Publications by authors named "Víctor Soto-Insuga"

11 Publications

  • Page 1 of 1

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

Hum Mol Genet 2021 Feb;29(24):3859-3871

Neuroscience Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Spain.

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.
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http://dx.doi.org/10.1093/hmg/ddaa220DOI Listing
February 2021

Utility of the transcranial doppler in the evaluation and follow-up of children with Sturge-Weber Syndrome.

Eur J Paediatr Neurol 2020 Jul 19;27:60-66. Epub 2020 Apr 19.

Department of Neuropediatrics, Hospital Infantil Universitario Niño Jesús, Madrid, Spain; Member of the Clinical Group Linked (GCV6) to the Networked Biomedical Research Centre for Rare Diseases (CIBERER), Carlos III Health Institute, Madrid, Spain.

Introduction: Sturge-Weber syndrome (SWS) is a neurocutaneous syndrome with typical clinical features including seizures, chronic hemiplegia, hemianopsia and intellectual impairment. Progressive clinical decline may be attributable, at least in part, to progressive venous ischemia. Transcranial Doppler (TCD) ultrasonography could be useful to monitor the degree of hemodynamic involvement and its progression.

Purpose: To determine whether there is an association between the degree of asymmetry in TCD and intensity of clinical and radiological involvement and whether there is a correlation between clinical changes and changes in serial TCD.

Methods: In fourteen SWS pediatric patients and two "possible cases" (infants younger than two years old without previously known brain involvement, but with other typical signs of SWS) mean flow velocity in the middle cerebral arteries (MCA) was measured by TCD in both hemispheres. The percent difference between hemispheres (asymmetry) was calculated. Clinical and radiological severity was scored using scales. The correlation between TCD asymmetry and SWS clinical and radiological scores was analyzed at baseline, as well as the correlation between the changes in the different variables (TCD asymmetry, clinical and radiological cores) during evolution and in relation to the changes due to therapy.

Results: The percentage of MCA velocity asymmetry was positively correlated with the clinical severity score (p = 0.04), and with seizure frequency (p = 0.014). Throughout evolution, therapeutic and clinical changes were associated with noticeable changes in transcranial doppler asymmetry in some cases.

Conclusions: TCD may provide a noninvasive method to assess the severity of blood flow abnormalities at baseline and a method to monitor children for progressive changes over time.
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http://dx.doi.org/10.1016/j.ejpn.2020.04.006DOI Listing
July 2020

Central sleep apnea in children with obstructive sleep apnea syndrome and improvement following adenotonsillectomy.

Pediatr Pulmonol 2019 11 2;54(11):1670-1675. Epub 2019 Aug 2.

Multidisciplinary Sleep Unit, Department of Respiratory Medicine, Fundación Jiménez Díaz, Madrid, Spain.

Background: Although the pathogenesis of central and obstructive events seems to be different, these two entities may somehow be related. We aimed to determine whether, as reported in previous research, the number of central sleep apnea (CSA) cases in a population of children with obstructive sleep apnea syndrome (OSAS) was greater than in patients without obstructive events, and if CSA worsens with increasing OSAS severity. As a second objective, we analyzed changes in central apnea index (CAI) after adenotonsillar surgery compared to changes when no surgery has been performed.

Methods: We retrospectively reviewed nocturnal polysomnography (PSG) data from children between 1 and 14 years of age with no neurological conditions or syndromes. Patients with CAI values greater than 5 per hour were diagnosed as having CSA. Improvements of greater than 50% in CAI on repeat PSG were considered to represent a real change.

Results: Data were available from 1279 PSG studies, resulting in 72 children with a CAI greater than 5 per hour (5.6%). Patients with OSAS showed a higher CAI (2.16) compared with those without OSAS (1.17), and this correlation increased with higher degrees of obstructive apnea severity. When adenotonsillectomy was performed due to OSAS, the CAI decreased by 1.37. The average decrease in PSG values was only 0.38 in cases where no surgery was performed.

