Análisis de utilidad del estudio genético en las epilepsias percibido por familiares y personal médico

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Pediatría. Fecha de lectura: 28-06-201

Disease-associated GRIN protein truncating variants trigger NMDA receptor loss-of-function

De novo GRIN variants, encoding for the ionotropic glutamate NMDA receptor subunits, have been recently associated with GRIN-related disorders, a group of rare paediatric encephalopathies. Current investigational and clinical efforts are focused to functionally stratify GRIN variants, towards precision therapies of this primary disturbance of glutamatergic transmission that affects neuronal function and brain. In the present study, we aimed to comprehensively delineate the functional outcomes and clinical phenotypes of GRIN protein truncating variants (PTVs)—accounting for ~20% of disease-associated GRIN variants—hypothetically provoking NMDAR hypofunctionality. To tackle this question, we created a comprehensive GRIN PTVs variants database compiling a cohort of nine individuals harbouring GRIN PTVs, together with previously identified variants, to build-up an extensive GRIN PTVs repertoire composed of 293 unique variants. Genotype–phenotype correlation studies were conducted, followed by cell-based assays of selected paradigmatic GRIN PTVs and their functional annotation. Genetic and clinical phenotypes meta-analysis revealed that heterozygous GRIN1, GRIN2C, GRIN2D, GRIN3A and GRIN3B PTVs are non-pathogenic. In contrast, heterozygous GRIN2A and GRIN2B PTVs are associated with specific neurological clinical phenotypes in a subunit- and domain-dependent manner. Mechanistically, cell-based assays showed that paradigmatic pathogenic GRIN2A and GRIN2B PTVs result on a decrease of NMDAR surface expression and NMDAR-mediated currents, ultimately leading to NMDAR functional haploinsufficiency. Overall, these findings contribute to delineate GRIN PTVs genotype–phenotype association and GRIN variants stratification. Functional studies showed that GRIN2A and GRIN2B pathogenic PTVs trigger NMDAR hypofunctionality, and thus accelerate therapeutic decisions for this neurodevelopmental condition.ISCIII, cofunded by European Regional Development Fund (ERDF), a way to build Europe (grants PI19/00348 and PI16/00851); Miguel Servet Program (CPII16/00021, ISCIII) and Serra Húnter Fellow to X.A.; SAF2016-77830-R to M.O.; European Regional development Fund (ERDF)-Ministerio de Ciencia e Innovación (grant BFU2017-83317-P) and Ministerio de Ciencia e Innovación-María de Maeztu (MDM-2017-0729) to D.S. and PI18/00111 [ISCIII, cofunded by European Regional Development Fund (ERDF), a way to build Europe] to À.G.-C. and N.J.-P.; Fundación Tatiana Pérez de Guzmán el Bueno PhD fellowship to A.S.-G.; crowdfunding initiative Precipita (FECYT) to F.M

Attention deficit hyperactivity disorder: Genetic association study in a cohort of spanish children

Background: Attention deficit hyperactivity disorder (ADHD) has a strong genetic component. The study is aimed to test the association of 34 polymorphisms with ADHD symptomatology considering the role of clinical subtypes and sex in a Spanish population. Methods: A cohort of ADHD 290 patients and 340 controls aged 6–18 years were included in a case–control study, stratified by sex and ADHD subtype. Multivariate logistic regression was used to detect the combined effects of multiple variants. Results: After correcting for multiple testing, we found several significant associations between the polymorphisms and ADHD (p value corrected ≤0.05): (1) SLC6A4 and LPHN3 were associated in the total population; (2) SLC6A2, SLC6A3, SLC6A4 and LPHN3 were associated in the combined subtype; and (3) LPHN3 was associated in the male sample. Multivariable logistic regression was used to estimate the influence of these variables for the total sample, combined and inattentive subtype, female and male sample, revealing that these factors contributed to 8.5, 14.6, 2.6, 16.5 and 8.5 % of the variance respectively. Conclusions: We report evidence of the genetic contribution of common variants to the ADHD phenotype in four genes, with the LPHN3 gene playing a particularly important role. Future studies should investigate the contribution of genetic variants to the risk of ADHD considering their role in specific sex or subtype, as doing so may produce more predictable and robust modelsThis study was supported by the following research grants: Fundacion Alicia Koplowitz (4019-004), Biobank of Fundacion Jimenez Diaz Hospital (RD09/0076/00101, Instituto de Salud Carlos III) and the Centre for Biomedical Network Research on Rare Diseases -CIBERER (06/07/0036). The work of CG-S is supported by a Fundacion Conchita Rabago Gran

