Biomedical subjects

David Hessl

Publications and source records attributed to David Hessl.

13 recordsLinked to original sources

PubMed2006

Amygdala dysfunction in men with the fragile X premutation.

Premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are associated with autism spectrum disorder in childhood, premature ovarian failure, and the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS, and perhaps the other clinical presentations among carriers, are thought to be due to toxic gain-of-function of elevated levels of the expanded-repeat FMR1 mRNA. Previous structural MRI studies have implicated the amygdala as a potential site of dysfunction underlying social deficits and/or risk for FXTAS. As a preliminary investigation of this possible association, adult males with the premutation, and male controls matched for IQ, age and education, completed three protocols that probe amygdala and sympathetic function: (i) a functional MRI paradigm that measures brain response to fearful faces; (ii) a fear-potentiated startle paradigm that differentiates responses to fearful faces and fearful non-social images and (iii) measurement of skin conductance level during a brief social encounter. Compared with controls, men with the FMR1 premutation demonstrated diminished brain activation in the amygdala and several brain areas that mediate social cognition while viewing fearful faces. The reduced amygdala activation in the premutation group was significantly associated with self-report of psychological symptoms on the Symptom Checklist-90--Revised. These men also displayed a lack of startle potentiation while viewing fearful faces and showed reduced skin conductance response when greeting an unfamiliar experimenter in comparison with the control group. The current findings may be related to social cognition deficits reported previously in children and adults with the premutation. The aetiology for this dysfunction may be elevated FMR1 mRNA or reduced FMR1 protein that occurs in carriers with higher premutation CGG repeat alleles.

Adult↗

PubMed2006

Molecular and cognitive predictors of the continuum of autistic behaviours in fragile X.

The distributions of scores for autistic behaviours obtained from the Autism Diagnostic Observation Scale-Generic (ADOS-G) were investigated in 147 males and females affected with the full mutation in the fragile X mental retardation 1 (FMR1) gene, in 59 individuals with the premutation, and in 42 non-fragile X relatives, aged 4-70 years. The scores representing communication and social interaction were continuously distributed across the two fragile X groups, and they were significantly elevated compared with the non-fragile X controls. Strong relationships were found between both these scores and FMRP deficits, but they became insignificant for social interaction, and the sum of social interaction and communication scores, when FSIQ was included as another predictor of autism scores. Other significant predictors of these scores in both sexes were those executive skills which related to verbal fluency, and to the regulation and control of motor behaviour. Overall, our data have shown that cognitive impairment, especially of verbal skills, best explains the comorbidity of autism and fragile X. This implies some more fundamental perturbations of specific neural connections which are essential for both specific behaviours and cognition. We also emphasize that FXS offers a unique molecular model for autism since FMRP regulates the translation of many other genes involved in synaptic formation and plasticity which should be natural targets for further exploration.

Adolescent↗

PubMed2006

Autism spectrum disorders and attention-deficit/hyperactivity disorder in boys with the fragile X premutation.