Conclusion: The results of this study suggest that although CSA is perceived to be mostly associated with central nervous system ventilatory control, there may be a connection with airway obstruction and in children with CSA and OSA diagnosis adenotonsillectomy may improve both conditions.
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http://dx.doi.org/10.1002/ppul.24469DOI Listing
November 2019

Glut1 deficiency is a rare but treatable cause of childhood absence epilepsy with atypical features.

Epilepsy Res 2019 08 21;154:39-41. Epub 2019 Apr 21.

Department of Pediatrics, Hospital Universitario Fundación Jiménez Díaz, UAM, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Neurology Lab and Epilepsy Unit, Department of Neurology, IIS- Fundación Jiménez Díaz, UAM, Madrid, Spain.

Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a rare genetic disorder caused by pathogenic variants in SLC2A1, resulting in impaired glucose uptake through the blood-brain barrier. Our objective is to analyze the frequency of GLUT1-DS in patients with absences with atypical features. Sequencing analysis and detection of copy number variation of the SLC2A1 gene was carried out in patients with atypical absences including: early-onset absence, intellectual disability, additional seizure types, refractory epilepsy, associated movement disorders, as well as those who have first-degree relatives with absence epilepsy or atypical EEG ictal discharges. Of the 43 patients analyzed, pathogenic variations were found in 2 (4.6%). Six atypical characteristics were found in these 2 patients. The greater the number of atypical characteristics presenting in patients with absence seizures, the more likely they have a SLC2A1 mutation. Although GLUT1-DS is an infrequent cause of absence epilepsy, recognizing this disorder is important, since initiation of a ketogenic diet can reduce the frequency of seizures, the severity of the movement disorder, and also improve the quality of life of the patients and their families.
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http://dx.doi.org/10.1016/j.eplepsyres.2019.04.003DOI Listing
August 2019

Molecular diagnosis of patients with epilepsy and developmental delay using a customized panel of epilepsy genes.

PLoS One 2017 30;12(11):e0188978. Epub 2017 Nov 30.

Neurology Lab and Epilepsy Unit, Department of Neurology, IIS- Fundación Jiménez Díaz, UAM, Madrid, Spain.

Pediatric epilepsies are a group of disorders with a broad phenotypic spectrum that are associated with great genetic heterogeneity, thus making sequential single-gene testing an impractical basis for diagnostic strategy. The advent of next-generation sequencing has increased the success rate of epilepsy diagnosis, and targeted resequencing using genetic panels is the a most cost-effective choice. We report the results found in a group of 87 patients with epilepsy and developmental delay using targeted next generation sequencing (custom-designed Haloplex panel). Using this gene panel, we were able to identify disease-causing variants in 17 out of 87 (19.5%) analyzed patients, all found in known epilepsy-associated genes (KCNQ2, CDKL5, STXBP1, SCN1A, PCDH19, POLG, SLC2A1, ARX, ALG13, CHD2, SYNGAP1, and GRIN1). Twelve of 18 variants arose de novo and 6 were novel. The highest yield was found in patients with onset in the first years of life, especially in patients classified as having early-onset epileptic encephalopathy. Knowledge of the underlying genetic cause provides essential information on prognosis and could be used to avoid unnecessary studies, which may result in a greater diagnostic cost-effectiveness.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188978PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708701PMC
January 2018

Pharmacogenetics of methylphenidate in childhood attention-deficit/hyperactivity disorder: long-term effects.

Sci Rep 2017 09 4;7(1):10391. Epub 2017 Sep 4.

