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Abstract Background: Few studies have addressed the effects of biological therapies on laboratory outcomes and changes in FEV1 in patients with severe asthma (SA) and chronic rhinosinusitis (CRS). We aimed to study the effect of three biological therapies on laboratory outcomes and FEV1 in Saudi Arabian patients with SA and CRS., Methods: From March to September 2022, a retrospective observational cohort study was undertaken at the severe asthma clinics of the Armed Forces Hospital-Southern Region (AFHSR) and King Khalid University Hospital, Abha, Saudi Arabia, to delineate the effects of 3 biological therapies (benralizumab, dupilumab, and omalizumab) in adults with SA and concomitant CRS in terms of FEV1 and laboratory parameters (serum IgE and eosinophilic counts)., Results: Eighty patients were enrolled, with a mean age of 46.68. There were 45 (56%) females and 35 (44%) males. There were significant improvements in FEV1 and laboratory parameters (serum IgE and eosinophilic counts) after 6 &12 months of biological therapies compared to pre-biological therapies (p<0.001, each). The response was different among different biological therapies. The improvements in FEV1, serum IgE, and eosinophilic counts were manifest with benralizumab and dupilumab but not with omalizumab., Conclusions: Results from the first study from two large Saudi Arabian tertiary centers for patients with severe asthma and chronic rhinosinusitis agree with and support those of worldwide real-life ones. One-year follow-up of patients with SA and CRS showed the effectiveness of benralizumab and dupilumab, but not omalizumab, regarding FEV1, serum IgE, and eosinophilic counts. Further prospective multicenter studies are warranted.

Background: Alzheimer's disease (AD) is a common, complex and multifactorial disease that may require screening across multiple routes of referral to enable early detection and subsequent future implementation of tailored interventions. Blood- and eye-based biomarkers show promise as low-cost, scalable and patient-friendly tools for early AD detection given their ability to provide information on AD pathophysiological changes and manifestations in the retina, respectively. Eye clinics provide an intriguing real-world proof-of-concept setting to evaluate the performance of these potential AD screening tools given the intricate connections between the eye and brain, presumed enrichment for AD pathology in the aging population with eye disorders, and the potential for an accelerated diagnostic pathway for under-recognized patient groups., Methods: The BeyeOMARKER study is a prospective, observational, longitudinal cohort study aiming to include individuals visiting an eye-clinic. Inclusion criteria entail being ≥ 50 years old and having no prior dementia diagnosis. Excluded eye-conditions include traumatic insults, superficial inflammation, and conditions in surrounding structures of the eye that are not engaged in vision. The BeyeOMARKER cohort (n = 700) will undergo blood collection to assess plasma p-tau217 levels and a brief cognitive screening at the eye clinic. All participants will subsequently be invited for annual longitudinal follow-up including remotely administered cognitive screening and questionnaires. The BeyeOMARKER + cohort (n = 150), consisting of 100 plasma p-tau217 positive participants and 50 matched negative controls selected from the BeyeOMARKER cohort, will additionally undergo Aβ-PET and tau-PET, MRI, retinal imaging including hyperspectral imaging (primary), widefield imaging, optical coherence tomography (OCT) and OCT-Angiography (secondary), and cognitive and cortical vision assessments., Results: We aim to implement the current protocol between April 2024 until March 2027. Primary outcomes include the performance of plasma p-tau217 and hyperspectral retinal imaging to detect AD pathology (using Aβ- and tau-PET visual read as reference standard) and to detect cognitive decline. Initial follow-up is ~ 2 years but may be extended with additional funding., Conclusions: We envision that the BeyeOMARKER study will demonstrate the feasibility of early AD detection based on blood- and eye-based biomarkers in alternative screening settings, and will improve our understanding of the eye-brain connection., Trial Registration: The BeyeOMARKER study (Eudamed CIV ID: CIV-NL-23-09-044086; registration date: 19th of March 2024) is approved by the ethical review board of the Amsterdam UMC., (© 2024. The Author(s).)

