Transdiagnostic Perspective of Impulsivity and Compulsivity in Obesity: From Cognitive Profile to Self-Reported Dimensions in Clinical Samples with and without Diabetes

Impulsivity; Compulsivity; Diabetes type 2Impulsivitat; Compulsivitat; Diabetis tipus 2Impulsividad; Compulsividad; Diabetes tipo 2Impulsive and compulsive behaviors have both been observed in individuals with obesity. The co-occurrence of obesity and type 2 diabetes (T2D) is more strongly associated with impulsivity, although there are no conclusive results yet. A multidimensional assessment of impulsivity and compulsivity was conducted in individuals with obesity in the absence or presence of T2D, compared with healthy, normal-weight individuals, with highly impulsive patients (gambling disorders), and with highly compulsive patients (anorexia nervosa). Decision making and novelty seeking were used to measure impulsivity, and cognitive flexibility and harm avoidance were used for compulsivity. For impulsivity, patients with obesity and T2D showed poorer decision-making ability compared with healthy individuals. For compulsivity, individuals with only obesity presented less cognitive flexibility and high harm avoidance; these dimensions were not associated with obesity with T2D. This study contributes to the knowledge of the mechanisms associated with diabetes and its association with impulsive-compulsive behaviors, confirming the hypothesis that patients with obesity and T2D would be characterized by higher levels of impulsivity.This manuscript and research were supported by grants from the Instituto de Salud Carlos III (ISCIII) (FIS PI14/00290, PI17/01167 and PI20/132) and (PI13/00462, PI16/00501, PI19/00576), by the SLT006/17/00246 grant, funded by the Department of Health of the Generalitat de Catalunya by the call “Acció instrumental de programes de recerca orientats en l’àmbit de la recerca i la innovació en salut” (PERIS) and co-funded by FEDER funds/European Regional Development Fund (ERDF), a way to build Europe. CIBERObn is an initiative of ISCIII. This research was also partially funded by EU-H2020 grants (Eat2beNICE/H2020-SFS-2016-2, Ref 728018; PRIME/H2020-SC1-BHC-2018-2020, Ref: 847879). CG-M receives a predoctoral grant from the University of Rovira i Virgili (2020PMFPIPF- 37). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

Utility of whole exome sequencing for the early diagnosis of pediatric-onset cerebellar atrophy associated with developmental delay in an inbred population

International audienceAbstractBackgroundCerebellar atrophy and developmental delay are commonly associated features in large numbers of genetic diseases that frequently also include epilepsy. These defects are highly heterogeneous on both the genetic and clinical levels. Patients with these signs also typically present with non-specific neuroimaging results that can help prioritize further investigation but don’t suggest a specific molecular diagnosis.MethodsTo genetically explore a cohort of 18 Egyptian families with undiagnosed cerebellar atrophy identified on MRI, we sequenced probands and some non-affected family members via high-coverage whole exome sequencing (WES; >97 % of the exome covered at least by 30x). Patients were mostly from consanguineous families, either sporadic or multiplex. We analyzed WES data and filtered variants according to dominant and recessive inheritance models.ResultsWe successfully identified disease-causing mutations in half of the families screened (9/18). These mutations are located in seven different genes, PLA2G6 being the gene most frequently mutated (n = 3). We also identified a recurrent de novo mutation in the KIF1A gene and a molybdenum cofactor deficiency caused by the loss of the start codon in the MOCS2A open-reading frame in a mildly affected subject.ConclusionsThis study illustrates the necessity of screening for dominant mutations in WES data from consanguineous families. Our identification of a patient with a mild and improving phenotype carrying a previously characterized severe loss of function mutation also broadens the clinical spectrum associated with molybdenum cofactor deficiency

The homozygous R504C mutation in MTO1 gene is responsible for ONCE syndrome

We report clinical and biochemical finding from three unrelated patients presenting ONCE (Optic Neuropathy, Cardiomyopathy and Encephalopathy with lactic acidosis and combined oxidative phosphorylation deficiency) syndrome. Whole-exome sequencing (WES) of the three patients and the healthy sister of one of them was used to identify the carry gene. Clinical and biochemical findings were used to filter variants, and molecular, in silico and genetic studies were performed to characterize the candidate variants. Mitochondrial DNA (mtDNA) defects involving mutations, deletions or depletion were discarded, whereas WES uncovered a double homozygous mutation in the MTO1 gene (NM_001123226:c.1510C>T, p.R504C, and c.1669G>A, p.V557M) in two of the patients and the homozygous mutation p.R504C in the other. Therefore, our data confirm p.R504C as pathogenic mutation responsible of ONCE syndrome, and p.V557M as a rare polymorphic variant.post-print712 K

