Advancing the Understanding of Vesicle-Associated Membrane Protein 1-Related Congenital Myasthenic Syndrome: Phenotypic Insights, Favorable Response to 3,4-Diaminopyridine, and Clinical Characterization of Five New Cases.

BACKGROUND: Congenital myasthenic syndromes (CMS) are a group of inherited neuromuscular junction (NMJ) disorders arising from gene variants encoding diverse NMJ proteins. Recently, the VAMP1 gene, responsible for encoding the vesicle-associated membrane protein 1 (VAMP1), has been associated with CMS. METHODS: This study presents a characterization of five new individuals with VAMP1-related CMS, providing insights into the phenotype. RESULTS: The individuals with VAMP1-related CMS exhibited early disease onset, presenting symptoms prenatally or during the neonatal period, alongside severe respiratory involvement and feeding difficulties. Generalized weakness at birth was a common feature, and none of the individuals achieved independent walking ability. Notably, all cases exhibited scoliosis. The clinical course remained stable, without typical exacerbations seen in other CMS types. The response to anticholinesterase inhibitors and salbutamol was only partial, but the addition of 3,4-diaminopyridine (3,4-DAP) led to significant and substantial improvements, suggesting therapeutic benefits of 3,4-DAP for managing VAMP1-related CMS symptoms. Noteworthy is the identification of the VAMP1 (NM_014231.5): c.340delA; p.Ile114SerfsTer72 as a founder variant in the Iberian Peninsula and Latin America. CONCLUSIONS: This study contributes valuable insights into VAMP1-related CMS, emphasizing their early onset, arthrogryposis, facial and generalized weakness, respiratory involvement, and feeding difficulties. Furthermore, the potential efficacy of 3,4-DAP as a useful therapeutic option warrants further exploration. The findings have implications for clinical management and genetic counseling in affected individuals. Additional research is necessary to elucidate the long-term outcomes of VAMP1-related CMS.

Genética del TDAH en la práctica clínica / Genetics of ADHD in clinical practice

Resumen El trastorno por déficit de atención/hiperactividad (TDAH) es un trastorno del neurodesarrollo complejo y heterogéneo desde una perspectiva causal, clínica y pro nóstica. La investigación refleja su carácter multifactorial con un papel destacado de los factores genéticos. Los estudios poblacionales han señalado históricamente la implicación de numerosas variantes genéticas de escaso tamaño de efecto, las cuales por sí mismas apenas incre mentan el riesgo de TDAH y difícilmente justifican su ele vada heredabilidad. Muchas de ellas están presentes en más del 60% de la población general, lo que sugiere su pa pel modulador más que causal. No obstante, gracias a la irrupción de nuevas técnicas genéticas en los últimos 15 años, se están identificando un mayor número de casos con trastornos genéticos (muchos de ellos monogénicos), cuyas variantes genéticas explican por sí mismas la presencia del TDAH. El estudio detallado de los antecedentes personales y familiares, así como una exploración física completa, puede ayudar a identificar algunos de ellos. La identificación de la causa en este conjunto de casos tiene un valor crucial en el asesoramiento clínico, el consejo genético-familiar y la anticipación pronóstica, así como en la realización o evitación de estudios complementarios y en el diseño del plan terapéutico.

Abstract Attention-deficit/hyperactivity disorder (ADHD) is a complex and heterogeneous neurodevelopmental disor der from a causal, clinical and prognostic perspective. Research reflects its multifactorial nature with a promi nent role of genetic factors. Population studies have historically pointed to the involvement of numerous genetic variants of small effect size, which hardly by themselves increase the risk of presenting the disorder and hardly justify its high heritability. Many of them are present in more than 60% of the general population, suggesting their modulatory rather than causal role. However, after the irruption of new genetic techniques in the last 15 years, a greater number of cases are be ing identified with genetic disorders (many of them monogenic), whose genetic variants alone explain the presence of ADHD. A detailed study of the personal and family history, as well as a complete physical examination, can help to identify some of them. The identification of the cause in this group of cases has a crucial value in clinical counseling, genetic-familial counseling and prognostic anticipation, as well as in the performance or avoidance of complementary stud ies and in the design of the intervention plan.

[Genetics of ADHD in clinical practice]. / Genética del TDAH en la práctica clínica.

