A precision medication study of atomoxetine in children with attention deficit hyperactivity disorder: CYP2D6 genetic testing and therapeutic drug monitoring / 中国当代儿科杂志

Atomoxetine is the first non-stimulant drug for the treatment of children and adults with attention deficit hyperactivity disorder (ADHD), and its safety and efficacy show significant differences in the pediatric population. This article reviews the genetic factors influencing the pharmacokinetic differences of atomoxetine from the aspect of the gene polymorphisms of the major metabolizing enzyme CYP2D6 of atomoxetine, and then from the perspective of therapeutic drug monitoring, this article summarizes the reference ranges of the effective concentration of atomoxetine in children with ADHD proposed by several studies. In general, there is an association between the peak plasma concentration of atomoxetine and clinical efficacy, but with a lack of data from the Chinese pediatric population. Therefore, it is necessary to establish related clinical indicators for atomoxetine exposure, define the therapeutic exposure range of children with ADHD in China, and combine CYP2D6 genotyping to provide support for the precision medication of atomoxetine.

DRD4 genotyping may differentiate symptoms of attention-deficit/hyperactivity disorder and sluggish cognitive tempo

Objective: Studies to reduce the heterogeneity of attention-deficit/hyperactivity disorder (ADHD) have increased interest in the concept of sluggish cognitive tempo (SCT). The aim of this study was to investigate if the prevalence of two variable-number tandem repeats (VNTRs) located within the 3′-untranslated region of the DAT1 gene and in exon 3 of the dopamine D4 receptor (DRD4) gene differ among four groups (31 subjects with SCT but no ADHD, 146 individuals with ADHD but no SCT, 67 subjects with SCT + ADHD, and 92 healthy controls). Methods: We compared the sociodemographic profiles, neurocognitive domains, and prevalence of two VNTRs in SCT and ADHD subjects versus typically developing (TD) controls. Results: The SCT without ADHD group had a higher proportion of females and lower parental educational attainment. Subjects in this group performed worse on neuropsychological tests, except for psychomotor speed and commission errors, compared to controls. However, the ADHD without SCT group performed significantly worse on all neuropsychological domains than controls. We found that 4R homozygosity for the DRD4 gene was most prevalent in the ADHD without SCT group. The SCT without ADHD group had the highest 7R allele frequency, differing significantly from the ADHD without SCT group. Conclusion: The 7R allele of DRD4 gene was found to be significantly more prevalent in SCT cases than in ADHD cases. No substantial neuropsychological differences were found between SCT and ADHD subjects.

Síndrome X frágil: presentación clínica, patología y tratamiento / Fragile X syndrome: clinical presentation, pathology and treatment

Resumen El síndrome X frágil es la condición monogenética que produce más casos de autismo y de discapacidad intelectual. La repetición de tripletes CGG (> 200) y su metilación conllevan el silenciamiento del gen FMR1. La proteína FMRP (producto del gen FMR1) interacciona con los ribosomas, controlando la traducción de mensajeros específicos y su pérdida produce alteraciones de la conectividad sináptica. El tamizaje de síndrome X frágil se realiza por reacción en cadena de la polimerasa. La recomendación actual de la Academia Americana de Pediatría es realizar pruebas a quienes presenten discapacidad intelectual, retraso global del desarrollo o antecedentes familiares de afección por la mutación o premutación. Países hispanos como Colombia, Chile y España reportan altas prevalencias de síndrome X frágil y han creado asociaciones o corporaciones nacionales de X frágil que buscan acercar a los pacientes a redes disponibles de diagnóstico y tratamiento.

Abstract Fragile X syndrome is the monogenetic condition that produces more cases of autism and intellectual disability. The repetition of CGG triplets (> 200) and their methylation entail the silencing of the FMR1 gene. The FMRP protein (product of the FMR1 gene) interacts with ribosomes by controlling the translation of specific messengers, and its loss causes alterations in synaptic connectivity. Screening for fragile X syndrome is performed by polymerase chain reaction. Current recommendation of the American Academy of Pediatrics is to test individuals with intellectual disability, global developmental retardation or with a family history of presence of the mutation or premutation. Hispanic countries such as Colombia, Chile and Spain report high prevalence of fragile X syndrome and have created fragile X national associations or corporations that seek to bring patients closer to available diagnostic and treatment networks.