Epilepsy with migrating focal seizures

To report new sporadic cases and 1 family with epilepsy of infancy with migrating focal seizures (EIMFSs) due to KCNT1 gain-of-function and to assess therapies' efficacy including quinidine. We reviewed the clinical, EEG, and molecular data of 17 new patients with EIMFS and KCNT1 mutations, in collaboration with the network of the French reference center for rare epilepsies. The mean seizure onset age was 1 month (range: 1 hour to 4 months), and all children had focal motor seizures with autonomic signs and migrating ictal pattern on EEG. Three children also had infantile spasms and hypsarrhythmia. The identified KCNT1 variants clustered as "hot spots" on the C-terminal domain, and all mutations occurred de novo except the p.R398Q mutation inherited from the father with nocturnal frontal lobe epilepsy, present in 2 paternal uncles, one being asymptomatic and the other with single tonic-clonic seizure. In 1 patient with EIMFS, we identified the p.R1106Q mutation associated with Brugada syndrome and saw no abnormality in cardiac rhythm. Quinidine was well tolerated when administered to 2 and 4-year-old patients but did not reduce seizure frequency. The majority of the KCNT1 mutations appear to cluster in hot spots essential for the channel activity. A same mutation can be linked to a spectrum of conditions ranging from EMFSI to asymptomatic carrier, even in the same family. None of the antiepileptic therapies displayed clinical efficacy, including quinidine in 2 patients

Impulsive Personality Traits Predicted Weight Loss in Individuals with Type 2 Diabetes after 3 Years of Lifestyle Interventions

Impulsivity has been associated with type 2 diabetes (T2D) and may negatively impact its management. This study aimed to investigate impulsive personality traits in an older adult population with T2D and their predicting role in long-term weight control and glycemic management, through glycated hemoglobin (HbA(1c)), following 3 years of intervention with a Mediterranean diet. The Impulsive Behavior Scale (UPPS-P) was administered as a measure of impulsive traits at baseline. Results showed higher total baseline scores of UPPS-P, and higher positive urgency in individuals with T2D, compared with those without T2D. The regression analysis in patients with T2D showed that sensation seeking and lack of perseverance predicted weight loss at follow-up. By contrast, impulsive traits did not predict follow-up levels of HbA(1c). In conclusion, the present findings suggest that higher impulsive traits in individuals with T2D seem to affect long-term weight control, but not glycemic control

Whole-exome and HLA sequencing in Febrile infection-related epilepsy syndrome

Febrile infection-related epilepsy syndrome (FIRES) is a devastating epilepsy characterized by new-onset refractory status epilepticus with a prior febrile infection. We performed exome sequencing in 50 individuals with FIRES, including 27 patient–parent trios and 23 single probands, none of whom had pathogenic variants in established genes for epilepsies or neurodevelopmental disorders. We also performed HLA sequencing in 29 individuals with FIRES and 529 controls, which failed to identify prominent HLA alleles. The genetic architecture of FIRES is substantially different from other developmental and epileptic encephalopathies, and the underlying etiology remains elusive, requiring novel approaches to identify the underlying causative factors

Monoallelic Variation in DHX9, the Gene Encoding the Dexh-Box Helicase DHX9, Underlies Neurodevelopment Disorders and Charcot-Marie-Tooth Disease

DExD/H-box RNA helicases (DDX/DHX) are encoded by a large paralogous gene family; in a subset of these human helicase genes, pathogenic variation causes neurodevelopmental disorder (NDD) traits and cancer. DHX9 encodes a BRCA1-interacting nuclear helicase regulating transcription, R-loops, and homologous recombination and exhibits the highest mutational constraint of all DDX/DHX paralogs but remains unassociated with disease traits in OMIM. Using exome sequencing and family-based rare-variant analyses, we identified 20 individuals with de novo, ultra-rare, heterozygous missense or loss-of-function (LoF) DHX9 variant alleles. Phenotypes ranged from NDDs to the distal symmetric polyneuropathy axonal Charcot-Marie-Tooth disease (CMT2). Quantitative Human Phenotype Ontology (HPO) analysis demonstrated genotype-phenotype correlations with LoF variants causing mild NDD phenotypes and nuclear localization signal (NLS) missense variants causing severe NDD. We investigated DHX9 variant-associated cellular phenotypes in human cell lines. Whereas wild-type DHX9 was restricted to the nucleus, NLS missense variants abnormally accumulated in the cytoplasm. Fibroblasts from an individual with an NLS variant also showed abnormal cytoplasmic DHX9 accumulation. CMT2-associated missense variants caused aberrant nucleolar DHX9 accumulation, a phenomenon previously associated with cellular stress. Two NDD-associated variants, p.Gly411Glu and p.Arg761Gln, altered DHX9 ATPase activity. The severe NDD-associated variant p.Arg141Gln did not affect DHX9 localization but instead increased R-loop levels and double-stranded DNA breaks. Dhx