Attention-deficit/hyperactivity disorder (ADHD) is a complex and heterogeneous neurodevelopmental disorder from a causal, clinical and prognostic perspective. Research reflects its multifactorial nature with a prominent role of genetic factors. Population studies have historically pointed to the involvement of numerous genetic variants of small effect size, which hardly by themselves increase the risk of presenting the disorder and hardly justify its high heritability. Many of them are present in more than 60% of the general population, suggesting their modulatory rather than causal role. However, after the irruption of new genetic techniques in the last 15 years, a greater number of cases are being identified with genetic disorders (many of them monogenic), whose genetic variants alone explain the presence of ADHD. A detailed study of the personal and family history, as well as a complete physical examination, can help to identify some of them. The identification of the cause in this group of cases has a crucial value in clinical counseling, genetic-familial counseling and prognostic anticipation, as well as in the performance or avoidance of complementary studies and in the design of the intervention plan.

El trastorno por déficit de atención/hiperactividad (TDAH) es un trastorno del neurodesarrollo complejo y heterogéneo desde una perspectiva causal, clínica y pronóstica. La investigación refleja su carácter multifactorial con un papel destacado de los factores genéticos. Los estudios poblacionales han señalado históricamente la implicación de numerosas variantes genéticas de escaso tamaño de efecto, las cuales por sí mismas apenas incrementan el riesgo de TDAH y difícilmente justifican su elevada heredabilidad. Muchas de ellas están presentes en más del 60% de la población general, lo que sugiere su papel modulador más que causal. No obstante, gracias a la irrupción de nuevas técnicas genéticas en los últimos 15 años, se están identificando un mayor número de casos con trastornos genéticos (muchos de ellos monogénicos), cuyas variantes genéticas explican por sí mismas la presencia del TDAH. El estudio detallado de los antecedentes personales y familiares, así como una exploración física completa, puede ayudar a identificar algunos de ellos. La identificación de la causa en este conjunto de casos tiene un valor crucial en el asesoramiento clínico, el consejo genético-familiar y la anticipación pronóstica, así como en la realización o evitación de estudios complementarios y en el diseño del plan terapéutico.

Tatton-Brown-Rahman syndrome: Novel pathogenic variants and new neuroimaging findings.

Tatton-Brown-Rahman syndrome (TBRS) or DNMT3A-overgrowth syndrome is characterized by overgrowth and intellectual disability associated with minor dysmorphic features, obesity, and behavioral problems. It is caused by variants of the DNMT3A gene. We report four patients with this syndrome due to de novo DNMT3A pathogenic variants, contributing to a deeper understanding of the genetic basis and pathophysiology of this autosomal dominant syndrome. Clinical and magnetic resonance imaging assessments were also performed. All patients showed corpus callosum anomalies, small posterior fossa, and a deep left Sylvian fissure; as well as asymmetry of the uncinate and arcuate fascicles and marked increased cortical thickness. These results suggest that structural neuroimaging anomalies have been previously overlooked, where corpus callosum and brain tract alterations might be unrecognized neuroimaging traits of TBRS syndrome caused by DNMT3A variants.

Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition.

Pathogenic variants in ATP-dependent chromatin remodeling proteins are a recurrent cause of neurodevelopmental disorders (NDDs). The NURF complex consists of BPTF and either the SNF2H (SMARCA5) or SNF2L (SMARCA1) ISWI-chromatin remodeling enzyme. Pathogenic variants in BPTF and SMARCA5 were previously implicated in NDDs. Here, we describe 40 individuals from 30 families with de novo or maternally inherited pathogenic variants in SMARCA1. This novel NDD was associated with mild to severe ID/DD, delayed or regressive speech development, and some recurrent facial dysmorphisms. Individuals carrying SMARCA1 loss-of-function variants exhibited a mild genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using Smarca1, Smarca5, and Bptfsingle and double mouse knockouts revealed the importance of NURF composition and dosage for proper forebrain development. Finally, we propose that genetic alterations affecting different NURF components result in a NDD with a broad clinical spectrum.

