Exploring the Contribution to ADHD of Genes Involved in Mendelian Disorders Presenting with Hyperactivity and/or Inattention

Attention-deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by hyperactivity, impulsivity, and/or inattention, which are symptoms also observed in many rare genetic disorders. We searched for genes involved in Mendelian disorders presenting with ADHD symptoms in the Online Mendelian Inheritance in Man (OMIM) database, to curate a list of new candidate risk genes for ADHD. We explored the enrichment of functions and pathways in this gene list, and tested whether rare or common variants in these genes are associated with ADHD or with its comorbidities. We identified 139 genes, causal for 137 rare disorders, mainly related to neurodevelopmental and brain function. Most of these Mendelian disorders also present with other psychiatric traits that are often comorbid with ADHD. Using whole exome sequencing (WES) data from 668 ADHD cases, we found rare variants associated with the dimension of the severity of inattention symptoms in three genes: KIF11, WAC, and CRBN. Then, we focused on common variants and identified six genes associated with ADHD (in 19,099 cases and 34,194 controls): MANBA, UQCC2, HIVEP2, FOPX1, KANSL1, and AUH. Furthermore, HIVEP2, FOXP1, and KANSL1 were nominally associated with autism spectrum disorder (ASD) (18,382 cases and 27,969 controls), as well as HIVEP2 with anxiety (7016 cases and 14,475 controls), and FOXP1 with aggression (18,988 individuals), which is in line with the symptomatology of the rare disorders they are responsible for. In conclusion, inspecting Mendelian disorders and the genes responsible for them constitutes a valuable approach for identifying new risk genes and the mechanisms of complex disorders.

ESTUDO DE CASO DE UMA PACIENTE COM TRANSTORNO DO ESPECTRO AUTISTA, COM BASE NO PRONTUÁRIO ODONTOLÓGICO DA FAESA

Autism Spectrum Disorders (ASD) are complex disorders that involve a patient's neurological development. They are characterized by changes in social interaction, language and motricity, as well as stereotypical and repetitive behaviors. Patients may also present hypersensitivity to loud noises and bright lights. To answer specific anamnesis for patients with ASD, also taking into account patients' information that don't fit in Kanner's classic description. The chosen method was the Descriptive Case Study model, established through filling a specific anamnesis directed at a patient with ASD. The Odontological Medical Record of the clinic at FAESA was the basis for the data collection. It was not possible to answer many of the questions in the anamnesis from the data available on the medical records. Most of the questions were answered through previous contact with the patient. Other questions could not be answered by any means. A specific anamnesis for ASD patients should be included during treatment at FAESA's clinics for Patients with Special Needs. Treatment of patients with autism is still a great challenge for dental surgeons, since it requires knowledge of the problem and specific, objective techniques to cause the least possible trauma.

Rationale, Mission and Vision for a National Centre of Affective Disorders in Germany

Affective disorders are common, complex disorders representing one of the major challenges to global health in the 21st century. To mitigate the burden of disease, substantial public health efforts need to be undertaken since research on the causes and adequate treatment requires multidisciplinary approaches. These should integrate translational, and clinical research, aided by technological advancements in collecting and analysing comprehensive data. Here we present the rationale, concept, mission and vision of the recently founded National Centre of Affective Disorders (NCAD) in Germany. NCAD founding partners build on their previous successful cooperation within the German Research Network for Mental Disorders funded by the Federal Ministry of Education and Research (BMBF). They form an internationally pre-eminent network of integrative excellence, leading in science and contributing significantly to the improved care of affective disorder patients. The partners will provide complementary structures and innovative methods across the entire translational continuum from bench to clinical and real-world settings. The vision of the NCAD is to foster cross-disciplinary research from basic neuroscience to public mental health by close translational collaboration between academia, non-university research institutions, and international partners, including industry, to deliver cutting-edge research, innovative clinical services and evidence-based training to young clinicians and scientists. The mission is to accomplish research in a highly translational manner, especially with respect to clinical studies in a trans-sectoral way. This approach aims to ensure continuous improvement in the treatment and care provided to patients and an interdisciplinary environment for high-level research and education in affective disorders.

