Thalamic reductions in children with chromosome 22q11.2 deletion syndrome

Children with chromosome 22q11.2 deletion syndrome (22q) suffer from physical and behavioral dysfunctions, including neuroanatomical anomalies, visuo-spatial processing deficits, and increased risk for psychopathology. Reduced total brain volume, parietal lobe volume, and cerebellar volumes, enlarged ventricles, and increased basal ganglia volumes have been reported. Since previous literature has related the pulvinar nucleus of the thalamus to visuo-spatial processing, we compared the thalamic volume in children with 22q to typically developing controls. Children with 22q showed a significant reduction of the thalamus compared with normally developing children, specifically in the posterior portion of the thalamus, including the pulvinar nucleus. These results provide the first evidence for a potential relationship between posterior thalamic reductions and the characteristic visuo-spatial deficits demonstrated in this group.     

Early developmental concerns in 22q11.2 deletion and duplication carriers

Background22q11.2 deletions (22qDEL) and duplications (22qDUP) are among the most common copy number variants (CNVs) associated with neurodevelopmental disorders (NDDs). Little is known about the earliest developmental features of 22q11.2 CNVs and whether developmental delays are detected in early childhood. This study primarily aimed to assess general development and social communication in 22q11.2 CNV carriers age 5 and under.MethodParticipants included parents of children age 5 and under with a reported genetic diagnosis of 22qDEL (N = 63) or 22qDUP (N = 30). In addition to questions addressing clinical and intervention information, two standardized parent questionnaires—the Ages & Stages Questionnaires, Third Edition (ASQ-3) and the Communication and Symbolic Behavior Scales Developmental Profile Infant/Toddler Checklist (ITC)—screened for developmental and social communication delays, respectively.ResultsDevelopmental delay and speech and/or language delay were the most commonly reported NDD diagnoses among young 22q11.2 CNV carriers, with prevalences at 19% and 17%, respectively. In the vast majority (91%) of 22q11.2 CNV carriers, parents reported concerns in at least one developmental domain, with 71% reporting global developmental concerns. 70% of parents of 22q11.2 CNV carriers age 2 and under also reported social communication concerns.ConclusionsThe high prevalence of reported developmental concerns in both CNV groups reinforces the need for close monitoring of early neurodevelopment in 22q11.2 CNV carriers with regard to both developmental delays and autism risk.     

Failure to detect the 22q11.2 duplication syndrome rearrangement among patients with schizophrenia

Chromosome aberrations have long been studied in an effort to identify susceptibility genes for schizophrenia. Chromosome 22q11.2 microdeletion is associated with DiGeorge and Velocardiofacial syndromes (DG/VCF) and provides the most convincing evidence of an association between molecular cytogenetic abnormality and schizophrenia. In addition, this region is one of the best replicated linkage findings for schizophrenia. Recently, the reciprocal microduplication on 22q11.2 has been reported as a new syndrome. Preliminary data indicates that individuals with these duplications also suffer from neuropsychiatric disorders. In this study we have investigated the appropriateness of testing schizophrenia patients for the 22q11.2 microduplication. We used multiplex ligation-dependent probe amplification (MLPA) to measure copy number changes on the 22q11.2 region in a sample of 190 patients with schizophrenia. Our results corroborate the prevalence of the 22q11.2 microdeletion in patients with schizophrenia and clinical features of DG/VCFS and do not suggest an association between 22q11.2 microduplication and schizophrenia.     

A sporadic case of Charcot-Marie-Tooth disease type 1 A associated with a duplication in chromosome 17 p11.2-p12]

Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant demyelinating peripheral neuropathy. Most patients with CMT1A including sporadic cases have been found to have a 1.5 megabase tandem DNA duplication in chromosome 17 p11.2-p12 (CMT1A duplication). We reported a 7-year-old girl with sporadic CMT 1 associated with the CMT1A duplication. The diagnosis of CMT 1 was based on the symmetrical distal muscle weakness, per cavus deformity, reduced motor and sensory nerve conduction velocities, and segmental de- and remyelinatin on sural nerve biopsy. To detect the CMT 1A duplication, peripheral myelin protein 22 (PMP-22) cDNA and a polymorphic marker in this region, VAW409 R3, were employed as probes for Southern blot analysis. Sporadic cases of autosomal dominant-CMT type 1 can not be clinically differentiated from recessive-CMT1. Testing for the CMT1A duplication is an important first step even in the molecular diagnosis of sporadic CMT1.     

