The severity of attention-deficit/hyperactivity disorder (ADHD) symptoms is a major predictor of ... more 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 inter...
The neurobiologic basis of autism is reviewed, with discussion of evidence from genetic, magnetic... more The neurobiologic basis of autism is reviewed, with discussion of evidence from genetic, magnetic resonance imaging, neuropathology, and functional neuroimaging studies. Although autism is a behaviorally valid syndrome, it is remarkably heterogeneous and involves multiple developmental domains as well as a wide range of cognitive, language, and socioemotional functioning. Although multiple etiologies are implicated, recent advances have identified common themes in pathophysiology. Genetic factors play a primary role, based on evidence from family studies, identification of putative genes using genome-wide linkage analyses, and comorbidities with known genetic mutations. The RELN gene, which codes for an extracellular protein guiding neuronal migration, has been implicated in autism. Numerous neuropathologic changes have been described, including macroencephaly, acceleration and then deceleration in brain growth, increased neuronal packing and decreased cell size in the limbic system...
Genetics in medicine : official journal of the American College of Medical Genetics
Complex genetic traits refer to those phenotypes not fitting patterns of Mendelian segregation an... more Complex genetic traits refer to those phenotypes not fitting patterns of Mendelian segregation and/or assortment but exhibiting a preferential familial clustering that cannot be explained by cultural or environmental causes. Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood and probably the most controversial. ADHD has been considered a complex genetic trait based upon the absence of a clear-cut boundary between affected and unaffected status. Furthermore, its high comorbidity with other disorders strongly suggests complex epistatic or pleiotropic effects acting in common with the environmental influences. This implies that the same gene or genes is or are associated with different and concurrently occurring phenotypes. In this study, we will review clinical and epidemiological aspects related to the ADHD phenotype, which are considered either as categorical or continuous traits. We also will discuss genetic models underlying...
Journal of child and adolescent psychopharmacology, 2004
Neuroleptics are generally highly effective in suppressing tics, but their many adverse effects l... more Neuroleptics are generally highly effective in suppressing tics, but their many adverse effects limit their usefulness. Animal studies have shown that, compared with both typical and atypical neuroleptics, metoclopramide has effects that are regionally circumscribed to rat motor striatum. Based on this observation and two prior case reports, metoclopramide was openly prescribed and individually titrated to diminish tics in 10 patients with Tourette syndrome. All patients improved on the Yale Global Tic Severity Scale by an average of 55%. Although we did not observe frank extrapyramidal symptoms, including tardive dyskinesia, these data are not sufficient to support clinical recommendations because of many limitations, including the absence of systematic ratings of nontic abnormal movements. However, controlled clinical studies and additional basic investigations of metoclopramide are warranted.
Human succinic semialdehyde dehydrogenase deficiency, an autosomal recessive disorder of γ-aminob... more Human succinic semialdehyde dehydrogenase deficiency, an autosomal recessive disorder of γ-aminobutyric acid (GABA) catabolism, was modeled by a murine model sharing the phenotype of ataxia and seizures. Magnetic resonance imaging (MRI) with volumetry was obtained on 7 patients versus controls, and MRI with stereology was derived in 3 murine genotypes: null, wild-type, and heterozygous mutants. All patients had T1 hypointensity and T2 hyperintensity in globus pallidus, and 5 also had similar changes in subthalamic and cerebellar dentate nuclei. There was a trend for patients to have a smaller cerebellar vermis. Homozygous null mice had significantly lower total brain and cerebellar volumes than wild-types and heterozygotes. Stereology confirmed cerebellar atrophy and was otherwise normal in multiple regions. Cerebellar volume loss is present in the murine disorder with a trend for cerebellar atrophy in patients. Reduced cerebellar volume can reflect neurodegeneration and may be rela...