Sueño en los trastornos del neurodesarrollo, déficit de atención e hiperactividad y en el espectro autista / Sleep in neurodevelopmental disorders

El sueño es uno de los actos fisiológicos más importantes para la estructuración funcional y anatómica de áreas del sistema nervioso central. Las alteraciones del sueño durante la infancia y su relación con trastornos del neurodesarrollo es compleja y sumam ente interesante, donde destaca la multiplicidad de causas de estos trastornos. Bajo esta premisa se realiza una revisión sobre las alteraciones del sueño en los trastornos del neurodesarrollo (TND), por déficit de atención e hiperactividad (TDAH) y del espectro autista (TEA). El sueño está presente desde la etapa fetal y va modificando su expresión en sintonía con la madurez del sistema nervioso central. Los trastornos del sueño y su relación con TDAH, TEA y otros TND son complejos, pero existen avances sobre la etiología de los mismos. Una mayor compresión de las funciones pleiotrópicas de los genes implicados en los trastornos del ciclo vigilia-sueño y en las desviaciones del desarrollo neurológico podría conducir a nuevas estrategias diagnósticas y terapéuticas de manera precoz con el fin de mejorar la calidad de vida del paciente, familiares y cuidadores.

The development and establishment of the normal sleep patterns are very important processes in the final anatomical and physiological architecture of the central nervous system. The relationship between sleep disturbances during childhood with neurodevelopmental disorders is complex and potentially synergistic. Sleep patterns are present since the fetal period but their structure and physiology is modified according with the maturation of the central nervous system. Sleep disorders and their relationship with attention deficit hyperactivity disorders(ADHD), autism spectrum disorders(ASD) and other neurodevelopmental disorders (TDN) are not well understood yet, but significant progresses have been made in understanding associations and potential etiological correlations. We reviewed sleep disturbances in NDT, in ADHD and in ASD. A greater understanding of the pleiotropic functions of the genes involved in sleep-wake cycle disorders and deviations from neurological developme nt could lead to new diagnostic and therapeut ic strategies in an early stage in order to improve the quality of life of the patient, relatives and caregivers.

Trastorno del desarrollo intelectual: Superposiciones con el trastorno del espectro autista y el trastorno por déficit de atención e hiperactividad / Intellectual developmental disability overlapping with autism spectrum disorder and attention deficit-hyperactivity disorder

Nunca dejará de ser interesante y relevante el tema de las discapacidades que abarcan la cognición y la adaptabilidad. La etiología genética tiene cada día más peso. La relación con otros trastornos del neurodesarrollo como el trastorno del espectro autista (TEA) y el trastorno por déficit de atención e hiperactividad (TDAH), es de importancia clínica, diagnóstica y terapéutica. Realizamos una revisión sobre el trastorno del desarrollo intelectual (TDI) y su implicación con el TEA y el TDAH. Desde Hipócrates hasta la actualidad los trastornos que afectan las habilidades de aprendizaje, conducta y socialización han sido sujeto de estudios y han variado sobre todo en la denominación como entidad y su percepción desde el punto de vista humano y social. La etiología del TDI en la mayoría de los casos es un enigma y los avances genéticos son la piedra angular para dilucidar el origen de este trastorno del neurodesarrollo, así como su relación con otros como el TEA y el TDAH. El trastorno del desarrollo intelectual, el más antiguo con respecto a definición, estudio y abordaje, aún presenta incógnitas sobre todo de origen etiológico. Su relación con otros trastornos del neurodesarrollo como el TEA y el TDAH es evidente por poseer áreas comunes de afectación, pudiendo ser diagnósticos coincidentes.

