Innate frequency-discrimination hyperacuity in Williams-Beuren syndrome mice.

Williams-Beuren syndrome (WBS) is a rare disorder caused by hemizygous microdeletion of ∼27 contiguous genes. Despite neurodevelopmental and cognitive deficits, individuals with WBS have spared or enhanced musical and auditory abilities, potentially offering an insight into the genetic basis of auditory perception. Here, we report that the mouse models of WBS have innately enhanced frequency-discrimination acuity and improved frequency coding in the auditory cortex (ACx). Chemogenetic rescue showed frequency-discrimination hyperacuity is caused by hyperexcitable interneurons in the ACx. Haploinsufficiency of one WBS gene, Gtf2ird1, replicated WBS phenotypes by downregulating the neuropeptide receptor VIPR1. VIPR1 is reduced in the ACx of individuals with WBS and in the cerebral organoids derived from human induced pluripotent stem cells with the WBS microdeletion. Vipr1 deletion or overexpression in ACx interneurons mimicked or reversed, respectively, the cellular and behavioral phenotypes of WBS mice. Thus, the Gtf2ird1-Vipr1 mechanism in ACx interneurons may underlie the superior auditory acuity in WBS.

Oxytocin receptor activation does not mediate associative fear deficits in a Williams Syndrome model.

Williams Syndrome results in distinct behavioral phenotypes, which include learning deficits, anxiety, increased phobias and hypersociability. While the underlying mechanisms driving this subset of phenotypes is unknown, oxytocin (OT) dysregulation is hypothesized to be involved as some studies have shown elevated blood OT and altered OT receptor expression in patients. A "Complete Deletion" (CD) mouse, modeling the hemizygous deletion in Williams Syndrome, recapitulates many of the phenotypes present in humans. These CD mice also exhibit impaired fear responses in the conditioned fear task. Here, we address whether OT dysregulation is responsible for this impaired associative fear memory response. We show direct delivery of an OT receptor antagonist to the central nervous system did not rescue the attenuated contextual or cued fear memory responses in CD mice. Thus, increased OT signaling is not acutely responsible for this phenotype. We also evaluated OT receptor and serotonin transporter availability in regions related to fear learning, memory and sociability using autoradiography in wild type and CD mice. While no differences withstood correction, we identified regions that may warrant further investigation. There was a nonsignificant decrease in OT receptor expression in the lateral septal nucleus and nonsignificant lowered serotonin transporter availability in the striatum and orbitofrontal cortex. Together, these data suggest the fear conditioning anomalies in the Williams Syndrome mouse model are independent of any alterations in the oxytocinergic system caused by deletion of the Williams locus.

Autism Spectrum Disorders: Analysis of Mobile Elements at 7q11.23 Williams-Beuren Region by Comparative Genomics.

Autism spectrum disorders (ASD) are a group of complex neurodevelopmental disorders, characterized by a deficit in social interaction and communication. Many genetic variants are associated with ASD, including duplication of 7q11.23 encompassing 26-28 genes. Symmetrically, the hemizygous deletion of 7q11.23 causes Williams-Beuren syndrome (WBS), a multisystem disorder characterized by "hyper-sociability" and communication skills. Interestingly, deletion of four non-exonic mobile elements (MEs) in the "canine WBS locus" were associated with the behavioral divergence between the wolf and the dog and dog sociability and domestication. We hypothesized that indel of these MEs could be involved in ASD, associated with its different phenotypes and useful as biomarkers for patient stratification and therapeutic design. Since these MEs are non-exonic they have never been discovered before. We searched the corresponding MEs and loci in humans by comparative genomics. Interestingly, they mapped on different but ASD related genes. The loci in individuals with phenotypically different autism and neurotypical controls were amplified by PCR. A sub-set of each amplicon was sequenced by Sanger. No variant resulted associated with ASD and neither specific phenotypes were found but novel small-scale insertions and SNPs were discovered. Since MEs are hyper-methylated and epigenetically modulate gene expression, further investigation in ASD is necessary.

Abnormal auditory event-related potentials in Williams syndrome.

