Publications by authors named "Joseph Toulouse"

12 Publications

  • Page 1 of 1

SCN1A-related epilepsy with recessive inheritance: Two further families.

Eur J Paediatr Neurol 2021 Jul 5;33:121-124. Epub 2021 Jun 5.

APHP.Sorbonne Université, Département de Génétique, Groupe Hospitalier Pitié Salpêtrière, Paris, France; Sorbonne Université, Institut du Cerveau, ICM, Inserm U1127, CNRS UMR 7225, Paris, France. Electronic address:

Background: Variants in SCN1A gene, encoding the voltage-gated sodium channel Na1.1, are associated with distinct epilepsy syndromes ranging from the relatively benign genetic epilepsy with febrile seizures plus (GEFS+) to Dravet syndrome, a severe developmental and epileptic encephalopathy (DEE). Most SCN1A pathogenic variants are heterozygous changes inherited in a dominant or de novo inheritance and many cause a loss-of-function of one allele. To date, recessive inheritance has been suggested in only two families with affected children harboring homozygous SCN1A missense variants while their heterozygous parents were asymptomatic. The aim of this report is to describe two additional families in which affected individuals have biallelic SCN1A variants possibly explaining their phenotype.

Methods And Results: We report two novel homozygous SCN1A missense variants in two patients from related parents. Both patients had fever-sensitive epilepsy beginning in the first months of life, followed by afebrile seizures, without severe cognitive impairment. Parents were asymptomatic. Next generation sequencing excluded a pathogenic variant in other genes involved in DEE. Estimation of pathogenicity scores by in-silico tools suggests that the impact of these SCN1A variants is less damaging than that of dominant pathogenic variants.

Conclusion: This study provides additional evidence that homozygous variants in SCN1A can cause GEFS+. This recessive inheritance would imply that hypomorphic variants may not necessarily cause epilepsy at the heterozygous state but may decrease the seizure threshold when combined.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2021.05.018DOI Listing
July 2021

KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum.

Brain 2021 Jun 11. Epub 2021 Jun 11.

Pediatric Neurology Department, Lyon University Hospital, 69500 Bron, France.

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy ((AD)SHE) to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies (DEE). This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 unpreviously published and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: i) EIMFS (152 individuals, 33 previously unpublished); ii) DEE other than EIMFS (non-EIMFS DEE) (37 individuals, 17 unpublished); iii) (AD)SHE (53 patients, 14 unpublished); iv) other phenotypes (6 individuals, 2 unpublished). In our cohort of 66 new cases, the most common phenotypic features were: a) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; b) in non-EIMFS DEE, possible onset with West syndrome, occurrence of atypical absences, possible evolution to DEE with SHE features; one case of sudden unexplained death in epilepsy (SUDEP); c) in (AD)SHE, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in about 50% of the patients, SUDEP in one individual; d) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the (AD)SHE-associated mutations to be clustered around the RCK2 domain in the C-terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS DEE did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset DEEs as well as in focal epilepsies, namely (AD)SHE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awab219DOI Listing
June 2021

Occurrence and risk factors associated with seizures in infants with severe bronchiolitis.

Eur J Pediatr 2021 Sep 12;180(9):2959-2967. Epub 2021 Apr 12.

Hospices Civils de Lyon, réanimation pédiatrique, Hôpital Femme Mère Enfant, F-69500, Bron, France.

Neurological morbidity is a growing concern in children with severe bronchiolitis. The aim of the study was to evaluate the frequency of occurrence and the factors associated with seizures in very young infants < 3 months of age, admitted to a pediatric intensive care unit (PICU) for severe bronchiolitis. We performed a single center retrospective cohort study evaluating occurrence of seizures in infants admitted to the PICU between 2010 and 2018 for severe bronchiolitis. We described characteristics of the patients, laboratory test, brain imaging, and electroencephalogram results, as well as the treatment used. We conducted a multivariable logistic regression to identify factors associated with the occurrence of seizures. A p value < 0.05 was considered significant. A total of 805 patients were included in the study; 722 (89.6%) were mechanically ventilated. Twenty-six infants (3.2%, 95% confidence interval, 95% CI [2.1%; 4.7%]) had seizures shortly prior to admission or during PICU stay. In the multivariable analysis, hyponatremia (odds ratio, OR: 4.6, 95%CI [1.86; 11.43], p = 0.001) and invasive ventilation (OR: 2.6, 95% CI [1.14; 5.9], p < 0.001) were associated with an increased likelihood of seizures occurrence.Conclusion: Seizures occur in at least 3% of very young infants with severe bronchiolitis, and the characteristics of these are different to those experienced by older infants, but they shared the same risk factors (hyponatremia and mechanical ventilation). This highlights the extrapulmonary morbidity associated with bronchiolitis in this population. What is Known: • Bronchiolitis is the leading cause of pediatric intensive care admission and use of mechanical ventilation in infants. • Neurological morbidities have to be investigated in this population at risk of neurological complications. What is New: • Seizure is a complication in at least 3% of very young infants with severe bronchiolitis. • Seizure characteristics are different, but the main risk factors are the same than in older infants (hyponatremia and mechanical ventilation).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00431-021-04070-7DOI Listing
September 2021

A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsies.