The subject of disabilities that include cognition and adaptability will never cease to be interesting and relevant. The genetic etiology has more weight every day. The relationship with other neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) is of clinical, diagnostic and therapeutic importance. The objective was to conduct a review of intellectual development disorder and its implication with ASD and ADHD. From Hippocrates to the present the disorders that affect learning, behavior and socialization skills have been the subject of studies and have varied, above all, in the denomination as an entity and its perception from the human and social point of view. The etiology of intellectual development disorders in most cases is an enigma and genetic advances are the cornerstone to elucidate the origin of this neurodevelopmental disorder, as well as its relationship with others such as ASD and ADHD. The disorder of intellectual development, the oldest one with respect to definition, study and approach, still presents mysteries above all of etiological origin. Its relationship with other neurodevelopmental disorders such as ASD and ADHD is evident by having common areas of involvement, which may be coincident diagnoses.

Déficit atencional con hiperactividad: trastorno multicausal de la conducta, con heredabilidad y comorbilidad genética moderadas / Heritability and genetic comorbidity of attention deficit disorder with hyperactivity

This review aims to summarize information about the genetic etiology of attention deficit disorder with hyperactivity (ADHD), with particular reference to the contributions of our research group. We also discuss the genetic comorbidity estimated from genome-wide single nucleotide polymorphisms (SNP´s) between ADHD and major psychiatric disorders such as schizophrenia (E), major depressive disorder (MDD), bipolar disorder (BD) and autism spectrum disorders (ASD). A high genetic comorbidity was found between E and BD (46%), a moderate comorbidity between MDD and E, MDD and BD and MDD and ADHD (18%, 22% and 10% respectively) and a low comorbidity between E and ASD (2.5%). Furthermore, we show evidence concerning the genetic determination of psychiatric diseases, which is significantly lower when it is estimated from genome-wide SNP´s rather than using traditional quantitative genetic methodology (ADHD = E = 23%, BD = 25%, MDD = 21% and ASD = 17%). From an evolutionary perspective, we suggest that behavioral traits such as hyperactivity, inattention and impulsivity, which play a role in ADHD and perhaps also other hereditary traits which are part of major psychiatric disorders, could have had a high adaptive value during the early stages of the evolution of Homo sapiens. However, they became progressively less adaptive and definitively disadvantageous, to the extreme that they are involved in frequently diagnosed major psychiatric disorders.

Mortalidad infantil por malformaciones congénitas en Chile: análisis temporal y espacial, 1997-2011 / Infant mortality from congenital malformations in Chile: temporal and spatial analysis, 1997-2011

OBJETIVO:Analizar la distribución espacial y temporal (1997-2011) de la mortalidad infantil por malformaciones congénitas (MC) en Chile. MÉTODOS: Los datos de nacimientos y muertes en menores de 1 año de edad codificados con la CIE-10 se obtuvieron del Instituto Nacional de Estadísticas. Para las regiones administrativas y las naturales (Norte Grande, Norte Chico, Central, Austral y Sur), sistemas (nervioso, cardiovascular, digestivo, genitourinario, musculo esquelético, anomalías cromosómicas) y 28 malformaciones específicas, se estimaron el porcentaje de muertes por MC (PM-MC) y la tasa de mortalidad infantil por MC (TMI-MC) en 3 períodos (1997-2001, 2002-2009, 2007-2011). La tendencia secular y la variación del riesgo de muerte se estimaron con un modelo de regresión de Poisson. RESULTADOS: Para todo Chile, la tendencia secular de la TMI-MC y el PM-MC fueron negativa y positiva, respectivamente (P < 0,01). La TMI-MC y el PM-MC exhibieron una heterogeneidad espacial discreta en las regiones administrativas y naturales. La región natural que más se acercó al patrón nacional fue la Central. La tendencia secular de la TMI-MC de los sistemas nervioso y cardíaco y de algunas MC específicas (anencefalia, espina bífida, y comunicaciones interauricular e interventricular) fue negativa. El patrón de mortalidad infantil por MC para todo Chile se caracteriza por presentar en el período 1997-2011 un descenso de la TMI-MC y un aumento del PM-MC. CONCLUSIONES: Los resultados indican que Chile se encuentra en un estadio avanzado de la transición epidemiológica de las causas de mortalidad infantil. Sin embargo, se observan disparidades interregionales de estos indicadores, más notorias en el sur del país.