Paradigmatic de novo GRIN1 variants recapitulate pathophysiological mechanisms underlying GRIN1-related disorder clinical spectrum

Background: GRIN-related disorders (GRD), the so-called grinpathies, is a group of rare encephalopathies caused by mutations affecting GRIN genes (mostly GRIN1, GRIN2A and GRIN2B genes), which encode for the GluN subunit of the N-methyl D-aspartate (NMDA) type ionotropic glutamate receptors. A growing number of functional studies indicate that GRIN-encoded GluN1 subunit disturbances can be dichotomically classified into gain- and loss-of-function, although intermediate complex scenarios are often present. Methods: In this study, we aimed to delineate the structural and functional alterations of GRIN1 disease-associated variants, and their correlations with clinical symptoms in a Spanish cohort of 15 paediatric encephalopathy patients harbouring these variants. Results: Patients harbouring GRIN1 disease-associated variants have been clinically deeplyphenotyped. Further, using computational and in vitro approaches, we identified different critical checkpoints affecting GluN1 biogenesis (protein stability, subunit assembly and surface trafficking) and/or NMDAR biophysical properties, and their association with GRD clinical symptoms. Conclusions: Our findings show a strong correlation between GRIN1 variants-associated structural and functional outcomes. This structural-functional stratification provides relevant insights of genotypephenotype association, contributing to future precision medicine of GRIN1-related encephalo

Prevalencia de trastornos del sueño en pacientes con neurofibromatosis tipo 1

Resumen: Introducción: La neurofibromatosis tipo 1 (NF1) asocia frecuentemente alteraciones neurológicas no relacionadas con neurofibromas, entre las que se encuentran los trastornos del sueño. Objetivos: Revisión de la prevalencia de trastornos de sueño en pacientes con NF1 y compararla con los datos descritos en la literatura, así como analizar la relación con el trastorno cognitivo y el trastorno por déficit de atención e hiperactividad (TDAH) en estos pacientes. Material y métodos: Estudio comparativo, retrospectivo, mediante la revisión de los datos recogidos entre enero de 2010 y enero de 2012 de pacientes diagnosticados de NF1 en un hospital de tercer nivel. Resultados: Se incluyeron 95 pacientes con NF1 pediátricos que respondieron correctamente a la Escala de alteraciones del sueño en la infancia de Bruni, encontrando una prevalencia de trastorno global del sueño del 6,3%, inferior al de la población pediátrica general. Aquellos pacientes con NF1 y TDAH presentaron mayor prevalencia de trastorno de inicio-mantenimiento del sueño (18 vs 6,3%), de transición sueño-vigilia (12,5 vs 6,3%) y somnolencia diurna (12,5 vs 7,9%) sin alcanzar significación estadística, sí encontrándose diferencia estadísticamente significativa en la subescala de hiperhidrosis nocturna (21,9 vs 6,3%; p < 0,05). Los pacientes con NF1 y cociente intelectual < 85 presentaron mayor prevalencia de somnolencia diurna (20 vs 6,7%) y mayor hiperhidrosis nocturna (11 vs 0%). Conclusiones: En nuestra cohorte de pacientes con NF1 no hemos encontrado aumento de la prevalencia de trastornos de sueño con respecto a la población pediátrica general, aunque algunos de estos trastornos son más frecuentes en caso de alteraciones cognitivas o TDAH. Abstract: Introduction: Neurofibromatosis type 1 (NF1) is frequently associated with neurological disorders unrelated to neurofibromas, including sleep disorders. Objectives: This article reviews the prevalence of sleep disorders in patients with NF1, compares rates to data reported in the literature, and analyses the relationship between cognitive disorder and attention deficit hyperactivity disorder (ADHD) in these patients. Material and methods: Comparative retrospective study reviewing data collected between January 2010 and January 2012 from patients diagnosed with NF1 in a tertiary hospital. Results: We included 95 paediatric patients with NF1 who completed the Bruni Sleep Disturbance Scale in Children. The overall prevalence of sleep disorders was 6.3%, which was lower than in the general paediatric population. Patients with NF1 and ADHD had a higher prevalence of sleep onset and maintenance disorders (18% vs 6.3%), sleep-wake transition disorders (12.5% vs 6.3%), and daytime sleepiness (12.5% vs 7.9%); differences were not statistically significant. A statistically significant difference was found in the subdomain of nocturnal hyperhidrosis (21.9% vs 6.3%, P  <  0.05). Patients with NF1 and IQ < 85 showed higher prevalence rates of daytime sleepiness (20% vs 6.7%) and of sleep hyperhidrosis (11% vs 0%). Conclusions: The prevalence of sleep disorders in our cohort of patients with NF1 was no higher than in the general paediatric population, although some of these disorders are more common in cases with cognitive disorders or ADHD. Palabras clave: Hiperhidrosis, Neurofibromatosis, Somnolencia, Sueño, Sueño-vigilia, Trastorno por déficit de atención e hiperactividad, Keywords: Hyperhidrosis, Neurofibromatosis, Sleepiness, Sleep, Sleep-wake, Attention deficit hyperactivity disorde

