Long-term follow-up of acute partial transverse myelitis.

BACKGROUND: Acute partial transverse myelitis (APTM) may be the first clinical symptom of multiple sclerosis (MS) or may remain a monophasic event. OBJECTIVES: To evaluate the risk of conversion to MS and long-term disability, and to determine prognosis factors for disability. DESIGN: We identified patients with no previous history of neurological disease who experienced APTM between January 1998 and December 2005 and were followed up at 3 university hospitals in France. Data on the patients' demographics and clinical states during follow-up, as well as data on cerebrospinal fluid (CSF) analysis, brain and spinal cord magnetic resonance imaging (MRI), and visual evoked potentials, were analyzed. SETTING: Neurology departments of 3 university hospitals in Lille, Strasbourg, and Rouen, France, respectively. PATIENTS: A total of 85 patients with no previous history of neurological disease who experienced APTM. RESULTS: The mean (SD) follow-up period was 104.8 (29.8) months. There were 57 women (67%) and 28 men (33%), with a mean (SD) age at onset of 36.7 (11.7) years. At the end of follow-up, 53 patients (62%) were classified as having MS with a mean (SD) Expanded Disability Status Scale score of 2.6 (1.8), 1 patient (1%) was classified as having postinfectious myelitis, 1 (1%) as having neuromyelitis optica, 1 (1%) as having Sjögren syndrome, and 29 (34%) still had APTM of undetermined etiology. Oligoclonal bands in CSF were more frequent in patients with MS (92%) than in patients with APTM of undetermined etiology (38%). Brain MRI results were abnormal in 87% of patients with MS and 27% of patients with APTM of undetermined etiology; visual evoked potentials were abnormal in 43% of patients with MS and 4% of patients with APTM of undetermined etiology. Oligoclonal bands in CSF (odds ratio, 15.76 [95% CI, 2.95-84.24]) and at least 1 MRI-detected brain lesion (odds ratio, 7.74 [95% CI, 2.42-24.74]) were independent predictive factors for conversion to MS. CONCLUSION: Our study confirms that abnormal brain MRI results and the presence of oligoclonal bands in CSF are 2 independent predictive factors for conversion to MS. No clinical, biological, or MRI factor at onset was predictive of long-term disability.journal article2012 MarimportedErratum in : Arch Neurol. 2012 Jun;69(6):789. Outerryck, Olivier [corrected to Outteryck, Olivier]

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 = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, 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

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Clinical and molecular findings of ataxia with oculomotor apraxia type 2 in 4 families.

International audienceBACKGROUND: Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease caused by SETX mutations in 9q34 resulting in cerebellar ataxia in association with peripheral neuropathy, cerebellar atrophy on imaging, an elevated alpha-fetoprotein (AFP) serum level, and occasional oculomotor apraxia. OBJECTIVE: To describe the clinical and molecular findings of 7 patients with a clinical presentation of AOA2 and their relatives. DESIGN: Case report. SETTING: Projet Hospitalier de Recherche Clinique. PATIENTS: Seven patients with AOA2 and their family members. INTERVENTION: Linkage analysis and direct sequencing of all exons of SETX were performed in all patients. Magnetic resonance imaging and electroneuromyography were performed and the patients' AFP serum levels were tested. RESULTS: We identified 7 patients with AOA2 from 4 unrelated families. Three novel SETX mutations were found. The clinical picture of the patients reported is fairly homogeneous and in accordance with the classic AOA2 presentation: onset from 13 to 18 years of progressive cerebellar ataxia and areflexia. Oculomotor apraxia was detected in 1 patient. Predominant axonal neuropathy and a diffuse cerebellar atrophy were found in the 4 patients tested. All patients had elevated AFP serum levels and 5 of 8 nonsymptomatic heterozygous relatives had moderately increased AFP serum levels as well. CONCLUSIONS: Ataxia with oculomotor apraxia type 2 is a homogeneous form of cerebellar ataxia with occasional oculomotor apraxia. Most nonsymptomatic heterozygous carriers present with increased AFP serum levels

The value of multidisciplinary team meetings MDTm ) in the diagnosis and management of childhood interstitial lung disease (chILD) among the RespiRare network

