Maladaptive conflict monitoring as evidence for executive dysfunction in children with chromosome 22q11.2 deletion syndrome

Using an adaptation of the Attentional Networks Test, we investigated aspects of executive control in children with chromosome 22q11.2 deletion syndrome (DS22q11.2), a common but not well understood disorder that produces non-verbal cognitive deficits and a marked incidence of psychopathology. The data revealed that children with DS22q11.2 demonstrated greater difficulty than controls in locating and processing target items in the presence of distracters. Importantly, children with DS22q11.2 showed a deficit in the ability to monitor and adapt to stimulus conflict. These data provide evidence of inadequate conflict adaptation in children with DS22q11.2, a problem that is also present in schizophrenia. The findings of specific executive dysfunction in this group may provide a linkage between particular genetic abnormalities and the development of psychopathology.     

Preservation of long-term memory and synaptic plasticity despite short-term impairments in the Tc1 mouse model of Down syndrome

Down syndrome (DS) is a genetic disorder arising from the presence of a third copy of the human chromosome 21 (Hsa21). Recently, O’Doherty and colleagues in an earlier study generated a new genetic mouse model of DS (Tc1) that carries an almost complete Hsa21. Since DS is the most common genetic cause of mental retardation, we have undertaken a detailed analysis of cognitive function and synaptic plasticity in Tc1 mice. Here we show that Tc1 mice have impaired spatial working memory (WM) but spared long-term spatial reference memory (RM) in the Morris watermaze. Similarly, Tc1 mice are selectively impaired in short-term memory (STM) but have intact long-term memory (LTM) in the novel object recognition task. The pattern of impaired STM and normal LTM is paralleled by a corresponding phenotype in long-term potentiation (LTP). Freely-moving Tc1 mice exhibit reduced LTP 1 h after induction but normal maintenance over days in the dentate gyrus of the hippocampal formation. Biochemical analysis revealed a reduction in membrane surface expression of the AMPAR (α-amino-3-hydroxy-5-methyl-4-propionic acid receptor) subunit GluR1 in the hippocampus of Tc1 mice, suggesting a potential mechanism for the impairment in early LTP. Our observations also provide further evidence that STM and LTM for hippocampus-dependent tasks are subserved by parallel processing streams.     

Attention in Williams syndrome and Down's syndrome: Performance on the new early childhood attention battery

Attentional problems are commonly reported as a feature of the behavioural profile in both Williams syndrome (WS) and Down's syndrome (DS). Recent studies have begun to investigate these impairments empirically, acknowledging the need for an approach that considers cross‐syndrome comparisons and developmental changes across the different component functions of attention. The present study assessed children with WS and DS using a new preschool attention battery (ECAB: early childhood attention battery), designed to be suitable for mental age 3–6 years including groups with developmental disorders. The ECAB has the advantage of giving an individual profile of attentional abilities for each child, covering different components of attention. In relation to test norms for their mental age, both groups showed a profile of strengths and weaknesses in the attention domain. Both syndrome groups performed relatively well on tests of sustained attention and poorly on aspects of selective attention and attentional control (executive function). The DS group showed a specific strength in auditory sustained attention, whilst the WS group showed a particular deficit in visuo‐spatial response control. There was also evidence for considerable differences in the developmental trajectory of these abilities across the two groups. The results provide evidence for syndrome‐specific patterns of impairment, and distinct profiles of strengths and weaknesses that may be useful in understanding the nature of everyday attention difficulties in these groups and tailoring interventions to meet these needs.     

Language and communicative development in Williams syndrome

Williams syndrome, a genetic disorder caused by a microdeletion of approximately 25 genes on chromosome 7q11.23, is associated with mild to moderate intellectual disability or learning difficulties. Most individuals with Williams syndrome evidence a cognitive profile including relative strengths in verbal short-term memory and language, and considerable weakness in visuospatial construction. The syndrome has often been argued to provide strong evidence for the independence of language from other aspects of cognition. We provide a brief history of early research on the language abilities of individuals with Williams syndrome and then review contemporary studies of language and cognition in Williams syndrome, beginning with a consideration of performance on standardized assessments. In the remainder of the article, we first consider early language acquisition, with a focus on speech production and perception, vocabulary acquisition, and communicative/pragmatic development and then consider the language abilities of school-age children and adolescents, focusing on semantics, grammar, and pragmatics. We argue that rather than being the paradigm case for the independence of language from cognition, Williams syndrome provides strong evidence of the interdependence of many aspects of language and cognition.     

