Williams syndrome: cognition, personality, and adaptive behavior

Williams syndrome is caused by a microdeletion of at least 16 genes on chromosome 7q11.23. The syndrome results in mild to moderate mental retardation or learning disability. The behavioral phenotype for Williams syndrome is characterized by a distinctive cognitive profile and an unusual personality profile. Relative to overall level of intellectual ability, individuals with Williams syndrome typically show a clear strength in auditory rote memory, a strength in language, and an extreme weakness in visuospatial construction. The personality of individuals with Williams syndrome involves high sociability, overfriendliness, and empathy, with an undercurrent of anxiety related to social situations. The adaptive behavior profile for Williams syndrome involves clear strength in socialization skills (especially interpersonal skills related to initiating social interaction), strength in communication, and clear weakness in daily living skills and motor skills, relative to overall level of adaptive behavior functioning. Literature relevant to each of the components of the Williams syndrome behavioral phenotype is reviewed, including operationalizations of the Williams syndrome cognitive profile and the Williams syndrome personality profile. The sensitivity and specificity of these profiles for Williams syndrome, relative to individuals with other syndromes or mental retardation or borderline normal intelligence of unknown etiology, is considered. The adaptive behavior profile is discussed in relation to the cognitive and personality profiles. The importance of operationalizations of crucial components of the behavioral phenotype for the study of genotype/phenotype correlations in Williams syndrome is stressed. MRDD Research Reviews 2000;6:148-158.     

22q11.2 deletion syndrome: genetics, neuroanatomy and cognitive/behavioral features keywords.

This paper presents a conceptual review of the genetic underpinnings of 22q11.2 Deletion Syndrome. The neuroanatomical, neuropsychological, behavioral, and psychiatric phenotype associated with 22q11.2 Deletion Syndrome is also explored, including variables that are thought to affect symptom expression. The history of the deletion syndrome is described, and future directions for continued research are discussed.     

22q11.2 Deletion Syndrome: Genetics,Neuroanatomy and Cognitive/Behavioral Features Keywords

This paper presents a conceptual review of the genetic underpinnings of 22q11.2 Deletion Syndrome. The neuroanatomical, neuropsychological, behavioral, and psychiatric phenotype associated with 22q11.2 Deletion Syndrome is also explored, including variables that are thought to affect symptom expression. The history of the deletion syndrome is described, and future directions for continued research are discussed.     

Williams syndrome: a genetic deletion disorder presenting clues to the biology of sociability and clinical challenges of hypersociability

Williams syndrome is a neurodevelopmental disorder that results from the deletion of approximately 25-30 genes spanning about 1.5 megabases in the q11.23 region of chromosome 7. Patients with this syndrome present with a combination of a distinctive elfin-like facial appearance; growth retardation; mild mental retardation; an inconsistent cognitive profile that includes visuospatial impairments with good facial discrimination and relatively preserved expressive language skills; and cardiovascular abnormalities. In addition, a striking behavioral feature of the syndrome is the high sociability and empathy that these patients show for others. The study of patients with "partial" deletions of the chromosome band 7q11.23, mutated genes in this region and knockout mice with deletions of specific genes in the homologous G1-G2 region of mouse chromosome 5 are clarifying some genotype/phenotype relationships. Furthermore, genes located in this region that are prominently expressed have been implicated in brain development and function. The neuropsychological profile of patients with Williams syndrome is heterogeneous, highlights important dissociations between cognitive functions and suggests that the behavioral dimensions of sociability, empathy, engageability, and talkativeness may be independent of, or not easily explained by, the cognitive deficits. Williams syndrome has enormous heuristic value because its pathological feature of heightened "sociability" can be a "deficit" symptom of major complex neuropsychiatric disorders, such as schizophrenia and autism. Data consistent with a core inability of patients with Williams syndrome to inhibit social approach suggest that this disorder may afford an opportunity to study the biological basis of the "drive" toward socialization. From a research perspective, the syndrome lends itself to neurobiological studies of sociability as a dimension that varies independently of cognition (or at least many separable cognitive processes). Importantly, from a clinical perspective, the syndrome challenges us to administer strategic psychosocial interventions that take advantage of the opportunities that "pathological" sociability provide, while avoiding its threats. An illustrative example of an effective strategically planned psychosocial intervention for a patient with Williams syndrome is briefly presented.     

