context of neuroinflammation.To conclude, our analysis enabled to refine clinical, neuropathological and MRI characteristics of patients with atypical MS and atypical inflammatory demyelinating disorders.The identification of âclustersâ of atypical MS with dramatic disability progression and early evidence of neurodegeneration should allow us to identify promising MRI and/or biological biomarkers of disease progression
Neuropathies ataxiantes chroniques (apport des explorations Ă©lectrophysiologiques dans le diagnostic)
MONTPELLIER-BU MĂ©decine UPM (341722108) / SudocMONTPELLIER-BU MĂ©decine (341722104) / SudocSudocFranceF
Etiologie et pathogenĂšse des divisions labio-maxillaires
TOULOUSE3-BU Santé-Centrale (315552105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF
Diffuse neurofibrillary tangles with calcification: A single entity or two disorders in a single patient?
International audienc
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