An Assessment of Ethnocultural Beliefs Regarding the Causes of Birth Defects and Genetic Disorders

With the expansion of genetic services to various cultural groups, genetic counselors encounter clients who hold diverse beliefs inscribed by their culture about health conditions. Thus, clients may attribute the cause of a birth defect or genetic condition to a culturally-based health belief. This present study was conducted as a pilot study in order to assess the beliefs about the causes of birth defects and genetic disorders held by women of different ethnocultural backgrounds. This study proposed that women who do not have a family history of a disorder will differ in their knowledge about the cause of a birth defect or genetic disorder compared to women who have an affected child. In addition, this study determined to what extent culturally-based health beliefs are attributed to being the cause of a birth defect or genetic disorder in the 1990s.     

The Amish: Perceptions of genetic disorders and services

Previous studies of the closed Amish population have proven to be valuable in the field of genetics, however they have not explored the Amish parents' opinions and attitudes concerning genetic conditions and services. This exploration is necessary in order to provide culturally sensitive health care to a population at an increased risk for certain genetic conditions. The purpose of the present study was to examine the Amish population's general knowledge of genetic disorders, services, and the terminology used in describing inherited conditions, as well as their attitudes toward medical care and ethical and reproductive issues. Information was obtained from 17 Amish families, 12 who had an incidence of a genetic condition and five who had one or more children with other special health care needs, during personal interviews conducted in their homes in Lancaster, Pennsylvania. Results of the interviews showed that the birth of an affected child did not deter subsequent reproduction, that the majority of the parents were never offered genetic counseling or prenatal testing, and that the parents are interested in understanding the cause of their children's problems and recurrence risks.     

Genetic linkage in bipolar disorder

Bipolar disorder is an etiologically complex syndrome that is clearly heritable. Multiple genes, working singly or in concert, are likely to cause susceptibility to bipolar disorder. Bipolar disorder genetics has progressed rapidly in the last few decades. However, specific causal genetic mutations for bipolar disorder have not been identified. Both candidate gene studies and complete genome screens have been conducted. They have provided compelling evidence for several potential bipolar disorder susceptibility loci in several regions of the genome. The strongest evidence suggests that bipolar disorder susceptibility loci may lie in one or more genomic regions on chromosomes 18, 4, and 21. Other regions of interest, including those on chromosomes 5 and 8, are also under investigation. New approaches, such as the use of genetically isolated populations and the use of endophenotypes for bipolar disorder, hold promise for continued advancement in the search to identify specific bipolar disorder genes.     

Neurobehavioral phenotype of Klinefelter syndrome

A defined genetic syndrome with neurobehavioral components offers an unusual paradigm for the correlation of genetic defects with neurodevelopmental abnormalities. The power of the combination of detailed behavioral, neuroanatomical, and genetic studies has been demonstrated in studies of other conditions involving the sex chromosomes, such as Fragile X syndrome (Mazzocco [2000] Ment Retard Develop Disabil Res Rev. 6:96-106) and Turner syndrome (Ross [2000] Ment Retard Develop Disabil Res Rev. 6:135-141). Although the behavioral and neurologic difficulties that have been identified in Klinefelter syndrome (KS) are in most cases milder than the consequences of many other genetic syndromes, the deficits in KS cause significant morbidity, representing a more common, but poorly understood, subtype of those with learning disabilities. Both as children and as adults, KS subjects appear to offer a powerful genetic model for the study of language and language-based learning disabilities. Although it has been proposed that the language-based learning difficulties of KS boys are similar to those of nonaneuploidic dyslexics [Bender et al., 1986; Geschwind et al., 1998], this is not yet well established. The co-morbid frontal-executive dysfunction observed in KS is also a likely contributor to learning difficulties and, perhaps, social cognition, in many KS patients. It is also proposed that altered left-hemisphere functioning, whether causing, or due to, altered functional and anatomical cerebral dominance, is at the core of KS subjects' language problems. Although X chromosomal loci can provide only part of the picture, the study of KS subjects, a population with a relatively homogeneous etiology for dyslexia/dysphasia and frontal-executive dysfunction, offers many advantages over such a study in the general population, in which both dyslexia and attentional disorders are quite genetically heterogeneous [Decker and Bender, 1988; Pennington, 1990; Grigorenko et al., 1997; Geschwind et al., 1998]. Furthermore, the interaction of genetic factors and hormonal influences in the cognitive phenotypes described remains an unexplored area for future investigation. MRDD Research Reviews 2000;6:117-124.     