OBJECTIVE: To analyze the spatial and temporal distribution (1997-2011) of infant mortality resulting from congenital malformations (CM) in Chile. METHODS: Data on births and deaths among infants aged less than one year using ICD-10 coding were obtained from the National Statistics Institute. The percentage of deaths from CM (PD-CM) and the infant mortality rate from CM (IMR-CM) during three different periods (1997-2001, 2002-2009, 2007-2011) were estimated for Chile's administrative and natural regions (Norte Grande, Norte Chico, Central, Austral, and Sur), broken down by systems (nervous, cardiovascular, digestive, genitourinary, musculoskeletal, and chromosomal abnormalities) and by 28 specific malformations. The secular trend and the variation in the risk of death were estimated using a Poisson regression model. RESULTS: For the whole of Chile, the secular trend for the IMR-CM was negative, and the secular trend for the PD-CM was positive (P < 0,01). The IMR-CM and the PD-CM both showed mild spatial heterogeneity in all administrative and natural regions. The Central region was the natural region that came closest to showing the pattern observed nationwide. The IMR-CM involving the nervous and cardiovascular systems and specific types of CM (anencephaly, spina bifida, and atrial and ventricular septal defects) showed a negative secular trend. For Chile as a whole, the pattern of infant mortality from CM is marked by a drop in the IMR-CM and by an increase in the PD-CM over the period from 1997 to 2011. CONCLUSION: The findings suggest that Chile is in the latter stages of the epidemiological transition with respect to the causes of infant mortality. However, these indicators show disparities between regions, more pronounced in the south of the country.

Development and applications of the SWAN rating scale for assessment of attention deficit hyperactivity disorder: a literature review

This study reviewed the use of the Strengths and Weaknesses of Attention-Deficit/Hyperactivity-symptoms and Normal-behaviors (SWAN) rating scale in diagnostic and evolutive approaches to attention deficit hyperactivity disorder (ADHD) and in correlational studies of the disorder. A review of articles published in indexed journals from electronic databases was conducted and 61 articles on the SWAN scale were analyzed. From these, 27 were selected to a) examine use of SWAN in research on attention disorders and b) verify evidence of its usefulness in the areas of genetics, neuropsychology, diagnostics, psychiatric comorbidities, neuroimaging, pharmacotherapy, and to examine its statistical reliability and validity in studies of diverse populations. This review of articles indicated a growing use of the SWAN scale for diagnostic purposes, for therapy, and in research on areas other than ADHD, especially when compared with other reliable scales. Use of the scale in ADHD diagnosis requires further statistical testing to define its psychometric properties.

Variación de alelos del gen receptor de dopamina DRD4 en escolares chilenos de diferente origen étnico y su relación con riesgo de déficit atencional/hiperactividad / DRD4 dopamine receptor alleles in Chilean students of different ethnic origin and its relation with the risk for attention deficit/hyperactivity disorder

Background: Worldwide diversity of alleles of D4 receptor gene (DRD4), linked to attention deficit hyperactivity disorder (ADHD), is mostly the result of length and single nucleotide polymorphisms in a 48-bp tandem repeat (VNTR). Alleles containing from two (2R) to eleven (11R) repeats have been identified. The most common are 4R, 7R and 2R. Aim: To study the association of ADHD risk with DRD4 genotypes in Chilean students. Subjects and Methods: ADHD risk data were obtained through the abbreviated Conner's Scale for School Teachers in 66 Aymara children (11 cases and 55 controls), 91 Rapa-Nui children (60 cases ad 31 controls) and 96 children from a mixed urban population from Santiago (51 cases and 45 controls). DNA extracted from saliva was amplified by polymerase chain reaction (PCR) to genotype the DRD4 VNTR. Results: The distribution of DRD4 alleles reveals that, beneath the 4R allele, 7R exhibits the second highest frequencies in Aymara and Santiago children. In Polynesian children, 2R ranks after 4R. A statistically significant association between ADHD risk and 2R/4R genotype was identified in Polynesian children (p < 0.05; odds ratio = 3.7). Conclusions: Different DRD4 genotypes are associated with ADHDphenotype in Chilean populations, probably as a consequence of their initial colonization history.

El trastorno por déficit de atención con hiperactividad: mito o realidad / Attention deficit hiperactivity disorder: myth or reality?