Individuals with Williams Syndrome (WS) have specific auditory characteristics, including hypoacusis and hyperacusis, and music appreciation skills. Little is known about the functionality of the central auditory nervous system (CANS) for sound processing in WS. Thus, the objective of the present study was to evaluate the functionality of the CANS in individuals with WS, based on auditory event-related potentials, as far as cognitive and behavioral aspects are concerned. The study was carried out with 17 individuals, seven females and ten males, between seven and 17 years old, with WS, and 17 individuals with typical development matched by sex and chronological age to individuals with WS. None of these individuals had middle ear impairment or hearing loss. The subjects were evaluated for intelligence quotient, loudness discomfort level, and auditory event-related potentials with Tone Burst stimuli, on the oddball paradigm; the parents also answered the MTA-SNAP-IV questionnaire. Hyperacusis was found in six WS individuals and two individuals with typical development. In the present study, WS individuals present longer latency and reduced amplitude for P1, N1, N2 and P3 components. These results, suggesting a delay and hypoactive responses of the CANS in this syndrome, that cannot be related to the cognitive or behavioral aspects of these individuals, but it indicates a cortical immaturity to process acoustic stimuli.

Functional play in young children with autism and Williams syndrome: A cross-syndrome comparison.

Functional play during early childhood paves the way to symbolic play and social communicative skills. However, functional play is surprisingly understudied in children with developmental disorders affecting social and communicative domains, such as Autism Spectrum Disorder (ASD) and Williams syndrome (WS). To address this issue and to evaluate both the quantity and quality of functional play in children with ASD and WS, we examined different play types using fine grained behavioral analysis with a group of age and IQ-matched developmentally delayed children with ASD (n = 14) and WS (n = 14) in comparison with 12 age-matched typically developing (TD) children. Significant differences were found in the quantity of functional play in the ASD and WS groups compared to TD children, with a limited breadth of object exploration found in children with ASD. While TD children engaged more frequently in functional versus nonfunctional play, this was not the case for children with ASD and WS, who showed the same amount of functional and nonfunctional play. Furthermore, functional play behavior was associated with intellectual and adaptive function in children with WS, but not ASD. These results point to the importance of intervention strategies that focus on functional play in improving developmental outcomes for children with ASD and WS.

Growth, body composition, and endocrine issues in Williams syndrome.

PURPOSE OF REVIEW: Williams syndrome is a multisystem disorder caused by a microdeletion on chromosome 7q. Throughout infancy, childhood, and adulthood, abnormalities in body composition and in multiple endocrine axes may arise for individuals with Williams syndrome. This review describes the current literature regarding growth, body composition, and endocrine issues in Williams syndrome with recommendations for surveillance and management by the endocrinologist, geneticist, or primary care physician. RECENT FINDINGS: In addition to known abnormalities in stature, calcium metabolism, and thyroid function, individuals with Williams syndrome are increasingly recognized to have low bone mineral density, increased body fat, and decreased muscle mass. Furthermore, recent literature identifies a high prevalence of diabetes and obesity starting in adolescence, and, less commonly, a lipedema phenotype in both male and female individuals. Understanding of the mechanisms by which haploinsufficiency of genes in the Williams syndrome-deleted region contributes to the multisystem phenotype of Williams syndrome continues to evolve. SUMMARY: Multiple abnormalities in growth, body composition, and endocrine axes may manifest in individuals with Williams syndrome. Individuals with Williams syndrome should have routine surveillance for these issues in either the primary care setting or by an endocrinologist or geneticist.

Pulmonary function in Williams-Beuren syndrome: Spirometric data of 22 Italian patients.

Williams-Beuren syndrome (WBS) is caused by an haploinsufficiency of the 7q11.2 region which involves the elastin gene (ELN). A deficiency of elastin is a known pathophysiological mechanism of emphysema/chronic obstructive pulmonary disease (COPD). A previous study hypothesized a higher risk of COPD in WBS patients. Herein, this phenomenon was further investigated looking for a possible correlation between COPD and WBS. Dynamic lung volumes (forced vital capacity [FVC], FEV1, FEV1/FVC) were measured in 22 patients (age range 18.9 ± 7.4 years) affected with WBS, genetically confirmed, correlating these parameters to respiratory risk factors. Dyspnea, cough and wheezing were detected in 6/22 (27%) patients. Obstructive and restrictive patterns were identified in 6/22 (27%) and 2/22 (9%) cases, respectively with no evidence of irreversible obstruction. CVF, FEV1 and FEV1/CVF mean values were all normal, with values of 91.3% (n.v. > 80%), 84.2% (n.v. > 80%) and 0.82 (n.v. > 0.7), respectively. The severity of the comorbidities did not show a cause-effect relation with the respiratory patterns, nevertheless patients treated with anti-hypertensive drugs had poorer pulmonary function. Our findings are in accordance with previous observations, showing that emphysema/COPD is not a typical finding in young patients with WBS. However, a respiratory function assessment should be included in the follow-up of WBS patients, especially in adolescents/young adults under treatment with anti-hypertensive drugs.