Epilepsia Open 2021 03 13;6(1):160-170. Epub 2021 Jan 13.

IRCCS Mondino Foundation Pavia Italy.

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies.

Methods: Members of the ( were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease.

Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers.

Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/epi4.12459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918306PMC
March 2021

Real-life use of videos in pediatric epilepsy consultations.

Epilepsy Behav 2021 01 10;114(Pt A):107636. Epub 2020 Dec 10.

APHP, Pediatric Neurology Department, Rare Epilepsy Center, CHU Robert Debré, Paris, France.

Paroxysmal events are usually not directly observed by physicians. The diagnosis remains challenging and relies mostly on the description of witnesses. The effectiveness of videos for seizure diagnosis has been validated by several studies, but their place in clinical practice is not yet clear. The aim of our study was to evaluate the real-life use of videos by child neurologists. We conducted a three-month prospective study in which child neurologists were asked to use a short questionnaire to evaluate all videos that were watched in their clinical practice for an initial diagnosis or during follow-up. A click-off meeting during the French pediatric neurology meeting allowed to recruit participants. A total of 165 questionnaires were completed by 15 physicians over the study period. The physicians were child neurologists working in secondary and tertiary/university hospitals, consulting children with epilepsy. Based on the evaluation of child neurologists, 51% of the videos consisted of epileptic seizures; 40%, nonepileptic paroxysmal events; and 9%, psychogenic nonepileptic seizures. Most of the videos were made on parental initiative. The use of video has modified the first diagnosis hypothesis in 35% of cases. The physicians' feelings regarding the interest of the video used during the diagnostic phase were similar to those of the video used during follow-up. It appears that videos have become a part of the epilepsy clinic and are helpful for diagnosis as well as during follow-up. Unfortunately, one of the limitations of this study is the absence of private practitioner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2020.107636DOI Listing
January 2021

Defining and expanding the phenotype of -associated developmental epileptic encephalopathy.

Neurol Genet 2019 Dec 10;5(6):e373. Epub 2019 Dec 10.

Department of Epilepsy Genetics and Precision Medicine (K.J.M., E.G., G.R., R.S.M.), The Danish Epilepsy Centre Filadelfia, Dianalund, Denmark; Institute for Regional Health Services (K.J.M., E.G., R.S.M.), University of Southern Denmark, Odense; Institute of Human Genetics (D.M., R. Jamra, A.F., J.R.L.), University of Leipzig Medical Center, Germany; Institute of Structural Biology (R. Janowski, D.N.), Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Department of Paediatric Radiology (C.R.), University of Leipzig Medical Center, Germany; Department of Epilepsy, Sleep and Pediatric Neurophysiology (J.T.), Lyon University Hospital, France; Neuropediatric Unit (A.-L.P., D.M.V., G.L.), Lyon University Hospital, France; Department of Medical Genetics (N.C., G.L.), Lyon University Hospital, France; GenDev Team (N.C.), CNRS UMR 5292, INSERM U1028, CNRL and University of Lyon, France; Department of Genetics (E.B.), University Medical Center Utrecht, The Netherlands; Department of Child Neurology (K.G.), Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands; Department of Paediatrics (A.P.B.), Copenhagen University Hospital Rigshospitalet, Denmark; Baylor College of Medicine (S.M., K.N.), Children's Hospital of San Antonio; Undiagnosed Diseases Program (G.B., C.P.), Genetic Services of Western Australia, Department of Health, Government of Western Australia, Perth; Western Australian Register of Developmental Anomalies (G.B., D.G.), Australia; Telethon Kids Institute and the School of Paediatrics and Child Health (G.B.), University of Western Australia, Perth; Linear Clinical Research (L.D.), WA, Australia; Center of Human Genetics (S.S), Jena University Hospital, Germany; Department of Neuropediatrics (A.D.), Jena University Hospital, Germany; Division of Neurology (K.L.H.), Children's Hospital of Philadelphia, PA; Division of Neuropediatrics (A.M.), University of Leipzig Medical Center, Germany; Amplexa Genetics (H.H.), Odense, Denmark; Clinic for Children (H.H.), Værløse, Denmark; Center for Integrative Brain Research (G.M.), Seattle Children's Research Institute, WA; Department of Pediatrics (G.M.), University of Washington, Seattle; Medical Genetics Unit (F.B.), Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy; Istituto Dermopatico dell'Immacolata (F.B.), IDI-IRCCS, Rome, Italy; Institute of Human Genetics (T.B., M.H.), University Medical Center Hamburg-Eppendorf, Germany; Childrens Hospital (J.D.), University Medical Center Hamburg-Eppendorf, Germany; University of Copenhagen (G.R.), Denmark; Institute for Human Genetics (P.M.), University Hospital Magdeburg, Germany; Children's Hospital A. Meyer (R.G., A.V.), University of Florence, Italy; and Institute of Pharmaceutical Biotechnology (D.N.), Ulm University, Germany.

