EEG as a translational biomarker and outcome measure in fragile X syndrome

Targeted treatments for fragile X syndrome (FXS) have frequently failed to show efficacy in clinical testing, despite success at the preclinical stages. This has highlighted the need for more effective translational outcome measures. EEG differences observed in FXS, including exaggerated N1 ERP amplitudes, increased resting gamma power and reduced gamma phase-locking in the sensory cortices, have been suggested as potential biomarkers of the syndrome. These abnormalities are thought to reflect cortical hyper excitability resulting from an excitatory (glutamate) and inhibitory (GABAergic) imbalance in FXS, which has been the target of several pharmaceutical remediation studies. EEG differences observed in humans also show similarities to those seen in laboratory models of FXS, which may allow for greater translational equivalence and better predict clinical success of putative therapeutics. There is some evidence from clinical trials showing that treatment related changes in EEG may be associated with clinical improvements, but these require replication and extension to other medications. Although the use of EEG characteristics as biomarkers is still in the early phases, and further research is needed to establish its utility in clinical trials, the current research is promising and signals the emergence of an effective translational biomarker

Overlapping phenotypes - a clinical and magnetic resonance imaging investigation of schizotypy and pervasive developmental disorders in adolescents with cognitive impairment

Introduction: The neurobiological bases of pervasive developmental disorders (PDD) and schizotypy are not well established. In addition there are clinical overlaps between the two which can make diagnostic determination difficult. The primary aim of this thesis was to explore the relationship between PDD and schizotypy by examining their associated clinical and brain structural features in a group of cognitively impaired adolescents. Methods: 138 adolescents receiving special educational assistance and 62 typically developing controls were recruited. Schizotypal features were measured using the Structured Interview for Schizotypy (SIS) and PDD features were measured using the Social Communication Questionnaire (SCQ). Each participant also received a standardised clinical interview and a magnetic resonance imaging (MRI) scan. Whole brain volume, midsagittal corpus callosum area and prefrontal lobe volume and gyrification index (GI) were measured using automated, semi-automated and manual region of interest techniques. The subjects in special education were considered in different groupings in three main analyses. In the first, the SIS was used to divide the subjects into those with and without schizotypal features. In the second, the standard SCQ cut-offs were used to divide the subjects into those with autism, those with non-specific pervasive developmental disorder (PDD-NOS) and those with neither. Finally, both the SIS and the SCQ were used contemporaneously to divide the subjects into 6 groups: schizotypal; autistic; PDD-NOS; comorbid schizotypy and autism; comorbid schizotypy and PDD-NOS; and neither schizotypal nor autistic. In each analysis the groups were compared to each other and to the controls with respect to the clinical features and brain structural measures. Results: The schizotypal subjects showed an increase in right prefrontal volume and changes in the anterior and posterior corpus callosum relative to those without schizotypy and the controls. The autism group had reduced right prefrontal GI relative to the other groups as well as anterior callosal changes. The PDD-NOS group had the highest level of psychiatric symptomatology on the CIS, in particular those who were comorbid for PDD-NOS and schizotypy. This comorbid group, both clinically and structurally resembled the schizotypy group rather than the PDD-NOS group. Conclusions: Distinct neuroanatomical differences can be seen in educationally impaired adolescents with schizotypal features and in those with autistic features. These can be related to the observed clinical impairment and may help to distinguish these disorders in the future. It is possible that adolescents with features of both schizotypy and PDD-NOS suffer from an underlying schizophrenia spectrum disorder rather than an autistic spectrum disorder

Clinical and behavioural features of SYNGAP1-related intellectual disability: a parent and caregiver description