Fragile X syndrome (FXS) is caused by a full mutation expansion (>200 CGG repeats) in the FMR1 gene that results in a deficiency of the fragile X mental retardation protein. Although most individuals with the premutation (55-200 CGG repeats) are considered unaffected by FXS, recent case studies have documented children with the premutation who have cognitive deficits, behavioral problems, and/or autism spectrum disorders. The objective of this study was to compare the prevalence of autism spectrum disorders (ASD) and attention-deficit hyperactivity disorder (ADHD) symptoms in boys with the premutation who presented as probands, in brothers with the premutation who did not present as probands, and in normal brothers of premutation and/or full mutation carriers. Participants included 43 male children: 14 probands who presented to clinic, 13 nonprobands who were identified through cascade testing (routine genetic testing of family members after identification of a proband) and confirmed to have the premutation, and a control group of 16 male siblings of individuals with the fragile X premutation or full mutation who were negative for the FMR1 mutation. Participants came from 1 of 2 collaborative sites: University of California, Davis and La Trobe University in Australia. Parents completed the Conners' Global Index-Parent Version for assessing symptoms of ADHD and the Social Communication Questionnaire (SCQ) for identifying symptoms of ASD. Children who were in the ASD range on the SCQ (n = 13) underwent further evaluation with either the Autism Diagnostic Observation Schedule-Generic (n = 10) or the Autism Diagnostic Interview-Revised (n = 3). A final diagnosis of ASD included clinical assessment utilizing DSM-IV-TR criteria in addition to the standardized assessments. There was a higher rate of ASD in boys with the premutation presenting as probands (p < 0.001) or nonprobands (p < .04) compared with sibling controls without the premutation. In addition, probands had a significant increase in ADHD symptoms compared with controls (p < .0001). Of the probands, 93% had symptoms of ADHD and 79% had ASD. In the nonproband premutation group, 38% had symptoms of ADHD and 8% had ASD. Thirteen percent of sibling controls had symptoms of ADHD and none had ASD. IQ scores were similar in all 3 groups (p = .13), but the use of psychotropic medications was significantly higher in probands with the premutation compared with that in controls (p < .0001). Developmental problems have been observed in premutation carriers, particularly those who present clinically with behavioral difficulties. Although this study is based on a small sample size, it suggests that premutation carriers, even those who do not present clinically, may be at increased risk for an ASD and/or symptoms of ADHD. If the premutation is identified through cascade testing, then further assessment should be carried out for symptoms of ADHD, social deficits, or learning disabilities.

Adolescent↗

PubMed2006

Social behavior and cortisol reactivity in children with fragile X syndrome.

OBJECTIVE: To examine the association between limbic-hypothalamic-pituitary-adrenal (L-HPA) axis reactivity and social behavior in children with fragile X syndrome (FXS). METHOD: Salivary cortisol changes and concurrent anxiety-related behaviors consistent with the behavioral phenotype of FXS were measured in 90 children with the fragile X full mutation and their 90 unaffected siblings during a social challenge task in the home. RESULTS: Boys and girls with FXS demonstrated more gaze aversion, task avoidance, behavioral signs of distress, and poorer vocal quality than the unaffected siblings. Multiple regression analyses showed that after accounting for effects of IQ, gender, age, quality of the home environment, and basal cortisol level, cortisol reactivity to the task was significantly associated with social gaze in children with FXS. The most gaze-aversive children with FXS had cortisol reductions, whereas those with more eye contact demonstrated the most cortisol reactivity. Unaffected siblings demonstrated an opposite pattern in which less eye contact was associated with increased cortisol reactivity. CONCLUSIONS: Results of the study suggest a unique relation between abnormal gaze behavior and L-HPA mediated stress reactivity in FXS.

Child↗

PubMed2006

Dementia with mood symptoms in a fragile X premutation carrier with the fragile X-associated tremor/ataxia syndrome: clinical intervention with donepezil and venlafaxine.

The authors present a case of a patient with dementia with mood symptoms and multiple neurological manifestations of fragile X-associated tremor/ataxia syndrome (FXTAS). Despite a gradually deteriorating neurological course, he was managed for 2 years with combination therapy of donepezil and venlafaxine, which resulted in improvement and relative stabilization of his psychiatric status. Psychiatrists are hereby alerted to the description of a novel dementia syndrome that may respond to pharmacological intervention commonly used for other dementias.

Aged↗

PubMed2005

Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation.

Until recently, individuals with premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene were believed to be psychologically unaffected. However, the recent documentation of abnormal elevation of FMR1 mRNA, discovery of fragile X-associated tremor/ataxia syndrome (FXTAS), and reports of psychiatric disorders in children and adults with the premutation have suggested a pathogenic gene-brain-behavior mechanism. In a large collaborative study, 68 men and 144 women with the FMR1 premutation completed a psychological symptoms checklist and FMR1 genetic testing, including determination of CGG repeat size, percentage of FMR1 protein (FMRP)-positive lymphocytes, and FMR1 mRNA levels. Relative to published norms, men and women with FXTAS symptoms reported higher levels of several types of psychological symptoms. In addition, men and women with the premutation and no overt evidence of FXTAS reported higher levels of obsessive-compulsive symptoms. Elevated FMR1 mRNA, but not CGG repeat size or reduced FMRP (as measured by immunocytochemistry), was significantly associated with increased psychological symptoms, predominantly obsessive-compulsive symptoms and psychoticism, in premutation men with and without FXTAS symptoms. There was no relationship between CGG repeat size, FMR1 mRNA or FMRP and psychological symptoms in premutation women unless the sample was restricted to those with skewed X-activation ratio toward >50% active premutation alleles. The results of this study support the hypothesis that FMR1 function is associated with psychological difficulties in individuals with the premutation, and provide evidence concordant with an RNA toxic gain-of-function model in a neuropsychiatric phenotype.