Objective: The study is aimed at widening the clinical and genetic spectrum and at assessing genotype-phenotype associations in encephalopathy.

Methods: Through diagnostic gene panel screening in an epilepsy cohort, and recruiting through GeneMatcher and our international network, we collected 10 patients with biallelic variants. In addition, we collected data on 12 patients described in the literature to further delineate the associated phenotype in a total cohort of 22 patients. Computer modeling was used to assess changes on protein folding.

Results: Biallelic pathogenic variants in cause a triad of progressive microcephaly, moderate to severe developmental delay, and early-onset epilepsy. Microcephaly was present at birth in 65%, and in all patients at follow-up. Moderate (14%) or severe (73%) developmental delay was characteristic, with no achievement of sitting (85%), walking (86%), or talking (90%). Additional features included irritability (91%), hypertonia/spasticity (75%), hypotonia (83%), stereotypic movements (75%), and short stature (56%). Seventy-nine percent had pharmacoresistant epilepsy with mainly neonatal onset. Characteristic cranial MRI findings include early-onset progressive atrophy of cerebral cortex (89%) and cerebellum (61%), enlargement of ventricles (95%), and age-dependent delayed myelination (88%). A small subset of patients displayed a less severe phenotype.

Conclusions: These data revealed first genotype-phenotype associations and may serve for improved interpretation of new variants and well-founded genetic counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXG.0000000000000373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927360PMC
December 2019

Trends in pediatric epilepsy surgery in Europe between 2008 and 2015: Country-, center-, and age-specific variation.

Epilepsia 2020 02 26;61(2):216-227. Epub 2019 Dec 26.

Claudio Munari Epilepsy Surgery Center, Niguarda Hospital, Milan, Italy.

Objective: To profile European trends in pediatric epilepsy surgery (<16 years of age) between 2008 and 2015.

Methods: We collected information on volumes and types of surgery, pathology, and seizure outcome from 20 recognized epilepsy surgery reference centers in 10 European countries.

Results: We analyzed retrospective aggregate data on 1859 operations. The proportion of surgeries significantly increased over time (P < .0001). Engel class I outcome was achieved in 69.3% of children, with no significant improvement between 2008 and 2015. The proportion of histopathological findings consistent with glial scars significantly increased between the ages of 7 and 16 years (P for trend = .0033), whereas that of the remaining pathologies did not vary across ages. A significant increase in unilobar extratemporal surgeries (P for trend = .0047) and a significant decrease in unilobar temporal surgeries (P for trend = .0030) were observed between 2008 and 2015. Conversely, the proportion of multilobar surgeries and unrevealing magnetic resonance imaging cases remained unchanged. Invasive investigations significantly increased, especially stereo-electroencephalography. We found different trends comparing centers starting their activity in the 1990s to those whose programs were developed in the past decade. Multivariate analysis revealed a significant variability of the proportion of the different pathologies and surgical approaches across countries, centers, and age groups between 2008 and 2015.

Significance: Between 2008 and 2015, we observed a significant increase in the volume of pediatric epilepsy surgeries, stability in the proportion of Engel class I outcomes, and a modest increment in complexity of the procedures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.16414DOI Listing
February 2020

[Disabled child. Orientation and management].

Rev Prat 2018 Oct;68(8):e327-e334

PU-PH, neuropédiatrie, CHU de Lyon - université Lyon 1, chef de service, service de neuropédiatrie, hôpital Femme-Mère-Enfant, 69677 Bron Cedex, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
October 2018

Reply to Micarelli et al. Commentary on The Balance of Sleep: Role of the Vestibular Sensory System.

Sleep Med Rev 2019 04 6;44:87-88. Epub 2018 Dec 6.

Department Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.smrv.2018.12.003DOI Listing
April 2019

Delineating syndrome: From congenital microcephaly to hyperkinetic encephalopathy.

