Mutations in sphingolipid metabolism genes are associated with ADHD.

Attention deficit hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder in children, with genetic factors accounting for 75-80% of the phenotypic variance. Recent studies have suggested that ADHD patients might present with atypical central myelination that can persist into adulthood. Given the essential role of sphingolipids in myelin formation and maintenance, we explored genetic variation in sphingolipid metabolism genes for association with ADHD risk. Whole-exome genotyping was performed in three independent cohorts from disparate regions of the world, for a total of 1520 genotyped subjects. Cohort 1 (MTA (Multimodal Treatment study of children with ADHD) sample, 371 subjects) was analyzed as the discovery cohort, while cohorts 2 (Paisa sample, 298 subjects) and 3 (US sample, 851 subjects) were used for replication. A set of 58 genes was manually curated based on their roles in sphingolipid metabolism. A targeted exploration for association between ADHD and 137 markers encoding for common and rare potentially functional allelic variants in this set of genes was performed in the screening cohort. Single- and multi-locus additive, dominant and recessive linear mixed-effect models were used. During discovery, we found statistically significant associations between ADHD and variants in eight genes (GALC, CERS6, SMPD1, SMPDL3B, CERS2, FADS3, ELOVL5, and CERK). Successful local replication for associations with variants in GALC, SMPD1, and CERS6 was demonstrated in both replication cohorts. Variants rs35785620, rs143078230, rs398607, and rs1805078, associated with ADHD in the discovery or replication cohorts, correspond to missense mutations with predicted deleterious effects. Expression quantitative trait loci analysis revealed an association between rs398607 and increased GALC expression in the cerebellum.

Trastorno con déficit de atención e hiperactividad: neurobiología a lo largo de la vida / Attention deficit hyperactivity disorder: neurobiology throughout life

Resumen El trastorno con déficit de atención e hiperactividad(TDAH) es el más frecuente motivo de consulta en neurología y psiquiatría en niños en edad escolar. Las manifestaciones clínicas incluyen niveles de inatención, hiperactividad e impulsividad más elevados que los esperados para la edad y el nivel de desarrollo. Desde las descripciones iniciales por un médico pediatra alemán, hasta nuestros días, existe cada día una mayor evidencia de que esta condición es una entidad neurobiológica, resultado la interacción de factores genéticos y medio ambientales que impactan el desarrollo y maduración cerebral del individuo. Muchas áreas científicas han proporcionado evidencia clara de esta base neurobiológica. Así mismo es claro que el TDAH es una entidad clínica que se presenta en todas las razas y estratos económicos con manifestaciones clínicas que cambian a lo largo de la vida del individuo. Entender y conocer las variaciones clínicas, los aspectos neurobiológicos y los factores que determinan el pronóstico a corto y largo plazo es el primer paso en el éxito de la intervención. En esta publicación se revisan algunos aspectos neurobiológicos a la luz del conocimiento actual en el contexto del impacto en el desarrollo y las manifestaciones a lo largo de la vida.

Abstract Attention Deficit Hyperactivity Disorder (ADHD) is the most frequent cause of consultation in clinical child neurology and child psychiatry in the school age group. The clinical manifestations include elevated levels of inattention, hyperactivity and impulsivity, above of what is expected for their age and level of development. First descriptions of this conditions to our days, it is growing evidence that support the notion that this is a strong neurobiological condition. Clinical manifestations in ADHD are the result of complex interaction of genetic factors and environmental aspects that impact the presentation and severity of the symptoms as well the development and the brain maturation of the a ected individual. This neurobiological evidence comes from many sources of science from genetics, to neuroimaging. In addition, it is also clear that ADHD is present in all ethnicities and socio-economic groups, with clinical manifestations that change along the life associated with the maturation processes of the brain. Understanding and recognizing clinical variations, the neurobiological aspects and the aspects that will determine the prognosis to the long and short term is the first step for the success of any intervention. This publication will review the current knowledge of some neurobiological aspects in the context of the impact in brain development and clinical manifestations along the life of the affected individual.