Background:Childhood interstitial lung disease (chILD) is a heterogeneous group of rare and severe diseases. Epidemiological data are limited and chILD is most likely under-diagnosed. As with all rare diseases, the establishment of networksof expertise and national or international databases are crucial for increasing chILD knowledge. The first multidisciplinary team meetings (MDTm) dedicated to chILD have been set up in frame of the RespiRare network inFrance since 2018. We aim to study the contribution of MDTm in the diagnosis and management of chILD.Methods:We conducted a retrospective and descriptive study on the chILD MDTm reports from 2018 to 2022. Each meeting was attended by a quorum and by pediatric pulmonologists, radiologists, geneticists and pulmonologists (mean 13 participants). They lasted for 2 hours and were held monthly via video conference. A written report followed the meeting.Results:178 chILD cases were discussed (45% females). The median age of onset was 0.5 years [IQR 0;7]. The MDTm allowed to rectify the chILD etiology for 33% (NEHI 20.2%, surfactant disorders 8.4%, sarcoidosis 2.8%, autoimmune chILD 1.6%, other chILD 41%, undefined chILD 19.6%) and to exclude chILD for 6.2%. A therapeutic change was proposed in 43%.Discussion and conclusion:Our experience shows that a dedicated MDTm provides a unique opportunity to improve chILD etiologic diagnosis and to adapt management and therapy in chILD

Effect of familial clustering in the genetic screening of 235 French ALS families

International audienceObjectives To determine whether the familial clustering of amyotrophic lateral sclerosis (ALS) cases and the phenotype of the disease may help identify the pathogenic genes involved. Methods We conducted a targeted next-generation sequencing analysis on 235 French familial ALS (FALS), unrelated probands to identify mutations in 30 genes linked to the disease. The genealogy, that is, number of cases and generations with ALS, gender, age, site of onset and the duration of the disease were analysed. Results Regarding the number of generations, 49 pedigrees had only one affected generation, 152 had two affected generations and 34 had at least three affected generations. Among the 149 pedigrees (63.4%) for which a deleterious variant was found, an abnormal G4C2 expansion in C9orf72 was found in 98 cases as well as SOD1 , TARBP or FUS mutations in 30, 9 and 7 cases, respectively. Considering pedigrees from the number of generations, abnormal G4C2 expansion in C9orf72 was more frequent in pedigrees with pairs of affected ALS cases, which represented 65.2% of our cohort. SOD1 mutation involved all types of pedigrees. No TARDBP nor FUS mutation was present in monogenerational pedigrees. TARDBP mutation predominated in bigenerational pedigrees with at least three cases and FUS mutation in multigenerational pedigrees with more than seven cases, on average, and with an age of onset younger than 45 years. Conclusion Our results suggest that familial clustering, phenotypes and genotypes are interconnected in FALS, and thus it might be possible to target the genetic screening from the familial architecture and the phenotype of ALS cases

Rational Design of Bisubstrate-Type Analogues as Inhibitors of DNA Methyltransferases in Cancer Cells

Aberrant DNA hypermethylation of promoter of tumor suppressor genes is commonly observed in cancer, and its inhibition by small molecules is promising for their reactivation. Here we designed bisubstrate analogues-based inhibitors, by mimicking each substrate, the <i>S</i>-adenosyl-l-methionine and the deoxycytidine, and linking them together. This approach resulted in quinazoline–quinoline derivatives as potent inhibitors of DNMT3A and DNMT1, some showing certain isoform selectivity. We highlighted the importance of (i) the nature and rigidity of the linker between the two moieties for inhibition, as (ii) the presence of the nitrogen on the quinoline group, and (iii) of a hydrophobic group on the quinazoline. The most potent inhibitors induced demethylation of <i>CDKN2A</i> promoter in colon carcinoma HCT116 cells and its reactivation after 7 days of treatment. Furthermore, in a leukemia cell model system, we found a correlation between demethylation of the promoter induced by the treatment, chromatin opening at the promoter, and the reactivation of a reporter gene

Clinical problems in rare interstitial lung diseases

International audienceIntroduction: Interstitial lung disease ( LD) in children (chlLD) is rare and Often severe. This study aims at analyzing the ep demiology of chlLD in France from 2000 to 2022.Methods: This study was retrospective and multicentric, A questionnaire was sent to all the RespiRare centers to collect the clinical, radiological, biological, histological and genetic data of the patients.Results: 617 patients (0-18 years) were included in 42 centers. 84 patients were excluded. The median age at diagnosis was 0.3 years with 17% of familial forms, The main investigations performed were: chest CT scan (92%), bronchoalveolar avage (52%), genetic ana ysis (78%), lung biopsy (23%). The main treatments were: corticosteroids (93%), oxygen therapy (52.2%), enteral nutrition (29%), hydroxychloroqu•ne (16%), azThromycin (26%), immunosuppressive drugs (210/0). The follovFup time was from O to 18,9 years (median duration 3,5years). The survival rate at 5 years was 68%. The overall incidence and preva ence were estimated at 38/million and 35/million children respectively.Conclusion: This arge chlLD epidemiological study confirms the Span •sh data with a higher incidence and prevalence than previous y described. The arge amount Of phenotypic data collected will allow better understanding ch LD and harmonizing their management