[Chest radiological lesions in COVID-19 : from classical imaging to artificial intelligence]. / Les aspects radiologiques de la pneumopathie à COVID-19 : de l'imagerie conventionnelle à l'intelligence artificielle.

In the course of the pandemic induced by the appearance of a new coronavirus (SARS-CoV-2; COVID-19) causing acute respiratory distress syndrome (ARDS), we had to rethink the diagnostic approach for patients suffering from respiratory symptoms. Indeed, although the use of RT-PCR remains the keystone of the diagnosis, the delay in diagnosis as well as the overload of the microbiological platforms have led us to make almost systematic the use of thoracic imaging for taking in charge of patients. In this context, thoracic imaging has shown a major interest in diagnostic aid in order to better guide the management of patients admitted to hospital. The most common signs encountered are particularly well described in thoracic computed tomography. Typical imaging combines bilateral, predominantly peripheral and posterior, multi-lobar, ground glass opacities. Of note, it is common to identify significant lesions in asymptomatic patients, with imaging sometimes preceding the onset of symptoms. Beyond conventional chest imaging, many teams have developed new artificial intelligence tools to better help clinicians in decision-making.

Dans le décours de la pandémie induite par l'apparition d'un nouveau coronavirus (SARS-CoV-2; COVID-19) à l'origine d'un syndrome de détresse respiratoire aigu (SDRA), nous avons dû repenser l'approche diagnostique des patients souffrant de symptômes respiratoires. En effet, bien que l'usage de la RT-PCR reste la clé de voûte du diagnostic, le retard de diagnostic ainsi que la surcharge des plateformes microbiologiques nous ont menés à rendre quasi systématique l'usage de l'imagerie thoracique pour la prise en charge des patients. L'imagerie thoracique a démontré, dans ce contexte, un intérêt majeur dans l'aide au diagnostic afin d'orienter, au mieux, la prise en charge des patients admis à l'hôpital. Les signes les plus couramment rencontrés sont particulièrement bien décrits en tomodensitométrie thoracique. L'imagerie typique associe des lésions en verre dépoli bilatérales, multi-lobaires, à prédominance périphérique et postérieure. Il est classique d'identifier des lésions significatives chez des patients asymptomatiques, l'imagerie précédant parfois l'apparition de symptômes. Au-delà de l'imagerie thoracique conventionnelle, de nombreuses équipes ont développé de nouveaux outils d'intelligence artificielle afin d'aider, au mieux, les cliniciens dans la prise de décisions.

A certified plasmid reference material for the standardisation of BCR-ABL1 mRNA quantification by real-time quantitative PCR.

Serial quantification of BCR-ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukaemia, but there is a substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR-ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08±0.13 × 10(6), 1.08±0.11 × 10(5), 1.03±0.10 × 10(4), 1.02±0.09 × 10(3), 1.04±0.10 × 10(2) and 10.0±1.5 copies/µl. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR-ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise a number of measured transcripts of e14a2 BCR-ABL1 and three control genes (ABL1, BCR and GUSB). The set of six plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (https://ec.europa.eu/jrc/en/reference-materials/catalogue/; CRM code ERM-AD623a-f).

Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations.

OBJECTIVES: Heterozygous mutations in STXBP1, encoding the syntaxin binding protein 1, have recently been identified in Ohtahara syndrome, an epileptic encephalopathy with very early onset. In order to explore the phenotypic spectrum associated with STXBP1 mutations, we analyzed a cohort of patients with unexplained early-onset epileptic encephalopathies. METHODS: We collected and clinically characterized 106 patients with early-onset epileptic encephalopathies. Mutation analysis of the STXBP1 gene was done using sequence analysis of the exon and intron-exon boundaries and multiplex amplification quantification to detect copy number variations. RESULTS: We identified 4 truncating mutations and 2 microdeletions partially affecting STXBP1 in 6 of the 106 patients. All mutations are predicted to abolish STXBP1 function and 5 mutations were proven to occur de novo. None of the mutation-carrying patients had Ohtahara syndrome. One patient was diagnosed with West syndrome at disease onset, while the initial phenotype of 5 further patients did not fit into a specific recognized epilepsy syndrome. Three of these patients later evolved to West syndrome. All patients had severe to profound mental retardation, and ataxia or dyskinetic movements were present in 5 patients. CONCLUSION: This study shows that mutations in STXBP1 are not limited to patients with Ohtahara syndrome, but are also present in 10% (5/49) of patients with an early-onset epileptic encephalopathy that does not fit into either Ohtahara or West syndrome and rarely in typical West syndrome. STXBP1 mutational analysis should be considered in the diagnostic evaluation of this challenging group of patients.

Four generations of epilepsy caused by an inherited microdeletion of the SCN1A gene.

