Hilgo Bruining

Psychiatric Characteristics in a Self-Selected Sample of Boys With Klinefelter Syndrome

BACKGROUND. Klinefelter syndrome is the most frequent chromosomal aneuploidy with a prevalence of 1 in 700. Klinefelter syndrome has been widely associated with cognitive impairment and language problems. No previous studies have systematically investigated the association of Klinefelter syndrome with psychiatric disorders in children and adolescents. To our knowledge, the only data available are from psychiatric inventories of adults with Klinefelter syndrome. OBJECTIVE. To explore the extent of psychiatric morbidity in children with Klinefelter syndrome. METHOD. Fifty-one subjects with Klinefelter syndrome aged 6 to 19 years were included through the Dutch Klinefelter association and 2 university medical centers. The sample was screened by using structured and standardized assessment procedures covering the full range of psychiatric problems and disorders. In addition, all boys were formally evaluated for the presence of a language disorder. RESULTS. A wide range of classifications could be applied, with language disorder (65% [33 of 51]) as the most prevalent disorder, followed by attention-deficit disorders (63% [32 of 51]) and autism spectrum disorder (27% [14 of 51]). Behavioral impairment was most evident among cases classified as autism spectrum disorder and psychotic disorder (12% [6 of 51]). CONCLUSIONS. Children with Klinefelter syndrome seem to be at risk for problems in social and language development, as well as for problems in regulation of emotion and behavior. This is reflected in the broad spectrum of psychiatric classifications applicable in the present selected sample. Health care professionals should be aware of an increased a priori possibility of psychiatric problems when confronted with a child with Klinefelter syndrome.

Dissecting the clinical heterogeneity of autism spectrum disorders through defined genotypes

Background The etiology of autism spectrum disorders (ASD) is largely determined by different genetic factors of variable impact. This genetic heterogeneity could be a factor to explain the clinical heterogeneity of autism spectrum disorders. Here, a first attempt is made to assess whether genetically more homogeneous ASD groups are associated with decreased phenotypic heterogeneity with respect to their autistic symptom profile. Methodology The autistic phenotypes of ASD subjects with 22q11 deletion syndrome (22q11DS) and ASD subjects with Klinefelter Syndrome (KS) were statistically compared to the symptom profile of a large (genetically) heterogeneous ASD sample. Autism diagnostic interview-revised (ADI-R) variables were entered in different statistical analyses to assess differences in symptom homogeneity and the feasibility of discrimination of group-specific ASD-symptom profiles. Principal Findings The results showed substantially higher symptom homogeneity in both the genetic disorder ASD groups in comparison to the heterogeneous ASD sample. In addition, a robust discrimination between 22q11-ASD and KS-ASD and idiopathic ASD phenotypes was feasible on the basis of a reduced number of autistic scales and symptoms. The lack of overlap in discriminating subscales and symptoms between KS-ASD and 22q11DS-ASD suggests that their autistic symptom profiles cluster around different points in the total diagnostic space of profiles present in the general ASD population. Conclusion The findings of the current study indicate that the clinical heterogeneity of ASDs may be reduced when subgroups based on a specific genotype are extracted from the idiopathic ASD population. The current strategy involving the widely used ADI-R offers a relatively straightforward possibility for assessing genotype-phenotype ASD relationships. Reverse phenotype strategies are becoming more feasible, given the accumulating evidence for the existence of genetic variants of large effect in a substantial proportion of the ASD population.

Food for thought: Dietary changes in essential fatty acid ratios and the increase in autism spectrum disorders

The last decades have shown a spectacular and partially unexplained rise in the prevalence of autism spectrum disorders (ASD). This rise in ASD seems to parallel changes in the dietary composition of fatty acids. This change is marked by the replacement of cholesterol by omega-6 (n-6) fatty acids in many of our food products, resulting in a drastically increased ratio of omega-6/omega-3 (n-6/n-3). In this context, we review the available knowledge on the putative role of fatty acids in neurodevelopment and describe how disturbances in n-6/n-3 ratios may contribute to the emergence of ASDs. Both clinical and experimental research is discussed. We argue that a change in the ratio of n-6/n-3, especially during early life, may induce developmental changes in brain connectivity, synaptogenesis, cognition and behavior that are directly related to ASD.

Behavioral signatures related to genetic disorders in autism.