An investigation into the relationship between Quality of pantomime gestures and visuospatial skills.

While children with developmental language disorder or Williams syndrome appear to use hand gestures to compensate for specific cognitive and communicative difficulties, they have different cognitive strength-weakness profiles. Their semantic and visuospatial skills potentially affect gesture quality such as iconicity. The present study focuses on untangling the unique contribution of these skills in the quality of gestures. An explicit gesture elicitation task was presented to 25 participants with developmental language disorder between 7 and 10 years of age, 25 age-matched peers with typical development, and 14 participants with Williams Syndrome (8-23 years). They gestured pictures of objects without using speech (pantomime). The iconicity, semantic richness, and representation technique of the pantomimes were coded. Participants' semantic association and visuospatial skills were formally assessed. Iconicity was slightly lower in individuals with Williams syndrome, which seems related to their visuospatial deficit. While semantic saliency was similar across participant groups, small differences in representation technique were found. Partial correlations showed that visuospatial skills and semantic skills were instrumental in producing clear pantomimes. These findings indicate that clinicians aiming to enhance individuals' natural iconic gestures should consider achieved iconicity, particularly in individuals with low visuospatial skills.

Whole exome sequencing in patients with Williams-Beuren syndrome followed by disease modeling in mice points to four novel pathways that may modify stenosis risk.

Supravalvular aortic stenosis (SVAS) is a narrowing of the aorta caused by elastin (ELN) haploinsufficiency. SVAS severity varies among patients with Williams-Beuren syndrome (WBS), a rare disorder that removes one copy of ELN and 25-27 other genes. Twenty percent of children with WBS require one or more invasive and often risky procedures to correct the defect while 30% have no appreciable stenosis, despite sharing the same basic genetic lesion. There is no known medical therapy. Consequently, identifying genes that modify SVAS offers the potential for novel modifier-based therapeutics. To improve statistical power in our rare-disease cohort (N = 104 exomes), we utilized extreme-phenotype cohorting, functional variant filtration and pathway-based analysis. Gene set enrichment analysis of exome-wide association data identified increased adaptive immune system variant burden among genes associated with SVAS severity. Additional enrichment, using only potentially pathogenic variants known to differ in frequency between the extreme phenotype subsets, identified significant association of SVAS severity with not only immune pathway genes, but also genes involved with the extracellular matrix, G protein-coupled receptor signaling and lipid metabolism using both SKAT-O and RQTest. Complementary studies in Eln+/-; Rag1-/- mice, which lack a functional adaptive immune system, showed improvement in cardiovascular features of ELN insufficiency. Similarly, studies in mixed background Eln+/- mice confirmed that variations in genes that increase elastic fiber deposition also had positive impact on aortic caliber. By using tools to improve statistical power in combination with orthogonal analyses in mice, we detected four main pathways that contribute to SVAS risk.

Sensory processing profiles and autistic symptoms as predictive factors in autism spectrum disorder and Williams syndrome.

