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.

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.

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.

[Genetics applied to clinical practice in neurodevelopmental disorders]. / Genética aplicada a la práctica clínica en trastornos del neurodesarrollo.

The medical literature contains a wide body of evidence supporting genetic involvement in neurodevelopmental disorders. Advances made in genetics and technology have increased the diagnostic cost-effectiveness of current studies from 3-5% to 30-40% in patients with intellectual disability or autism spectrum disorders. In this regard, chromosomal microarray studies display greater diagnostic power than conventional techniques (karyotype, subtelomeric analyses, etc.). The latest protocols in the biomedical field of the genetic study of these disorders cite chromosomal microarrays as the first-line analysis, while also recommending other specific studies depending on the patient's clinical features (fragile X syndrome, PTEN mutation, etc.). In the evaluation of other neurodevelopmental disorders (attention deficit hyperactivity disorder, learning disorders, etc.), the number of genetic tests carried out is limited and conditioned by the clinical characteristics or the patient's familial or personal history. Even in these situations, there are no genetic referral or evaluation protocols.

TITLE: Genetica aplicada a la practica clinica en trastornos del neurodesarrollo.Las evidencias geneticas de los trastornos del neurodesarrollo estan ampliamente sustentadas en la literatura medica. Los avances en la genetica y la tecnologia han incrementado la rentabilidad diagnostica de los estudios actuales de un 3-5% a un 30-40% en los pacientes con discapacidad intelectual o trastornos del espectro autista. En este sentido, los estudios por microarrays cromosomicos muestran un mayor poder diagnostico que las tecnicas convencionales (cariotipo, analisis de subtelomeros…). Los protocolos mas recientes en el apartado biomedico del estudio genetico de estos trastornos situan los microarrays cromosomicos como analisis de primera linea, recomendando otros estudios especificos segun las caracteristicas clinicas del paciente (sindrome X fragil, mutacion en PTEN...). En la evaluacion de otros trastornos del neurodesarrollo (trastorno por deficit de atencion/hiperactividad, trastornos del aprendizaje...), la realizacion de pruebas geneticas esta limitada y condicionada a las caracteristicas clinicas o antecedentes familiares o personales del paciente; incluso en estas situaciones, no existen protocolos de evaluacion o derivacion genetica.

[Autism and attention deficit hyperactivity disorder: pharmacological intervention]. / Autismo y trastorno por déficit de atención/hiperactividad: intervención farmacológica.

The cardinal symptoms of attention deficit hyperactivity disorder (ADHD)--inattention, hyperactivity and impulsiveness--are not specific and may be found in the general population and in other disorders. These symptoms are present in over 50% of patients with autism spectrum disorders (ASD). It thus seems quite clear that both problems can coexist in these patients. The usual pharmacological treatments for ADHD, methylphenidate and atomoxetine, appear to be useful in reducing the above-mentioned symptoms in patients with ADHD and ASD. Effectiveness seems to be lower in patients with ASD and tolerance is slightly poorer. This may be conditioned by a number of variables, including: the complexity of ASD, association with mental retardation, polypharmacotherapy, and so on. Given the long-term tolerance profile of methylphenidate and atomoxetine, these treatments appear to be a good alternative with which to improve the problems of attention and self-control these patients have. Nevertheless, further controlled studies are needed to confirm this proposition.

TITLE: Autismo y trastorno por deficit de atencion/hiperactividad: intervencion farmacologica.Los sintomas cardinales del trastorno por deficit de atencion/hiperactividad (TDAH), la inatencion, la hiperactividad y la impulsividad, no son especificos y pueden encontrarse en la poblacion general y en otros trastornos. Estos sintomas se encuentran presentes en mas del 50% de los pacientes con trastornos del espectro autista (TEA). Parece clara, por tanto, la coexistencia de ambos problemas en estos pacientes. Los tratamientos farmacologicos habituales para el TDAH, el metilfenidato y la atomoxetina, parecen ser utiles en la reduccion de los sintomas senalados en pacientes con TDAH y TEA. La eficacia en los pacientes con TEA parece ser inferior, y la tolerancia, levemente peor. Esto puede estar condicionado por numerosas variables: complejidad del TEA, asociacion con el retraso mental, polifarmacoterapia... Dado el perfil de tolerancia a largo plazo del metilfenidato y la atomoxetina, estos tratamientos se muestran como una buena alternativa para la mejora de los problemas atencionales y autocontrol de estos pacientes; sin embargo, son necesarios mas estudios controlados para afirmar esta propuesta.