Auditory information is beneficial for adults with Down syndrome in a continuous bimanual task

Much recent research using discrete unimanual tasks has indicated that individuals with Down syndrome (DS) have more difficulty performing verbal-motor tasks as compared to visual-motor tasks (see Perceptual-Motor Behavior in Down Syndrome, Human Kinetics, Champaign, IL, 2000, p. 305 for a review). In continuous tasks, however, individuals with DS perform better when movement is guided by auditory information compared to visual information (Downs Syndr.: Res. Prac. 4 (1996) 25; J. Sport Exercise Psy. 22 (2000) S90). The aim of the present study was to investigate if there are any differences for adults with DS between visual, auditory and verbal guidance in a continuous bimanual task. Ten adults with DS, 10 adults without DS and 10 typically developing children drew lines bimanually towards the body (down) and away from the body (up) following three different guidance conditions: visual (flashing line), auditory (high tone, low tone), and verbal (“up”, “down”). All participants produced mostly in-phase movements and were close to the 1000 ms target time for all guidance conditions. The adults with DS, however, displayed greater variability in their movement time, movement amplitude and bimanual coordination than adults without DS. For all groups, the left hand was slower and more variable in producing the lateral movements than the right hand. The results regarding guidance information suggest that auditory information is beneficial for repetitive bimanual tasks for adults with DS. Possible mechanisms that cause these results will be discussed.     

Progress toward discovery of susceptibility genes for bipolar manic-depressive illness and schizophrenia

The inconsistency in linkage results that has bedeviled psychiatric genetics has been observed to occur regularly in common diseases with complex inheritance. Nonetheless, in two such instances--noninsulin-dependent diabetes mellitus (NIDDM) and inflammatory bowel disease (IBD)--susceptibility genes have been discovered based on the follow-ups of linkage findings. In bipolar illness disorder (BPD) and schizophrenia (SZ), there are some linkage reports with replication of other studies similar to the situation in NIDDM and IBD before the successful positional cloning efforts. Two of the regions with linkage reports, BPD and SZ, on the long arms of chromosomes 13 and 22, show linkage to the same markers in both diseases. This lends some plausibility to the hypothesis of some shared genetic predispositions for both disorders. Cytogenetic evidence offers another positional approach to susceptibility genes. The velocardiofacial syndrome is associated with deletions very close to the linkage region on chromosome 22, and with psychiatric manifestations of both BPD and SZ. Endophenotypes of SZ, previously demonstrated to the be heritable, have been found to have chromosomal linkage in at least one study. These include eye-tracking abnormalities linked to 6p, and an abnormality of the P50 cortical evoked potential linked to chromosome 15. Variants in specific genes have been associated with susceptibility to the psychiatric illnesses. These genetic findings may contribute to etiologic subcategorization of BPD and SZ, and the development of new treatment approaches. A table of genetic terms is included for review     

Spatial-simultaneous working memory and selective interference in Down syndrome

Several studies have suggested that individuals with Down syndrome (DS) have impairments in some aspects of the visuospatial domain. It has been reported that they are particularly impaired in the spatial-simultaneous working memory (WM) even in advantageous conditions such as when information is grouped to form a configuration. This study aimed to assess the performance of individuals with DS carrying out a spatial-simultaneous WM task in single and dual selective interference conditions in order to better explore the characteristics of their impairment in this area.

Groups of individuals with DS and mentally age-matched typically developing (TD) children were asked to carry out a spatial-simultaneous WM task in a single- and in two dual-task conditions. In the single condition, the participants were required to recall an increasing number of positions of red squares presented simultaneously in a matrix. In the dual-task conditions, together with the spatial-simultaneous WM task, the participants were asked to carry out an articulatory suppression task or a tapping task.