El trastorno por déficit de atención e hiperactividad es una de las condiciones neuropsiquiátricas más frecuentes en la infancia y adolescencia. Su diagnóstico y tratamiento han sido objeto de interés y también de controversias, tanto en la comunidad científica como en la población general. La evidencia científica actual respalda la formulación de su diagnóstico y tratamiento. También permite comprender mejor su etiología y mecanismos fisiopatológicos. Neurobiológicamente, los factores genéticos parecen altamente determinantes en la gran mayoría de los casos. Sin embargo, existen factores ambientales que influyen en la génesis, expresión y evolución del cuadro. Este artículo plantea la necesidad de realizar diagnósticos y tratamientos integrales que incorporen variables biopsicosociales, con el fin de evitar que niños y adolescentes queden ensombrecidos bajo etiquetas clínicas. Asimismo, busca realizar una revisión de aspectos clínicos y neurobiológicos, refutando con evidencias una serie de conceptos erróneos de amplia divulgación. Tanto el diagnóstico como el tratamiento deben promover en los niños y jóvenes con trastorno por déficit atencional e hiperactividad su mayor potencial de desarrollo.

Attention deficit hyperactivity disorder is one of the most common neuropsychiatric conditions in childhood and adolescence. Its diagnosis and treatment have been of interest and controversy, both in the scientific community and in the general population. Current scientific evidence supports the formulation of the diagnosis and treatment and better understanding of etiology and pathophysiological mechanisms. From a neurobiological perspective, genetic factors seem strongly determinant in most cases, but there are also environmental factors that influence the genesis, expression and clinical evolution. In addition to conducting a review of clinical and neurobiological evidence refuting a series of widely disseminated misconceptions, this article discusses the need of comprehensive diagnosis and treatment, incorporating biopsychosocial variables in order to avoid misconstrued labels that may affect children and adolescents. Both diagnosis and treatment should be at service of promoting the highest potential of ADHD children and youngsters.

Trastorno por déficit de atención/hiperactividad (TDAH) revisión: ¿hacia dónde vamos ahora? / Attention-deficit/hyperactivity disorder (ADHD) review: where are we going?

El TDAH fue descrito hace casi 150 años, definido actualmente por el DSM-IV como un determinado grado de déficit de atención y/o hiperactividad-impulsividad que resulta desadaptativo en relación con el nivel de desarrollo del niño. Está asociado a gran discapacidad y alta comorbilidad psiquiátrica, por lo que se ha convertido en uno de los trastornos psiquiátricos infantiles más estudiados. En el presente artículo se revisa cómo ha ido evolucionando el concepto de TDAH desde una perspectiva histórica, evolucionista y neuropsiquiátrica, mencionando las principales hipótesis, estudios y aportes de la ciencia que han influido en su mejor comprensión. Se revisarán los temas más relevantes en relación al desarrollo del DSM-V y cómo éste debería replantearse de acuerdo a los nuevos hallazgos y a la literatura publicada a la fecha.

ADHD was first described almost 150 years ago, defined in the DSM-IV as a disruptive behavior disorder characterized by the presence of impairing behavior patterns that display abnormal levels of inattention, hyperactivity and impulsivity. It has been associated to important discapacity and psychiatric comorbidity, becoming one of the most studied child psychiatric disorders. We review how the concept of ADHD has evolved, from an historic, evolutionary and neuropsychiatric point of view, mentioning the mayor scientific hypothesis, studies and findings that have influenced its better understanding. In addition we review literature available about the most relevant item related to the development of DSM-V, and discuss about how the diagnosis should be reformulated according to these new findings and current available literature.