Hippocampal volume reduction in chromosome 22q11.2 deletion syndrome (22q11.2DS): A longitudinal study of morphometry and symptomatology

Recent studies observed an association between the structural integrity of the hippocampal structure and the manifestations of clinically significant psychotic symptoms in participants at high risk for psychosis. The present study sought to investigate the longitudinal trajectory of the hippocampal volume and its subregions among a sample of participants affected by 22q11.2 deletion syndrome (22q11.2DS), a neurogenetic disorder associated with elevated risk for psychosis. We specifically investigated possible correlations between hippocampal volumes, as measured by magnetic resonance imaging (MRI), and the manifestation of positive psychotic symptoms (hallucinations and delusions). Regional hippocampal volumes were measured twice with cerebral MRI obtained at 3-year intervals in 30 healthy participants and 31 gender-matched 22q11.2 microdeletion carriers aged 6 to 22. We examined potential associations between psychotic symptom manifestations and volumetric parameters at both time points. We found a hippocampal body-driven significant reduction in hippocampal volume among patients with 22q11DS compared to controls. No significant group by time interaction for the total or the subregional volumes were observed. In patients, larger hippocampal head at baseline was associated with the presence of hallucinations at follow-up. We first discuss the reduced hippocampal body finding in light of potentially abnormal mesiocortical circuits. We further discuss the association between baseline hippocampal head volume in participants with 22q11DS as a possible marker related to the later unfolding of psychotic symptoms.     

Impaired multiple object tracking in children with chromosome 22q11.2 deletion syndrome

Background

Williams syndrome (WS) is a rare genetic disorder caused by the deletion of approximately 25 genes at 7q11.23 that involves mild to moderate intellectual disability (ID). When using functional magnetic resonance imaging (fMRI) to compare individuals with ID to typically developing individuals, there is a possibility that differences in IQ contribute to between-group differences in BOLD signal. If IQ is correlated with BOLD signal, then group-level analyses should adjust for IQ, or else IQ should be matched between groups. If, however, IQ is not correlated with BOLD signal, no such adjustment or criteria for matching (and exclusion) based on IQ is necessary.

Methods

In this study, we aimed to test this hypothesis systematically using four extant fMRI datasets in WS. Participants included 29 adult subjects with WS (17 men) demonstrating a wide range of standardized IQ scores (composite IQ mean = 67, SD = 17.2). We extracted average BOLD activation for both cognitive and task-specific anatomically defined regions of interest (ROIs) in each individual and correlated BOLD with composite IQ scores, verbal IQ scores and non-verbal IQ scores in Spearman rank correlation tests.

Results

Of the 312 correlations performed, only six correlations (2%) in four ROIs reached statistical significance at a P value < 0.01, but none survived correction for multiple testing. All six correlations were positive. Therefore, none supports the hypothesis that IQ is negatively correlated with BOLD response.

Conclusions

These data suggest that the inclusion of subjects with below normal IQ does not introduce a confounding factor, at least for some types of fMRI studies with low cognitive load. By including subjects who are representative of IQ range for the targeted disorder, findings are more likely to generalize to that population.     

A novel candidate region for ALS on chromosome 14q11.2

Sequence variations with biologic effect in ALS have been identified in the gene for vascular endothelial growth factor (VEGF). The gene for a related protein, angiogenin, lies on chromosome 14q11.2. Analysis of the angiogenin (ANG) gene in the authors' population has demonstrated a significant allelic association with the rs11701 single nucleotide polymorphism (SNP) and identified a novel mutation in two individuals with sporadic ALS that potentially inhibits angiogenin function. These observations propose a candidate region for ALS on chromosome 14q11.2 and suggest that other genes with similar function to VEGF may be important in the pathogenesis of ALS.     

Visuospatial and numerical cognitive deficits in children with chromosome 22q11.2 deletion syndrome

This article presents some of the earliest evidence of visuospatial and numerical cognitive deficits in children with the chromosome 22q11.2 deletion syndrome; a common but ill-understood genetic disorder resulting in medical complications, cognitive impairment, and brain morphologic changes. Relative to a group of typically developing controls, deleted children performed more poorly on tests of visual attentional orienting, visual enumeration and relative numerical magnitude judgment. Results showed that performance deficits in children with the deletion could not be explained by a global deficit in psychomotor speed. Instead, our findings are supportive of the hypothesis that visuospatial and numerical deficits in children with the chromosome 22q11.2 deletion are due, at least in part, to posterior parietal dysfunction.     