Background: The mismatch between the limited availability versus the high demand of participants who are in the pre-dementia phase of Alzheimer's disease (AD) is a bottleneck for clinical studies in AD. Nevertheless, potential enrollment barriers in the pre-dementia population are relatively under-reported. In a large European longitudinal biomarker study (the AMYPAD-PNHS), we investigated main enrollment barriers in individuals with no or mild symptoms recruited from research and clinical parent cohorts (PCs) of ongoing observational studies., Methods: Logistic regression was used to predict study refusal based on sex, age, education, global cognition (MMSE), family history of dementia, and number of prior study visits. Study refusal rates and categorized enrollment barriers were compared between PCs using chi-squared tests., Results: 535/1856 (28.8%) of the participants recruited from ongoing studies declined participation in the AMYPAD-PNHS. Only for participants recruited from clinical PCs (n = 243), a higher MMSE-score (β =  - 0.22, OR = 0.80, p < .05), more prior study visits (β =  - 0.93, OR = 0.40, p < .001), and positive family history of dementia (β = 2.08, OR = 8.02, p < .01) resulted in lower odds on study refusal. General study burden was the main enrollment barrier (36.1%), followed by amyloid-PET related burden (PC research  = 27.4%, PC clinical  = 9.0%, X 2  = 10.56, p = .001), and loss of research interest (PC clinical  = 46.3%, PC research  = 16.5%, X 2  = 32.34, p < .001)., Conclusions: The enrollment rate for the AMYPAD-PNHS was relatively high, suggesting an advantage of recruitment via ongoing studies. In this observational cohort, study burden reduction and tailored strategies may potentially improve participant enrollment into trial readiness cohorts such as for phase-3 early anti-amyloid intervention trials. The AMYPAD-PNHS (EudraCT: 2018-002277-22) was approved by the ethical review board of the VU Medical Center (VUmc) as the Sponsor site and in every affiliated site., (© 2023. The Author(s).)