As has already been shown in other studies, individuals with DS were found to be impaired in carrying out a spatial-simultaneous WM task and showed a worse performance with respect to the TD group in both the conditions.

These findings indicate that individuals with DS use the same coding modality as TD children of the same mental age. Just as the TD children, they performed lower in the dual- than in the single-task condition and there was no difference between the verbal and visuospatial conditions.     

Learning by observation and learning by doing in Down and Williams syndromes

New skills may be learned by active experience (experiential learning or learning by doing) or by observation of others’ experience (learning by observation). In general, learning by observation reduces the time and the attempts needed to learn complex actions and behaviors. The present research aimed to compare learning by observation and learning by doing in two clinical populations with different etiology of intellectual disability (ID), as individuals with Down syndrome (DS) and individuals with Williams syndrome (WS), with the hypothesis that specific profiles of learning may be found in each syndrome. To this end, we used a mixture of new and existing data to compare the performances of 24 individuals with DS, 24 individuals with WS and 24 typically developing children on computerized tasks of learning by observation or learning by doing. The main result was that the two groups with ID exhibited distinct patterns of learning by observation. Thus, individuals with DS were impaired in reproducing the previously observed visuo‐motor sequence, while they were as efficient as TD children in the experiential learning task. On the other hand, individuals with WS benefited from the observational training while they were severely impaired in detecting the visuo‐motor sequence in the experiential learning task (when presented first). The present findings reinforce the syndrome‐specific hypothesis and the view of ID as a variety of conditions in which some cognitive functions are more disrupted than others because of the differences in genetic profile and brain morphology and functionality. These findings have important implications for clinicians, who should take into account the genetic etiology of ID in developing learning programs for treatment and education.     

Language phenotypes and intervention planning: bridging research and practice

This paper focuses on the communication and language phenotypes associated with three genetic disorders: Down syndrome, Williams syndrome, and fragile X syndrome. It is argued that there is empirical evidence that these disorders predispose children to specific profiles of strength and weakness in some areas of speech, language, and communication, and that intervention planning for children with each syndrome may take an approach informed by these profiles. Issues related to within-group variability, shared outcomes among syndromes, and the need for empirical validation for syndrome-specific recommendations are discussed.     

Assessment of Parental Disclosure of a 22q11.2 Deletion Syndrome Diagnosis and Implications for Clinicians

Most children with chromosome 22q11.2 deletion syndrome (22q11DS) have an IQ in the range that may allow them to be capable of understanding a genetic diagnosis despite mild intellectual disabilities. However, there are no publications that relate to the disclosure of a 22q11DS diagnosis to the affected child, or the factors that influence parents’ disclosure to the child. A pilot study was conducted including eight semi-structured interviews with caregivers of children with 22q11DS, 10 to 17?years of age, to investigate the factors that influence how parents inform their children of the diagnosis. Six of eight participants had disclosed the diagnosis to the child, and most of these parents felt they could have benefited from additional advice from professionals to increase their confidence and success, as well as the child’s comprehension of the information. Those who had not informed the child were uncertain about the words to use, how to initiate the conversation, or were concerned about the child’s level of understanding. Our results demonstrate that genetics professionals should help prepare caregivers for conversations with their children about the diagnosis of 22q11DS, monitor the understanding of the diagnosis over time, and provide ongoing support.     

Evaluating Attributions for an Illness Based Upon the Name: Chronic Fatigue Syndrome, Myalgic Encephalopathy and Florence Nightingale Disease

In recent years, considerable discussion has occurred about stigma surrounding the name given to an illness currently known as chronic fatigue syndrome (CFS). Although patients and medical personnel have expressed varying opinions on this issue, no studies have evaluated how beliefs about the illness change based upon the type of name used for diagnostic purposes. Proposals have been put forth to rename the illness with an eponym (a famous patient's or researcher's name) or with a less trivial sounding, more medically based type of name. In this study, attributions about CFS were measured in three groups of medical trainees. All groups read the same case study of a person with classic symptoms of chronic fatigue syndrome, with the only difference being in the type of name given. Trainees then were asked to provide attributions about certain aspects of the illness, including its cause, severity, and prognosis. Results suggested that, across name conditions, most trainees appeared to consider the symptom complex of CFS a serious illness resulting in poor quality of life. In addition, findings indicated that the name, chronic fatigue syndrome, may be regarded less seriously than the Myalgic Encephalopathy name with respect to some important aspects of the illness. In this study, specialty of medical trainee also played a role in how the illness was perceived.     

