Shruti Garg

Autism and other psychiatric comorbidity in neurofibromatosis type 1: evidence from a population‐based study

Aim  To investigate psychopathology in children with neurofibromatosis type 1 (NF1), particularly the prevalence of autism spectrum disorder (ASD) and attention‐deficit–hyperactivity disorder (ADHD) symptomatology, using a population‐based sampling approach.

Neurofibromatosis type 1 and autism spectrum disorder.

OBJECTIVE: To determine the prevalence of autism spectrum disorder (ASD) in Neurofibromatosis Type 1 (NF1). METHODS: Second-phase population-based epidemiologic study using an allcase NF1 registry in a defined UK 4.1 million population area. A total of 109 (52.7%) of 207 responders from the initial screening phase were grouped by using the parent-rated Social Responsiveness Scale (SRS) as significant ASD (SRS≥76; n = 32), moderate ASD (SRS ≥ 60<76; n = 29), or non-ASD (SRS <60, n = 48). Twenty-three cases from the significant ASD group, 16 from moderate ASD, and 8 from non-ASD (total n = 47), invited proportionately by random selection, were seen for detailed confirmatory ascertainment. Assessments on Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Scale-Generic, and verbal IQ were combined by using standard Collaborative Program for Excellence in Autism criteria into an ASD categorization for each case (ASD, broad ASD with partial features, non-ASD). A preplanned weighted analysis was used to derive prevalence estimates for the whole population. RESULTS: Fourteen (29.5%) of 47 showed ASD, 13 (27.7%) broad ASD, and 20 (42.5%) non-ASD. The ASD/broad ASD group showed male predominance (1.7:1.0), but did not differ significantly from the non-ASD group on IQ, age, socioeconomic status, inheritance, physical severity, or education. The population prevalence estimate is 24.9% ASD (95% confidence interval 13.1%–42.1%) and 20.8% broad ASD (95% confidence interval 10.0%–38.1%); a total of 45.7% showing some ASD spectrum phenotype. CONCLUSIONS: Findings indicate high prevalence of ASD in NF1, with implications for clinical practice and further research into NF1 as a single-gene model for autism.

Autism and other psychiatric comorbidity in NF1 ? evidence from a population based study

Aim  To investigate psychopathology in children with neurofibromatosis type 1 (NF1), particularly the prevalence of autism spectrum disorder (ASD) and attention‐deficit–hyperactivity disorder (ADHD) symptomatology, using a population‐based sampling approach.

Disease Burden and Symptom Structure of Autism in Neurofibromatosis Type 1: A Study of the International NF1-ASD Consortium Team (INFACT)

Importance Recent reports have demonstrated a higher incidence of autism spectrum disorder (ASD) and substantially elevated autistic trait burden in individuals with neurofibromatosis type 1 (NF1). However, important discrepancies regarding the distribution of autistic traits, sex predominance, and association between ASD symptoms and attentional problems have emerged, and critical features of the ASD phenotype within NF1 have never been adequately explored. Establishing NF1 as a monogenic cause for ASD has important implications for affected patients and for future research focused on establishing convergent pathogenic mechanisms relevant to the potential treatment targets for ASD. Objective To characterize the quantitative autistic trait (QAT) burden in a pooled NF1 data set. Design, Setting, and Participants Anonymized, individual-level primary data were accumulated from 6 tertiary referral centers in the United States, Belgium, United Kingdom, and Australia. A total of 531 individuals recruited from NF1 clinical centers were included in the study. Main Outcomes and Measures Distribution of ASD traits (Social Responsiveness Scale, second edition [SRS-2], with T scores of ≥75 associated with a categorical ASD diagnosis); attention-deficit/hyperactivity disorder (ADHD) traits (4 versions of Conners Rating Scale, with T scores of ≥65 indicating clinically significant ADHD symptoms); ASD symptom structure, latent structure, base rate derived from mixture modeling; and familiality. Results Of the 531 patients included in the analysis, 247 were male (46.5%); median age was 11 years (range, 2.5-83.9 years). QAT scores were continuously distributed and pathologically shifted; 13.2% (95% CI, 10.3%-16.1%) of individuals scored within the most severe range (ie, above the first percentile of the general population distribution) in which the male to female ratio was markedly attenuated (1.6:1) relative to idiopathic ASD. Autistic symptoms in this NF1 cohort demonstrated a robust unitary factor structure, with the first principal component explaining 30.9% of the variance in SRS-2 scores, and a strong association with ADHD symptoms (r = 0.61). Within-family correlation for QAT burden (intraclass correlation coefficient, 0.73 in NF1-affected first-degree relatives) exceeded that observed in the general population and ASD family samples. Conclusions and Relevance This study provides confirmation that the diversity of mutations that give rise to NF1 function as quantitative trait loci for ASD. Moreover, the within-family correlation implicates a high degree of mutational specificity for this associated phenotype. Clinicians should be alerted to the increased frequency of this disabling comorbidity, and the scientific community should be aware of the potential for this monogenic disorder to help elucidate the biological features of idiopathic autism.