Riesgo de déficit atencional/hiperactividad en escolares Aymara, Rapa-Nui y de Santiago de Chile: Posible contribución de polimorfismos genéticos del sistema dopaminérgico / Risk of attention deficit/hyperactivity disorder in Aymara and Rapa-Nui school children: Association with dopaminergic system polymorphisms

Background: Attention deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurobiological disorder of childhood onset, characterized by hyperactivity, impulsiveness or inattentiveness. Aim: To search for differences in risk for ADHD and its components among Chilean native and mixed populations and to look forpossible associations with dopamine receptor D4 (DRD4) and dopamine transporter 1 (DAT1) polymorphisms. Material and Methods: School teachers were requested to complete the Conners test, which uses DSM-IV criteria, to screen for ADHD risk among Aymara and Rapa-Nui students. Results: Rapa-Nui children from Easter Island had the highest risk of hyperactivity/impulsiveness. Aymara children from the Arica-Parinacota Region had lower scores. Although inattentiveness scores had lower differences between groups, overall ADHD score differences among studied populations were highly significant. DRD4 and DAT1 alleles had a heterogeneous distribution. Easter islanders had more divergent frequencies, mostprobably as a result of separate migration routes utilized at different timeperiods during the colonization of America and Polynesia. Conclusions: The comparison of ADHD risk parameters between Rapa-Nui and Aymara children showed marked differences. Allele distri-bution of dopamine polymorphisms in Easter Island was also significantly different from northern Chile, due probably to different colonization histories. These findings suggest that higher ADHD risk scores in Easter Island children may be linked to the presence of different DRD4 alleles.

Interacción de factores genéticos y ambientales en el trastorno por déficit de atención con hiperactividad: estudio de caso de gemelos / Interaction of genetic and environmental factors in attention deficit hyperactivity disorder: case study of twins

El Trastorno por Déficit de Atención con Hiperactividad (TDAH) es el trastorno neurocomportamental más común en la infancia, afecta aproximadamente del 3-5 por ciento de la población en edad escolar. Se caracteriza por déficit en la atención, baja regulación del nivel de actividad ante las demandas situacionales e impulsividad. Si bien se manifiesta en conductas consideradas habituales en la infancia, éstas se presentan con más frecuencia y mayor intensidad que lo observado en niños sin el diagnóstico. Las últimas investigaciones sobre el diagnóstico del TDAH avanzan en el conocimiento de los factores genéticos implicados en este trastorno. En el 70 - 80 por ciento de los niños los síntomas del trastorno persisten en la adolescencia, sumándose en los adolescentes las características propias de esta etapa; esto conlleva un aumento en las dificultades de conducta, de rendimiento académico y de relaciones interpersonales. El objetivo del presente trabajo es presentar el análisis de aspectos evolutivos, neuropsicológicos, académicos, familiares y sociales en un caso de gemelos varones adolescentes con diagnóstico de TDAH considerando la interacción de factores genéticos y ambientales que pudieran influenciar la expresión clínica del trastorno.

Attention Deficit Hyperactivity Disorder (ADHD) is the most common neurobehavioral disorder in childhood, affects approximately 3-5 percent of school-age population. It is characterized by deficits in attention, down-regulation of the activity level to situational demands and impulsivity. Although it is manifested in what it is considered normal behavior in childhood, they occur more frequently and with greater intensity than seen in children without diagnosis. Recent research on the diagnosis of ADHD advances in knowledge of genetic factors involved in this disorder. In 70 to 80 percent of children, disorder symptoms persist into adolescence, joining those characteristics proper of this stage. This entails an increase in behavior difficulties, academic performance and interpersonal relationships. The aim of this paper is to present the analysis of evolutionary, neuropsychological, academic, social and family aspects in a case of twin boys diagnosed with ADHD considering the interaction of genetic and environmental factors that may influence the clinical expression of the disorder.

Identification of a Novel Deletion Region in 3q29 Microdeletion Syndrome by Oligonucleotide Array Comparative Genomic Hybridization / 대한진단검사의학회지