Speech perception and motor control in children with Down syndrome.

Twelve children with and without Down syndrome (DS) performed eight subtests of an apraxia battery to determine under what conditions children with DS had difficulty performing representational and nonrepresentational gestures. Participants with DS also completed a dichotic listening test. Participants with DS performed just as well as control participants on all aspects of the apraxia battery except a subtest in which they were required to pantomime tool use from verbal instruction. This suggests that children with DS have difficulty generating an action from memory following verbal instruction. Given the sufficient context or visual demonstration, children with DS performed similar to the other participants. As well, there was a great deal of within-group variability for dichotic listening ear advantage. Participants with a greater left ear advantage on the dichotic listening test committed more errors on an imitation test that also included a verbal component than participants with a greater right ear advantage.     

Neuropsychological Deficits in Relation to Symptoms of ADHD: Independent Contributions and Interactions

Twelve children with and without Down syndrome (DS) performed eight subtests of an apraxia battery to determine under what conditions children with DS had difficulty performing representational and nonrepresentational gestures. Participants with DS also completed a dichotic listening test. Participants with DS performed just as well as control participants on all aspects of the apraxia battery except a subtest in which they were required to pantomime tool use from verbal instruction. This suggests that children with DS have difficulty generating an action from memory following verbal instruction. Given the sufficient context or visual demonstration, children with DS performed similar to the other participants. As well, there was a great deal of within-group variability for dichotic listening ear advantage. Participants with a greater left ear advantage on the dichotic listening test committed more errors on an imitation test that also included a verbal component than participants with a greater right ear advantage.     

Brain imaging in neurogenetic conditions: realizing the potential of behavioral neurogenetics research

Behavioral neurogenetics research is a new method of scientific inquiry that focuses on investigation of neurodevelopmental dysfunction associated with specific genetic conditions. This research method provides a powerful tool for scientific inquiry into human gene-brain-behavior linkages that complements more traditional research approaches. In particular, the use of specific genetic conditions as models of common behavioral and cognitive disorders occurring in the general population can reveal insights into neurodevelopmental pathways that might otherwise be obscured or diluted when investigating more heterogeneous, behaviorally defined subject groups. In this paper, we review five genetic conditions that commonly give rise to identifiable neurodevelopmental and neuropsychiatric disability in children: fragile X syndrome, velo-cardio-facial syndrome, Williams syndrome, Turner syndrome, and Klinefelter syndrome. While emphasis is placed on describing the brain morphology associated with these conditions as revealed by neuroimaging studies, we also include information pertaining to molecular genetic, postmortem, and neurobehavioral investigations to illustrate how behavioral neurogenetics research can contribute to an improved understanding of brain disorders in childhood.     

Communication of Psychiatric Risk in 22q11.2 Deletion Syndrome: A Pilot Project

Individuals with 22q11.2 deletion syndrome (22q11.2DS) have an increased chance of developing a psychiatric disorder. While parents of children affected by 22q11.2DS typically receive counseling about risk for non-psychiatric health concerns, genetic counselors may be reluctant to discuss psychiatric risk. Further education of genetic counselors may be necessary to encourage discussion of psychiatric risk with these families. The goal of this project was to develop recommendations for genetic counselors to provide psychiatric risk information to families affected by 22q11.2DS. The recommendations were developed by synthesizing resources in the literature about risk communication. These recommendations were refined following an online focus group meeting with five health care professionals who were recruited for participation from 22q11.2DS clinics across the U.S.A. The focus group data revealed three themes related to discussion of psychiatric risk: 1) Stepwise approach, 2) Discussing treatment options and reducing risks, and 3) Addressing stigma. These recommendations may be used as a foundation for a future clinical protocol to encourage discussion about the risk for psychiatric illness at an earlier point in the diagnostic process for 22q11.2DS and to provide improved information, support and resources to affected families.