Probiotic Releasing Angiotensin (1-7) in a Drosophila Model of Alzheimer’s Disease Produces Sex-Specific Effects on Cognitive Function

Background: While extensive research on the brain has failed to identify effective therapies, using probiotics to target the gut microbiome has shown therapeutic potential in Alzheimer’s disease (AD). Genetically modified probiotics (GMP) are a promising strategy to deliver key therapeutic peptides with high efficacy and tissue specificity. Angiotensin (Ang)-(1-7) levels inversely correlate to AD severity, but its administration is challenging. Our group has successfully established a GMP-based method of Ang-(1-7) delivery. Objective: Since Drosophila represents an excellent model to study the effect of probiotics on complex disorders in a high throughput manner, we tested whether oral supplementation with Lactobacillus paracasei releasing Ang-(1-7) (LP-A) delays memory loss in a Drosophila AD model. Methods: Flies overexpressing the human amyloid-β protein precursor and its β-site cleaving enzyme in neurons were randomized to receive four 24-h doses of Lactobacillus paracasei alone (LP), LP-A or sucrose over 14 days. Memory was assessed via an aversive phototaxic suppression assay. Results: Optimal dilution,1:2, was determined based on palatability. LP-A improved memory in trained AD males but worsened cognition in AD females. LP-supplementation experiments confirmed that Ang-(1-7) conferred additional cognitive benefits in males and was responsible for the deleterious cognitive effects in females. Sex-specific differences in the levels of angiotensin peptides and differential activation of the kynurenine pathway of tryptophan metabolism in response to supplementation may underlie this male-only therapeutic response. Conclusion: In summary, LP-A ameliorated the memory deficits of a Drosophila AD model, but effects were sex-specific. Dosage optimization may be required to address this differential response.

High-impact rare genetic variants in severe schizophrenia

Extreme phenotype sequencing has led to the identification of high-impact rare genetic variants for many complex disorders but has not been applied to studies of severe schizophrenia. We sequenced 112 individuals with severe, extremely treatment-resistant schizophrenia, 218 individuals with typical schizophrenia, and 4,929 controls. We compared the burden of rare, damaging missense and loss-of-function variants between severe, extremely treatment-resistant schizophrenia, typical schizophrenia, and controls across mutation intolerant genes. Individuals with severe, extremely treatment-resistant schizophrenia had a high burden of rare loss-of-function (odds ratio, 1.91; 95% CI, 1.39 to 2.63; P = 7.8 × 10−5) and damaging missense variants in intolerant genes (odds ratio, 2.90; 95% CI, 2.02 to 4.15; P = 3.2 × 10−9). A total of 48.2% of individuals with severe, extremely treatment-resistant schizophrenia carried at least one rare, damaging missense or loss-of-function variant in intolerant genes compared to 29.8% of typical schizophrenia individuals (odds ratio, 2.18; 95% CI, 1.33 to 3.60; P = 1.6 × 10−3) and 25.4% of controls (odds ratio, 2.74; 95% CI, 1.85 to 4.06; P = 2.9 × 10−7). Restricting to genes previously associated with schizophrenia risk strengthened the enrichment with 8.9% of individuals with severe, extremely treatment-resistant schizophrenia carrying a damaging missense or loss-of-function variant compared to 2.3% of typical schizophrenia (odds ratio, 5.48; 95% CI, 1.52 to 19.74; P = 0.02) and 1.6% of controls (odds ratio, 5.82; 95% CI, 3.00 to 11.28; P = 2.6 × 10−8). These results demonstrate the power of extreme phenotype case selection in psychiatric genetics and an approach to augment schizophrenia gene discovery efforts.

