Genetic contributions to visuospatial cognition in Williams syndrome: insights from two contrasting partial deletion patients

Background Williams syndrome (WS) is a rare neurodevelopmental disorder arising from a hemizygotic deletion of approximately 27 genes on chromosome 7, at locus 7q11.23. WS is characterised by an uneven cognitive profile, with serious deficits in visuospatial tasks in comparison to relatively proficient performance in some other cognitive domains such as language and face processing. Individuals with partial genetic deletions within the WS critical region (WSCR) have provided insights into the contribution of specific genes to this complex phenotype. However, the combinatorial effects of different genes remain elusive. Methods We report on visuospatial cognition in two individuals with contrasting partial deletions in the WSCR: one female (HR), aged 11 years 9 months, with haploinsufficiency for 24 of the WS genes (up to GTF2IRD1), and one male (JB), aged 14 years 2 months, with the three most telomeric genes within the WSCR deleted, or partially deleted. Results Our in-depth phenotyping of the visuospatial domain from table-top psychometric, and small- and large-scale experimental tasks reveal a profile in HR in line with typically developing controls, albeit with some atypical features. These data are contrasted with patient JB’s atypical profile of strengths and weaknesses across the visuospatial domain, as well as with more substantial visuospatial deficits in individuals with the full WS deletion. Conclusions Our findings point to the contribution of specific genes to spatial processing difficulties associated with WS, highlighting the multifaceted nature of spatial cognition and the divergent effects of genetic deletions within the WSCR on different components of visuospatial ability. The importance of general transcription factors at the telomeric end of the WSCR, and their combinatorial effects on the WS visuospatial phenotype are also discussed

Cross-Domain Associations Between Motor Ability, Independent Exploration, and Large-Scale Spatial Navigation; Attention Deficit Hyperactivity Disorder, Williams Syndrome, and Typical Development

In typical infants, the achievement of independent locomotion has a positive impact on the development of both small-scale and large-scale spatial cognition. Here we investigated whether this association between the motor and spatial domain: (1) persists into childhood and (2) is detrimental to the development of spatial cognition in individuals with motor deficits, namely, individuals with attention deficit hyperactivity disorder (ADHD) and individuals with Williams syndrome (WS). Despite evidence of a co-occurring motor impairment in many individuals with ADHD, little is known about the developmental consequences of this impairment. Individuals with WS demonstrate impaired motor and spatial competence, yet the relationship between these two impairments is unknown. Typically developing (TD) children (N = 71), individuals with ADHD (N = 51), and individuals with WS (N = 20) completed a battery of motor tasks, a measure of independent exploration, and a virtual reality spatial navigation task. Retrospective motor milestone data were collected for the ADHD and WS groups. Results demonstrated a relationship between fine motor ability and spatial navigation in the TD group, which could reflect the developmental impact of the ability to manually manipulate objects, on spatial knowledge. In contrast, no relationships between the motor and spatial domains were observed for the ADHD or WS groups. Indeed, while there was evidence of motor impairment in both groups, only the WS group demonstrated an impairment in large-scale spatial navigation. The motor-spatial relationship in the TD, but not the ADHD and WS groups, suggests that aspects of spatial cognition can develop via a developmental pathway which bypasses input from the motor domain

Corrigendum to: Comparative study of obstetric antiphospholipid syndrome (OAPS) and non-criteria obstetric APS (NC-OAPS): report of 1640 cases from EUROAPS registry

Rheumatology 2020;59:1306–1314. doi:https://doi.org/10.1093/rheumatology/kez419 In the original article, the affiliation of co-author Cecilia Beatrice Chighizola should have read: “Experimental Laboratory of Immunological and Rheumatologic Researches, Istituto Auxologico Italiano, IRCCS, Cusano Milanino, Milan, Italy”. These details have been corrected only in this corrigendum to preserve the published version of record

Electrophysiological study of local/global processing in Williams syndrome

Persons with Williams syndrome (WS) demonstrate pronounced deficits in visuo-spatial processing. The purpose of the current study was to examine the preferred level of perceptual analysis in young adults with WS (n = 21) and the role of attention in the processing of hierarchical stimuli. Navon-like letter stimuli were presented to adults with WS and age-matched typical controls in an oddball paradigm where local and global targets could appear with equal probability. Participants received no explicit instruction to direct their attention toward a particular stimulus level. Behavioral and event-related potential (ERP) data were recorded. Behavioral data indicated presence of a global precedence effect in persons with WS. However, their ERP responses revealed atypical brain mechanisms underlying attention to local information. During the early perceptual analysis, global targets resulted in reduced P1 and enhanced N150 responses in both participant groups. However, only the typical comparison group demonstrated a larger N150 to local targets. At the more advanced stages of cognitive processing, a larger P3b response to global and local targets was observed in the typical group but not in persons with WS, who instead demonstrated an enhanced P3a to global targets only. The results indicate that in a perceptual task, adults with WS may experience greater than typical global-to-local interference and not allocate sufficient attentional resources to local information

Drawing firmer conclusions: autistic children show no evidence of a local processing bias in a controlled copying task

Drawing tasks are frequently used to test competing theories of visuospatial skills in autism. Yet, methodological differences between studies have led to inconsistent findings. To distinguish between accounts based on local bias or global deficit, we present a simple task that has previously revealed dissociable local/global impairments in neuropsychological patients. Autistic and typical children copied corner elements, arranged in a square configuration. Grouping cues were manipulated to test whether global properties affected the accuracy of reproduction. All children were similarly affected by these manipulations. There was no group difference in the reproduction of local elements, although global accuracy was negatively related to better local processing for autistic children. These data speak against influential theories of visuospatial differences in autism