BACKGROUND: The 3q29 microdeletion syndrome is a genomic disorder characterized by mental retardation, developmental delay, microcephaly, and slight facial dysmorphism. In most cases, the microdeletion spans a 1.6-Mb region between low-copy repeats (LCRs). We identified a novel 4.0- Mb deletion using oligonucleotide array comparative genomic hybridization (array CGH) in monozygotic twin sisters. METHODS: G-banded chromosome analysis was performed in the twins and their parents. Highresolution oligonucleotide array CGH was performed using the human whole genome 244K CGH microarray (Agilent Technologies, USA) followed by validation using FISH, and the obtained results were analyzed using the genome database resources. RESULTS: G-banding revealed that the twins had de novo 46,XX,del(3)(q29) karyotype. Array CGH showed a 4.0-Mb interstitial deletion on 3q29, which contained 39 genes and no breakpoints flanked by LCRs. In addition to the typical characteristics of the 3q29 microdeletion syndrome, the twins had attention deficit-hyperactivity disorder, strabismus, congenital heart defect, and gray hair. Besides the p21-activated protein kinase (PAK2) and discs large homolog 1 (DLG1) genes, which are known to play a critical role in mental retardation, the hairy and enhancer of split 1 (HES1) and antigen p97 (melanoma associated; MFI2) genes might be possible candidate genes associated with strabismus, congenital heart defect, and gray hair. CONCLUSIONS: The novel 4.0-Mb 3q29 microdeletion found in the twins suggested the occurrence of genomic rearrangement mediated by mechanisms other than nonallelic homologous recombination. Molecular genetic and functional studies are required to elucidate the contribution of each gene to a specific phenotype.

Aspectos explicativos de comorbilidad en los TGD, el síndrome de Asperger y el TDAH: estado de la cuestión / Explanatory aspects of comorbidity in PDD, Asperger syndrome and ADHD: the current state

El presente artículo revisa la evidencia científica reciente sobre los aspectos comórbidos de los Trastornos Generalizados del Desarrollo (TGD), especialmente los tipos de alto funcionamiento, y el Trastorno por Déficit de Atención con Hiperactividad (TDAH). Se comentan varios estudios desde diferentes perspectivas (epidemiología, investigación neurocognitiva y genética). Finalmente, las áreas investigadas coinciden en la necesidad de reformular los criterios diagnósticos del DSM-IV y la CIE-10 en futuras clasificaciones de los TGD.

The present article reviews the recent scientific evidence about the comorbid aspects of Pervasive Developmental Disorders (PDD), especially high-functioning types, and Attention-Deficit Hyperactivity Disorder (ADHD). Several studies from different perspectives (epidemiology, neurocognitive research and genetics) are discussed. Finally, the investigated areas coincide with the need to reformulate the DSM-IV and the ICD-10 diagnostic criteria in future classifications of PDD.

Aspectos controvertidos en el trastorno de déficit de atención / Controversial aspects of the attention deficit disorder

En las últimas décadas hemos visto como se han ido distanciando quienes están a favor de reconocer al TDAH como un trastorno del neurodesarrollo con fuerte base neurobiológica, que responde a un tratamiento específico de modalidad interdisciplinar y por otro lado, quienes piensan, sostienen y defienden que la evidencia científica acumulada no es suficiente para justificar la presencia de este cuadro como una anormalidad del desarrollo que merecería un abordaje terapéutico propio. Se describen las hipótesis del modelo atencional versus modelo de autorregulación, Se exponen las bases neurobiológicas del trastorno, haciendo un análisis desde las neuroimágenes funcionales, como por ejemplo el PET (tomografía por emisión de positrones), SPECT (tomografía de emisión de fotón único) y la RMF (resonancia magnética funcional), neuroanatomía, neurofisiología, neuroquímica de neurotransmisores hasta la genética. Luego se hace hincapié en las características del abordaje diagnóstico adecuado, analizando las áreas cognitivas involucradas en el trastorno, que nos posibilitará diferenciar los tipos de TDAH y en algunos casos el origen del trastorno, ya sea fenotipo o fenocopia. También se enumera una recopilación sobre la evidencia preexistente con respecto al tratamiento del TDAH y cuales tienen que ser las características de un abordaje completo e interdisciplinar. Por ultimo se hace un análisis de toda la información y se dan conclusiones útiles para la comprensión del trastorno.

In the last decades there have been those in favor of recognizing the attention deficit disorder (ADD) as a neurodevelopment entity with a strong neurobiological basis responding to a specific interdisciplinary treatment versus those who think, sustain and defend that the accumulated scientific evidence is not sufficient to justify the disorder as a development anomaly in need of a specific therapeutic outline. The attention model versus the autoregulation model are described. The neurological basis of the disorder is discussed analyzing the use of functional neuroimages such as PET (positron emission tomography), SPECT (single photon emission tomography) and FMR (functional magnetic resonance) neuroanatomy, neurophysiology, neurochemistry of neurotransmitters up to genetics. The importance of an adequate diagnosis is emphasized, analyzing the cognitive areas involved and trying to differentiate the ADD types, and to determine in some cases the phenotype or phenocopy of the disorder. The different treatments advocated are discussed taking into account the interdisciplinary approaches. Finally, a complete analysis of the information available is presented and conclusions are drawn to facilitate the understanding of this disorder.