Abstract: We sought to examine incidence and predictors of eosinophilic myocardial hypersensitivity (EMH) in a cohort of patients in the home inotrope program of a quaternary cardiac transplant center. Patients on home inotropes with progression to heart transplantation or ventricular assist device (VAD) between January 2000 and May 2020 were included. EMH was diagnosed by the presence of an interstitial predominate eosinophilic infiltrate within the myocardium by experienced cardiac pathologists. From a cohort of 74 patients, 58% (43) were on dobutamine and 42% (31) were on milrinone. Dobutamine was associated with EMH incidence of 14% (6/43), with zero cases in the milrinone cohort. Mean age was 52 ± 12 years, 22% were female. More than half (62%) were nonischemic dilated cardiomyopathies, the remainder were ischemic cardiomyopathy. Dobutamine dose [250 (200-282) vs. 225 (200-291) μg/min] and duration of therapy [41 (23-79) vs. 53 (24-91) days] was similar between those with and without EMH. Median change in eosinophil count was 0.31 × 10 9 /L in the EMH group compared with only 0.03 × 10 9 /L in the non-EMH cohort, P = 0.02. Increase in peripheral eosinophil count of >0.20 × 10 9 /L demonstrated good discrimination between those with and without EMH, c-statistic 0.83 (95% CI 0.66-1.0). Heart failure hospitalization occurred in 83% of the EMH group versus 59% in the non-EMH group, P = 0.26. Requirement for VAD was significantly higher in the EMH group (83% vs. 41%, P = 0.05). In conclusion, EMH occurred in 14% of patients receiving home dobutamine. Rising eosinophil count should prompt physicians to consider EMH and switch to milrinone to avoid possible escalation to VAD., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Mutations in genes that lead to dysfunctional cilia can cause a broad spectrum of human disease phenotypes referred to as ciliopathies. Many ciliopathy-associated proteins are localized to the evolutionary conserved ciliary transition zone (TZ) subdomain. We identified biallelic missense and nonsense mutations in the gene encoding the transmembrane protein TMEM218 in unrelated patients with features related to Bardet-Biedl, Joubert and Meckel-Gruber syndrome (MKS) and characterized TMEM218 as a major component of the ciliary TZ module. Co-immunoprecipitation assays resulted in the physical interaction of TMEM218 with the MKS module member TMEM67/Meckelin that was significantly reduced by the TMEM218 missense change harboured by one of our patients. We could further validate its pathogenicity by functional in vivo analysis in zebrafish (Danio rerio) as a well-established vertebrate model for ciliopathies. Notably, ciliopathy-related phenotypes were most prominent by genetic interactions with the NPHP module component Nphp4. Conclusively, we describe TMEM218 as a new disease gene for patients with a wide spectrum of syndromic ciliopathy phenotypes and provide evidence for a synergistic interaction of TMEM218 and the NPHP module crucial for proper ciliary function., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Alterations in the MYH7 gene can cause cardiac and skeletal myopathies. MYH7-related skeletal myopathies are extremely rare, and the vast majority of causal variants in the MYH7 gene are predicted to alter the rod domain of the of ß-cardiac myosin molecule, resulting in distal muscle weakness as the predominant manifestation. Here we describe two unrelated patients harboring an in-frame deletion in the MYH7 gene that is predicted to result in deletion of a single amino acid (p.Glu500del) in the head domain of ß-cardiac myosin. Both patients display an unusual skeletal myopathy phenotype with congenital axial stiffness and muscular hypertonus, but no cardiac involvement., Results: Clinical data, MRI results and histopathological data were collected retrospectively in two unrelated boys (9 and 3.5 years old). Exome sequencing uncovered the same 3-bp in-frame deletion in exon 15 (c.1498&#95;1500delGAG) of the MYH7 gene of both patients, a mutation which deletes a highly conserved glutamate residue (p.Glu500del) in the relay loop of the head domain of the ß-cardiac myosin heavy chain. The mutation occurred de novo in one patient, whereas mosaicism was detected in blood of the father of the second patient. Both boys presented with an unusual phenotype of prenatal polyhydramnios, congenital axial stiffness and muscular hypertonus. In one patient the phenotype evolved into an axial/proximal skeletal myopathy without distal involvement or cardiomyopathy, whereas the other patient exhibited predominantly stiffness and respiratory involvement. We review and compare all patients described in the literature who possess a variant predicted to alter the p.Glu500 residue in the ß-cardiac myosin head domain, and we provide in-silico analyses of potential effects on polypeptide function., Conclusion: The data presented here expand the phenotypic spectrum of mutations in the MYH7 gene and have implications for future diagnostics and therapeutic approaches., (© 2022. The Author(s).)

Budding uninhibited by benzimidazoles (BUB1) contributes to multiple mitotic processes. Here, we describe the first two patients with biallelic BUB1 germline mutations, who both display microcephaly, intellectual disability, and several patient-specific features. The identified mutations cause variable degrees of reduced total protein level and kinase activity, leading to distinct mitotic defects. Both patients’ cells show prolonged mitosis duration, chromosome segregation errors, and an overall functional spindle assembly checkpoint. However, while BUB1 levels mostly affect BUBR1 kinetochore recruitment, impaired kinase activity prohibits centromeric recruitment of Aurora B, SGO1, and TOP2A, correlating with anaphase bridges, aneuploidy, and defective sister chromatid cohesion. We do not observe accelerated cohesion fatigue. We hypothesize that unresolved DNA catenanes increase cohesion strength, with concomitant increase in anaphase bridges. In conclusion, BUB1 mutations cause a neurodevelopmental disorder, with clinical and cellular phenotypes that partially resemble previously described syndromes, including autosomal recessive primary microcephaly, mosaic variegated aneuploidy, and cohesinopathies.

