Exome Sequencing Reveals Novel Variants and Expands the Genetic Landscape for Congenital Microcephaly

Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of neurodevelopmental disorders. The underlying etiology is highly heterogeneous and can be either environmental or genetic. Disruption of any one of multiple biological processes, such as those underlying neurogenesis, cell cycle and division, DNA repair or transcription regulation, can result in microcephaly. This etiological heterogeneity manifests in a clinical variability and presents a major diagnostic and therapeutic challenge, leaving an unacceptably large proportion of over half of microcephaly patients without molecular diagnosis. To elucidate the clinical and genetic landscapes of congenital microcephaly, we sequenced the exomes of 191 clinically diagnosed patients with microcephaly as one of the features. We established a molecular basis for microcephaly in 71 patients (37%), and detected novel variants in five high confidence candidate genes previously unassociated with this condition. We report a large number of patients with mutations in tubulin-related genes in our cohort as well as higher incidence of pathogenic mutations in MCPH genes. Our study expands the phenotypic and genetic landscape of microcephaly, facilitating differential clinical diagnoses for disorders associated with most commonly disrupted genes in our cohort.

Peripheral polyneuropathy from electrodiagnostic tests: a 10-year etiology and neurophysiology overview

ABSTRACT Background: Polyneuropathies are characterized by a symmetrical impairment of the peripheral nervous system, resulting in sensory, motor and/or autonomic deficits. Due to the heterogeneity of causes, an etiological diagnosis for polyneuropathy is challenging. Objective: The aim of this study was to determine the main causes of polyneuropathy confirmed by electrodiagnostic (EDX) tests in a tertiary service and its neurophysiological aspects. Methods: This observational cross-sectional study from a neuromuscular disorders center included individuals whose electrodiagnostic tests performed between 2008 and 2017 confirmed a diagnosis of polyneuropathy. Through analysis of medical records, polyneuropathies were classified according to etiology and neurophysiological aspect. Results: Of the 380 included patients, 59.5% were male, with a median age of 43 years. The main etiologies were: inflammatory (23.7%), hereditary (18.9%), idiopathic (13.7%), multifactorial (11.1%), and diabetes (10.8%). The main electrophysiological patterns were axonal sensorimotor polyneuropathy (36.1%) and “demyelinating and axonal” sensorimotor polyneuropathy (27.9%). Axonal patterns showed greater etiological heterogeneity, with a predominance of idiopathic and multifactorial polyneuropathy, while demyelinating and “demyelinating and axonal” polyneuropathies had a significantly fewer etiologies, with a predominance of hereditary and inflammatory polyneuropathies. Conclusion: The main causes of polyneuropathy confirmed by EDX test in this study were those that presented a severe, atypical and/or rapidly progressing pattern. Other causes were hereditary and those that defy clinical reasoning, such as multiple risk factors; some polyneuropathies did not have a specific etiology. EDX tests are useful for etiological diagnosis of rare polyneuropathies, because neurophysiological patterns are correlated with specific etiologies.

Brain mapping across 16 autism mouse models reveals a spectrum of functional connectivity subtypes

Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modeled minimizing environmental contributions. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches.

Association Between Weight Gain, Psychological, Sociodemographic Factors, and Physical Activity in Bariatric Patients: A Network Perspective

Background Weight gain affects about 10-20% of patients after bariatric surgery (BS). It’s a phenomenon that’s difficult to understand and to intervene due to its complexity and etiological heterogeneity. In the present study, we investigated, from a network analysis perspective, the associations between weight regain, psychological, sociodemographic factors and physical activity in patients undergoing BS. Methods The sample consisted of 124 patients, of both sexes, aged 39 ± 9.1 years, who had undergone surgical intervention for more than 18 months. After voluntary consent, respondents answered questionnaires and instruments directly on the Google Forms platform. Results The weight gain was negatively associated with the items of depression, anxiety and stress, binge eating and with the dimensions of the personality questionnaire (negative affectivity -0.182; detachment -0.078; antagonism -0.107; disinterest - 0.198 and psychoticism -0.158). Conclusion Characteristics of disinterest and negative affectivity and most of the items on the depression, anxiety and stress scale had a greater expected influence, indicating that these are the most sensitive variables to intervention and who need more attention from health professionals.Level of evidence: Level III, evidence obtained from well-designed case-control analytic studies.

Validation of the Italian Version of the Functional Oral Intake Scale (FOIS-It) Against Fiberoptic Endoscopic Evaluation of Swallowing and Nutritional Status

The Functional Oral Intake Scale (FOIS) is a reliable and valid tool to assess functional oral intake of food and liquids in patients with oropharyngeal dysphagia (OD). Its validity was established for stroke patients against Videofluoroscopic Swallowing Study in English and Chinese and against Fiberoptic Endoscopic Evaluation of Swallowing (FEES) in German. FOIS was cross-culturally validated into Italian (FOIS-It), but construct validity against instrumental assessment and nutritional status was not investigated. The study aims at contributing to the validation of the FOIS-It, by performing convergent and known-group validity against FEES and nutritional status in patients with OD of different etiologies. Overall, 220 adult patients with OD of etiological heterogeneity were recruited. FOIS-It score and Body Mass Index (BMI) were collected. FEES was performed to assess swallowing safety and efficiency based on the Penetration-Aspiration Scale (PAS) and the Yale Pharyngeal Residue Severity Rating Scale (YPRSRS). Moderate to weak associations with PAS (ρ = − .37, p < .01), YPRSRS in the pyriform sinuses (ρ = − .20, p < .01), and BMI (ρ = .24, p < .01) were detected with Spearman’s correlation. FOIS-It distribution was compared with the Mann–Whitney U and Kruskal–Wallis tests. Significantly lower FOIS-It scores were detected among patients with penetration/aspiration (PAS > 2) and penetration (PAS > 2 ≤ 5) for all consistencies (p < .01), aspiration (PAS > 5) of liquids and semisolids (p < .001), residue in the pyriform sinuses (YPRSRS > 3) with semisolids (p < .001) and solids (p = .02), and malnutrition (BMI ≤ 18.5; p = .019). FOIS-It appears as a valid tool to assess functional oral intake against FEES’ measures of swallowing safety and efficiency and nutritional status in patients with OD of etiological heterogeneity.