Prevalence of sleep disorders in patients with neurofibromatosis type 1

Introduction: Neurofibromatosis type 1 (NF1) is frequently associated with neurological disorders unrelated to neurofibromas, including sleep disorders. Objectives: This article reviews the prevalence of sleep disorders in patients with NF1, compares rates to data reported in the literature, and analyses the relationship between cognitive disorder and attention deficit hyperactivity disorder (ADHD) in these patients. Material and methods: Comparative retrospective study reviewing data collected between January 2010 and January 2012 from patients diagnosed with NF1 in a tertiary hospital. Results: We included 95 paediatric patients with NF1 who completed the Bruni Sleep Disturbance Scale in Children (SDSC). The overall prevalence of sleep disorders was 6.3%, which was lower than in the general paediatric population. Patients with NF1 and ADHD had a higher prevalence of sleep onset and maintenance disorders (18% vs 6.3%), sleep-wake transition disorders (12.5% vs 6.3%), and daytime sleepiness (12.5% vs 7.9%); differences were not statistically significant. A statistically significant difference was found in the subdomain of nocturnal hyperhidrosis (21.9% vs 6.3%, P < .05). Patients with NF1 and IQ < 85 showed higher prevalence rates of daytime sleepiness (20% vs 6.7%) and of sleep hyperhidrosis (11% vs 0%). Conclusions: The prevalence of sleep disorders in our cohort of patients with NF1 was no higher than in the general paediatric population, although some of these disorders are more common in cases with cognitive disorders or ADHD. Resumen: Introducción: La neurofibromatosis tipo 1 (NF1) asocia frecuentemente alteraciones neurológicas no relacionadas con neurofibromas, entre las que se encuentran los trastornos del sueño. Objetivos: Revisión de la prevalencia de trastornos de sueño en pacientes con NF1 y compararla con los datos descritos en la literatura, así como analizar la relación con el trastorno cognitivo y el trastorno por déficit de atención e hiperactividad (TDAH) en estos pacientes. Material y métodos: Estudio comparativo, retrospectivo, mediante la revisión de los datos recogidos entre enero de 2010 y enero de 2012 de pacientes diagnosticados de NF1 en un hospital de tercer nivel. Resultados: Se incluyeron 95 pacientes con NF1 pediátricos que respondieron correctamente a la Escala de alteraciones del sueño en la infancia de Bruni, encontrando una prevalencia de trastorno global del sueño del 6,3%, inferior al de la población pediátrica general. Aquellos pacientes con NF1 y TDAH presentaron mayor prevalencia de trastorno de inicio-mantenimiento del sueño (18 vs 6,3%), de transición sueño-vigilia (12,5 vs 6,3%) y somnolencia diurna (12,5 vs 7,9%) sin alcanzar significación estadística, sí encontrándose diferencia estadísticamente significativa en la subescala de hiperhidrosis nocturna (21,9 vs 6,3%; p < 0,05). Los pacientes con NF1 y cociente intelectual < 85 presentaron mayor prevalencia de somnolencia diurna (20 vs 6,7%) y mayor hiperhidrosis nocturna (11 vs 0%). Conclusiones: En nuestra cohorte de pacientes con NF1 no hemos encontrado aumento de la prevalencia de trastornos de sueño con respecto a la población pediátrica general, aunque algunos de estos trastornos son más frecuentes en caso de alteraciones cognitivas o TDAH. Keywords: Hyperhidrosis, Neurofibromatosis, Sleepiness, Sleep, Sleep-wake, Attention deficit hyperactivity disorder, Palabras clave: Hiperhidrosis, Neurofibromatosis, Somnolencia, Sueño, Sueño-vigilia, Trastorno por déficit de atención e hiperactivida