Linkage and association analysis of ADHD endophenotypes in extended and multigenerational pedigrees from a genetic isolate.

Attention-deficit/hyperactivity disorder (ADHD) is a heritable, chronic, neurodevelopmental disorder with serious long-term repercussions. Despite being one of the most common cognitive disorders, the clinical diagnosis of ADHD is based on subjective assessments of perceived behaviors. Endophenotypes (neurobiological markers that cosegregate and are associated with an illness) are thought to provide a more powerful and objective framework for revealing the underlying neurobiology than syndromic psychiatric classification. Here, we present the results of applying genetic linkage and association analyses to neuropsychological endophenotypes using microsatellite and single nucleotide polymorphisms. We found several new genetic regions linked and/or associated with these endophenotypes, and others previously associated to ADHD, for example, loci harbored in the LPHN3, FGF1, POLR2A, CHRNA4 and ANKFY1 genes. These findings, when compared with those linked and/or associated to ADHD, suggest that these endophenotypes lie on shared pathways. The genetic information provided by this study offers a novel and complementary method of assessing the genetic causes underpinning the susceptibility to behavioral conditions and may offer new insights on the neurobiology of the disorder.

A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD.

In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10(-8)) and 11q and 17p (P<1 × 10(-6)). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q-11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.

Isolated seizures in rats do not cause neuronal injury.

BACKGROUND: Previous studies have shown that status epilepticus can lead to neuronal injury. However, the effect of a small number of isolated seizures is uncertain. METHODS: We used structural MRI and neuropathology to study the effects of isolated seizures induced by kainic acid (KA), (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazole-4-yl)propanoic acid (ATPA), and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate in rats. A group of animals received normal saline. After seizure induction, animals were followed for 12 weeks. RESULTS: ATPA and KA led to small but significant increases in ADC. There were no changes in T2 signal intensity or hippocampal volume. Blinded pathological examination showed no differences between animals receiving saline or glutamatergic agents. CONCLUSION: Our study suggests that isolated seizures cause minimal neuronal injury in rats.

A two-locus genetic interaction between LPHN3 and 11q predicts ADHD severity and long-term outcome.

The severity of attention-deficit/hyperactivity disorder (ADHD) symptoms is a major predictor of long-term ADHD outcome. To investigate if two-locus interactions might predict ADHD severity, we studied a sample of 1341 individuals from families clustering ADHD, using the Vanderbilt Assessment Scale for Parents. Latent class cluster analysis was used to construct symptom profiles and classify ADHD severity. Single nucleotide polymorphisms (SNPs) spanning ADHD-linked chromosomal regions on chromosomes 4, 5, 10, 11, 12 and 17 were genotyped. SNPs associated with ADHD severity were identified and potential two-locus genetic interactions were tested. We found that SNPs within the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 not only to increase the risk of developing ADHD but also to increase ADHD severity. All these genes are identified to have a major role in shaping both brain development and function. These findings demonstrate that genetic interactions may predict the severity of ADHD, which in turn may predict long-term ADHD outcome.

A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication.

Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.

Arterial spin labeling demonstrates that focal amygdalar glutamatergic agonist infusion leads to rapid diffuse cerebral activation.

OBJECTIVES: To investigate acute effects of intra-amygdalar excitatory amino acid administration on blood flow, relaxation time and apparent diffusion coefficient in rat brain. MATERIALS AND METHODS: Several days after MR-compatible cannula placement in right basolateral amygdala, anesthetized rats were imaged at 7 T. Relative cerebral blood flow (CBF) was measured before and 60 min after infusion of 10 nmol KA, cAMPA, ATPA, or normal saline using arterial spin labeling. Quantitative T(2) and diffusion-weighted images were acquired. rCBF, T(2) and ADC values were evaluated in bilateral basolateral amygdala, hippocampus, basal ganglia, frontal and parietal regions. RESULTS: KA led to the highest, and ATPA lowest bilateral rCBF increases. Time courses varied among drugs. T(2) for KA and AMPA was higher while ADC was lower for KA. CONCLUSIONS: Intra-amygdalar injection of GluR agonists evoked bilateral seizure activity and increased rCBF, greater for KA and AMPA than selective ATPA GluR5 activation.

[The neurobiology of learning difficulties: neurofibromatosis type 1 as a model for researching and treating learning disorders]. / Neurobiología de los trastornos del aprendizaje: neurofibromatosis de tipo 1 como modelo para investigar y tratar los trastornos del aprendizaje.