Association Between Weight Gain, Psychological, Sociodemographic Factors, and Physical Activity in Bariatric Patients: A Complex System

Weight gain affects about 10-20% of patients after bariatric surgery. It is a phenomenon that is difficult to understand and to intervene due to its complexity and etiological heterogeneity. In the present study, we investigated, from a network analysis perspective, the associations between weight regain, psychological, sociodemographic factors and physical activity in patients undergoing bariatric surgery. The sample consisted of 124 patients, of both sexes, aged 39 &plusmn; 9.1 years, who had undergone surgical intervention for more than 18 months. After voluntary consent, respondents answered questionnaires and instruments directly on the Google Forms platform. The results indicated that weight gain was negatively associated with the items of depression, anxiety and stress, binge eating and with the dimensions of the personality questionnaire (negative affectivity -0.182; detachment -0.078; antagonism -0.107; disinterest - 0.198 and psychoticism -0.158). The centrality indicators revealed that the characteristics of disinterest and negative affectivity and most of the items on the depression, anxiety and stress scale had a greater expected influence (values ​​from 1,043 to 1,502), indicating that these are the most sensitive variables to intervention and who need more attention from health professionals.

The Etiological Heterogeneity of Bicuspid Aortopathy between Ascending and Root Morphotype

Background: Valve-related hemodynamics and intrinsically regulated matrix proteases are 2 determined pathogenetic factors associated with medial elastin degeneration in bicuspid aortopathy. This study analyzed the association between elastic fiber deterioration and the 2 pathogenetic factors in ascending and root morphotypes, aiming to elucidate the etiological heterogeneity between the 2 morphotypes. Methods: Four-dimensional flow cardiac magnetic resonance was used to measure the regional wall shear stress (WSS) on the ascending aorta, and matrix metalloproteinase (MMP) expression was assessed by immunoblotting. After histopathology analysis of aortic tissue, we assessed whether elevated regional WSS and increased MMP expression corresponded with medial elastin thinning. Results: Increased regional WSS corresponded with medial elastin thinning in both morphotypes. Increased expression of different MMP isoforms corresponded with medial elastin degeneration in bicuspid aortopathy. The significantly increased expression of MMP-2 corresponded with a decrease of elastic fiber thickness in the ascending morphotype (P = .046), whereas elastic fiber thinning was associated with high levels of MMP-3 expression (P = .012) in the root morphotype. No association was observed between regional WSS and MMP expression. Conclusion: There is no difference in the effect of valve-related hemodynamics between ascending and root morphotype, and MMPs are not involved in the process of elastic fiber degeneration induced by increased WSS. The increased expression of different MMP isoforms was observed in the context of elastic fiber degeneration between the 2 morphotypes, implying that heterogeneity between them is revealed in the different intrinsic pathway of medial elastin degradation.

Brain mapping across 16 autism mouse models reveals a spectrum of functional connectivity subtypes

Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modelled minimizing environmental contributions. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches.

Response-locked component of error monitoring in psychopathy: A systematic review and meta-analysis of error-related negativity/positivity

Prior findings reported that externalizing behaviors are closely related to disturbances in error monitoring. It has been suggested that these impairments are not applied to individuals with psychopathy. However, mixed results are reported in the field considering the etiological heterogeneity of the psychopathy construct. Most of the scales for the assessment of psychopathic traits use a modern conception of psychopathy. This conception suggests a pathological personality construct comprising factor conceptualization rather than a unitary construct. Deficits in error-related processing measures with event-related potential components are reported among individuals with psychopathy, but it is unclear whether these deficits are modulated by an interpersonal-affective or an impulsive-antisocial dimension

When to Suspect a Diagnosis of Amyloidosis

Amyloidosis is a group of complex diseases caused by extracellular deposition of pathological insoluble fibrillary protein in organs and tissues and may result in severe organ dysfunction. Despite the etiological heterogeneity of systemic amyloidosis, the clinical manifestations of the different forms of amyloidosis largely overlap and depend upon the effected organ. The signs and symptoms that should raise suspicion for the potential diagnosis of amyloidosis are usually nonspecific; therefore, establishing the diagnosis is difficult, and early diagnosis requires clinical suspicion. Light chain (AL) amyloidosis may present with highly specific signs such as macroglossia and periorbital purpura, but these signs are insensitive. Amyloidosis is still underdiagnosed, even though treatments are now available and are effective in improving patient’s survival and quality of life. Cardiac amyloidosis is the major determinant of survival, and the earlier it is detected the better the survival. All MGUS patients should be routinely screened for AL amyloidosis by a focused history and physical examination and routine assessment of urine albumin. The aim of this review is to provide clinicians with knowledge about the signs and symptoms that raise the suspicion of amyloidosis, bearing in mind the importance of early diagnosis of this disease.