Identification des bases génétiques des encephalopathies épileptiques

Introduction : Les encéphalopathies épileptiques (EE) constituent un groupe de pathologies où l’activité épileptique (répétition des crises épileptiques et/ou anomalies électroencéphalographies) est responsable d’une atteinte cognitive, sensorielle et motrice. Les EE sont définies selon leurs caractéristiques cliniques et EEG dans la classification élaborée par Ligue Internationale contre les Epilepsies (Berg et al. 2010). La distinction en différentes formes d’EE selon le phénotype clinique-EEG reflète des mécanismes physiopathologiques différents. Une base génétique est suspectée comme étant responsable de la majorité des cas d’EE. Méthodes : Ce travail débute d’une analyse clinique avec la constitution des groupes homogènes de patients grâce un phénotypage extensif. Des nouvelles techniques de séquençage à haut débit ont été appliquées à l’étude des cohortes homogènes des patients atteints d’EE afin de mieux en comprendre les bases génétiques. Résultats : Cette approche nous a permis d’identifier, à partir d’une cohorte de patients atteints de crises focales migrantes du nourrisson (MFSI), KCNT1 comme le gène impliqué dans plus de la moitié des cas de MFSI. Nous avons identifié également un autre gène, QARS, impliqué dans une forme familiale des MFSI associée à une microcéphalie progressive. Nous avons analysé les caractéristiques électro-cliniques des patients porteurs d’une mutation du gène STXBP1 permettant de mieux détailler le phénotype associé à ces mutations et de préciser donc, quels patients sont candidats à l’étude de ce gène. Enfin, nous avons décrit un cas d’épilepsie myoclono-astatique chez lequel une mutation du gène CHD2 a été identifiée. Conclusions : L’interaction dynamique et réciproque entre clinique et génétique constitue une approche fondamentale pour mettre en place des études génétiques rationnelles et ciblées et afin de pouvoir détecter, comprendre et interpréter les résultats génétiques dans des maladies rares, les EE, pour lesquelles nous ne disposons pas de larges familles “multiplex”. Une fois une anomalie génétique identifiée, le “retour à la clinique” est indispensable afin de pouvoir détailler le phénotype électroclinique associé à chaque anomalie génétique.Introduction: Epileptic encephalopathies (EE) are a group of conditions in which cognitive, sensorial, and motor functions deteriorate as a consequence of epileptic activity (recurrence of epileptic seizures and EEG abnormalities) (Nabbout, 2003). EE are classified according to clinical and EEG features in the «Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005-2009» (Berg et al. 2010). The distinction of different forms of EE according to the electro-clinical phenotype reflects different pathophysiological mechanisms. A genetic basis is supposed to cause the majority of EE. Methods: This work starts from the clinics with the constitution of homogeneous cohorts of patients affected by EE. The new technics of next generation sequencing have been applied to the study of homogeneous cohorts of patients with EE in order to gain insight into their genetic bases and pathophysiological mechanisms. Results: This approach allowed the identification of KCNT1 as the major gene causing migrating focal seizures of infancy (MFSI) in more than half of patients. We also identified QARS as a gene involved in a familial form of MFSI with a progressive microcephaly.\u2028We finally analyzed electro-clinical phenotype of patients with STXBP1 mutations in order to better detail their phenotype and better select patients who are candidate to STXBP1 analysis. Finally, we reported a patient affected by myoclonic astatic epilepsy and harboring a CHD2 gene mutation. Conclusions: The dynamic and reciprocal interaction between clinics and genetics constitutes a necessary approach to target genetic studies and to gain insight into genetic and pathophysiological mechanisms of rare conditions such as EE, where large “multiplex” families are lacking. Once a genetic abnormality identified, it is essential to come back to clinics in order to detail the electroclinical phenotype associated with a genetic abnormalities and to performed genotype-phenotype correlations