INTRODUCTION: Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, with a prevalence of around 1:3500. The most important concern for patients and their families is the increased risk of developing benign and malignant tumours in the central and peripheral nervous systems. Up to 80% of patients, however, experience difficulties in learning processes. Symptoms compatible with attention deficit hyperactivity disorder are present in as many as 60% of patients. Learning difficulties are the chief cause of morbidity throughout their lives. DEVELOPMENT: Some recent studies have made it possible to offer a better description of the cognitive and developmental phenotype in patients with NF1. Similarly, advances in our understanding of the underlying molecular and cellular processes in cognitive impairment and access to sophisticated molecular genetics techniques have allowed a number of scientific disciplines to work together in the search for an understanding and potential solution to the cognitive disorders in this population. CONCLUSIONS: Preclinical studies show the enormous potential of certain pharmacological interventions. Transferring the results obtained in the treatment of learning difficulties in animal models of NF1 to the treatment of patients is a step that is currently under development. If it were effective, it would open the door to numerous areas of research that would rapidly increase our knowledge and the possibilities of intervention in this and many other learning disorders.

[Genetic and molecular aspects in attention deficit hyperactivity disorder: the search for the genes involved in clinical diagnosis]. / Aspectos genéticos y moleculares en el trastorno por déficit de atención/hiperactividad: búsqueda de los genes implicados en el diagnóstico clínico.

INTRODUCTION AND DEVELOPMENT: Attention deficit hyperactivity disorder (ADHD) is still today one of the most widely researched medical problems around the world. It is the most common neuropsychiatric diagnosis in school-age children. The fact that it will affect the patient throughout their whole life together with the social and economic impact it has on the individual and on society are clearly acknowledged and are a motive for concern. The clinician who is faced with treating these patients has no doubt that this entity presents in familial groups. This gives rise to obvious difficulties when it comes to establishing therapeutic processes. Although intensive searches for genetic markers have been carried out, methodological problems that arise in the definition of phenotypes, as well as in the selection of genetic techniques and the genes targeted for research, have meant that less progress has been made in these studies than was initially expected. Some of the aspects that have been advancing in recent years include clarification of the clinical phenotype to be studied, the analysis of clinical information to be used for the selection of the genetic sample and agreements about the genes the search is to be focused on. Today several genetic markers that are highly associated with the entity are known. CONCLUSIONS: We are very close to identifying specific genes, although this is only the first step towards understanding the underlying problem; how to use that information to benefit the patient is a challenge that researchers are currently facing.

Aspectos genéticos y moleculares en el trastorno por déficit de atención/hiperactividad: búsqueda de los genes implicados en el diagnóstico clínico / Genetic and molecular aspects in attention deficit hyperactivity disorder: the search for the genes involved in clinical diagnosis

Introducción y desarrollo. El trastorno por déficit de atención/hiperactividad (TDAH) sigue siendo uno de los problemas médicos más extensamente investigado en todo el mundo. Constituye el diagnóstico neuropsiquiátrico más común en niños en edad escolar. Su persistencia a lo largo de la vida y el impacto social y económico en el individuo y en la sociedad son claramente reconocidos y constituyen un motivo de preocupación. Para el clínico que se enfrenta al tratamiento de estos pacientes, no hay duda de que esta entidad se presenta en grupos familiares. Esto genera dificultades claras a la hora de establecer procesos terapéuticos. Aun cuando la búsqueda de marcadores genéticos ha sido intensa, problemas metodológicos de definición de los fenotipos, así como la selección de las técnicas genéticas y los genes objetivos de investigación, han llevado a que los progresos obtenidos sean inferiores a las expectativas puestas en estas investigaciones. La clarificación de aspectos como el fenotipo clínico estudiado, los tipos de muestras utilizadas, los análisis de la información clínica para la selección de la muestra genética, así como las decisiones de acuerdo con los genes en los cuales se va a enfocar la búsqueda, son algunos de los aspectos que han venido evolucionando a lo largo de los últimos años. Hoy conocemos marcadores genéticos altamente asociados con la entidad. Conclusión. Estamos muy cerca de la identificación de genes específicos, sin embargo éste es sólo el paso inicial para la comprensión del problema subyacente, y el uso de esa información en beneficio del paciente es un reto que los investigadores afrontan en este momento

