Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP

Background In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking. Methods We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires. Results We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. Conclusions This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.This work was supported by grants from the European Research Area Networks Network of European Funding for Neuroscience Research through the Research Foundation–Flanders and the Chief Scientist Office–Ministry of Health (to RFK, GV, IG). This research was supported, in part, by grants from the Simons Foundation Autism Research Initiative (Grant No. SFARI 303241 to EEE) and National Institutes of Health (Grant No. R01MH101221 to EEE). This work was also supported by the Italian Ministry of Health and ‘5 per mille’ funding (to CR). For many individuals, sequencing was provided by research initiatives like the Care4Rare Research Consortium in Canada or the Deciphering Developmental Disorders (DDD) study in the UK. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (Grant No. HICF-1009–003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (Grant No. WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee, and GEN/284/12 granted by the Republic of Ireland Research Ethics Committee). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network

Microbiome to Brain:Unravelling the Multidirectional Axes of Communication

The gut microbiome plays a crucial role in host physiology. Disruption of its community structure and function can have wide-ranging effects making it critical to understand exactly how the interactive dialogue between the host and its microbiota is regulated to maintain homeostasis. An array of multidirectional signalling molecules is clearly involved in the host-microbiome communication. This interactive signalling not only impacts the gastrointestinal tract, where the majority of microbiota resides, but also extends to affect other host systems including the brain and liver as well as the microbiome itself. Understanding the mechanistic principles of this inter-kingdom signalling is fundamental to unravelling how our supraorganism function to maintain wellbeing, subsequently opening up new avenues for microbiome manipulation to favour desirable mental health outcome

Gastric tonometry in healthy volunteers: effect of ranitidine on calculated intramural pH

OBJECTIVE: To determine if intraluminal production of CO2 leads to underestimation of gastric intramural pH (pHi) by tonometry. DESIGN: Nonrandomized controlled study. PATIENTS: Healthy volunteers. INTERVENTIONS: NG tonometers were placed in healthy volunteers. Some of the volunteers (n = 11) were pretreated with ranitidine to prevent secretion of protons into the gastric lumen. Others (n = 13) were untreated (i.e., gastric acid secretion was uninhibited). MEASUREMENTS AND MAIN RESULTS: Gastric pHi was calculated from the arterial (HCO3-) and the tonometrically determined intraluminal PCO2 using the Henderson-Hasselbalch equation. Intraluminal PCO2 was significantly higher in the control group (54 +/- 14 torr [7.2 +/- 1.9 kPa]) than in the ranitidine-treated group (42 +/- 4 torr [5.6 +/- 0.4 kPa], p = .02). Mean gastric luminal pH was 1.9 +/- 0.6 in the control group as compared with 6.7 +/- 0.7 in volunteers treated with ranitidine (p less than .01). Mean calculated gastric pHi was 7.30 +/- 0.11 in the untreated group and 7.39 +/- 0.03 in the ranitidine-treated group (p less than .03). CONCLUSIONS: These data suggest that intraluminal production of CO2 from the titration of gastric HCO3- by secreted H+ can result in the underestimation of gastric pHi by tonometry. This phenomenon can be eliminated by H2-receptor blockade