[From inattentive-type attention deficit hyperactivity disorder to the restrictive type]. / Trastorno por deficit de atencion/hiperactividad: del tipo inatento al tipo restrictivo.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a very heterogeneous neurobiological condition. It is the most common neurodevelopmental disorder in the childhood population. Its prevalence is estimated to be 3-6% in school-age children. AIM. To review the characteristics of patients with inattentive subtype ADHD, including those who could be grouped in a more homogenous subtype which the DSM-5 proposes for classification as the restrictive subtype. DEVELOPMENT: The characteristic triad of symptoms consists of attention deficit, hyperactivity and impulsivity. The diagnostic criteria are defined in the DSM-IV-TR. For those with deterioration due to ADHD with no significant hyperactivity problems, this manual offers a confusing diagnostic label. Indeed, the neurobiological substrate underlying the diverse subtypes seems to be different in certain aspects, since the frontostriatal circuit appears to be more affected in combined ADHD, while the frontoparietal circuit is more compromised in the inattentive subtype. For these and other reasons, the DSM-5 will reformulate the different subtypes of ADHD and will probably include a new subgroup that will comprise those patients who satisfy at least six inattention criteria and fewer than two criteria for hyperactivity-impulsivity (restrictive ADHD). CONCLUSIONS: The definition of this subgroup could make it easier to detect some patients who have so far received little attention from the point of view of both research and clinical practice.

Social and leadership abilities in attention deficit/hyperactivity disorder: relation with cognitive-attentional capacities.

OBJECTIVE: We have analyzed social and leadership abilities in children with ADHD and their relationship with execution of tasks involving sustained attention and inhibitory control. PATIENTS AND METHODS: A retrospective analysis of 170 patients with ADHD was performed. We evaluated leadership and social abilities, measured through the Behavior Assessment System for Children (BASC) and their relations with the results of different neuropsychological tests, including Wechsler scale for children (WISC-IV) and Conners' continuous performance (CPT II). RESULTS: In the differential analysis between the IQ, results of the tests and their relation to BASC scores, a statistically significant relation was observed between attentional capacity expected according to the patient's intelligence and social skills scores (according to BASC filled out by mothers and teachers) and leadership (according to all informants) sections. CONCLUSIONS: Attentional difficulties are closely related to social competence in patients with ADHD, either by a direct cause-effect relationship or a shared dysexecutive substrate of this disorder.

[Alcoholic foetopathy: an update]. / Fetopatia alcoholica: puesta al dia.

INTRODUCTION: In recent years a great deal of attention has been given to the role of prenatal exposure to alcohol in the production of a wide range of disorders known as foetal alcohol spectrum disorders (FASD). Foetal alcohol syndrome represents the classic syndrome and the most serious manifestation caused by the epigenetic changes induced by such exposure. It is considered to be the number one preventable cause of congenital defects and mental deficiency. AIM: To update the body of knowledge on this group of disorders by reviewing the most important aspects in terms of the epidemiology, diagnostic criteria and treatment, with special emphasis on the associated cognitive and behavioural alterations. DEVELOPMENT: The worldwide prevalence of alcohol spectrum disorders could be around 1%. Today there are a number of diagnostic systems available for FASD. The most commonly used are the diagnostic criteria of the Institute of Medicine. The cognitive and behavioural alterations cover a wide range of disorders that are associated to the psychosocial environment in which the child develops. The executive functions are usually found to be affected and most patients associate attention deficit hyperactivity disorder. Few studies have been conducted on the effectiveness of treatments such as methylphenidate or atomoxetine in this population. CONCLUSIONS: It is necessary to know the clinical, physical and cognitive manifestations of intrauterine exposure to alcohol. Likewise, randomised placebo-controlled randomised studies are needed to estimate the effectiveness of psychostimulants and atomoxetine in the treatment of these children.