Introduction and development. Attention deficit hyperactivity disorder (ADHD) is still today one of the most widely researched medical problems around the world. It is the most common neuropsychiatric diagnosis in school-age children. The fact that it will affect the patient throughout their whole life together with the social and economic impact it has on the individual and on society are clearly acknowledged and are a motive for concern. The clinician who is faced with treating these patients has no doubt that this entity presents in familial groups. This gives rise to obvious difficulties when it comes to establishing therapeutic processes. Although intensive searches for genetic markers have been carried out, methodological problems that arise in the definition of phenotypes, as well as in the selection of genetic techniques and the genes targeted for research, have meant that less progress has been made in these studies than was initially expected. Some of the aspects that have been advancing in recent years include clarification of the clinical phenotype to be studied, the analysis of clinical information to be used for the selection of the genetic sample and agreements about the genes the search is to be focused on. Today several genetic markers that are highly associated with the entity are known. Conclusions. We are very close to identifying specific genes, although this is only the first step towards understanding the underlying problem; how to use that information to benefit the patient is a challenge that researchers are currently facing

[The neuroanatomy of attention deficit/hyperactivity disorder]. / Neuroanatomia del trastorno por deficit de atencion con hiperactividad.

Neuroimaging techniques are increasingly being applied to the study of attention deficit/hyperactivity disorder (ADHD). This review focuses on magnetic resonance imaging studies of the brain anatomy of ADHD, which have now been conducted for over a decade. Most studies have focused on frontal striatal regions and have tended to find smaller volumes in children with ADHD relative to controls. Recently published analyses with the largest sample of patients and controls found that ADHD is associated with a statistically significant global reduction in brain volume in both boys and girls of 3 4%, which is confirmed in a meta analysis of this global measure. Specific regional differences have been found in many studies in the basal ganglia with the most prominent differences being found in the cerebellum.

[Tourette syndrome: an analysis of its comorbidity and specific treatment]. / Sindrome de Tourette: analisis de la comorbilidad y sus tratamientos especificos.

INTRODUCTION AND METHOD: Tic disorders can be severe enough to be incapacitating, but in most cases the observation of tics should alert the clinician to the possible presence of other conditions that may be more impairing even if less directly observable. The comorbid diagnoses that are best documented are obsessive compulsive disorder and attention deficit/hyperactivity disorder (ADHD). CONCLUSIONS: Treatment of Tourette syndrome combined with ADHD is often challenging. Alpha 2 agonists, such as guanfacine, or non stimulant options such as atomoxetine, where available, are worth considering, although many individuals with Tourette syndrome and ADHD can be successfully treated with judicious doses of stimulant medications.

Clinical spectrum of succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder affecting CNS gamma-aminobutyric acid (GABA) degradation. SSADH, in conjunction with GABA transaminase, converts GABA to succinate. In the absence of SSADH, GABA is converted to 4-OH-butyrate. The presence of 4-OH-butyrate, a highly volatile compound, may be undetected on routine organic acid analysis. Urine organic acid testing was modified at the authors' institution in 1999 to screen for the excretion of 4-OH-butyrate by selective ion monitoring gas chromatography-mass spectrometry in addition to total ion chromatography. Since then, five patients with 4-hydroxybutyric aciduria have been identified. The authors add the clinical, neuroimaging, and EEG findings from a new cohort of patients to 51 patients reported in the literature with clinical details. Ages ranged from 1 to 21 years at diagnosis. Clinical findings include mild-moderate mental retardation, disproportionate language dysfunction, hypotonia, hyporeflexia, autistic behaviors, seizures, and hallucinations. Brain MRI performed in five patients at the authors' institution revealed symmetric increased T2 signal in the globus pallidi. SSADH deficiency is an under-recognized, potentially manageable neurometabolic disorder. Urine organic acid analysis should include a sensitive method for the detection of 4-hydroxybutyrate and should be obtained from patients with mental retardation or neuropsychiatric disturbance of unknown etiology.

[Syndrome of attention deficit with hyperactivity as the expression of an organic functional disorder]. / El sindrome de déficit de atención con hiperactividad como expresion de un trastorno funcional orgánico.

INTRODUCTION: The diagnosis of ADHD can be determined reliably from the clinical history, but the causes and pathophysiology of the disorder remain unclear. CONCLUSIONS: Recent findings using magnetic resonance imaging, and imaging with PET and SPECT, as well as studies that probe brain functioning through transcranial magnetic stimulation suggest that circuits linking prefrontal cortex, striatum, and cerebellum are not functioning normally in ADHD.