A Review of the Current Mammalian Models of Alzheimer’s Disease and Challenges That Need to Be Overcome

Alzheimer’s disease (AD) is one of the looming health crises of the near future. Increasing lifespans and better medical treatment for other conditions mean that the prevalence of this disease is expected to triple by 2050. The impact of AD includes both the large toll on individuals and their families as well as a large financial cost to society. So far, we have no way to prevent, slow, or cure the disease. Current medications can only alleviate some of the symptoms temporarily. Many animal models of AD have been created, with the first transgenic mouse model in 1995. Mouse models have been beset by challenges, and no mouse model fully captures the symptomatology of AD without multiple genetic mutations and/or transgenes, some of which have never been implicated in human AD. Over 25 years later, many mouse models have been given an AD-like disease and then ‘cured’ in the lab, only for the treatments to fail in clinical trials. This review argues that small animal models are insufficient for modelling complex disorders such as AD. In order to find effective treatments for AD, we need to create large animal models with brains and lifespan that are closer to humans, and underlying genetics that already predispose them to AD-like phenotypes.

Biomarker discovery studies for patient stratification using machine learning analysis of omics data: a scoping review

ObjectiveTo review biomarker discovery studies using omics data for patient stratification which led to clinically validated FDA-cleared tests or laboratory developed tests, in order to identify common characteristics and derive recommendations for future biomarker projects.DesignScoping review.MethodsWe searched PubMed, EMBASE and Web of Science to obtain a comprehensive list of articles from the biomedical literature published between January 2000 and July 2021, describing clinically validated biomarker signatures for patient stratification, derived using statistical learning approaches. All documents were screened to retain only peer-reviewed research articles, review articles or opinion articles, covering supervised and unsupervised machine learning applications for omics-based patient stratification. Two reviewers independently confirmed the eligibility. Disagreements were solved by consensus. We focused the final analysis on omics-based biomarkers which achieved the highest level of validation, that is, clinical approval of the developed molecular signature as a laboratory developed test or FDA approved tests.ResultsOverall, 352 articles fulfilled the eligibility criteria. The analysis of validated biomarker signatures identified multiple common methodological and practical features that may explain the successful test development and guide future biomarker projects. These include study design choices to ensure sufficient statistical power for model building and external testing, suitable combinations of non-targeted and targeted measurement technologies, the integration of prior biological knowledge, strict filtering and inclusion/exclusion criteria, and the adequacy of statistical and machine learning methods for discovery and validation.ConclusionsWhile most clinically validated biomarker models derived from omics data have been developed for personalised oncology, first applications for non-cancer diseases show the potential of multivariate omics biomarker design for other complex disorders. Distinctive characteristics of prior success stories, such as early filtering and robust discovery approaches, continuous improvements in assay design and experimental measurement technology, and rigorous multicohort validation approaches, enable the derivation of specific recommendations for future studies.

Cerebrofacial vascular metameric syndrome is caused by somatic pathogenic variants in PIK3CA

Disorganized morphogenesis of arteries, veins, capillaries, and lymphatic vessels results in vascular malformations. Most individuals with isolated vascular malformations have postzygotic (mosaic), activating pathogenic variants in a handful of oncogenes within the PI3K–RAS–MAPK pathway (Padia et al., Laryngoscope Investig Otolaryngol 4: 170–173 [2019]). Activating pathogenic variants in the gene PIK3CA, which encodes for the catalytic subunit of phosphatidylinositol 3-kinase, are present in both lymphatic and venous malformations as well as arteriovenous malformations in other complex disorders such as CLOVES syndrome (congenital, lipomatous, overgrowth, vascular malformations, epidermal anevi, scoliosis) (Luks et al., Pediatr Dev Pathol 16: 51 [2013]; Luks et al., J Pediatr 166: 1048–1054.e1–5 [2015]; Al-Olabi et al., J Clin Invest 128: 1496–1508 [2018]). These vascular malformations are part of the PIK3CA-related overgrowth spectrum, a spectrum of entities that have regionalized disordered growth due to the presence of tissue-restricted postzygotic PIK3CA pathogenic variants (Keppler-Noreuil et al., Am J Med Genet A 167A: 287–295 [2015]). Cerebrofacial vascular metameric syndrome (CVMS; also described as cerebrofacial arteriovenous metameric syndrome, Bonnet–Dechaume–Blanc syndrome, and Wyburn–Mason syndrome) is the association of retinal, facial, and cerebral vascular malformations (Bhattacharya et al., Interv Neuroradiol 7: 5–17 [2001]; Krings et al., Neuroimaging Clin N Am 17: 245–258 [2007]). The segmental distribution, the presence of tissue overgrowth, and the absence of familial recurrence are all consistent with CVMS being caused by a postzygotic mutation, which has been hypothesized by previous authors (Brinjiki et al., Am J Neuroradiol 39: 2103–2107 [2018]). However, the genetic cause of CVMS has not yet been described. Here, we present three individuals with CVMS and mosaic activating pathogenic variants within the gene PIK3CA. We propose that CVMS be recognized as part of the PIK3CA-related overgrowth spectrum, providing justification for future trials using pharmacologic PIK3CA inhibitors (e.g., alpelisib) for these difficult-to-treat patients.