Microduplication 22q11.2 in a child with autism spectrum disorder: clinical and genetic study

Microduplication of the 22q11.2 chromosomal region has been recognized since 1999 and has been associated with a highly variable phenotype. Neurodevelopmental impairment and behavioural problems are very common in patients with 22q11.2 duplication. Autism spectrum disorders (ASDs) have previously been reported in only two patients with 22q11.2 duplication and striking dysmorphic features. We report here on a 4‐year‐old male of healthy consanguineous parents presenting with ASD according to DSMIV, revised, criteria as a primary manifestation. The child walked at 16 months and started to say one word and some sounds. Parents noticed a subsequent developmental arrest. At 4 years his functional development age, evaluated by the Psychoeducational Profile, was roughly 6 months. Mild non‐specific facial dysmorphism was noted. Genetic analyses of the child demonstrated a de novo microduplication of the 22q11.2 chromosomal region. This genetic anomaly was best seen in interphases of blood lymphocytes and in buccal smear nuclei. Our case illustrates once again the clinical heterogeneity of the 22q11.2 duplication as well as the wide genetic complexity of ASD. We suggest that genetic evaluation of ASD should include fluorescence in‐situ hybridization analysis of the 22q11.2 chromosomal region.     

Atypical development of the executive attention network in children with chromosome 22q11.2 deletion syndrome

Impairment in the executive control of attention has been found in youth with chromosome 22q11.2 deletion syndrome (22q11.2DS). However, how this impairment is modified by other factors, particularly age, is unknown. Forty-six typically developing and 53 children with 22q11.2DS were tested with the attention networks task (ANT) in this cross-sectional study. We used logarithmic transform and linear modeling to assess age effects on the executive index of the ANT. Mixed modeling accounted for between subject variability, age, handedness, catecholamine-O-transferase (COMT; codon 158) genotype, and gender on performance for all experimental conditions (cue × flanker) and their two-level interactions. Children with 22q11.2DS showed a relative, age-dependent executive index impairment but not orienting or alerting network index impairments. In factorial analysis, age was a major predictor of overall performance. There was a significant effect of the 22q11.2DS on overall performance. Of note, children with 22q11.2DS are specifically vulnerable to incongruent flanker interference, especially at younger ages. We did not find an overall effect of COMT genotype or handedness. Children with 22q11.2DS demonstrated age-related impairment in the executive control of attention. Future investigation will likely reveal that there are different developmental trajectories of executive attentional function likely related to the development of schizophrenia in 22q11.2DS.     

Hematological abnormalities in a patient with a 22q11.2 deletion

We report a case of a 28-year-old man carrying a 22q11.2 deletion and presenting with giant platelets, thrombocytopenia and leukocyte inclusion bodies. In our patient, platelet glycoproteins were normally expressed on membranes and platelet function was preserved. The May-Hegglin anomaly or Sebastian syndrome associated with the 22q11.2 deletion was suggested. Atypical features also included the lack of any cardiovascular defect, T cell deficit or palate anomaly, generally common with this deletion.     

Overlapping numerical cognition impairments in children with chromosome 22q11.2 deletion or Turner syndromes

Children with one of two genetic disorders (chromosome 22q11.2 deletion syndrome and Turner syndrome) as well typically developing controls, participated in three cognitive processing experiments. Two experiments were designed to test cognitive processes involved in basic aspects numerical cognition. The third was a test of simple manual motor reaction time. Despite significant differences in global intellectual abilities, as measured by IQ tests, performance on the two numerical cognition tasks differed little between the two groups of children with genetic disorders. However, both performed significantly more poorly than did controls. The pattern of results are consistent with the hypothesis that impairments were not due to global intellectual ability but arose in specific cognitive functions required by different conditions within the tasks. The fact that no group differences were found in the reaction time task, despite significant differences in the standardized processing speed measure, further supports the interpretation that specific cognitive processing impairments and not global intellectual or processing speed impairments explain the pattern of results. The similarity in performance on these tasks of children with unrelated genetic disorders counters the view that numerical cognition is under any direct genetic control. Instead, our findings are consistent with the view that disturbances in foundational spatiotemporal cognitive functions contribute to the development of atypical representations and processes in the domains of basic magnitude comparison and simple numerical enumeration.     

Neurogenic arthrogryposis multiplex congenita and velopharyngeal incompetence associated with chromosome 22q11.2 deletion

We report a case of neurogenic arthrogryposis multiplex congenita and velopharyngeal incompetence in association with a chromosome 22q11.2 deletion in a 5-month-old boy, the only child of a non-consanguineous couple without relevant antecedents. Specifically, polymerase chain reaction amplification of microsatellite markers revealed a noninherited microdeletion in position D22S306. This phenotype has not been reported previously in association with chromosome 22q11.2 deletions, and these findings raise the possibility that at least some cases of neurogenic arthrogryposis multiplex congenita might be due to genetic defects of this type.     