During the last two decades, neuroimaging studies have improved our knowledge of brain developmen... more During the last two decades, neuroimaging studies have improved our knowledge of brain development and contributed to our understanding of disorders involving the developing brain. Differences in cerebral anatomy have been determined in autism spectrum disorder (ASD). Morphological studies by magnetic resonance imaging have provided evidence of structural differences in ASD compared with the normal population. This has enhanced our view of autism as a neurobiological disorder corresponding with different stages and events in brain development. Alterations in volume of the total brain and specifically the cerebellum, frontal lobe, and limbic system have been identified. There appears to be a pattern of increased and then decreased rate of brain growth over time. We integrate these observations with neurobehavioral findings to provide a developmental hypothesis of the pathophysiology of autism. Semin Pediatr Neurol 11:205-213
In a neurofibromatosis type 1 murine model, treatment with lovastatin reversed cognitive disabili... more In a neurofibromatosis type 1 murine model, treatment with lovastatin reversed cognitive disabilities. We report on a phase I study examining the safety and tolerability of lovastatin in children with neurofibromatosis type 1. Twenty-four children with neurofibromatosis type 1 underwent a doseescalation protocol for 3 months to identify the maximum tolerated dose and potential toxicity. Minimal side effects were evident, and no child experienced dose-limiting toxicity. Cognitive evaluations were completed before and after treatment, and the results suggested improvement in areas of verbal and nonverbal memory. Additional analyses, using reliable change indices, indicated improvements exceeding those of test-retest or practice effects in some participants. These observations may be analogous to the improvements observed in a neurofibromatosis type 1 murine model treated with lovastatin, although further study and replication are required. The safety and preliminary cognitive results support the need for a larger phase II trial in this population.
Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting th... more 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 familybased 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.
Journal of the American Academy of Child & Adolescent Psychiatry, 2008
Objective-Genetic studies of attention-deficit/hyperactivity disorder (ADHD) generally use discre... more Objective-Genetic studies of attention-deficit/hyperactivity disorder (ADHD) generally use discrete DSM-IV subtypes to define diagnostic status. To improve correspondence between phenotypic variance and putative susceptibility genes, multivariate classification methods such as latent class analysis (LCA) have been proposed. The aim of this study was to perform LCA in a sample of 1,010 individuals from a nationwide recruitment of unilineal nuclear families with at least one child with ADHD and another child either affected or clearly unaffected.
Difficulties in neurocognition and social interaction are the most prominent causes of morbidity ... more Difficulties in neurocognition and social interaction are the most prominent causes of morbidity and long-term disability in children with neurofibromatosis type 1 (NF1). Symptoms of attention-deficit-hyperactivity disorder (ADHD) have also been extensively recognized in NF1. However, systematic evaluation of symptoms of autism spectrum disorder (ASD) in children with NF1 has been limited. We present a retrospective, cross-sectional study of the prevalence of symptoms of ASD and ADHD and their relationship in a consecutive series of 66 patients from our NF1 clinic. The Social Responsiveness Scale and the Vanderbilt ADHD Diagnostic Parent Rating Scale were used to assess symptoms of ASD and ADHD. Sixty-six participants (42 males, 24 females) were included in this study. Mean age at assessment was 10 years 11 months (SD 5 y 4 mo). Forty percent of our NF1 sample had raised symptom levels reaching clinical significance on the Social Responsiveness Scale (T ≥ 60), and 14% reached levels...
New findings suggest that attention deficit and hyperactivity disorder (ADHD) is the most common ... more New findings suggest that attention deficit and hyperactivity disorder (ADHD) is the most common behavioral variant associated with a mental condition. ADHD prevalence reaches figures of 18% in populations worldwide. Furthermore, genetic variants conferring susceptibility to develop ADHD are not rare but very frequent and eventually totally fixed in some populations. These patterns of evolution can be associated with the fact that this behavioral trait had provided selective advantage. However, this behavioral trait is now under scrutiny because of new emerging social necessities. Recent molecular and clinical evidence supports Thom Hartmann's Hunter-Farmer theory, reaffirming that ADHD might be an anachronic behavioral trait.
Succinic semialdehyde dehydrogenase deficiency is a rare disorder of the degradation pathway of g... more Succinic semialdehyde dehydrogenase deficiency is a rare disorder of the degradation pathway of gamma-aminobutyric acid. The disorder is detected when 4-hydroxybutyric aciduria is present on urine organic acid analysis, and is subsequently confirmed by enzyme measurement on leucocytes. The disorder has been identified in approximately 350 individuals worldwide. We review the clinical features in 60 patients. The most common characteristics are developmental delay maximally involving expressive language, hypotonia, mental retardation, ataxia, and behavioral problems. Seizures occur in approximately half of patients, and include tonic-clonic, absence, and myoclonic seizures, including status epilepticus. Electroencephalographic findings are background slowing and generalized and focal epileptiform discharges. Magnetic resonance imaging typically reveals increased T2-weighted signal of the globus pallidus bilaterally, with variable involvement of white matter and the cerebellar dentate nucleus. Preliminary human cerebrospinal fluid measurements are consistent with neurometabolic aberrations documented in the murine animal model, with elevations in gamma-aminobutyric acid, gamma-hydroxybutyrate, and homocarnosine, and low glutamine. Succinic semialdehyde dehydrogenase deficiency may be an underrecognized neurometabolic disorder with a nonspecific and wide phenotypic spectrum, and carries implications for a comprehensive fundamental understanding of interrelations between multiple neurotransmitter systems.