BACKGROUND: SYNGAP1-related intellectual disability (ID) is a recently described neurodevelopmental disorder that is caused by pathogenic variation in the SYNGAP1 gene. To date, the behavioural characteristics of this disorder have mainly been highlighted via the prevalence of existing diagnoses in case series. We set out to detail the behavioural features of this disorder by undertaking interviews with those who have a child with SYNGAP1-related ID to allow them to describe their child’s behaviour. METHODS: We conducted 27 semi-structured interviews with parents and caregivers which covered basic information (e.g., age, gender), family history, perinatal history, past medical history, developmental history, epilepsy, behavioural history, and a general description of their child’s behaviour. RESULTS: Using a mixed quantitative and qualitative approach, the responses from the parents indicated that those with SYNGAP1-related ID showed high rates of autism spectrum disorder (52%), difficulties with fine and gross motor skills, delays in language development, and a high prevalence of epilepsy (70%). A qualitative analysis highlighted their general behaviour affected the themes of daily living skills, distress-related behaviours, emotional regulation, difficulties with change, a lack of danger awareness, and sensory differences. Sensory features described involved auditory, visual, tactile, gustatory, and proprioceptive themes. CONCLUSIONS: Our findings and behavioural descriptions provide important insights as well as implications for the diagnosis and care of those with SYNGAP1-related ID. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s11689-022-09437-x

Visual social attention in SYNGAP1-related intellectual disability

SYNGAP1-ID is a neurodevelopmental disorder caused by a mutation of the SYNGAP1 gene. Characterized by moderate to severe developmental delay, it is associated with several physical and behavioral issues as well as additional diagnoses, including autism. However, it is not known whether social cognitive differences seen in SYNGAP1-ID are similar to those previously identified in idiopathic or other forms of autism. This study therefore investigated visual social attention in SYNGAP1-ID. Eye movements were recorded across three passive viewing tasks (face scanning, pop-out, and social preference) of differing social complexity in 24 individuals with SYNGAP1-ID and 12 typically developing controls. We found that SYNGAP1-ID participants looked at faces less than the controls, and when they did look at faces, they had less time looking at and fewer fixations to the eyes. For the pop-out task, where social and nonsocial objects (Phone, car, face, bird, and face-noise) were presented in an array, those with SYNGAP1-ID spent significantly less time looking at the phone stimulus as well as fewer fixations to the face compared with the typically developing controls. When looking at two naturalistic scenes side by side, one social in nature (e.g., with children present) and the other not, there were no differences between the SYNGAP1-ID group and typically developing controls on any of the examined eye tracking measures. This study provides novel findings on the social attention of those with SYNGAP1-ID and helps to provide further evidence for using eye tracking as an objective measure of the social phenotype in this population in future clinical trials.</p

Profiling Autism and Attention Deficit Hyperactivity Disorder Traits in Children with SYNGAP1-Related Intellectual Disability

SYNGAP1-related ID is a genetic condition characterised by global developmental delay and epilepsy. Individuals with SYNGAP1-related ID also commonly show differences in attention and social communication/interaction and frequently receive additional diagnoses of Autism Spectrum Disorder (ASD) or Attention Deficit Hyperactivity Disorder (ADHD). We thus set out to quantify ASD and ADHD symptoms in children with this syndrome. To assess ASD and ADHD, parents and caregivers of a child with SYNGAP1-related ID (N = 34) or a typically developing control (N = 21) completed the Social Responsiveness Scale-2, the Social Communication Questionnaire with a subset of these also completing the Conners-3. We found that those with SYNGAP1-related ID demonstrated higher levels of autistic traits on both the SRS and SCQ than typically developing controls. On the SRS, those with SYNGAP1-related ID scored highest for restricted repetitive behaviours, and were least impaired in social awareness. On the Conners-3, those with SYNGAP1-related ID also showed a high prevalence of ADHD traits, with scores demonstrating difficulties with peer relations but relatively low occurrence of symptoms for DSM-5 conduct disorder and DSM-5 oppositional defiant disorder. Hierarchical clustering analysis highlighted distinct SYNGAP1-related ID subgroups for both ASD and ADHD traits. These findings provide further characterisation of the SYNGAP1-related ID behavioural phenotype, guiding diagnosis, assessment and potential interventions.</p