POGZ -related disorders (also known as White-Sutton syndrome) encompass a wide range of neurocognitive abnormalities and other accompanying anomalies. Disease severity varies widely among POGZ patients and studies investigating genotype-phenotype association are scarce. Therefore, our aim was to collect data on previously unreported POGZ patients and perform a large-scale phenotype-genotype comparison from published data. Overall, 117 POGZ patients' genotype and phenotype data were included in the analysis, including 12 novel patients. A severity scoring system was developed for the comparison. Mild and severe phenotypes were compared with the types and location of the variants and the predicted presence or absence of nonsense-mediated RNA decay (NMD). Missense variants were more often associated with mild phenotypes ( p = 0.0421) and truncating variants predicted to escape NMD presented with more severe phenotypes ( p < 0.0001). Within this group, variants in the prolin-rich region of the POGZ protein were associated with the most severe phenotypes ( p = 0.0004). Our study suggests that gain-of-function or dominant negative effect through escaping NMD and the location of the variants in the prolin-rich domain of the protein may play an important role in the severity of manifestations of POGZ -associated neurodevelopmental disorders.

Purpose: Haploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS., Methods: We report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status., Results: The expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes., Conclusion: We refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature., Competing Interests: Conflict of Interest The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics. The other authors declare no conflicts of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. All rights reserved.)

Optimal pharmacokinetic models for quantifying amyloid beta (Aβ) burden using both [ 18 F]flutemetamol and [ 18 F]florbetaben scans have previously been identified at a region of interest (ROI) level. The purpose of this study was to determine optimal quantitative methods for parametric analyses of [ 18 F]flutemetamol and [ 18 F]florbetaben scans. Forty-six participants were scanned on a PET/MR scanner using a dual-time window protocol and either [ 18 F]flutemetamol (N=24) or [ 18 F]florbetaben (N=22). The following parametric approaches were used to derive DVR estimates: reference Logan (RLogan), receptor parametric mapping (RPM), two-step simplified reference tissue model (SRTM2) and multilinear reference tissue models (MRTM0, MRTM1, MRTM2), all with cerebellar grey matter as reference tissue. In addition, a standardized uptake value ratio (SUVR) was calculated for the 90-110 min post injection interval. All parametric images were assessed visually. Regional outcome measures were compared with those from a validated ROI method, i.e. DVR derived using RLogan. Visually, RPM, and SRTM2 performed best across tracers and, in addition to SUVR, provided highest AUC values for differentiating between Aβ-positive vs Aβ-negative scans ([ 18 F]flutemetamol: range AUC=0.96-0.97 [ 18 F]florbetaben: range AUC=0.83-0.85). Outcome parameters of most methods were highly correlated with the reference method (R 2 ≥0.87), while lowest correlation were observed for MRTM2 (R 2 =0.71-0.80). Furthermore, bias was low (≤5%) and independent of underlying amyloid burden for MRTM0 and MRTM1. The optimal parametric method differed per evaluated aspect; however, the best compromise across aspects was found for MRTM0 followed by SRTM2, for both tracers. SRTM2 is the preferred method for parametric imaging because, in addition to its good performance, it has the advantage of providing a measure of relative perfusion (R 1 ), which is useful for measuring disease progression., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: We identified variation in delivery of guideline recommended care at our institution, and undertook a project to design a heart failure (HF) model of care., Aim: To maximise time patients with HF spend well in the community by delivering best practice guidelines to reduce variation in care improving overall outcomes., Methods: This quality improvement project focused on reducing variation in process measures of care. The HF model of care included electronic HF care bundles, a patient education pack with staff training on delivering HF patient education, referral of all HF patients to the Hospital Admissions Risk Program for phone call within 72 h, and a nurse-pharmacist early follow-up clinic. Outcomes were assessed using interrupted time series analyses., Results: The pre-intervention group comprised 1585 patients, and post-intervention 1720 patients with a primary diagnosis of HF admitted under general cardiology and general medicine. Interrupted time series analysis indicated 30-day readmissions did not change in overall trend (-0.2% per month, P = 0.479) but a significant immediate step-down of 7.8% was seen (P = 0.018). For 90-day readmissions, a significant trend reduction over the time period was seen (-0.6% per month, P = 0.017) with a significant immediate step-down (-9.4%, P = 0.001). Emergency department representations, in-patient mortality and length of stay did not change significantly. Improvements in process measures were seen at audit., Conclusion: This model of care resulted in overall trends of reductions in 30- and 90-day readmissions, without increasing emergency department representations, mortality and length of stay. This model will be adapted as the electronic medical record is introduced at our institution., (© 2020 Royal Australasian College of Physicians.)