Department of Genetics, IIS - Fundación Jiménez Díaz University Hospital (IIS-FJD, UAM). Avda. Reyes Católicos, 2, Madrid, 28040, Spain.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in which a significant proportion of patients do not respond to treatment. The objective of this study was to examine the role of genetic risk variants in the response to treatment with methylphenidate (MPH). The effectiveness of MPH was evaluated based on variations in the CGI-S and CGAS scales over a 12-month treatment period using linear mixed effects models. A total of 208 ADHD patients and 34 polymorphisms were included in the analysis. For both scales, the response was associated with time, extended-release MPH/both formulations, and previous MPH treatment. For the CGI-S scale, response was associated with SLC6A3 rs2550948, DRD4 promoter duplication, SNAP25 rs3746544, and ADGRL3 rs1868790. Interactions between the response over time and SLC6A3 and DRD2 were found in the CGI-S and CGAS scales, respectively. The proportion of the variance explained by the models was 18% for the CGI-S and 22% for the CGAS. In this long-term study, the effects of SLC6A3, DRD4, SNAP25, and ADGRL3 on response to treatment reflect those observed in previous studies. In addition, 2 previously unreported interactions with response to treatment over a 12-month period were found (SLC6A3 and DRD2).
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http://dx.doi.org/10.1038/s41598-017-10912-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5583388PMC
September 2017

[Do children with attention deficit and hyperactivity disorder (ADHD) have a diferent gait pattern? Relationship between idiopathic toe-walking and ADHD].

An Pediatr (Barc) 2018 Apr 10;88(4):191-195. Epub 2017 Jul 10.

Servicio de Rehabilitación, Hospital Universitario Fundación Jiménez Díaz, Madrid, España.

Introduction: Idiopathic toe-walking (ITW) is described as a gait pattern with no contact between the heels and the ground in children older than 3years. The diagnosis is clinical, making it necessary to rule out other neurological and orthopaedic conditions. A relationship between ITW and vestibular dysfunction and/or proprioceptive sensibility has been proposed. Children with neurodevelopmental disorders (autism, language and cognitive disorders) often have ITW.

Objectives: To determine the frequency of ITW in children with attention deficit disorder and hyperactivity (ADHD).

Patients And Method: A study was conducted on children diagnosed with ADHD, with normal neurological examination, with no alterations in MRI scan, cognitive disorder or autism. A complete clinical anamnesis was performed and Achilles shortening was measured with a goniometer.

Results: The study included 312 children with a mean age of 11 years (73.7% boys). The ADHD combined subtype was the most frequent (53.8%), followed by the inattentive (44.9%), and hyperactive (1.3%). ITW was observed in 20.8% of patients, particularly in the combined subtype (P=.054). Only 32 of them (49.2%) had Achilles shortening. ITW was associated with sociability disorders (P=.01), absence of pain in legs (P=.022), and family history of ITW (P=.004). Only 11% had previously visited a doctor for this reason.

Conclusions: As in other neurodevelopmental disorders, children with ADHD have frequently more ITW and Achilles shortening than controls, especially if they presented with a social communication disorder or a family history of ITW. An early diagnosis is essential to establish effective treatments.
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http://dx.doi.org/10.1016/j.anpedi.2017.01.010DOI Listing
April 2018

[Insomnia in children and adolescents. A consensus document].

An Pediatr (Barc) 2017 Mar 28;86(3):165.e1-165.e11. Epub 2016 Jul 28.

Laboratorio de Cronobiología, Universidad de Murcia, Murcia, España.

Insomnia is very common during childhood (30% of children under 5), and causes a serious cognitive and emotional consequence in learning, as well as significant medical comorbidity. It also affects the quality of life, not only of the child, but also of the whole family. Paediatrician training in its diagnosis and treatment is usually poor. For this reason a consensus document is presented on the management of insomnia in children and adolescents. This has been developed by members of the Spanish Paediatrics Association, the Spanish Sleep Society, the Spanish Society of Paediatric Outpatient and Primary Care, the Spanish Adolescent Medicine Society, the Spanish Child and Adolescent Society, and the Spanish Paediatric Neurology Society. The group suggests that diagnosis must be clinical and complementary tests will only be required in doubtful cases or when a differential diagnosis is needed. Likewise, treatment should be mainly based on cognitive-behavioural therapy and the modification of sleeping habits. Using medicines and other substances to make the sleep easier is currently quite common, even although there are no clinical guidelines to support this.
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http://dx.doi.org/10.1016/j.anpedi.2016.06.005DOI Listing
March 2017

[The importance of sleep problems in children with headache and other neurodevelopmental disorders in neuropaediatric services].