An 8q21 deletion in a patient with comorbid psychosis and mental retardation

Systematic investigations indicate that some of the recognized psychiatric disorders can be identified among those with mental retardation due to chromosomal abnormalities. We report a psychotic patient with mild mental retardation (intelligence quotient: 68) and minor anomalies that had a chromosomal aberration not previously described in a psychotic patient. Our patient highlights the importance of the cytogenetic study in psychiatric patients with comorbid mental retardation or minor anomalies. In addition, her psychosis symptoms may be helpful to propose a new candidate gene for psychosis.     

Socioeconomic Status and Psychological Function in Children with Chromosome 22q11.2 Deletion Syndrome: Implications for Genetic Counseling

The purpose of this study is to examine the association between parental socio-economic status (SES) and childhood neurocognition and behavior in children with chromosome 22q11.2 deletion syndrome (22q11DS). Although undoubtedly, the deletion of genes in the 22q11.2 interval is primarily responsible for the psychological manifestations, little is known about the role of the environment in either mitigating or contributing to these problems. We examined the association of parental socio-economic status (SES) with cognition and behavior in children with 22q11DS (n = 65) and matched healthy control subjects (n = 52), since SES is a component of family resources. We found that in children with 22q11DS, higher SES correlated with better overall functioning (p < .01) and social skills (p < .01), and less frequent oppositional defiant behavior (p < .001). These findings were in contrast to the control subjects in whom SES correlated with cognition and achievement, but not behavior. Our results indicate that environmental factors influence the behavioral phenotype in children with 22q11DS, providing a framework for developing appropriate interventions. As such, genetic counseling for families with 22q11DS may include consideration of family resources and inclusion of other health professionals, such as social workers, to explore with the family available social supports and resources.     

Attention and language in fragile X

Fragile X syndrome (FXS) is a well-recognized cause of mental retardation and developmental delay in males. Alongside the well-documented clinical characteristics of the condition, recent advances in technology and methodology have begun to define FXS at a number of different levels: genetic, brain structure and function, cognition, and behavior. This article suggests that the FXS phenotype is not merely a juxtaposition of spared and impaired functions but rather may be characterized by an inhibitory control deficit that interferes with the individual's ability to modulate output causing perseverative responding across various skill areas. It is further suggested that an inability to modulate arousal may be at least one cause for the inhibitory control deficit that typifies the FXS phenotype. The approach to understanding atypical development outlined here holds exciting promise for future research in FXS and other developmental disorders.     

Reducing attention‐maintained behavior through the use of positive punishment,differential reinforcement of low rates,and response marking

A differential reinforcement of low (DRL) rates procedure was implemented as a changing criterion design with positive punishment and response marking to reduce attention‐maintained behavior of screaming, profanity, and disruptive behaviors of three adolescent males. One participant was diagnosed with static encephalopathy and attention deficit hyperactivity disorder (ADHD) and severe mental retardation, the other two were diagnosed with Down syndrome, one with moderate mental retardation, and the other with severe mental retardation. Through response marking, a verbal warning was delivered immediately following the initial occurrence of a target behavior. A special token (positive punishment) was immediately delivered with a verbal cue and placed on a behavior board following the next occurrence of that behavior. Appropriate requests (hand‐raising) for attention was acknowledged and reinforced with verbal praise. The DRL procedure, combined with positive punishment and response marking, was successful in decreasing the frequency of targeted behaviors amongst all participants. Copyright © 2009 John Wiley & Sons, Ltd.     

Behavioral phenotype of RSH/Smith-Lemli-Opitz syndrome

Smith-Lemli-Opitz syndrome (SLOS, RSH/SLO syndrome, MIM 270400) is an autosomal recessive multiple malformation/mental retardation syndrome initially described by Smith et al. [1964] that is due to a defect in cholesterol biosynthesis. The behavioral phenotype of Smith-Lemli-Opitz syndrome demonstrates cognitive abilities from borderline intellectual functioning to profound mental retardation, sensory hyperreactivity, irritability, language impairment, sleep cycle disturbance, self-injurious behavior, and autism spectrum behaviors. In a recent study of 28 subjects, 14 subjects (50%) with SLOS also exhibited the behavior of throwing themselves backward in a characteristic upper body movement ("opisthokinesis") and 2 adolescents had a stretching motion of the upper body accompanied by hand flicking [Tierney et al., 1999]. In that same study, 6 of 13 subjects (46%) met the Autism Diagnostic Interview-Revised (ADI-R) algorithm criteria (Lord et al. [1993] Infant Mental Health 14:234-252; Lord et al. [1994] J Autism Dev Disord 24:659-685) and the Diagnostic and Statistical Manual (APA [1994] DSM-IV) diagnostic criteria for autistic disorder. Smith-Lemli-Opitz syndrome is a metabolic disorder that is associated with autism. MRDD Research Reviews 2000;6:131-134.     