BACKGROUND: Unusual sensory responses were included in the diagnostic criteria for autism spectrum disorder (ASD), yet they are also common among individuals with other neurodevelopmental disorders, including Williams syndrome (WS). Cross-syndrome comparisons of sensory atypicalities and the evaluation of their syndrome specificity however have rarely been undertaken. We aimed to (1) examine and compare the sensory profiles in ASD and WS groups and (2) investigate whether autistic symptoms, including sensory processing scores, can predict a group membership. METHODS: Parents of 26 children with ASD and intellectual disability, 30 parents of children with ASD (no intellectual disability) and 26 with WS aged between 4 and 16 years were recruited. Parents completed the Sensory Profile to provide information about their children's sensory experiences and the Social Responsiveness Scale - Second Edition (SRS-2) to assess the degree of social impairment in their children. RESULTS: No significant differences were found in sensory processing scores between the three groups. Binary logistic regression analyses were undertaken with sensory quadrants and SRS-2 total score as factors. Models significantly predicted group membership, with Low Registration, Sensory Sensitivity and SRS-2 total score being significant predictors. CONCLUSIONS: The findings suggest that high rates of sensory atypicalities are a common neurodevelopmental characteristic that do not reliably distinguish between WS and ASD groups. Low Registration and Sensory Sensitivity-related behaviours might, however, be more specific to ASD. Further work is needed to explore what behaviours within sensory profiles can discriminate between neurodevelopmental disorders and should be included in diagnostic classifications.

Williams-Beuren Syndrome: The Role of Cardiac CT in Diagnosis.

Williams-Beuren syndrome is a multisystem genetic disorder associated with cardiovascular abnormalities, the most common of which is some variation of arterial stenosis. We describe a case of Williams-Beuren syndrome with multiple cardiovascular structural and arterial abnormalities and demonstrate the unique role of cardiac computed tomography in diagnosis.

A cross-syndrome approach to the social phenotype of neurodevelopmental disorders: Focusing on social vulnerability and social interaction style.

BACKGROUND: Following Annette Karmiloff-Smith's approach to cognitive research, this study applied a cross-syndrome approach to the social phenotype, focusing on social vulnerability (SV) and the factors that contribute to it. AIMS: To (i) identify syndrome-specific differences in SV across four neurodevelopmental disorder (NDD) groups, (ii) determine the contribution of intellectual disability (ID), age or gender to SV, and (iii) explore its relationship with social interaction style (SIS). METHODS AND PROCEDURES: 262 parents of children: Autism (n = 29), Williams syndrome (n = 29), Attention deficit hyperactivity disorder (n = 36), Fragile X syndrome (n = 18), and Neurotypical (n = 150) reported on their child's SV, quality of SIS and other factors (ID, age, gender). OUTCOMES AND RESULTS: Heightened SV was not syndrome-specific. Instead it was found equally across NDD groups (and not in the neurotypical group), and independently of ID, age and gender. Different atypical SISs were also distributed across NDD groups and each were significantly related to SV, independent of the factors above and beyond neurodevelopmental diagnosis. CONCLUSIONS AND IMPLICATIONS: The findings emphasise that social phenotypes are best understood as distributed across diagnostic boundaries and offer opportunities to further test the role of varied atypical SISs in the development of heightened SV.

Growth assessment in children with Williams-Beuren syndrome: a systematic review.

Williams-Beuren syndrome (WBS) is a rare genetic disease caused by a sporadic heterozygous microdeletion in 7q11.23. It is characterized by distinctive facial appearance, cardiopathy, short stature, intellectual disability, and endocrine abnormalities. To evaluate the growth pattern of patients with WBS and to identify the prevalence of malnutrition, overweight, and obesity in this population, a systematic review of studies published in English, between 1987 and 2018, was performed following the PRISMA protocol using the PubMed, Cochrane, and BIREME databases. Original articles and articles that evaluated growth status using weight, or height, or head circumference (HC), or body mass index (BMI) of individuals with WBS were included. Case reports, articles with data from other syndromes, and articles that did not present as a central theme the evaluation of growth were not included. WBS presented specific growth pattern, characterized by intrauterine growth restriction, low weight, length, and HC at birth. This global growth delay persisted during childhood and adolescence. BMI was not different to the reference population, and obesity was not observed in childhood. The mechanisms that determine this typical growth pattern are not totally clear; however, the typical pubertal development of these patients and the intrinsic and secondary lesions caused by microdeletion at 7q11.23 seem to be the major factors involved. Conclusion: Patients with WBS have a growth pattern different from the general reference population. The reference charts for normal population should not be used for WBS patients because it often underestimate their growth. Specific growth charts for WBS patients are necessary.