Rev Neurol 2016 Jan;62(2):61-7

UAM. Universidad Autonoma de Madrid. Hospital Universitario La Paz, 28046 Madrid, Espana.

Introduction: Sleep disorders are common in children with neurological disorders. The aim of this study is to know the opinion of neuropediatricians and the prevalence of these disturbances in Spain.

Patients And Methods: Multicenter cross-sectional study (12 Spanish hospitals, 15 researchers). BEARS survey was collected in three groups: A (2-5 years), (6-12 years), and C (> 12 years). The opinion of neuropediatricians was also collected.

Results: 939 questionnaires were filled. The main results in groups B and C were ADHD (32.4% and 30.1% respectively) and headache (25.1% and 27.6% respectively), whereas in group A neurodevelopmental disorders (32.4%) and epilepsy (21.4%) were the main diagnoses. Disturbances in at least one area of sleep were found in 92% of children in group A (n = 209, mean 3 years), 64.2% in group B (n = 534, mean 9.4 years) and 58.2% in group C (n = 196, mean 13.7 years). Sixty-one surveys were answered by neuropediatricians (16.75% of the total sent), estimating that less than a quarter of the patients (24.5%) suffered. Even, up to 23% of doctors claimed that the prevalence of sleep disorders was < 10%.

Conclusions: 58-92% of parents-patients under follow up at a neuropediatrician office in Spain have some degree of disturbed sleep. Although most neurologists emphasize the importance of an early diagnosis and treatment of sleep disorders in children with neurological disorders, its frequency is often underestimated (risk of underdiagnosis).
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January 2016

Attention deficit hyperactivity disorder: genetic association study in a cohort of Spanish children.

Behav Brain Funct 2016 Jan 8;12(1). Epub 2016 Jan 8.

Department of Genetics, IIS-Fundación Jiménez Díaz University Hospital (IIS-FJD, UAM), Avda. Reyes Católicos 2, 28040, Madrid, Spain.

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 models.
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http://dx.doi.org/10.1186/s12993-015-0084-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4706690PMC
January 2016

[Analysis of a series of cases with an initial diagnosis of acute disseminated encephalomyelitis over the period 2000-2010].

Rev Neurol 2013 Oct;57(7):297-305

Hospital Infantil Universitario Nino Jesus, 28009 Madrid, Espana.

Introduction: Acute disseminated encephalomyelitis (ADEM) is a demyelinating disease that essentially affects the white matter of the central nervous system. The diagnosis is based on clinical-imaging and developmental findings. Magnetic resonance imaging of the brain is the most useful diagnostic tool. The disease course is usually monophasic and the preferred initial treatment is with corticoids.

Patients And Methods: We conducted a retrospective study of 18 patients with a presumptive diagnosis of ADEM. Symptoms, imaging findings, progress and treatment were analysed. The definitive diagnosis was established in 12 patients, excluding one patient with positive polymerase chain reaction for herpes simplex virus in cerebrospinal fluid, one with a clinical picture that was consistent but normal magnetic resonance imaging of the brain, and four with an onset that was similar to ADEM whose definitive diagnoses were: Rassmusen's syndrome, haemophagocytic syndrome, brain tumour, and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes).

Results: The median age was 31 months with no predominance of either sex. Infection of the upper respiratory tract was the most frequent cause in children over 2 years of age and of the gastrointestinal tract in those under the age of 2. All of them presented altered levels of consciousness and multifocal neurological deficits. The most frequent imaging finding was multifocal alteration of the white matter in both hemispheres. Corticoids were the preferred treatment in most cases. Progression was favourable in nearly all patients except for two, who were left with important sequelae.

Conclusions: ADEM may present at any age, including in infants. There are a number of conditions that can mimic ADEM in the early stages.
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October 2013