Uncommon genetic syndromes and narrative production - Case Studies with Williams, Smith-Magenis and Prader- Willi Syndromes

This study compares narrative production among three syndromes with genetic microdeletions: Williams syndrome (WS), Smith-Magenis syndrome (SMS), and Prader-Willi syndrome (PWS), characterized by intellectual disabilities and relatively spared language abilities. Our objective is to study the quality of narrative production in the context of a common intellectual disability. To elicit a narrative production, the task Frog! Where Are You was used. Then, structure, process, and content of the narrative process were analysed in the three genetic disorders:WS (n52), SMS (n52), and PWS (n52). Data show evidence of an overall low narrative quality in these syndromes, despite a high variability within different measures of narrative production. Results support the hypothesis that narrative is a highly complex cognitive process and that, in a context of intellectual disability, there is no evidence of particular ‘hypernarrativity’ in these syndromes.This research was supported by the grants FEDER –

Super-resolution imaging as a method to study GPCR dimers and higher-order oligomers

The study of G protein-coupled receptor (GPCR) dimers and higher-order oligomers has unveiled mechanisms for receptors to diversify signaling and potentially uncover novel therapeutic targets. The functional and clinical significance of these receptor–receptor associations has been facilitated by the development of techniques and protocols, enabling researchers to unpick their function from the molecular interfaces, to demonstrating functional significance in vivo, in both health and disease. Here we describe our methodology to study GPCR oligomerization at the single-molecule level via super-resolution imaging. Specifically, we have employed photoactivated localization microscopy, with photoactivatable dyes (PD-PALM) to visualize the spatial organization of these complexes to <10 nm resolution, and the quantitation of GPCR monomer, dimer, and oligomer in both homomeric and heteromeric forms. We provide guidelines on optimal sample preparation, imaging parameters, and necessary controls for resolving and quantifying single-molecule data. Finally, we discuss advantages and limitations of this imaging technique and its potential future applications to the study of GPCR function

Molecular Systematic of Three Species of Oithona (Copepoda, Cyclopoida) from the Atlantic Ocean: Comparative Analysis Using 28S rDNA

Species of Oithona (Copepoda, Cyclopoida) are highly abundant, ecologically important, and widely distributed throughout the world oceans. Although there are valid and detailed descriptions of the species, routine species identifications remain challenging due to their small size, subtle morphological diagnostic traits, and the description of geographic forms or varieties. This study examined three species of Oithona (O. similis, O. atlantica and O. nana) occurring in the Argentine sector of the South Atlantic Ocean based on DNA sequence variation of a 575 base-pair region of 28S rDNA, with comparative analysis of these species from other North and South Atlantic regions. DNA sequence variation clearly resolved and discriminated the species, and revealed low levels of intraspecific variation among North and South Atlantic populations of each species. The 28S rDNA region was thus shown to provide an accurate and reliable means of identifying the species throughout the sampled domain. Analysis of 28S rDNA variation for additional species collected throughout the global ocean will be useful to accurately characterize biogeographical distributions of the species and to examine phylogenetic relationships among them

Serum kidney injury molecule 1 and β2-microglobulin perform as well as larger biomarker panels for prediction of rapid decline in renal function in type 2 diabetes

Aims/hypothesis: As part of the Surrogate Markers for Micro- and Macrovascular Hard Endpoints for Innovative Diabetes Tools (SUMMIT) programme we previously reported that large panels of biomarkers derived from three analytical platforms maximised prediction of progression of renal decline in type 2 diabetes. Here, we hypothesised that smaller (n ≤ 5), platform-specific combinations of biomarkers selected from these larger panels might achieve similar prediction performance when tested in three additional type 2 diabetes cohorts. Methods: We used 657 serum samples, held under differing storage conditions, from the Scania Diabetes Registry (SDR) and Genetics of Diabetes Audit and Research Tayside (GoDARTS), and a further 183 nested case–control sample set from the Collaborative Atorvastatin in Diabetes Study (CARDS). We analysed 42 biomarkers measured on the SDR and GoDARTS samples by a variety of methods including standard ELISA, multiplexed ELISA (Luminex) and mass spectrometry. The subset of 21 Luminex biomarkers was also measured on the CARDS samples. We used the event definition of loss of >20% of baseline eGFR during follow-up from a baseline eGFR of 30–75 ml min−1 [1.73 m]−2. A total of 403 individuals experienced an event during a median follow-up of 7 years. We used discrete-time logistic regression models with tenfold cross-validation to assess association of biomarker panels with loss of kidney function. Results: Twelve biomarkers showed significant association with eGFR decline adjusted for covariates in one or more of the sample sets when evaluated singly. Kidney injury molecule 1 (KIM-1) and β2-microglobulin (B2M) showed the most consistent effects, with standardised odds ratios for progression of at least 1.4 (p < 0.0003) in all cohorts. A combination of B2M and KIM-1 added to clinical covariates, including baseline eGFR and albuminuria, modestly improved prediction, increasing the area under the curve in the SDR, Go-DARTS and CARDS by 0.079, 0.073 and 0.239, respectively. Neither the inclusion of additional Luminex biomarkers on top of B2M and KIM-1 nor a sparse mass spectrometry panel, nor the larger multiplatform panels previously identified, consistently improved prediction further across all validation sets. Conclusions/interpretation: Serum KIM-1 and B2M independently improve prediction of renal decline from an eGFR of 30–75 ml min−1 [1.73 m]−2 in type 2 diabetes beyond clinical factors and prior eGFR and are robust to varying sample storage conditions. Larger panels of biomarkers did not improve prediction beyond these two biomarkers