CDKL5 Deficiency Disorder Without Epilepsy.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) has epilepsy as a cardinal feature. Here we report two new female patients and review six previously published patients, one male and five females, with features of CDD but who never developed epilepsy. In contrast with the classical and severe CDD phenotype, they presented with milder gross motor delays, autism spectrum disorder, and no visual cortical impairment. Prolonged video electroencephalography was normal in adult cases but showed interictal frontal-temporal bilateral spikes and sharp waves in sleep in the three-year-old girl. Causative CDKL5 variants included two likely gene damaging (nonsense and frameshift) and six missense variants, being de novo or maternally inherited from asymptomatic females with skewed X-chromosome inactivation (two missense variants). Our data indicate that a milder form of CDD without epilepsy can occur in some cases without clear correlation with specific variants in the CDKL5 gene.

El impacto del TDAH sobre la lectura / The impact of ADHD on reading

Resumen Más allá de la frecuente coexistencia del trastorno por déficit de atención con hiperactividad (TDAH) y el trastorno específico del aprendizaje de la lectura, la presente revisión pretende examinar la evidencia empírica disponible sobre cómo el TDAH impacta negativamente sobre el aprendizaje de la lectura. Los datos existentes apuntan a que la presencia del trastorno (especialmente los síntomas de falta de atención), puede afectar a i) la correcta adquisición de lectura, ya sea de manera directa o a través de su influencia sobre los precursores de la lectura; ii) las propias habilidades de decodificación (precisión y fluidez lectora), tanto de manera directa como indirecta a través de su influencia sobre procesos cognitivos como la distracción o las funciones ejecutivas; y ii) la comprensión lectora, probablemente de manera indirecta por las dificultades eje cutivas y en la memoria de trabajo verbal características del TDAH. Estas conclusiones presentan importantes implicaciones para caracterizar e intervenir mejor sobre las dificultades lectoras en el TDAH, ya sean clínicas o subclínicas.

Abstract Beyond the frequent coexistence of attention deficit hyperactivity disorder (ADHD) and reading dis order (dyslexia), the present review aims to examine the available empirical evidence on how ADHD negatively impacts on learning to read. Existing data suggest that the presence of the disorder (especially inattention symp toms), may affect i) the correct acquisition of reading, either directly or through its influence on the precursors to reading; ii) decoding skills themselves (reading accuracy and fluency), both directly and indirectly through its influence on cognitive processes such as distractibility or executive functions; and iii) reading comprehension, probably indirectly through the executive and verbal memory difficulties characteristic of ADHD. These findings have important implications for better characterizing and intervening on reading difficulties in ADHD, whether clinical or subclinical.

[The impact of ADHD on reading]. / El impacto del TDAH sobre la lectura.

Beyond the frequent coexistence of attention deficit hyperactivity disorder (ADHD) and reading disorder (dyslexia), the present review aims to examine the available empirical evidence on how ADHD negatively impacts on learning to read. Existing data suggest that the presence of the disorder (especially inattention symptoms), may affect i) the correct acquisition of reading, either directly or through its influence on the precursors to reading; ii) decoding skills themselves (reading accuracy and fluency), both directly and indirectly through its influence on cognitive processes such as distractibility or executive functions; and iii) reading comprehension, probably indirectly through the executive and verbal memory difficulties characteristic of ADHD. These findings have important implications for better characterizing and intervening on reading difficulties in ADHD, whether clinical or subclinical.

Más allá de la frecuente coexistencia del trastorno por déficit de atención con hiperactividad (TDAH) y el trastorno específico del aprendizaje de la lectura, la presente revisión pretende examinar la evidencia empírica disponible sobre cómo el TDAH impacta negativamente sobre el aprendizaje de la lectura. Los datos existentes apuntan a que la presencia del trastorno (especialmente los síntomas de falta de atención), puede afectar a i) la correcta adquisición de lectura, ya sea de manera directa o a través de su influencia sobre los precursores de la lectura; ii) las propias habilidades de decodificación (precisión y fluidez lectora), tanto de manera directa como indirecta a través de su influencia sobre procesos cognitivos como la distracción o las funciones ejecutivas; y ii) la comprensión lectora, probablemente de manera indirecta por las dificultades ejecutivas y en la memoria de trabajo verbal características del TDAH. Estas conclusiones presentan importantes implicaciones para caracterizar e intervenir mejor sobre las dificultades lectoras en el TDAH, ya sean clínicas o subclínicas.

Bi-Allelic c.1746G>T; p.Leu582= Variants in TUBGCP4 in a Boy with Autism: Clinical Data and Literature Review.