MeCP2 haplodeficiency and early-life stress interaction on anxiety-like behavior in adolescent female mice

Background Early-life stress can leave persistent epigenetic marks that may modulate vulnerability to psychiatric conditions later in life, including anxiety, depression and stress-related disorders. These are complex disorders with both environmental and genetic influences contributing to their etiology. Methyl-CpG Binding Protein 2 (MeCP2) has been attributed a key role in the control of neuronal activity-dependent gene expression and is a master regulator of experience-dependent epigenetic programming. Moreover, mutations in the MECP2 gene are the primary cause of Rett syndrome and, to a lesser extent, of a range of other major neurodevelopmental disorders. Here, we aim to study the interaction of MeCP2 with early-life stress in variables known to be affected by this environmental manipulation, namely anxiety-like behavior and activity of the underlying neural circuits. Methods Using Mecp2 heterozygous and wild-type female mice we investigated the effects of the interaction of Mecp2 haplodeficiency with maternal separation later in life, by assessing anxiety-related behaviors and measuring concomitant c-FOS expression in stress- and anxiety-related brain regions of adolescent females. Moreover, arginine vasopressin and corticotropin-releasing hormone neurons of the paraventricular hypothalamic nucleus were analyzed for neuronal activation. Results In wild-type mice, maternal separation caused a reduction in anxiety-like behavior and in the activation of the hypothalamic paraventricular nucleus, specifically in corticotropin-releasing hormone-positive cells, after the elevated plus maze. This effect of maternal separation was not observed in Mecp2 heterozygous females that per se show decreased anxiety-like behavior and concomitant decreased paraventricular nuclei activation. Conclusions Our data supports that MeCP2 is an essential component of HPA axis reprogramming and underlies the differential response to anxiogenic situations later in life.

Symptom burden of people with progressive ataxia, and its wider impact on their friends and relatives: a cross-sectional study

Background: Progressive ataxias are complex disorders that result in a wide variety of symptoms. Whilst we currently have a relatively good understanding of the symptom patterns associated with the various types of ataxia, and how these diseases progress over time, their impact on the person with ataxia is less well understood. In addition, little is known about how carers, friends and families are affected by them. This paper aims to provide preliminary information on the presence and impact of medical symptoms and day-to-day challenges on people with ataxia and their friends and relatives. Method: Data were extracted from a survey by Ataxia UK for their members. The views of 366 people with ataxia and 52 friends and relatives are reported. Data were analysed for the entire groups, as well as for the three most common ataxia types represented in the sample, Friedreich’s ataxia, inherited ataxia (excluding Friedreich’s ataxia), and cerebellar ataxia of unknown cause. Results: The survey confirmed the symptom patterns described in previous research, but further showed that the impact of these symptoms can vary across ataxia populations. Similar findings were observed for day-to-day challenges. Friends and relatives experienced similar challenges to people with ataxia, indicating that support provided has to consider those supporting people with ataxia as well as the patient. Respondents also highlighted limitations in terms of accessing support services, and not all services were able to cater fully to their specific needs. Conclusion: This study begins to provide information that can be used in further research to explore the needs of people with ataxia and their carers, friends, and relatives. Such research will support treatment trial design, ensuring patients’ needs are considered, help to tailor support services to their needs, and ensure health care professionals have the necessary skills to fully address them.