Comprehensive RNA Analysis of the NF1 Gene in Classically Affected NF1 Affected Individuals Meeting NIH Criteria has High Sensitivity and Mutation Negative Testing is Reassuring in Isolated Cases With Pigmentary Features Only

Background The detection rate for identifying the underlying mutation in neurocutaneous syndromes is affected by the sensitivity of the mutation test and the heterogeneity of the disease based on the diagnostic criteria. Neurofibromatosis type (NF1) has been defined for 29 years by the National Institutes for Health (NIH) criteria which include ≥ 6 Café au Lait macules (CAL) as a defining criterion. The discovery of SPRED1 as a cause of Legius syndrome which is manifested by CAL, freckling and learning difficulties has introduced substantial heterogeneity to the NIH criteria. Methods We have defined the sensitivity of comprehensive RNA analysis on blood of presumed NF1 patients meeting NIH criteria with at least one nonpigmentary criterion and determined the proportion of children with ≥ 6 CAL and no family history that has an NF1 or SPRED1 genetic variant. RNA analysis was carried out from 04/2009–12/2015 on 361 NF1 patients. Findings A presumed causative NF1 mutation was found in 166/171 (97.08%–95% CI 94.56–99.6%) of familial cases and 182/190 (95.8%–95% CI 92.93–98.65%) sporadic de novo cases. Two of thirteen (15%) mutation negative individuals had dysembryoplastic neuroepithelial tumour (DNET) compared to 2/348 (0.6%) with an NF1 variant (p = 0.007). No SPRED1 variants were found in the thirteen individuals with no NF1 variant. Of seventy-one individuals with ≥ 6 CAL and no non-pigmentary criterion aged 0–20 years, 47 (66.2%) had an NF1 variant six (8.5%) a SPRED1 variant and 18 (25.3%) no disease causing variant. Using the 95.8% detection rate the likelihood of a child with ≥ 6 CAL having constitutional NF1 drops from 2/3 to 1/9 after negative RNA analysis. Interpretation RNA analysis in individuals with presumed NF1 has high sensitivity and includes a small subset with DNET without an NF1 variant. Furthermore negative analysis for NF1/SPRED1 provides strong reassurance to children with ≥ 6 CAL that they are unlikely to have NF1.

Autism spectrum disorder and other neurobehavioural comorbidities in rare disorders of the Ras/MAPK pathway

To investigate the cognitive and behavioural phenotype in rare disorders of the Ras/MAPK pathway, namely Noonan, cardiofaciocutaneous (CFC), and Costello syndromes, particularly prevalence of autism spectrum disorder (ASD) and attention‐deficit–hyperactivity disorder (ADHD).

Cognition in children with neurofibromatosis type 1: data from a population-based study

This study aimed to investigate the core cognitive deficits in children with neurofibromatosis type 1 (NF1).