Bi-allelic mutations in the TUBGCP4 gene have been recently associated with autosomal recessive microcephaly with chorioretinopathy. However, little is known about the genotype-phenotype characteristics of this disorder. Here, we describe a 5-year-old male patient with autism and a normal occipitofrontal circumference. No retinal abnormalities were observed. Brain MRI revealed the presence of enlarged sheaths of both tortuous optic nerves; both eyes had shorter axial lengths. Whole-exome sequencing in trio revealed synonymous TUBGCP4 variants in homozygous state: c.1746G>T; p.Leu582=. This synonymous variant has been previously described and probably leads to skipping of exon 16 of TUBGCP4. These results broaden the clinical spectrum of this new syndrome and suggest that TUBGCP4 bi-allelic mutations may underlie complex neurodevelopmental disorders.

Mutations in the COL18A1 gen associated with knobloch syndrome and structural brain anomalies: a novel case report and literature review of neuroimaging findings.

. COL18A1 gene mutations have been associated with Knobloch syndrome, which is characterized by ocular and brain abnormalities. Here we report a 4.5 years-old male child with autism and two novel COL18A1 mutations (NM_030582.4: c.1883_1891dup and c.1787C>T). Hypermetropic astigmatism, but not brain migration disorders, was observed. However, an asymmetric pattern of cerebellar perfusion and a smaller arcuate fascicle were found.  Low levels of collagen XVIII were also observed in the patient´s serum. Thus, biallelic loss-of-function mutations in COL18A1 may be a new cause of autism  without the brain malformations typically reported in patients with Knobloch syndrome.

Déficits neuropsicológicos, intensidad sintomática y repercusión funcional en el trastorno por déficit de atención con hiperactividad / Neuropsychological deficits, symptom intensity and functional impairment in attention deficit hyperactivity disorder

Resumen Este estudio pretende contribuir a una mejor comprensión del trastorno por déficit de atención con hiperactividad (TDAH) examinado de manera exhaustiva la relación entre dos de los principales déficits cognitivos del trastorno (la atención y el control inhibitorio), la sintomatología (falta de atención e hipe ractividad/impulsividad) y la repercusión funcional en 85 niños/as y adolescentes con TDAH sin otros trastornos comórbidos. Encontramos, con independencia del funcionamiento intelectual general y de la edad, que i) un mayor déficit atencional e inhibitorio, predijo una mayor gravedad de los síntomas del TDAH, ii) un mayor déficit atencional e inhibitorio predijo un mayor deterioro funcional, pero no de una manera directa sino a través de los síntomas, y iii) una mayor severidad sintomática predijo una mayor repercusión funcional. Comenzar a explorar y comprender la complejidad del TDAH es clave para avanzar en nuestro conocimiento del trastorno y para la correcta toma de decisiones clínicas.

Abstract This study aims to contribute to a better understanding of at tention deficit hyperactivity disorder (ADHD) by comprehensively examining the relationship between two of the main cognitive deficits of the disorder (attention and inhibitory control), symptomatology (inattention and hyperactivity/impulsivity) and functional impairment in 85 children and adolescents with ADHD without other comorbid disorders. We found, independent of general intellectual functioning and age, that i) greater atten tional and inhibitory deficits predicted greater severity of ADHD symptoms, ii) greater attentional and inhibitory deficits predicted greater functional impairment, but not in a direct way but through symptoms, and iii) greater symptomatic severity predicted greater functional impairment. Beginning to explore and understand the com plexity of ADHD is key to advance our knowledge of the disorder and for correct clinical decision making.

[Neuropsychological deficit, symptom intensity and functional impairment in attention deficit hyperactivity disorder]. / Déficits neuropsicológicos, intensidad sintomática y repercusión funcional en el trastorno por déficit de atención con hiperactividad.

This study aims to contribute to a better understanding of attention deficit hyperactivity disorder (ADHD) by comprehensively examining the relationship between two of the main cognitive deficits of the disorder (attention and inhibitory control), symptomatology (inattention and hyperactivity/impulsivity) and functional impairment in 85 children and adolescents with ADHD without other comorbid disorders. We found, independent of general intellectual functioning and age, that i) greater attentional and inhibitory deficits predicted greater severity of ADHD symptoms, ii) greater attentional and inhibitory deficits predicted greater functional impairment, but not in a direct way but through symptoms, and iii) greater symptomatic severity predicted greater functional impairment. Beginning to explore and understand the complexity of ADHD is key to advance our knowledge of the disorder and for correct clinical decision making.