Social, neurodevelopmental, endocrine, and head size differences associated with atypical deletions in Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) is a multisystem disorder caused by a hemizygous deletion on 7q11.23 encompassing 26-28 genes. An estimated 2-5% of patients have "atypical" deletions, which extend in the centromeric and/or telomeric direction from the WBS critical region. To elucidate clinical differentiators among these deletion types, we evaluated 10 individuals with atypical deletions in our cohort and 17 individuals with similarly classified deletions previously described in the literature. Larger deletions in either direction often led to more severe developmental delays, while deletions containing MAGI2 were associated with infantile spasms and seizures in patients. In addition, head size was notably smaller in those with centromeric deletions including AUTS2. Because children with atypical deletions were noted to be less socially engaged, we additionally sought to determine how atypical deletions relate to social phenotypes. Using the Social Responsiveness Scale-2, raters scored individuals with atypical deletions as having different social characteristics to those with typical WBS deletions (p = .001), with higher (more impaired) scores for social motivation (p = .005) in the atypical deletion group. In recognizing these distinctions, physicians can better identify patients, including those who may already carry a clinical or FISH WBS diagnosis, who may benefit from additional molecular evaluation, screening, and therapy. In addition to the clinical findings, we note mild endocrine findings distinct from those typically seen in WBS in several patients with telomeric deletions that included POR. Further study in additional telomeric deletion cases will be needed to confirm this observation.

Mathematical development in Williams syndrome: A systematic review.

BACKGROUND: The current systematic review is the first to systematically explore and synthesis research to date on mathematical abilities in Williams syndrome (WS), a rare genetic disorder that results in an uneven cognitive profile. As mathematical development is complex and relies on both domain-specific and domain-general abilities, it is currently not clear what mathematical abilities have been examined in WS and also what the current gaps in this research area are. METHODS AND PROCEDURES: A total of 27 studies across 22 publications were identified through a systematic review search process. RESULTS: Overall, all mathematical abilities, except for simple counting and subitizing abilities, were reported to be impaired but in line with overall mental-age abilities. However, the literature to date has not established the underlying causes of these mathematical difficulties in WS. Some studies suggested that mathematical abilities in WS follow an atypical developmental pathway with a greater reliance on verbal abilities than in typical development but coupled with impaired understanding of counting and knowledge of the number system more broadly. However, most included studies used different assessments of mathematical skills and there is a lack of studies that have examined more than one particular aspect of mathematical development within the same study. In addition, studies have often included large age ranges and small participant samples, despite the known large individual variability in WS. CONCLUSION: Although we know mathematical abilities in WS are impaired, this area is under-researched and there is a lack of longitudinal studies that provide insight into the cognitive mechanisms that underpin mathematical development in WS. Therefore, there is a lack of an evidence-base to inform interventions or educational practice.

Stenosis coexists with compromised α1-adrenergic contractions in the ascending aorta of a mouse model of Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) is a rare disorder caused by a heterozygous deletion of 26-28 contiguous genes that affects the brain and cardiovascular system. Here, we investigated whether WBS affects aortic structure and function in the complete deletion (CD) mouse model harbouring the most common deletion found in WBS patients. Thoracic aortas from 3-4 months-old male CD mice and wild-type littermates were mounted in wire myographs or were processed for histomorphometrical analysis. Nitric oxide synthase (NOS) isoforms and oxidative stress levels were assessed. Ascending aortas from young adult CD mice showed moderate (50%) luminal stenosis, whereas endothelial function and oxidative stress were comparable to wild-type. CD mice showed greater contractions to KCl. However, α1-adrenergic contractions to phenylephrine, but not with a thromboxane analogue, were compromised. Decreased phenylephrine responses were not affected by selective inducible NOS blockade with 1400 W, but were prevented by the non-selective NOS inhibitor L-NAME and the selective neuronal NOS inhibitor SMTC. Consistently, CD mice showed increased neuronal NOS expression in aortas. Overall, aortic stenosis in CD mice coexists with excessive nNOS-derived NO signaling that compromises ascending aorta α1-adrenergic contractions. We suggest that increased neuronal NOS signaling may act as a physiological 'brake' against the detrimental effects of stenosis.

Discrepancy between musical ability and language skills in children with Williams syndrome.