Corpus callosum morphology and ventricular size in chromosome 22q11.2 deletion syndrome

In this paper, novel methods were used to map the corpus callosum morphology of children with chromosome 22q11.2 deletion syndrome in order to further investigate changes to that structure and to examine their possible effects on cognitive function. The callosal profiles were extracted from the centermost MRI midsagittal slice by supervised thresholding and the structure's boundary and midline were computed automatically. Difference analysis was based on non-rigid registration, in which a template image is warped to conform to the shape of each corpus callosum in the sample. Boundaries and midlines were registered to a template and the results used to determine the average callosal shapes for children with the deletion and for controls. Pointwise registration also enabled the detailed evaluation of callosal curvature, width, area and length. Significant differences between the two groups were found in shape, size and bending angle. Results showed group differences that were concentrated in the anterior part of the structure, more specifically in the rostrum, which was larger and longer in the group with the syndrome. Correlation analyses showed that ventricular enlargement does not fully account for callosal morphology differences in children with the deletion. However, areal measurements did reveal important relationships between changes in callosal morphology and cognitive function. These novel findings reveal intricate relationships between genetic and disease-specific factors in the callosal anatomy and the potential impact of those changes on cognitive functions.     

Evidence of gray matter reduction and dysfunction in chromosome 22q11.2 deletion syndrome

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with cognitive deficits and morphometric brain abnormalities in childhood and a markedly elevated risk of schizophrenia in adolescence/early adulthood. Determining the relationship between neurocognition and neuroimaging findings would yield crucial information about childhood neurodevelopment and provide a basis for the study of the trajectory that occurs on the pathway to psychosis. We compared morphometric brain findings between non-psychotic children with 22q11DS (n = 22) and healthy controls (n = 16), and examined the association between neurocognitive functioning and morphometric brain findings. Volumetric regional gray matter differences between the 22q11DS and control subjects were measured, and correlations of the regional gray matter volumes and neurocognition were performed. Children with 22q11DS demonstrated reductions in gray matter in several brain regions, chiefly the frontal cortices, the cingulate gyrus and the cerebellum. The volumetric reductions in these salient areas were associated with poor performance in sustained attention, executive function and verbal memory; however, the relation of brain volume with cognitive performance did not differ between the patient and control groups. Thus, children with 22q11DS demonstrate gray matter reductions in multiple brain regions that are thought to be relevant to schizophrenia. The correlation of these volumetric reductions with poor neurocognition indicates that these brain regions may mediate higher neurocognitive functions implicated in schizophrenia.     

Hippocampal volume reduction in children with chromosome 22q11.2 deletion syndrome is associated with cognitive impairment

Background  

Previous investigations of individuals with chromosome 22q11.2 deletion syndrome (DS22q11.2) have reported alterations in both brain anatomy and cognitive function. Neuroanatomical studies have reported multiple abnormalities including changes in both gray and white matter in the temporal lobe, including the amygdala and hippocampus. Separate investigations of cognitive abilities have established the prevalence of general intellectual impairment, although the actual extent to which a single individual is affected varies greatly within the population. The present study was designed to examine structures within the temporal lobe and assess their functional significance in terms of cognition in children with DS22q11.2.     

A cross-sectional study of the development of volitional control of spatial attention in children with chromosome 22q11.2 deletion syndrome

For decades, researchers have sought to clarify the nature of the social communication impairments in autism, highlighting impaired or atypical 'social attention' as a key measurable construct that helps to define the core impairment of social communication. In this paper, we provide an overview of research on social attention impairments in autism and their relation to deficiencies in neural circuitry related to social reward. We offer a framework for considering social attention as a potential moderator or mediator of response to early behavioral intervention, and as an early indicator of efficacy of behavioral and/or pharmacological treatments aimed at addressing the social impairments in autism.     

Atypical developmental trajectory of functionally significant cortical areas in children with chromosome 22q11.2 deletion syndrome

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic disorder associated with neurocognitive impairments. This article focuses on the cortical gyrification changes that are associated with the genetic disorder in 6-15-year-old children with 22q11.2DS, when compared with a group of age-matched typically developing (TD) children. Local gyrification index (lGI; Schaer et al. [2008]: IEEE Trans Med Imaging 27:161-170) was used to characterize the cortical gyrification at each vertex of the pial surface. Vertex-wise statistical analysis of lGI differences between the two groups revealed cortical areas of significant reduction in cortical gyrification in children with 22q11.2DS, which were mainly distributed along the medial aspect of each hemisphere. To gain further insight into the developmental trajectory of the cortical gyrification, we examined age as a factor in lGI changes over the 6-15 years of development, within and across the two groups of children. Our primary results pertaining to the developmental trajectory of cortical gyrification revealed cortical regions where the change in lGI over the 6-15 years of age was significantly modulated by diagnosis, implying an atypical development of cortical gyrification in children with 22q11.2DS, when compared with the TD children. Significantly, these cortical areas included parietal structures that are associated, in typical individuals, with visuospatial, attentional, and numerical cognition tasks in which children with 22q11.2DS show impairments.