Este estudio pretende contribuir a una mejor comprensión del trastorno por déficit de atención con hiperactividad (TDAH) examinado de manera exhaustiva la relación entre dos de los principales déficits cognitivos del trastorno (la atención y el control inhibitorio), la sintomatología (falta de atención e hiperactividad / impulsividad) y la repercusión funcional en 85 niños/as y adolescentes con TDAH sin otros trastornos comórbidos. Encontramos, con independencia del funcionamiento intelectual general y de la edad, que i) un mayor déficit atencional e inhibitorio, predijo una mayor gravedad de los síntomas del TDAH, ii) un mayor déficit atencional e inhibitorio predijo un mayor deterioro funcional, pero no de una manera directa sino a través de los síntomas, y iii) una mayor severidad sintomática predijo una mayor repercusión funcional. Comenzar a explorar y comprender la complejidad del TDAH es clave para avanzar en nuestro conocimiento del trastorno y para la correcta toma de decisiones clínicas.

A mild clinical and neuropsychological phenotype of Renpenning syndrome: A new case report with a maternally inherited PQBP1 missense mutation.

Mutations in the PQBP1 gene are associated with Renpenning syndrome (RENS1, MIM# 309500). Most cases are characterized by intellectual disability, but a detailed neuropsychological profile has not yet been established. The present case study of a 8.5 years-old male child with a missense novel mutation in the PQBP1 gene expands existing understanding of this syndrome by presenting a milder clinical and neuropsychological phenotype. Whole exome trio analysis sequencing revealed a maternally inherited PQBP1 missense mutation in chromosome X [NM_001032383.1, c.727C > T (p.Arg243Trp)]. Variant functional studies demonstrated a significant reduction in the interaction between PQBP1 and the component of the nuclear pre-mRNA splicing machinery, U5-15KD. A comprehensive neuropsychological assessment revealed marked deficits in processing speed, attention and executive functioning (including planning, inhibitory control and working memory) without intellectual disability. Several components of language processing were also impaired. These results support that this mutation partially disrupts the function of this gene, which is known to play critical roles in embryonic and neural development. As most of the genomic PQBP1 abnormalities associated with intellectual disability have been found to be loss-of-function mutations, we hypothesize that a partial loss-of-function of this variant is associated with a mild behavioral and neuropsychological phenotype.

Biallelic ELMO3 mutations and loss of function for DOCK-mediated RAC1 activation result in intellectual disability.

The engulfment and cell motility 3 (ELMO3) protein belongs to the ELMO-family of proteins. ELMO proteins form a tight complex with the DOCK1-5 guanine nucleotide exchange factors that regulate RAC1 spatiotemporal activation and signalling. DOCK proteins and RAC1 are known to have fundamental roles in central nervous system development. Here, we searched for homozygous or compound heterozygous mutations in the ELMO3 gene in 390 whole exomes sequenced in trio in individuals with neurodevelopmental disorders compatible with a genetic origin. We found a compound heterozygous mutation in ELMO3 (c.1153A>T, p.Ser385Cys and c.1009 G > A, p.Val337Ile) in a 5 year old male child with autism spectrum disorder (ASD) and developmental delay. These mutations did not interfere with the formation of an ELMO3/DOCK1 complex, but markedly impaired the ability of the complex to promote RAC1-GTP-loading. Consequently, cells expressing DOCK1 and either of the ELMO3 mutants displayed impaired migration and invasion. Collectively, our results suggest that biallelic loss-of-function mutations in ELMO3 may cause a developmental delay and provide new insight into the role of ELMO3 in neurodevelopmental as well as the pathological consequences of ELMO3 mutations.

Biallelic SYNE2 Missense Mutations Leading to Nesprin-2 Giant Hypo-Expression Are Associated with Intellectual Disability and Autism.