BACKGROUND: Children with Williams syndrome (WS) show a marked interest in music, a characteristic often explored in clinical settings. However, the actual musical abilities of patients with WS remain debatable due to some of the relevant data being derived from experimental tasks that require a verbal response, despite the known language impairments in WS. The present study aimed to examine musical ability in children with WS using a newly invented pitch discrimination task with minimal involvement of language and clarify its relationship with language skill. METHODS: Eleven children with WS participated in the study. We used a novel pitch discrimination task that required minimal language use. Two piano tones were presented sequentially, and children were asked to give a non-verbal response as to whether the second tone was higher than, lower than, or the same as the first tone. RESULTS: Pitch discrimination performance in children with WS was lower than the level predicted for their chronological age (CA), even in the non-verbal task. Pitch discrimination ability and verbal mental age (VMA) were shown to be dissociated, such that children with WS with a lower skill level for language showed an unexpectedly higher level of pitch discrimination ability and vice versa. CONCLUSIONS: Our results indicated reduced musical ability with respect to CA in children with WS. The dissociation between musical ability and language skills may indicate unique developmental relationships that differ from those in normal children. These findings provide new evidence to support the importance of assessing actual musical ability in WS prior to implementing interventional music therapy.

Visuospatial bias in line bisection in Williams syndrome.

BACKGROUND: Recently, a study using the subjective straight-ahead task showed that individuals with Williams syndrome (WS) present a bias in the representation of body perception. The aim of the present study is to examine the horizontal midline body representation in WS participants using the bisection line task, which is an important benchmark for an egocentric frame of reference. METHOD: Fifteen WS participants (mean age = 21.7 ± 9.5 years) were compared with two typical development control groups: one composed of 15 participants matched on chronological age and one composed of 15 children matched on mental age. The task consisted of dividing each line in a series of 18 lines into two equal halves by drawing a vertical mark with a pencil in the centre of the line. RESULTS: Individuals with WS presented a significant leftward bias in comparison to mental age and chronological age groups. CONCLUSIONS: The leftward deviation in WS could be linked to the body representation bias and difficulties in the development of the egocentric reference system. An early detection of such deviation should help in the development of targeted interventions for WS individuals to improve visual-spatial skills and learning.

Altered Neocortical Dynamics in a Mouse Model of Williams-Beuren Syndrome.

Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by moderate intellectual disability and learning difficulties alongside behavioral abnormalities such as hypersociability. Several structural and functional brain alterations are characteristic of this syndrome, as well as disturbed sleep and sleeping patterns. However, the detailed physiological mechanisms underlying WBS are mostly unknown. Here, we characterized the cortical dynamics in a mouse model of WBS previously reported to replicate most of the behavioral alterations described in humans. We recorded the laminar local field potential generated in the frontal cortex during deep anesthesia and characterized the properties of the emergent slow oscillation activity. Moreover, we performed micro-electrocorticogram recordings using multielectrode arrays covering the cortical surface of one hemisphere. We found significant differences between the cortical emergent activity and functional connectivity between wild-type mice and WBS model mice. Slow oscillations displayed Up states with diminished firing rate and lower high-frequency content in the gamma range. Lower firing rates were also recorded in the awake WBS animals while performing a marble burying task and could be associated with the decreased spine density and thus synaptic connectivity in this cortical area. We also found an overall increase in functional connectivity between brain areas, reflected in lower clustering and abnormally high integration, especially in the gamma range. These results expand previous findings in humans, suggesting that the cognitive deficits characterizing WBS might be associated with reduced excitability, plus an imbalance in the capacity to functionally integrate and segregate information.

Sleep is atypical across neurodevelopmental disorders in infants and toddlers: A cross-syndrome study.

This cross-syndrome study focuses on sleep and its relationship with language development. Children with neurodevelopmental disorders present with language delay. Typical language development is constrained by numerous factors including sleep. Sleep is often disrupted in adolescents/adults with neurodevelopmental disorders. We therefore hypothesised that sleep may be disrupted, and correlate with language development, in infants/toddlers with neurodevelopmental disorders. To test our hypothesis, we obtained sleep and vocabulary size data from 75 infants/toddlers with one of three neurodevelopmental disorders (Down syndrome [DS], fragile X syndrome [FXS], Williams syndrome [WS]). Sleep was indeed disrupted in these children. It was also positively associated with receptive vocabulary size in the infants/toddlers with DS and WS (we could not test the relationship between sleep and language in FXS due to lack of power). We argue that disrupted sleep may be a common occurrence in very young children with neurodevelopmental disorders, and it may relate to their ability to acquire their first language.