Potential cognitive endophenotypes in multigenerational families: segregating ADHD from a genetic isolate.

Endophenotypes are neurobiological markers cosegregating and associated with illness. These biomarkers represent a promising strategy to dissect ADHD biological causes. This study was aimed at contrasting the genetics of neuropsychological tasks for intelligence, attention, memory, visual-motor skills, and executive function in children from multigenerational and extended pedigrees that cluster ADHD in a genetic isolate. In a sample of 288 children and adolescents, 194 (67.4%) ADHD affected and 94 (32.6%) unaffected, a battery of neuropsychological tests was utilized to assess the association between genetic transmission and the ADHD phenotype. We found significant differences between affected and unaffected children in the WISC block design, PIQ and FSIQ, continuous vigilance, and visual-motor skills, and these variables exhibited a significant heritability. Given the association between these neuropsychological variables and ADHD, and also the high genetic component underlying their transmission in the studied pedigrees, we suggest that these variables be considered as potential cognitive endophenotypes suitable as quantitative trait loci (QTLs) in future studies of linkage and association.

Mental, motor, and language development of toddlers with neurofibromatosis type 1.

OBJECTIVE: To examine the mental, motor, and language development of toddlers with neurofibromatosis type 1 (NF1). STUDY DESIGN: In this cross-sectional study, 39 toddlers with NF1 (aged 21-30 months) and 42 age-matched control children were assessed using the Bayley Scales of Infant Development, Second Edition. Basic vocabulary was assessed with the language subtests from the Wechsler Preschool and Primary Scale of Intelligence, Third Edition. Parents completed questionnaires evaluating the children's expressive language, behavior, and executive functioning. The χ(2) test, independent t test, Mann-Whitney U test, and analysis of covariance were used to examine differences between the two groups. RESULTS: The toddlers with NF1 had significantly poorer mental and motor development than the control participants. Parental responses indicated that most of the children with NF1 had delayed language skills. No differences in behavior and executive functioning were noted between the two groups of children. CONCLUSIONS: Children with NF1 as young as age 30 months demonstrate early signs of mental, motor, and language difficulties. Age 2 years may be the appropriate time to perform an initial developmental assessment to identify mental, motor, and language impairments in children with NF1.

Hipotiroidismo primario como causa de pubertad precoz e hiperplasia hipofisiaria

La hiperplasia hipofisiaria originada por falla primaria de un órgano endocrino no es rara. Se han informado casos de hipotiroidismo primario en niños y adultos como etiología de hipertrofia de la hipófisis (1-8). En ocasiones se han observado casos de adenomas y microadenomas hipofisiarios causados por esta alteración, tanto en humanos como en animales de experimentación (2, 6, 9, 10); otras entidades en las cuales se ha documentado aumento del tamaño de la hipófisis incluyen falla gonadal primaria y en pacientes con adrenalectomía total (1, 5). Los primeros casos informados se remontan a 1851 (5); en 1960 Van Wyck y Grumbach describieron un síndrome en niños caracterizado por pubertad precoz, galactorrea, hipotiroidismo primario y aumento del tamaño de la silla turca (!!); a partir de este momento los informes en la literatura demuestran la asociación entre estos dos hallazgos, que pueden llevar a notables confusiones diagnósticas y terapéuticas, debido a las alteraciones endocrinológicas y neurológicas asociadas; un diagnóstico adecuado permitirá un tratamiento oportuno de acuerdo a la patología de base. Las principales alteraciones neurológicas asociadas se producen por compresión de la vía visual por la hiperplasia de la hipófisis, ocasionando desde cambios leves en los campos visuales, papiledema, hasta ceguera (2, 6). Nosotros describimos el caso de una niña con pubertad precoz, talla baja y aumento del tamaño de la hipófisis, demostrado por estudios neurorradiológicos, en quien disminuyó el tamaño hipofisiario luego del tratamiento de sustitución hormonal.