Neurobiologia y diagnóstico del trastorno por déficit de atención / The neurobiology of attention deficit/hyperactivity disorder

El trastorno por déficit de atención e hiperactividad (TOAH) es la condición neurobiológica más prevalente en niños y adolescentes, asociada a importante impacto funcional, personal, familiar y social. La evidencia científica actual provee de fundamentos sólidos acerca de sus bases neurobiológicas: alta heredabilidad, identificación de varios genes implicados en su etiología; perfil neuropsicológico con evidencias de disfunción ejecutiva, desregulación motivación/recompensa, déficits en activación; alteraciones estructurales y de funcionamiento de la corteza prefrontal (CPF) y sus conexiones con el striatum y cerebelo; desbalances de los sistemas dopaminérgico y noradrenérgico, blancos de los tratamientos farmacológicos. En esta revisión se destaca los aportes de las aproximaciones multidisciplinarias (p.e. genética/neuropsicológica/imágenes funcionales) para la comprensión de esta condición heterogénea que se conceptualiza hoy como multifactorial en su origen y con múltiples procesos fisiopatológicos subyacentes. La activa investigación en curso, acerca la posibilidad de contar con marcadores biológicos para el diagnóstico de TDAH y con información gen ética de valor para la elección de fármacos de mayor efectividad y menos efectos adversos.

Attention-deficit/hyperactivity disorder is the most prevalent neurobiological condition in children and adolescents, with significant personal and social functional impairments. There is now strong scientific data providing foundation to its biologic basis. High heritability; several genes involved in its etiology; neuropsychological profile showing executive dysfunction, motivation/reward, dysregulation and activation deficits; altered structure and function of prefrontal cortex and its striatal and cerebellar connections, imbalance of dopaminergic and noradrenergic systems, target of pharmacologic treatment. In this review the contribution af multidisciplinary studies (genetic/neuropsychology/ functional imaging) to the comprehension of this complex and multifactarial canditian is highlighted. Ongoing active research promises new important developments such as biolagic diagnostic markers far clinical purpases and useful genetic data in order ta select pharmacologic treatment, improve efficiency and reduce side effects.

Combinación de genotipos DRD4 y DAT1 constituye importante factor de riesgo en miembros de familias de Santiago de Chile con déficit atencional / Combination of DRD4 and DAT1 genotypes is an important risk factor for attention déficit disorder with hyperactivity families living in Santiago, Chile

Background: Attention deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurobiological disorder of childhood onset, characterized by hyperactivity, impulsiveness, and/or inattentiveness. Aún: To search forpossible associations between dopamine receptor D4 (DRD4) and dopamine transponer 1 (DATl) polymorphisms and ADHD in Chilean families. Material and methods: We extended a previous family-based discordant sib pair analysis that included 26 cases diagnosed according to DSM-IV entena and 25 controls (healthy siblings of cases), adding 14 cases and 11 controls. Results: Both loci, individually classified as homozygotes or heterozygotes for the DRD4 7-repeat and DATl 10-repeat alleles, did not exhibit genotype frequency differences between affected children and their healthy siblings. However, the simultaneous presence of both DRD4 7-repeat heterozygosity and DATl 10 allele homozygosity was significantly higher (22.5 percent) in cases (40), compared with (2.8 percent) unaffected siblings (36), with an odds-ratio of 10.16. Conclusions: The genotype combination DRD4/7 heterozygotes and DAT1/10 homozygotes is a high risk factors in Chilean families for ADHD. Increased density of dopamine transporters in ADHD brains, along with abundance of 7-repeat D4 receptors in prefrontal cortex, which is impaired in ADHD patients, make the observed gene-gene interaction worthy of studies to understand the functional basis ofADHD.