Sleep abnormalities in the synaptopathies—SYNGAP1-related intellectual disability and Phelan–McDermid syndrome

Neurodevelopmental disorders are frequently associated with sleep disturbances. One class of neurodevelopmental disorders, the genetic synaptopathies, is caused by mutations in genes encoding proteins found at the synapse. Mutations in these genes cause derangement of synapse development and function. We utilized a validated sleep instrument, Children’s Sleep Habits Questionnaire (CSHQ) to examine the nature of sleep abnormalities occurring in individuals with two synaptopathies—Phelan–McDermid syndrome (PMD) (N = 47, male = 23, female = 24, age 1–46 years) and SYNGAP1-related intellectual disability (SYNGAP1-ID) (N = 64, male = 31, female = 33, age 1–64 years), when compared with unaffected siblings (N = 61, male = 25, female = 36, age 1–17 years). We found that both PMD and SYNGAP1-ID have significant sleep abnormalities with SYNGAP1-ID having greater severity of sleep disturbance than PMD. In addition, sleep disturbances were more severe for PMD in individuals 11 years and older compared with those less than 11 years old. Individuals with either disorder were more likely to use sleep aids than unaffected siblings. In conclusion, sleep disturbances are a significant phenotype in the synaptopathies PMD and SYNGAP1-ID. Improved sleep is a viable endpoint for future clinical trials for these neurodevelopmental disorders

Evaluation of a Screening Instrument for Autism Spectrum Disorders in Prisoners

There have been concerns that individuals with autism spectrum disorders (ASDs) are over-represented but not recognised in prison populations. A screening tool for ASDs in prisons has therefore been developed

"A Group of Fellow Travellers Who Understand": Interviews With Autistic People About Post-diagnostic Peer Support in Adulthood

Receiving a diagnosis of autism in adulthood can be a life changing event, impacting identity, relationships, and mental health. A lack of post-diagnostic support has been highlighted by autistic adults, their allies, clinicians, and service providers. It can be a source of distress for autistic adults, reinforcing feelings of social isolation and rejection. Peer support could be a cost-effective, flexible, and sustainable model to provide community-based support for autistic adults. However, there is little research on the value of peer support, despite calls from the autistic community. This qualitative study explored autistic experiences and needs post-diagnosis, identifying specific ways that peer support may benefit them, and exploring the limitations of peer support. Twelve autistic adults who had all received an autism diagnosis in adulthood completed a semi-structured interview focussing on the diagnostic experience, post-diagnostic support needed and provided, engagement with the autistic community, and post-diagnostic peer support. Thematic analysis of interview transcripts resulted in four themes: (1) Mismatch in support needed and provided; (2) Community connection; (3) Flexible and personalised support; and (4) Sustainability. Participants indicated that peer support may be a useful mechanism to support autistic adults’ post-diagnosis and offers unique opportunities not available through other support channels. Though informal peer support exists, it could be more sustainable and effective if well-supported and funded

A holistic approach to fragile X syndrome integrated guidance for person‐centred care

Background: The Fragile X community has expressed a desire for centralised, national guidelines in the form of integrated guidance for Fragile X Syndrome (FXS). Methods: This article draws on existing literature reviews, primary research and clinical trials on FXS, a Fragile X Society conference workshop and first‐hand experience of clinicians who have worked with those living with FXS over many years. Results: The article scopes proposed integrated guidance over the life course, including appendices of symptoms, comorbidities and referral options for FXS and Fragile X Premutation Associated Conditions. Conclusion: Integrated guidance would provide an authoritative source for doctors, health professionals, therapists, care workers, social workers, educators, employers, families and those living with FXS, so that a holistic, person‐centred approach can be taken across the United Kingdom to garner the best outcomes for those with FXS