Effects of COMT genotype on behavioral symptomatology in the 22q11.2 Deletion Syndrome.

The 22q11.2 Deletion Syndrome (DiGeorge/velocardiofacial syndrome) is associated with elevated rates of psychosis, and is also characterized by severe attentional difficulties and executive dysfunction. Behavioral manifestations of this syndrome could result from haploinsufficiency of the catechol-O-methyltransferase (COMT) gene, located within the 22q11 region. The goal of the present study was to examine COMT genotype in relation to behavioral symptomatology in this syndrome. Val158/108Met was genotyped in 38 patients (16 Met/-, 22 Val/-) with confirmed 22q11.2 deletions who had received the Child Behavior Checklist (CBCL) as part of a comprehensive evaluation. Results indicated that the Val genotype was associated with significantly greater internalizing and externalizing behavioral symptomatology in children with 22q11.2 deletions. Val allele status was associated with a greater-than-four-fold increase in risk for clinically significant behavior problems in children with this syndrome. These data are consistent with previous findings of increased psychopathology associated with the Val genotype in normal individuals and suggest that a functional genetic polymorphism in the 22q11 region may influence behavior in individuals with COMT haploinsufficiency.     

Effects of Comt Genotype on Behavioral Symptomatology in the 22q11.2 Deletion Syndrome

The 22q11.2 Deletion Syndrome (DiGeorge/velocardiofacial syndrome) is associated with elevated rates of psychosis, and is also characterized by severe attentional difficulties and executive dysfunction. Behavioral manifestations of this syndrome could result from haploinsufficiency of the catechol-O-methyltransferase (COMT) gene, located within the 22q11 region. The goal of the present study was to examine COMT genotype in relation to behavioral symptomatology in this syndrome. Val^158/108Met was genotyped in 38 patients (16 Met/-, 22 Val/-) with confirmed 22q11.2 deletions who had received the Child Behavior Checklist (CBCL) as part of a comprehensive evaluation. Results indicated that the Val genotype was associated with significantly greater internalizing and externalizing behavioral symptomatology in children with 22q11.2 deletions. Val allele status was associated with a greater-than-four-fold increase in risk for clinically significant behavior problems in children with this syndrome. These data are consistent with previous findings of increased psychopathology associated with the Val genotype in normal individuals and suggest that a functional genetic polymorphism in the 22q11 region may influence behavior in individuals with COMT haploinsufficiency.     

Word identification in adults with mild mental retardation: does IQ influence reading achievement?

OBJECTIVE: To assess the relationship between word identification and intelligence in adults with mild mental retardation (IQ < 80). METHOD: A standardized evaluation was administered to 67 adults with mild mental retardation. The evaluation included a psychiatric interview, the WAIS-R, and a 2-h interview with a speech therapist and reading tests. RESULTS: Causes of mental retardation were diverse in the sample, and IQ scores ranged from 43 to 79 (mean score = 64). All subjects exhibited reading impairment, including 69% with severe impairment. No subject with an IQ score under 65 was able to perform adequately in the word identification tasks. Word identification was correlated with total and verbal IQ, but not with performance IQ. CONCLUSION: Our results suggest that, in contrast to subjects with normal intelligence, IQ score is correlated with reading in subjects with mild mental retardation. Finally, remediation should be preferentially implemented for subjects with IQ score greater than 65.     

Prompting procedures as establishing operations for escape‐maintained behavior

In the current study, we report on a young man with Nager's Syndrome, mild mental retardation, and deafness who exhibited severe problem behavior during demand situations. Initial functional analysis suggested that problem behavior was maintained by gaining escape from instructional demands. However, further analysis suggested that the individual was responding to escape the prompting procedure rather than the work tasks themselves. Copyright © 2006 John Wiley & Sons, Ltd.     

Autism and 15q11-q13 disorders: behavioral, genetic, and pathophysiological issues

New insights into biological factors that underlie autism may be gained by comparing autism to other neurodevelopmental disorders that have autistic features and relatively well-delineated genetic etiologies or neurobiological findings. This review moves beyond global diagnoses of autism and instead uses an endophenotypic approach to compare specific clusters of autistic symptomatology to features of chromosome 15q11-q13 disorders. Paternally or maternally derived deficiencies of 15q11-q13 result in Prader-Willi or Angelman syndromes, and we first use a global approach to review potential autism susceptibility genes in the 15q11-q13 region. We then use a more trait-based approach to suggest possible ties between specific phenotypic characteristics of autism and Prader-Willi syndrome, namely savant-like skills. We conclude with insights from pathophysiological studies that implicate altered development of specific neuron types and circuits in the cerebral cortex as part of the pathophysiological processes associated with autism and mental retardation.     