Autism spectrum disorder (ASD) is a group of neurological and developmental disabilities characterised by clinical and genetic heterogeneity. The current study aimed to expand ASD genotyping by investigating potential associations with SYNE2 mutations. Specifically, the disease-causing variants of SYNE2 in 410 trios manifesting neurodevelopmental disorders using whole-exome sequencing were explored. The consequences of the identified variants were studied at the transcript level using quantitative polymerase chain reaction (qPCR). For validation, immunofluorescence and immunoblotting were performed to analyse mutational effects at the protein level. The compound heterozygous variants of SYNE2 (NM_182914.3:c.2483T>G; p.(Val828Gly) and NM_182914.3:c.2362G>A; p.(Glu788Lys)) were identified in a 4.5-year-old male, clinically diagnosed with autism spectrum disorder, developmental delay and intellectual disability. Both variants reside within the nesprin-2 giant spectrin repeat (SR5) domain and are predicted to be highly damaging using in silico tools. Specifically, a significant reduction of nesprin-2 giant protein levels is revealed in patient cells. SYNE2 transcription and the nuclear envelope localisation of the mutant proteins was however unaffected as compared to parental control cells. Collectively, these data provide novel insights into the cardinal role of the nesprin-2 giant in neurodevelopment and suggest that the biallelic hypomorphic SYNE2 mutations may be a new cause of intellectual disability and ASD.

Abnormal frontal gyrification pattern and uncinate development in patients with KBG syndrome caused by ANKRD11 aberrations.

KBG syndrome is characterized by dental, craniofacial and skeletal anomalies, short stature and global developmental delay or intellectual disability. It is caused by microdeletions or truncating mutations of ANKRD11. We report four unrelated probands with this syndrome due to de novo ANKRD11 aberrations that may contribute to a better understanding of the genetics and pathophysiology of this autosomal dominant syndrome. Clinical, cognitive and MRI assessments were performed. Three of the patients showed normal intellectual functioning, whereas the fourth had a borderline level of intellectual functioning. However, all of them showed deficits in various cognitive and socioemotional processes such as attention, executive functions, empathy or pragmatic language. Moreover, all probands displayed marked asymmetry of the uncinate fascicles and an abnormal gyrification pattern in the left frontal lobe. Thus, structural neuroimaging anomalies seem to have been overlooked in this syndrome. Disturbed frontal gyrification and/or lower structural integrity of the uncinate fascisulus might be unrecognized neuroimaging features of KBG syndrome caused by ANKRD11 aberrations. Present results also point out that this syndrome is not necessarily associated with global developmental delay and intellectual disability, but it can be related to other neurodevelopmental disorders or subclinical levels of attention-deficit hyperactivity disorder, autism, communication disorders or specific learning disabilities.

ANO3 and early-onset dyskinetic encephalopathy.

Mutations in the ANO3 gene have been associated with autosomal dominant craniocervical dystonia. However, little else is known about the genotype-phenotype characteristics of this disorder. Here we describe a 3 years-old girl with distal myoclonic dystonia. Whole exome sequencing in trio revealed a de novo missense ANO3 variant not previously described in international databases. A global psychomotor regression was observed once dystonia was present. Brain MRI changes paralleled these findings: whereas MRI at the age of 18 months was normal, mild brain and cerebellar atrophy was observed 18 months later. These results suggest that missense mutations in ANO3 may underlie complex disorders particularly characterized by early psychomotor regression and dystonia.

[Genetic studies and neurodevelopment. From effectiveness to genetic models]. / Estudios genéticos y neurodesarrollo. De la utilidad al modelo genético.

Advances in genetics have been able to support the clinical suspicion on the large hereditary component of most of these neurodevelopmental disorders (NDD). Initial studies on heritability, linkage or association showed from the beginning the great contribution of genotypic variation to the clinic in general, and to NDD in particular. The effectiveness of genetic studies in clinical practice, targeted to aetiological diagnosis, should not be ignored. Most of these are protocolized in the study of disorders such as intellectual disability and autism; within these, the array comparative genomic hybridization have supported a greater diagnostic effectiveness with respect to historical cytogenetic techniques (3 vs. 10% respectively). However, the irruption and success of molecular genetic sequencing techniques, particularly the exome and genome in trio, analyzing the parents (diagnostic rates of 30-50%), are conditioning the modification of the genetic algorithms in the diagnosis of different NDD. The greater knowledge of causal variants in intellectual disability and autism is also modifying the polygenic theoretical models established to date.