BackgroundAutism spectrum disorder (ASD) is well recognized to be genetically heterogeneous. It is assumed that the genetic risk factors give rise to a broad spectrum of indistinguishable behavioral presentations.MethodsWe tested this assumption by analyzing the Autism Diagnostic Interview-Revised (ADI-R) symptom profiles in samples comprising six genetic disorders that carry an increased risk for ASD (22q11.2 deletion, Down’s syndrome, Prader-Willi, supernumerary marker chromosome 15, tuberous sclerosis complex and Klinefelter syndrome; total n = 322 cases, groups ranging in sample sizes from 21 to 90 cases). We mined the data to test the existence and specificity of ADI-R profiles using a multiclass extension of support vector machine (SVM) learning. We subsequently applied the SVM genetic disorder algorithm on idiopathic ASD profiles from the Autism Genetics Resource Exchange (AGRE).ResultsGenetic disorders were associated with behavioral specificity, indicated by the accuracy and certainty of SVM predictions; one-by-one genetic disorder stratifications were highly accurate leading to 63% accuracy of correct genotype prediction when all six genetic disorder groups were analyzed simultaneously. Application of the SVM algorithm to AGRE cases indicated that the algorithm could detect similarity of genetic behavioral signatures in idiopathic ASD subjects. Also, affected sib pairs in the AGRE were behaviorally more similar when they had been allocated to the same genetic disorder group.ConclusionsOur findings provide evidence for genotype-phenotype correlations in relation to autistic symptomatology. SVM algorithms may be used to stratify idiopathic cases of ASD according to behavioral signature patterns associated with genetic disorders. Together, the results suggest a new approach for disentangling the heterogeneity of ASD.

Sex-dependent novelty response in neurexin-1α mutant mice.

Neurexin-1 alpha (NRXN1α) belongs to the family of cell adhesion molecules (CAMs), which are involved in the formation of neuronal networks and synapses. NRXN1α gene mutations have been identified in neuropsychiatric diseases including Schizophrenia (SCZ) and Autism Spectrum Disorder (ASD). In order to get a better understanding of the pleiotropic behavioral manifestations caused by NRXN1α gene mutations, we performed a behavioral study of Nrxn1α heterozygous knock-out (+/−) mice and observed increased responsiveness to novelty and accelerated habituation to novel environments compared to wild type (+/+) litter-mates. However, this effect was mainly observed in male mice, strongly suggesting that gender-specific mechanisms play an important role in Nrxn1α-induced phenotypes.

Enhancing the value of psychiatric mouse models; differential expression of developmental behavioral and cognitive profiles in four inbred strains of mice

The behavioral characterization of animal models of psychiatric disorders is often based upon independent traits measured at adult age. To model the neurodevelopmental aspects of psychiatric pathogenesis, we introduce a novel approach for a developmental behavioral analysis in mice. C57BL/6J (C57) mice were used as a reference strain and compared with 129S1/SvImJ (129Sv), BTBR T+tf/J (BTBR) and A/J (AJ) strains as marker strains for aberrant development. Mice were assessed at pre-adolescence (4 weeks), adolescence (6 weeks), early adulthood (8 weeks) and in adulthood (10-12 weeks) on a series of behavioral tasks measuring general health, neurological reflexes, locomotor activity, anxiety, short- and long-term memory and cognitive flexibility. Developmental delays in short-term object memory were associated with either a hypo-reactive profile in 129Sv mice or a hyper-reactive profile in BTBR mice. Furthermore, BTBR mice showed persistent high levels of repetitive grooming behavior during all developmental stages that was associated with the adult expression of cognitive rigidity. In addition, strain differences in development were observed in puberty onset, touch escape, and body position. These data showed that this longitudinal testing battery provides sufficient behavioral and cognitive resolution during different development stages and offers the opportunity to address the behavioral developmental trajectory in genetic mouse models for neurodevelopmental disorders. Furthermore, the data revealed that the assessment of multiple behavioral and cognitive domains at different developmental stages is critical to determine confounding factors (e.g., impaired motor behavior) that may interfere with the behavioral testing performance in mouse models for brain disorders.

Increased power of resting-state gamma oscillations in autism spectrum disorder detected by routine electroencephalography

Experimental studies suggest that increased resting-state power of gamma oscillations is associated with autism spectrum disorder (ASD). To extend the clinical applicability of this finding, we retrospectively investigated routine electroencephalography (EEG) recordings of 19 patients with ASD and 19 age- and gender-matched controls. Relative resting-state condition gamma spectral power was variable, but on average significantly increased in children with ASD. This effect remained when excluding electrodes associated with myogenic gamma activity. These findings further indicate that increased resting-state gamma activity characterizes a subset of ASD and may also be detected by routine EEG as a clinically accessible and well-tolerated investigation.

Paradoxical Benzodiazepine Response: A Rationale for Bumetanide in Neurodevelopmental Disorders?