Prompt-aided instruction of mirror-image discriminations: Abrupt prompt removal,time delay,and self-evaluation

This study compared three types of prompt-elimination procedures for helping children respond to left-right mirror-image stimuli. Three populations participated: normally developing preschoolers, students with mild mental retardation, and students with moderate mental retardation. All subjects were first trained to discriminate the stimuli in the presence of multiple pictorial prompts. These prompts required the subjects to discriminate the compounds on the basis of orientation. Then the prompts were eliminated, abruptly, with a time-delay procedure, or with a procedure requiring subjects to use the prompts to self-evaluate the accuracy of their responses. The results showed the following. First, most subjects rapidly discriminated the compound stimuli. Second, about 50% of the subjects of each population discriminated the task stimuli even when the prompts were abruptly removed. Time delay was highly effective with the normally developing preschoolers and students with mild mental retardation, but not with students with moderate mental retardation. The self-evaluation procedure was effective with all three populations.     

Subregion-specific dendritic spine abnormalities in the hippocampus of Fmr1 KO mice

Fragile X syndrome (FXS) is the most common inherited form of mental retardation and is caused by the lack of fragile X mental retardation protein (FMRP). In the brain, spine abnormalities have been reported in both patients with FXS and Fmr1 knockout mice. This altered spine morphology has been linked to disturbed synaptic transmission related to altered signaling in the excitatory metabotropic glutamate receptor 5 (mGluR5) pathway. We investigated hippocampal protrusion morphology in adult Fmr1 knockout mice. Our results show a hippocampal CA1-specific altered protrusion phenotype, which was absent in the CA3 region of the hippocampus. This suggests a subregion-specific function of FMRP in synaptic plasticity in the brain.     

Case study: Use of propranolol to reduce aggressive behavior in a woman who is mentally retarded

Although neuroleptic medications are frequently used to treat the aggressive behavior of persons with mental retardation, little empirical support exists for their efficacy. In the case study reported here, the beta-blocker propranolol was used to treat the aggressive behavior of a 23-year-old woman with severe mental retardation. Initiation of treatment was correlated with a dramatic decrease in aggression and a less pronounced improvement in self-injurious behavior (SIB). An increase in resting heart-rate was associated with a significant increase in aggression, and progressive increases in propranolol dosage were correlated with reductions in heart rate and in significant behavioral improvement. Consideration of propranolol as a less intrusive, and possibly more effective, pharmacologic treatment for the aggressive behavior of persons with mental retardation is discussed.     

Atypical neuropsychological profile in a boy with 22q11.2 Deletion Syndrome.

In this article the general and specific cognitive impairments of the boy R.H. with a de novo deletion 22q11.2 are described. His full-scale IQ was 73, and he obtained only slightly better verbal than non-verbal subtest scores. Neuropsychological assessment revealed specific impairments in perceptual categorization of objects presented suboptimal, matching of unfamiliar faces, and verbal learning and memory. In contrast, he performed in accordance with his intelligence level on other visual perceptual tasks, on non-verbal learning and memory tasks, and on attention tasks. Voxel-wise statistical comparison of a high-resolution T1-weighted magnetic resonance image of R.H's brain with similar images obtained from 14 normal control children revealed as major abnormalities a reduction of the right inferior parietal and superior occipital lobe, and a bilateral reduction of deep white matter behind the inferior frontal gyrus. These cognitive impairments and MRI abnormalities are not commonly described in 22q11.2 Deletion Syndrome and may indicate a larger heterogeneity in the neurocognitive phenotype than currently evidenced. At least in this boy the microdeletion seems to have interfered with the development and functioning of particular neural subsystems, while the structure and functioning of other subsystems was left intact.     

Use of a multicomponent treatment for food refusal

We examined the use of a multicomponent treatment for food refusal exhibited by a 5-year-old boy who had been diagnosed with mild to moderate mental retardation. Treatment consisted of access to highly preferred tangible items, which were removed contingent on problem behavior or not accepting a bite, and differential reinforcement of alternative behavior. Treatment resulted in an increase in food acceptance to 100% of bite offers and near-zero rates of problem behavior. In addition, the participant's caregivers were successfully trained to implement the treatment.