Los avances en la genética han podido apoyar la sospecha que aportaba la experiencia clínica sobre el gran componente hereditario de la mayor parte de estos trastornos del neurodesarrollo (TND). Los estudios iniciales de heredabilidad, ligamiento o asociación evidenciaron desde los inicios la gran contribución de la variación genotípica a la clínica en general, y a los TND en particular. No debe obviarse la utilidad de los estudios genéticos en el ejercicio clínico, encaminados al diagnóstico etiológico. La mayor parte de los mismos están protocolizados en el estudio de trastornos como la discapacidad intelectual y el autismo; dentro de éstos, la hibridación por arrays cromosómicos ha aportado una mayor rentabilidad diagnóstica respecto a técnicas citogenéticas históricas (3 vs. 10% respectivamente). Sin embargo, la irrupción y rentabilidad de técnicas de genética molecular por secuenciación, particularmente la exómica y genómica en trío, analizando a padres, (tasas diagnósticas del 30-50%), están condicionando la modificación de los algoritmos genéticos en el diagnóstico de trastornos graves del neurodesarrollo. El mayor conocimiento de variantes causales de discapacidad intelectual y autismo está igualmente modificando los modelos teóricos poligénicos establecidos hasta la fecha.

Estudios genéticos y neurodesarrollo: De la utilidad al modelo genético / Genetic studies and neurodevelopment. From effectiveness to genetic models]

Los avances en la genética han podido apoyar la sospecha que aportaba la experiencia clínica sobre el gran componente hereditario de la mayor parte de estos trastornos del neurodesarrollo (TND). Los estudios iniciales de heredabilidad, ligamiento o asociación evidenciaron desde los inicios la gran contribución de la variación genotípica a la clínica en general, y a los TND en particular. No debe obviarse la utilidad de los estudios genéticos en el ejercicio clínico, encaminados al diagnóstico etiológico. La mayor parte de los mismos están protocolizados en el estudio de trastornos como la discapacidad intelectual y el autismo; dentro de éstos, la hibridación por arrays cromosómicos ha aportado una mayor rentabilidad diagnóstica respecto a técnicas citogenéticas históricas (3 vs. 10% respectivamente). Sin embargo, la irrupción y rentabilidad de técnicas de genética molecular por secuenciación, particularmente la exómica y genómica en trío, analizando a padres, (tasas diagnósticas del 30-50%), están condicionando la modificación de los algoritmos genéticos en el diagnóstico de trastornos graves del neurodesarrollo. El mayor conocimiento de variantes causales de discapacidad intelectual y autismo está igualmente modificando los modelos teóricos poligénicos establecidos hasta la fecha.

Advances in genetics have been able to support the clinical suspicion on the large hereditary component of most of these neurodevelopmental disorders (NDD). Initial studies on heritability, linkage or association showed from the beginning the great contribution of genotypic variation to the clinic in general, and to NDD in particular. The effectiveness of genetic studies in clinical practice, targeted to aetiological diagnosis, should not be ignored. Most of these are protocolized in the study of disorders such as intellectual disability and autism; within these, the array comparative genomic hybridization have supported a greater diagnostic effectiveness with respect to historical cytogenetic techniques (3 vs. 10% respectively). However, the irruption and success of molecular genetic sequencing techniques, particularly the exome and genome in trio, analyzing the parents (diagnostic rates of 30-50%), are conditioning the modification of the genetic algorithms in the diagnosis of different NDD. The greater knowledge of causal variants in intellectual disability and autism is also modifying the polygenic theoretical models established to date.

Attention-deficit/hyperactivity disorder and lifestyle habits in children and adolescents.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent disorders in the child and adolescent population, with a known impact on learning, social relations and quality of life. However, the lifestyle habits of patients with this disorder have been poorly studied. MATERIAL AND METHODS: A total of 160 children and adolescents, aged between 6 and 16 years, participated in the study. Half of them were treatment-naïve patients with a clinical diagnosis of ADHD according to DSM-IV-TR criteria, and without comorbidities. The remaining 80 participants were typically developing (TD) controls without known neurodevelopmental or psychiatric disorders. Parents of all participants completed a questionnaire about their children´s lifestyle habits (e.g, daily hours of sleep, media use and study). RESULTS: The groups had a similar socioeconomic background and did not differ with respect to age and sex distribution. However, patients with ADHD spent more time than TD children studying, and less time watching TV, playing video games, using computers and playing with other people. They also slept fewer hours per night than children and adolescents with TD. ADHD and TD groups spent similar time reading, listening to music and playing sports. CONCLUSIONS: The results of this study suggest that children and adolescents with ADHD have different lifestyle habits compared to age- and sex-matched controls. These findings are not explained by comorbid disorders or medication/ psychological treatment.