Female↗

PubMed2005

GRAND ROUNDS: an atypical progressive dementia in a male carrier of the fragile X premutation: an example of fragile X-associated tremor/ataxia syndrome.

This case study describes a 65-year-old man initially diagnosed with an atypical rapidly progressive dementia who subsequently participated in a research project at the MIND Institute at the University of California-Davis, where he was diagnosed with a recently identified neurodegenerative syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS). He was a carrier of the fragile X premutation and in later life developed tremor, gait ataxia, parkinsonism, and cognitive deficits that progressed very rapidly. This case study provides a detailed description of the individual's history, presenting symptoms, neuropsychological test results, and postmortem neuropathological analysis. Pathological findings showed diagnostic features of both FXTAS and Alzheimer's disease, which might help to explain the rapid progression of his dementia.

Aged↗

PubMed2004

The neuroanatomy and neuroendocrinology of fragile X syndrome.

Fragile X syndrome (FXS), caused by a single gene mutation on the X chromosome, offers a unique opportunity for investigation of gene-brain-behavior relationships. Recent advances in molecular genetics, human brain imaging, and behavioral studies have started to unravel the complex pathways leading to the cognitive, psychiatric, and physical features that are unique to this syndrome. In this article, we summarize studies focused on the neuroanatomy and neuroendocrinology of FXS. A review of structural imaging studies of individuals with the full mutation shows that several brain regions are enlarged, including the hippocampus, amygdala, caudate nucleus, and thalamus, even after controlling for overall brain volume. These regions mediate several cognitive and behavioral functions known to be aberrant in FXS such as memory and learning, information and sensory processing, and social and emotional behavior. Two regions, the cerebellar vermis, important for a variety of cognitive tasks and regulation of motor behavior, and the superior temporal gyrus, involved in processing complex auditory stimuli, are reported to be reduced in size relative to controls. Functional imaging, typically limited to females, has emphasized that individuals with FXS do not adequately recruit brain regions that are normally utilized by unaffected individuals to carry out various cognitive tasks, such as arithmetic processing or visual memory tasks. Finally, we review a number of neuroendocrine studies implicating hypothalamic dysfunction in FXS, including abnormal activation of the hypothalamic-pituitary-adrenal (HPA) axis. These studies may help to explain the abnormal stress responses, sleep abnormalities, and physical growth patterns commonly seen in affected individuals. In the future, innovative longitudinal studies to investigate development of neurobiologic and behavioral features over time, and ultimately empirical testing of pharmacological, behavioral, and even molecular genetic interventions using MRI are likely to yield significant positive changes in the lives of persons with FXS, as well as increase our understanding of the development of psychiatric and learning problems in the general population.

Adolescent↗

PubMed2003

Biological and environmental contributions to adaptive behavior in fragile X syndrome.

Fragile X syndrome is the most common cause of inherited developmental disability. The purpose of the present study is to understand how both biological and environmental influences affect the development of adaptive behavior in children with fragile X. In-home assessments were conducted on 120 children (80 boys and 40 girls) with the fragile X full mutation and their unaffected siblings (58 boys and 62 girls). Hierarchical multiple regression analyses were utilized. Independent variables included biological or demographic variables specific to the child (age, gender, full-scale IQ, and FMRP percentage), as well as factors specific to his/her environment (household income, home environment, maternal psychopathology, and effectiveness of educational/therapeutic services). Results of these analyses showed that for both boys with fragile X and the control sibling group, adaptive behavior was predicted by IQ, age, gender, and home environment. For girls with fragile X, adaptive behavior was most strongly associated with IQ. Adaptive behavior was not significantly associated with FMRP in boys or girls with fragile X. By examining the relative influences of biological and environmental factors on adaptive behavior in children with fragile X, we begin to lay the foundation for the development of more specific treatment studies in children with this disorder.