Perspectives on the enablers of e-heath adoption: an international interview study of leading practitioners

Studies examining the application of information technology to the delivery of health-care services often highlight the anticipated benefits. In consequence, the benefits of health-care information technology adoption, often referred to as ‘e-health’, are widely reported yet there is limited empirical evidence as to how such benefits can be realized. Design and implementation guidelines have been considered from a socio-technical perspective and there is support for the successful application of these principles. There are also some global surveys on the topic, but these often report only statistical data and lack richness of content. This study draws on existing literature to examine whether the principles of health-care information technology adoption are currently applied in practice. The paper presents a timely international analysis of the drivers, critical enablers and successful deployment strategies for e-health from the perspective of leading practitioners. The study considers the adoption of e-health in 15 countries. A qualitative research design was used and semistructured interviews were conducted with 38 thought leaders with expertise in health-care information systems and technology. The study presents a comparative analysis of the lessons learned from implementing, integrating and embedding e-health in practice, and presents a four-phase approach from the perspective of practitioners for the accelerated deployment of e-health systems: (i) develop a strategic approach, (ii) engage the workforce, (iii) capitalize on information technology and (iv) partner with the patient/citizen.

Annual Research Review: The state of autism intervention science: progress, target psychological and biological mechanisms and future prospects

BACKGROUND There has been recent systematic review of key evidence in psychosocial intervention in autism but little review of biological treatments. METHODS We analyse the current literature from the perspective of intervention and mechanism targets across social and biological development. RESULTS The overall quality of trials evidence in autism intervention remains relatively low, despite some recent progress. Many treatments in common use have little or no evidence base. This is very concerning in such an important disorder. A variety of psychosocial interventions can show effect to improve some short-term effects on childrens immediate dyadic social interactions, for instance with caregivers. But showing true effectiveness in this developmental disorder requires generalisation of such effects into wider social contexts, on autism symptoms and in long-term progress in development. Only a few interventions so far have begun to show this. A number of early phase interventions on biological targets have shown real promise, but none has yet progressed to larger scale effectiveness trials on behavioural or symptom outcomes. CONCLUSIONS There has been enough progress in psychosocial intervention research now to be able to begin to identify some evidence-based practice in autism treatment. To consolidate and improve outcomes, the next phase of intervention research needs improved trial design, and an iterative approach building on success. It may also include the testing of potential synergies between promising biological and psychosocial interventions.

Temporal trends in antidepressant prescribing to children in UK primary care, 2000–2015

BACKGROUND The prevalence of antidepressant prescribing in children and adolescents increased steadily in the United States and parts of Europe between 2005 and 2012 despite regulatory safety warnings. Little is known about the characteristics of those being prescribed antidepressants for the first time. METHODS A longitudinal study of antidepressant prescribing in 3-17 year olds was carried out using data from the UK Clinical Practice Research Datalink (CPRD) between 2000 and 2015. Changes in the incidence of first ever antidepressant prescriptions and the characteristics of those being prescribed them was examined. RESULTS Incidence of first ever prescriptions nearly doubled between 2006 and 2015 rising from 1.60 (95%CI: 1.51, 1.69) to 3.12 (3.00, 3.25) per 1000 person years. Only 21% of the 1721 patients with incident prescriptions in 2015 could be linked to a depression diagnosis, with an additional 22% of prescriptions linked to alternative indications. The incidence of prescriptions linked to a depression diagnosis increased between 2012 and 2015, with an adjusted incidence rate ratio of 1.46 (1.26, 1.70). Antidepressant prescribing for depression and other indications has been increasing most rapidly in 15 to 17 year old females. LIMITATIONS Diagnoses are not directly linked to prescriptions in CPRD, so linkage must be inferred by temporal proximity. CONCLUSIONS Antidepressant prescribing in children increased between 2006 and 2015. This is, at least in part, due to a rise in alternative uses of antidepressants, including the treatment of anxiety, chronic pain and migraines.