Close Window. Close Window. Thank you for choosing to subscribe to the eTOC for Genetics in Medic... more Close Window. Close Window. Thank you for choosing to subscribe to the eTOC for Genetics in Medicine. Enter your Email address: Wolters Kluwer Health may email you for journal alerts and information, but is committed to ...
ADHD Attention Deficit and Hyperactivity Disorders, 2011
Endophenotypes are neurobiological markers cosegregating and associated with illness. These bioma... more 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.
In the Neurofibromatosis type 1 (NF1) mouse model, lovastatin, used clinically for hypercholester... more In the Neurofibromatosis type 1 (NF1) mouse model, lovastatin, used clinically for hypercholesterolemia, improves cognitive dysfunction. While such impairment has been studied in NF1, the neural substrates remain unclear. The aim of this imaging add-on to a phase-1 open-label trial was to examine the effect of lovastatin on Default Network (DN) resting state functional connectivity (RSFC). Seven children with NF1 (aged 11.9±2.2; 1 female) were treated with lovastatin once daily for 12 weeks. A 7-minute 3-Tesla echo-planar-imaging scan was collected one day before beginning treatment (off-drug) and the last day of treatment (on-drug) while Manuscript performing a Flanker task. After regressing-out task-associated variance, we used the residual time series as "continuous resting-state data" for RSFC analyses using 11 DN regions of interest. For qualitative comparisons, we included a group of 19 typically developing children (TDC) collected elsewhere. In the on-drug condition, lovastatin increased long-range positive RSFC within DN core regions (i.e., anterior medial prefrontal cortex and posterior cingulate cortex, PCC). In addition, lovastatin produced less diffuse local RSFC in the dorsomedial prefrontal cortex and PCC. The pattern of RSFC observed in the NF1 participants when on-drug closely resembled the RSFC patterns exhibited by the TDC. Lovastatin administration in this open trial regulated anterior-posterior long-range and local RSFC within the DN. These preliminary results are consistent with a role for lovastatin in normalization of developmental processes and with apparent benefits in a mouse NF1 model.
The severity of attention-deficit/hyperactivity disorder (ADHD) symptoms is a major predictor of ... more 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 inter...
The neurobiologic basis of autism is reviewed, with discussion of evidence from genetic, magnetic... more The neurobiologic basis of autism is reviewed, with discussion of evidence from genetic, magnetic resonance imaging, neuropathology, and functional neuroimaging studies. Although autism is a behaviorally valid syndrome, it is remarkably heterogeneous and involves multiple developmental domains as well as a wide range of cognitive, language, and socioemotional functioning. Although multiple etiologies are implicated, recent advances have identified common themes in pathophysiology. Genetic factors play a primary role, based on evidence from family studies, identification of putative genes using genome-wide linkage analyses, and comorbidities with known genetic mutations. The RELN gene, which codes for an extracellular protein guiding neuronal migration, has been implicated in autism. Numerous neuropathologic changes have been described, including macroencephaly, acceleration and then deceleration in brain growth, increased neuronal packing and decreased cell size in the limbic system...
Genetics in medicine : official journal of the American College of Medical Genetics
Complex genetic traits refer to those phenotypes not fitting patterns of Mendelian segregation an... more Complex genetic traits refer to those phenotypes not fitting patterns of Mendelian segregation and/or assortment but exhibiting a preferential familial clustering that cannot be explained by cultural or environmental causes. Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood and probably the most controversial. ADHD has been considered a complex genetic trait based upon the absence of a clear-cut boundary between affected and unaffected status. Furthermore, its high comorbidity with other disorders strongly suggests complex epistatic or pleiotropic effects acting in common with the environmental influences. This implies that the same gene or genes is or are associated with different and concurrently occurring phenotypes. In this study, we will review clinical and epidemiological aspects related to the ADHD phenotype, which are considered either as categorical or continuous traits. We also will discuss genetic models underlying...
Journal of child and adolescent psychopharmacology, 2004
Neuroleptics are generally highly effective in suppressing tics, but their many adverse effects l... more Neuroleptics are generally highly effective in suppressing tics, but their many adverse effects limit their usefulness. Animal studies have shown that, compared with both typical and atypical neuroleptics, metoclopramide has effects that are regionally circumscribed to rat motor striatum. Based on this observation and two prior case reports, metoclopramide was openly prescribed and individually titrated to diminish tics in 10 patients with Tourette syndrome. All patients improved on the Yale Global Tic Severity Scale by an average of 55%. Although we did not observe frank extrapyramidal symptoms, including tardive dyskinesia, these data are not sufficient to support clinical recommendations because of many limitations, including the absence of systematic ratings of nontic abnormal movements. However, controlled clinical studies and additional basic investigations of metoclopramide are warranted.