Adaptation, Psychological↗

PubMed2003

Factors associated with parenting stress in mothers of children with fragile X syndrome.

Whereas previous research has demonstrated elevated levels of parenting stress in parents of children with general developmental disability, there has been little investigation of stress in parents of children specifically affected by the common neurogenetic disorder fragile X syndrome (FraX). This study elucidates stress profiles in mothers of children with FraX and delineates the contribution of child characteristics, home environment, and maternal psychological functioning to specific dimensions of parental stress. Data on child, home, and family characteristics were collected from 75 families with a child affected by FraX. These characteristics were entered into multiple regression analyses with a domain or subscale of the Parenting Stress Index as the dependent variable in each analysis. The results demonstrated that aspects of child behavior, family cohesion, household income, and maternal psychopathology differentially correlate with specific dimensions of parenting stress. Determining the relative contribution of factors associated with stress will assist in the development of interventions to improve parental well-being in mothers of children with FraX.

Adolescent↗

PubMed2002

Diurnal salivary cortisol in pediatric posttraumatic stress disorder.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of posttraumatic stress disorder (PTSD). Additional information on basal cortisol levels in children exposed to trauma and experiencing PTSD symptoms may contribute to the understanding of the role of this axis in PTSD. METHODS: Fifty-one children (30 boys and 21 girls, mean age 10.7 years) with a history of exposure to trauma and PTSD symptoms were compared with 31 age- and gender-matched healthy control subjects. Salivary cortisol was obtained from participants during home measurements and was collected four times a day (prebreakfast, prelunch, predinner, and prebed) for up to 3 consecutive days. RESULTS: The clinical group demonstrated significantly elevated cortisol levels when compared with the control group. In addition, exploratory analyses revealed that girls with PTSD symptoms had significantly elevated cortisol levels when compared with boys with PTSD symptoms. CONCLUSIONS: The physiologic response of children with history of trauma and with PTSD symptoms may be characterized by heightened adrenal activity.

Adolescent↗

PubMed2002

Genetic and environmental influences on the cognitive outcomes of children with fragile X syndrome.

OBJECTIVE: To measure the genetic and environmental factors influencing the cognitive outcomes in children with fragile X, a common genetic disorder causing cognitive impairments. METHOD: In-home evaluations were conducted on 120 children (80 boys and 40 girls) with the fragile X full mutation and their unaffected siblings. RESULTS: Multiple regression analyses show that the cognitive outcomes for girls with fragile X are most strongly predicted by the mean IQ of their parents, with a small proportion of the variance accounted for by the quality of their home environment. FMR1 protein (FMRP) was associated with girls' levels of distractibility. Mean parental IQ was associated only with boys' Performance IQs, while FMRP was associated with boys' Full Scale IQs. The quality of boys' home environments accounted for more of the variance in their cognitive outcomes than it did for affected girls. CONCLUSIONS: Both biological/genetic factors and environmental factors are significant predictors of IQ in children with fragile X syndrome; however, the influence of specific factors differs between girls and boys. These findings lay the foundation for further investigation into biological and environmental interventions.

Child↗

PubMedDate not supplied

Preschool outcomes of children of depressed mothers: role of maternal behavior, contextual risk, and children's brain activity.

Children of depressed mothers are at risk for behavioral and emotional problems. Infants of depressed mothers exhibit behavioral disturbances and atypical frontal brain activity. The mechanisms by which children develop such vulnerabilities are not clear. Three-year-old children of mothers with (N = 65) and without (N = 59) a history of depression were assessed in terms of behavior problems and brain electrical activity. Children of mothers with chronic depression exhibited lower frontal and parietal brain activation compared with children of mothers without depression and those whose depression remitted. Depressed mothers reported higher contextual risk (e.g., marital discord and stress) and their children had more behavior problems. Children's frontal brain activation and contextual risk level mediated the relation between maternal depression and child behavior problems.

Adult↗