OBJECTIVES: The aim of this study was to determine the genetic defect in a 4-generational family with an epileptic disorder characterized by febrile and afebrile polymorphic seizures and mild to severe mental retardation by means of analyzing the neuronal voltage-gated sodium channel alpha-subunit gene SCN1A for mutations. METHODS: A Bulgarian family was ascertained and clinically assessed, followed by mutation analysis of the SCN1A gene using direct sequencing to detect point mutations and multiplex amplicon quantification to identify copy number variations. RESULTS: A microdeletion encompassing the entire SCN1A gene segregating with all affected members was identified in this family. Additional analysis showed that the unaffected father of the proband is mosaic for the deletion. So far, SCN1A deletions, predicted to lead to haploinsufficiency, are exclusively identified in isolated patients with Dravet or contiguous gene syndromes. Because of the severe phenotype, SCN1A deletion carriers are usually not able to live independently and start a family, and hence do not transmit the disease. CONCLUSIONS: We report an inherited SCN1A gene deletion not exclusively associated with Dravet syndrome. Moreover, our results demonstrate that SCN1A haploinsufficiency can cause a significant intrafamilial clinical variability including moderately affected to syndromal patients. The involvement of multiple genetic and environmental factors could be the basis of this difference in phenotype severity.

Familial occipitotemporal lobe epilepsy and migraine with visual aura: linkage to chromosome 9q.

OBJECTIVE: To map the disease-causing locus in a large Belgian family with occipitotemporal lobe epilepsy associated with migraine with visual aura and to describe the clinical, electrophysiologic, and imaging characteristics. METHODS: DNA samples from 21 family members were obtained and an 8 cM density genome-wide scan was performed. The authors interviewed 21 individuals and performed interictal EEG in 14 and brain MRI in 13 individuals. RESULTS: Nine at risk family members and one deceased individual had epilepsy with occipital and temporal lobe symptomatology, variable age at onset, usually good prognosis, no epileptic EEG features, and normal brain MRI. Five of the 10 patients had a history of migraine with aura (p = 0.0026). Seizures and migraine attacks occurred as separate episodes in all but one patient. Three patients described light flashes both as epileptic and migraine aura. Epilepsy and migraine started at the same age in three patients and remitted simultaneously in two. The epileptic phenotype had a dominant mode of inheritance with a reduced penetrance of 75%. A conclusive two-point lod score of 3.3 was obtained for marker D9S257 at recombination fraction zero. Haplotype analysis defined a candidate region of 9.95 cM (5.96 Mb) between markers GATA152H04 and D9S253 located at chromosome 9q21-q22 based upon recombinations in affected individuals. CONCLUSIONS: The clinical association in this family of occipitotemporal lobe epilepsy and migraine with visual aura and the conclusive linkage of the occipitotemporal lobe epilepsy/migraine with aura trait to a single locus suggests a common monogenic gene defect.

A novel GABRG2 mutation associated with febrile seizures.

Mutations in the gene encoding the gamma2 subunit of the gamma-aminobutyric acid type A receptor (GABRG2) have been reported to cause childhood absence epilepsy (CAE), febrile seizures (FS), and generalized epilepsy with FS plus (GEFS+). The authors analyzed GABRG2 in 47 unrelated patients with CAE, FS, and GEFS+ and identified a novel mutation that cosegregated with FS. Electrophysiologic studies demonstrated altered current desensitization and reduced benzodiazepine enhancement in mutant receptors.

A novel susceptibility locus at 2p24 for generalised epilepsy with febrile seizures plus.

Generalised epilepsy with febrile seizures plus (GEFS+) is a clinically and genetically heterogeneous epilepsy syndrome. Using positional cloning strategies, mutations in SCN1B, SCN1A, and GABRG2 have been identified as genetic causes of GEFS+. In the present study, we describe a large four generation family with GEFS+ in which we performed a 10 cM density genome-wide scan. We obtained conclusive evidence for a novel GEFS+ locus on chromosome 2p24 with a maximum two point logarithm of the odds (LOD) score of 4.22 for marker D2S305 at zero recombination. Fine mapping and haplotype segregation analysis in this family delineated a candidate region of 3.24 cM, corresponding to a physical distance of 4.2 Mb. Linkage to 2p24 was confirmed (p = 0.007) in a collection of 50 nuclear and multiplex families with febrile seizures and epilepsy. Transmission disequilibrium testing and association studies provided further evidence (p < 0.05) that 2p24 is a susceptibility locus for febrile seizures and epilepsy. Furthermore, we could reduce the candidate region to a 2.14 cM interval, localised between D2S1360 and D2S2342, based upon an ancestral haplotype. Identification of the disease gene at this locus will contribute to a better understanding of the complex genetic aetiology of febrile seizures and epilepsy.

De novo KCNQ2 mutations in patients with benign neonatal seizures.

Benign familial neonatal convulsions (BFNC) are characterized by unprovoked seizures during the first weeks of life with spontaneous remission after a few months. Mutations have been identified in the voltage-gated potassium ion channels KCNQ2 and KCNQ3. The authors performed a mutation analysis of KCNQ2 and KCNQ3 in six patients of whom four had no family history of neonatal seizures. The authors identified three KCNQ2 mutations in four patients that all arose de novo.