Human succinic semialdehyde dehydrogenase deficiency, an autosomal recessive disorder of γ-aminob... more Human succinic semialdehyde dehydrogenase deficiency, an autosomal recessive disorder of γ-aminobutyric acid (GABA) catabolism, was modeled by a murine model sharing the phenotype of ataxia and seizures. Magnetic resonance imaging (MRI) with volumetry was obtained on 7 patients versus controls, and MRI with stereology was derived in 3 murine genotypes: null, wild-type, and heterozygous mutants. All patients had T1 hypointensity and T2 hyperintensity in globus pallidus, and 5 also had similar changes in subthalamic and cerebellar dentate nuclei. There was a trend for patients to have a smaller cerebellar vermis. Homozygous null mice had significantly lower total brain and cerebellar volumes than wild-types and heterozygotes. Stereology confirmed cerebellar atrophy and was otherwise normal in multiple regions. Cerebellar volume loss is present in the murine disorder with a trend for cerebellar atrophy in patients. Reduced cerebellar volume can reflect neurodegeneration and may be rela...
During the last two decades, neuroimaging studies have improved our knowledge of brain developmen... more During the last two decades, neuroimaging studies have improved our knowledge of brain development and contributed to our understanding of disorders involving the developing brain. Differences in cerebral anatomy have been determined in autism spectrum disorder (ASD). Morphological studies by magnetic resonance imaging have provided evidence of structural differences in ASD compared with the normal population. This has enhanced our view of autism as a neurobiological disorder corresponding with different stages and events in brain development. Alterations in volume of the total brain and specifically the cerebellum, frontal lobe, and limbic system have been identified. There appears to be a pattern of increased and then decreased rate of brain growth over time. We integrate these observations with neurobehavioral findings to provide a developmental hypothesis of the pathophysiology of autism. Semin Pediatr Neurol 11:205-213
In a neurofibromatosis type 1 murine model, treatment with lovastatin reversed cognitive disabili... more In a neurofibromatosis type 1 murine model, treatment with lovastatin reversed cognitive disabilities. We report on a phase I study examining the safety and tolerability of lovastatin in children with neurofibromatosis type 1. Twenty-four children with neurofibromatosis type 1 underwent a doseescalation protocol for 3 months to identify the maximum tolerated dose and potential toxicity. Minimal side effects were evident, and no child experienced dose-limiting toxicity. Cognitive evaluations were completed before and after treatment, and the results suggested improvement in areas of verbal and nonverbal memory. Additional analyses, using reliable change indices, indicated improvements exceeding those of test-retest or practice effects in some participants. These observations may be analogous to the improvements observed in a neurofibromatosis type 1 murine model treated with lovastatin, although further study and replication are required. The safety and preliminary cognitive results support the need for a larger phase II trial in this population.
Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting th... more 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 familybased 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.
Journal of the American Academy of Child & Adolescent Psychiatry, 2008
Objective-Genetic studies of attention-deficit/hyperactivity disorder (ADHD) generally use discre... more Objective-Genetic studies of attention-deficit/hyperactivity disorder (ADHD) generally use discrete DSM-IV subtypes to define diagnostic status. To improve correspondence between phenotypic variance and putative susceptibility genes, multivariate classification methods such as latent class analysis (LCA) have been proposed. The aim of this study was to perform LCA in a sample of 1,010 individuals from a nationwide recruitment of unilineal nuclear families with at least one child with ADHD and another child either affected or clearly unaffected.
Difficulties in neurocognition and social interaction are the most prominent causes of morbidity ... more Difficulties in neurocognition and social interaction are the most prominent causes of morbidity and long-term disability in children with neurofibromatosis type 1 (NF1). Symptoms of attention-deficit-hyperactivity disorder (ADHD) have also been extensively recognized in NF1. However, systematic evaluation of symptoms of autism spectrum disorder (ASD) in children with NF1 has been limited. We present a retrospective, cross-sectional study of the prevalence of symptoms of ASD and ADHD and their relationship in a consecutive series of 66 patients from our NF1 clinic. The Social Responsiveness Scale and the Vanderbilt ADHD Diagnostic Parent Rating Scale were used to assess symptoms of ASD and ADHD. Sixty-six participants (42 males, 24 females) were included in this study. Mean age at assessment was 10 years 11 months (SD 5 y 4 mo). Forty percent of our NF1 sample had raised symptom levels reaching clinical significance on the Social Responsiveness Scale (T ≥ 60), and 14% reached levels...