Neurol Genet 2018 Dec 7;4(6):e281. Epub 2018 Nov 7.

Objective: To provide new insights into the related clinical and imaging phenotypes and refine the phenotype-genotype correlation in syndrome.

Methods: We analyzed the clinical and imaging phenotypes of a cohort of 45 patients with a pathogenic or likely pathogenic variant and performed phenotype-genotype correlations.

Results: A total of 37 different heterozygous mutations were identified, of which 18 are novel. We described a broad spectrum of neurodevelopmental phenotypes, characterized by severe postnatal microcephaly and developmental delay accompanied by a hyperkinetic movement disorder, stereotypes and sleep disorders, and epileptic seizures. Our data highlighted 3 patterns of gyration, including frontal pachygyria in younger patients (26.7%), moderate simplified gyration (24.4%) and mildly simplified or normal gyration (48.9%), corpus callosum hypogenesis mostly in its frontal part, combined with moderate-to-severe myelination delay that improved and normalized with age. Frameshift and nonsense mutations in the N-terminus of , which are the most common mutation types, show the most severe clinical features and MRI anomalies. However, patients with recurrent frameshift mutations c.460dupG and c.256dupC had variable clinical and imaging presentations.

Conclusions: These findings have implications for genetic counseling, providing evidence that N-terminal mutations and large deletions lead to more severe syndrome, although genotype-phenotype correlations are not necessarily straightforward in recurrent mutations. Together, these analyses support the view that syndrome is a specific disorder characterized by frontal pachygyria and delayed myelination in its most severe form and hypogenetic corpus callosum in its milder form.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXG.0000000000000281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244024PMC
December 2018

The balance of sleep: Role of the vestibular sensory system.

Sleep Med Rev 2018 12 8;42:220-228. Epub 2018 Sep 8.

Dept. Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.

The vestibular system encodes linear and angular head motion supporting numerous functions from gaze stabilization and postural control, to high-level cortical functions involving spatial cognition, including self-body perception, verticality perception, orientation, navigation and spatial memory. At the brainstem and mesencephalic levels, the vestibular organs also influence postural blood pressure regulation, bone density and muscle composition via specific vestibulo-sympathetic efferences and have been shown to act as a powerful synchronizer of circadian rhythms. Here, we review the evidence that sleep deprivation and sleep apnea syndrome alter vestibular-related oculo-motor and postural control, and that, in turn, vestibular pathologies induce sleep disturbances. We suggest that sleep-related neuroplasticity might serve the adaptation and compensation processes following vestibular lesions in patients. Interestingly, a reciprocal neuroanatomical route between the vestibular nuclei and the orexinergic neurons has been reported. While orexinergic modulation of the vestibular nuclei related to postural control has been suggested, we postulate that vestibular inputs might in turn influence the sleep-wake state switch, informing the brain about the daily quantity of motion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.smrv.2018.09.001DOI Listing
December 2018

Differential regulation of NMDA receptor-expressing neurons in the rat hippocampus and striatum following bilateral vestibular loss demonstrated using flow cytometry.

Neurosci Lett 2018 09 21;683:43-47. Epub 2018 Jun 21.

Dept. of Pharmacology and Toxicology, School of Biomedical Sciences, and the Brain Health Research Centre, University of Otago, Dunedin, New Zealand; Brain Research New Zealand, Centre of Research Excellence, New Zealand; The Eisdell Moore Centre, University of Auckland, New Zealand. Electronic address:

There is substantial evidence that loss of vestibular function impairs spatial learning and memory related to hippocampal (HPC) function, as well as increasing evidence that striatal (Str) plasticity is also implicated. Since the N-methyl-d-aspartate (NMDA) subtype of glutamate receptor is considered essential to spatial memory, previous studies have investigated whether the expression of HPC NMDA receptors changes following vestibular loss; however, the results have been contradictory. Here we used a novel flow cytometric method to quantify the number of neurons expressing NMDA receptors in the HPC and Str following bilateral vestibular loss (BVL) in rats. At 7 and 30 days post-op., there was a significant increase in the number of HPC neurons expressing NMDA receptors in the BVL animals, compared to sham controls (P ≤ 0.004 and P ≤ 0.0001, respectively). By contrast, in the Str, at 7 days there was a significant reduction in the number of neurons expressing NMDA receptors in the BVL group (P ≤ 0.05); however, this difference had disappeared by 30 days post-op. These results suggest that BVL causes differential changes in the number of neurons expressing NMDA receptors in the HPC and Str, which may be related to its long-term impairment of spatial memory.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neulet.2018.06.035DOI Listing
September 2018
-->