El síndrome de déficit de atención con hiperactividadcomo expresión de un trastorno funcional orgánico / Syndrome of attention deficit with hyperactivity as the expression of an organic functional disorder

Introducción. El diagnóstico de SDAHA se determina de acuerdo con la historia clínica; sin embargo, las causas y la fisiopatología del trastorno en sí permanecen aún sin clarificar. Conclusiones. Estudios recientes usando imágenes de resonancia magnética, estudios de PET y SPECT, así como estudios que evalúan el funcionamiento cerebral y la estimulación magnética transcraneal, sugieren que alteraciones en los circuitos neurales que unen la corteza prefrontal, el estriado y el cerebelo se implicarían en las manifestaciones clínicas de pacientes con SDAHA (AU)

[Right hemisphere syndrome in children: functional and maturity correlation of non-verbal learning disabilities]. / Síndrome del hemisferio derecho en niños: correlación funcional y madurativa de los trastornos del aprendizaje no verbales.

INTRODUCTION: This review presents the maturational model of the right hemisphere syndrome in children, its clinical manifestations and its relationship with non-verbal learning disabilities. DEVELOPMENT AND CONCLUSIONS: The white matter model proposed by Rourke is presented and the clinical symptoms that are generally associated with right hemisphere dysfunction, independent of which hemisphere is affected, are highlighted. It has been proposed that the right hemisphere have proportionally more white matter than the left hemisphere which implies different adaptation processes for each one after brain lesions. There are different factors that determine these results: brain plasticity acts in different ways in each hemisphere; early brain injuries, affect specially right hemispheric functioning in its abilities to be in charge of new material processing and building new schemes that are also used by the left hemisphere. Some pathologies that are related with the clinical manifestations of non-verbal learning disabilities are presented. According with this model, they display basic neuropsychological features, even though their clinical manifestations could change between them. The Attention Deficit Hyperactivity disorder is specially considered as the most recent evidence of right hemispheric dysfunction, although results in this pathology are controversial, from the neuropsychological point of view. In general, the right hemisphere lesion in children has different implications when it is compared with adult's lesions. The white matter model could explain different processes in the plasticity brain mechanism. Preservation of basic language aspects is observed, but a deficit in non-verbal abilities that interferes with normal functioning is a rule. A specific clinical profile of assets and deficits is presented in most of the cases. These characteristics should be considered in treatment implementations.

Neuróloga y neuropsicóloga infantil. Santafé de bogotá, colombia / Right hemisphere syndrome in children: functional and maturity/maturing correlation of non-verbal learning disabilities

Introducción. Esta revisión analiza un modelo de maduración del síndrome del hemisferio derecho en los niños, sus manifestaciones clínicas y su relación con los problemas del aprendizaje no verbal. Desarrollo y conclusiones. Se describe el modelo propuesto por Rourke de la sustancia blanca y los síntomas clínicos que van generalmente asociados con la disfunción del hemisferio derecho, al margen de qué hemisferio sea el afectado. Se ha señalado que el hemisferio derecho tiene proporcionalmente más sustancia blanca que el izquierdo, lo que implica un proceso de adaptación diferente para cada uno de los hemisferios tras la lesión cerebral. Hay factores diferentes que determinan estos hallazgos. La plasticidad cerebral tiene diferentes modos de actuar en cada hemisferio. Las heridas cerebrales tempranas afectan principalmente al funcionamiento del hemisferio derecho en sus capacidades del proceso de materia nueva y de la construcción de nuevos esquemas, que son también del uso del hemisferio izquierdo. Se presentan algunos cuadros patológicos relacionados con las manifestaciones clínicas de los trastornos del aprendizaje no verbal. El trastorno por déficit de atención con hiperactividad se considera como evidencia reciente de disfunción del hemisferio derecho, aunque los resultados anatomopatológicos no son concluyentes desde el punto de vista neurofisiológico. En general, la lesión del hemisferio derecho en niños tiene implicaciones diferentes al compararlo con las lesiones del adulto. El modelo de la sustancia blanca podría explicar procesos diferentes en el mecanismo de la plasticidad cerebral. Se observa la conservación de algunos aspectos del lenguaje básico, pero el déficit de las habilidades no verbales que interfiere en el funcionamiento normal es la regla. Se presenta en la mayoría de los casos un perfil clínico específico de habilidades y deficiencias. Estas características deben de tenerse en cuenta a la hora de indicar el tratamiento (AU)