New findings suggest that attention deficit and hyperactivity disorder (ADHD) is the most common ... more New findings suggest that attention deficit and hyperactivity disorder (ADHD) is the most common behavioral variant associated with a mental condition. ADHD prevalence reaches figures of 18% in populations worldwide. Furthermore, genetic variants conferring susceptibility to develop ADHD are not rare but very frequent and eventually totally fixed in some populations. These patterns of evolution can be associated with the fact that this behavioral trait had provided selective advantage. However, this behavioral trait is now under scrutiny because of new emerging social necessities. Recent molecular and clinical evidence supports Thom Hartmann's Hunter-Farmer theory, reaffirming that ADHD might be an anachronic behavioral trait.
Succinic semialdehyde dehydrogenase deficiency is a rare disorder of the degradation pathway of g... more Succinic semialdehyde dehydrogenase deficiency is a rare disorder of the degradation pathway of gamma-aminobutyric acid. The disorder is detected when 4-hydroxybutyric aciduria is present on urine organic acid analysis, and is subsequently confirmed by enzyme measurement on leucocytes. The disorder has been identified in approximately 350 individuals worldwide. We review the clinical features in 60 patients. The most common characteristics are developmental delay maximally involving expressive language, hypotonia, mental retardation, ataxia, and behavioral problems. Seizures occur in approximately half of patients, and include tonic-clonic, absence, and myoclonic seizures, including status epilepticus. Electroencephalographic findings are background slowing and generalized and focal epileptiform discharges. Magnetic resonance imaging typically reveals increased T2-weighted signal of the globus pallidus bilaterally, with variable involvement of white matter and the cerebellar dentate nucleus. Preliminary human cerebrospinal fluid measurements are consistent with neurometabolic aberrations documented in the murine animal model, with elevations in gamma-aminobutyric acid, gamma-hydroxybutyrate, and homocarnosine, and low glutamine. Succinic semialdehyde dehydrogenase deficiency may be an underrecognized neurometabolic disorder with a nonspecific and wide phenotypic spectrum, and carries implications for a comprehensive fundamental understanding of interrelations between multiple neurotransmitter systems.
Close Window. Close Window. Thank you for choosing to subscribe to the eTOC for Genetics in Medic... more Close Window. Close Window. Thank you for choosing to subscribe to the eTOC for Genetics in Medicine. Enter your Email address: Wolters Kluwer Health may email you for journal alerts and information, but is committed to ...
ADHD Attention Deficit and Hyperactivity Disorders, 2011
Endophenotypes are neurobiological markers cosegregating and associated with illness. These bioma... more 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.
In the Neurofibromatosis type 1 (NF1) mouse model, lovastatin, used clinically for hypercholester... more In the Neurofibromatosis type 1 (NF1) mouse model, lovastatin, used clinically for hypercholesterolemia, improves cognitive dysfunction. While such impairment has been studied in NF1, the neural substrates remain unclear. The aim of this imaging add-on to a phase-1 open-label trial was to examine the effect of lovastatin on Default Network (DN) resting state functional connectivity (RSFC). Seven children with NF1 (aged 11.9±2.2; 1 female) were treated with lovastatin once daily for 12 weeks. A 7-minute 3-Tesla echo-planar-imaging scan was collected one day before beginning treatment (off-drug) and the last day of treatment (on-drug) while Manuscript performing a Flanker task. After regressing-out task-associated variance, we used the residual time series as "continuous resting-state data" for RSFC analyses using 11 DN regions of interest. For qualitative comparisons, we included a group of 19 typically developing children (TDC) collected elsewhere. In the on-drug condition, lovastatin increased long-range positive RSFC within DN core regions (i.e., anterior medial prefrontal cortex and posterior cingulate cortex, PCC). In addition, lovastatin produced less diffuse local RSFC in the dorsomedial prefrontal cortex and PCC. The pattern of RSFC observed in the NF1 participants when on-drug closely resembled the RSFC patterns exhibited by the TDC. Lovastatin administration in this open trial regulated anterior-posterior long-range and local RSFC within the DN. These preliminary results are consistent with a role for lovastatin in normalization of developmental processes and with apparent benefits in a mouse NF1 model.
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