The diuretic agent bumetanide has recently been put forward as a novel, promising treatment of behavioral symptoms in autism spectrum disorder (ASD) and related conditions. Bumetanide can decrease neuronal chloride concentrations and may thereby reinstate γ-aminobutyric acid (GABA)-ergic inhibition in patients with neurodevelopmental disorders. However, strategies to select appropriate candidates for bumetanide treatment are lacking. We hypothesized that a paradoxical response to GABA-enforcing agents such as benzodiazepines may predict the efficacy of bumetanide treatment in neurodevelopmental disorders. We describe a case of a 10-year-old girl with ASD, epilepsy, cortical dysplasia, and a 15q11.2 duplication who had exhibited marked behavioral arousal after previous treatment with clobazam, a benzodiazepine. We hypothesized that this response indicated the presence of depolarizing excitatory GABA and started bumetanide treatment with monitoring of behavior, cognition, and EEG. The treatment resulted in a marked clinical improvement in sensory behaviors, rigidity, and memory performance, which was substantiated by questionnaires and cognitive assessments. At baseline, the girl’s EEG showed a depression in absolute α power, an electrographic sign previously related to ASD, which was normalized with bumetanide treatment. The effects of bumetanide on cognition and EEG seemed to mirror the “nonparadoxical” responses to benzodiazepines in healthy subjects. In addition, temporal lobe epilepsy and cortical dysplasia have both been linked to disturbed chloride homeostasis and seem to support our assumption that the observed paradoxical response was due to GABA-mediated excitation. This case highlights that a paradoxical behavioral response to GABA-enforcing drugs may constitute a framework for targeted treatment with bumetanide.

The parent-of-origin of the extra X chromosome may differentially affect psychopathology in Klinefelter syndrome

BACKGROUND Several genetic mechanisms have been proposed for the variability of the Klinefelter syndrome (KS) phenotype such as the parent-of-origin of the extra X chromosome. Parent-of-origin effects on behavior in KS can possibly provide insights into X-linked imprinting effects on psychopathology that may be extrapolated to other populations. Here, we investigated whether the parent-of-origin of the supernumerary X chromosome influences autistic and schizotypal symptom profiles in KS. METHODS Parent-of-origin of the X chromosome was determined through analysis of the polymorphic CAG tandem repeat of the androgen receptor gene. Autistic traits (Autism Diagnostic Interview-Revised) were measured in a younger KS sample (n = 33) with KS and schizotypal traits (Schizotypal Personality Questionnaire) were assessed in an older KS sample (n = 43). Scale scores on these questionnaires were entered in statistical analyses to test parent-of-origin effects. RESULTS The results show that parent-of-origin of the X chromosome is reflected in autistic and schizotypal symptomatology. Differences were shown in the degree of both schizotypal and autistic symptoms between the parent-of-origin groups. Furthermore, the parent-of-origin could be correctly discriminated in more than 90% of subjects through Autism Diagnostic Interview-Revised scales and in around 80% of subjects through Schizotypal Personality Questionnaire scales. CONCLUSIONS These findings point to parent-of-origin effects on psychopathology in KS and indicate that imprinted X chromosomal genes may have differential effects on autistic and schizotypal traits. Further exploration of imprinting effects on psychopathology in KS is needed to confirm and expand on our findings.

Genetic mapping in mice reveals the involvement of Pcdh9 in long-term social and object recognition and sensorimotor development

BACKGROUND Quantitative genetic analysis of basic mouse behaviors is a powerful tool to identify novel genetic phenotypes contributing to neurobehavioral disorders. Here, we analyzed genetic contributions to single-trial, long-term social and nonsocial recognition and subsequently studied the functional impact of an identified candidate gene on behavioral development. METHODS Genetic mapping of single-trial social recognition was performed in chromosome substitution strains, a sophisticated tool for detecting quantitative trait loci (QTL) of complex traits. Follow-up occurred by generating and testing knockout (KO) mice of a selected QTL candidate gene. Functional characterization of these mice was performed through behavioral and neurological assessments across developmental stages and analyses of gene expression and brain morphology. RESULTS Chromosome substitution strain 14 mapping studies revealed an overlapping QTL related to long-term social and object recognition harboring Pcdh9, a cell-adhesion gene previously associated with autism spectrum disorder. Specific long-term social and object recognition deficits were confirmed in homozygous (KO) Pcdh9-deficient mice, while heterozygous mice only showed long-term social recognition impairment. The recognition deficits in KO mice were not associated with alterations in perception, multi-trial discrimination learning, sociability, behavioral flexibility, or fear memory. Rather, KO mice showed additional impairments in sensorimotor development reflected by early touch-evoked biting, rotarod performance, and sensory gating deficits. This profile emerged with structural changes in deep layers of sensory cortices, where Pcdh9 is selectively expressed. CONCLUSIONS This behavior-to-gene study implicates Pcdh9 in cognitive functions required for long-term social and nonsocial recognition. This role is supported by the involvement of Pcdh9 in sensory cortex development and sensorimotor phenotypes.