Purpose: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome)., Methods: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers., Results: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined., Conclusion: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.

Purpose: This study aimed to delineate the genetic basis of congenital ocular motor apraxia (COMA) in patients not otherwise classifiable., Methods: We compiled clinical and neuroimaging data of individuals from six unrelated families with distinct clinical features of COMA who do not share common diagnostic characteristics of Joubert syndrome or other known genetic conditions associated with COMA. We used exome sequencing to identify pathogenic variants and functional studies in patient-derived fibroblasts., Results: In 15 individuals, we detected familial as well as de novo heterozygous truncating causative variants in the Suppressor of Fused (SUFU) gene, a negative regulator of the Hedgehog (HH) signaling pathway. Functional studies showed no differences in cilia occurrence, morphology, or localization of ciliary proteins, such as smoothened. However, analysis of expression of HH signaling target genes detected a significant increase in the general signaling activity in COMA patient-derived fibroblasts compared with control cells. We observed higher basal HH signaling activity resulting in increased basal expression levels of GLI1, GLI2, GLI3, and Patched1. Neuroimaging revealed subtle cerebellar changes, but no full-blown molar tooth sign., Conclusion: Taken together, our data imply that the clinical phenotype associated with heterozygous truncating germline variants in SUFU is a forme fruste of Joubert syndrome.

Due to development of molecular techniques at hand, the number of genomic sequence variants detected in patient investigations is rising constantly. The number of potentially involved genes in hereditary hearing loss is rising simultaneously.In this overview, current methods for diagnostic workup on a molecular and functional level for variants of the SLC26A4 gene are described. Based on the description of the physiological function of the resulting protein Pendrin, molecular investigations for interpretation of the function are explained. Based on these investigations, the potential clinical consequences of a variant may be predicted more precisely and simplify routine reporting of a proven genotype and a phenotype, at hand. Finally, subsequent clinical investigations necessary, such as perchlorate discharge test, as well as therapeutic options are discussed., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: NAA10 is the catalytic subunit of the major N-terminal acetyltransferase complex NatA which acetylates almost half the human proteome. Over the past decade, many NAA10 missense variants have been reported as causative of genetic disease in humans. Individuals harboring NAA10 variants often display variable degrees of intellectual disability (ID), developmental delay, and cardiac anomalies. Initially, carrier females appeared to be oligo- or asymptomatic with X-inactivation pattern skewed towards the wild type allele. However, recently it has been shown that NAA10 variants can cause syndromic or non-syndromic intellectual disability in females as well. The impact of specific NAA10 variants and the X-inactivation pattern on the individual phenotype in females remains to be elucidated., Case Presentation: Here we present a novel de novo NAA10 (NM&#95;003491.3) c.[47A > C];[=] (p.[His16Pro];[=]) variant identified in a young female. The 10-year-old girl has severely delayed motor and language development, disturbed behavior with hyperactivity and restlessness, moderate dilatation of the ventricular system and extracerebral CSF spaces. Her blood leukocyte X-inactivation pattern was skewed (95/5) towards the maternally inherited X-chromosome. Our functional study indicates that NAA10 p.(H16P) impairs NatA complex formation and NatA catalytic activity, while monomeric NAA10 catalytic activity appears to be intact. Furthermore, cycloheximide experiments show that the NAA10 H16P variant does not affect the cellular stability of NAA10., Discussion and Conclusions: We demonstrate that NAA10 p.(His16Pro) causes a severe form of syndromic ID in a girl most likely through impaired NatA-mediated Nt-acetylation of cellular proteins. X-inactivation analyses showed a skewed X-inactivation pattern in DNA from blood of the patient with the maternally inherited allele being preferentially methylated/inactivated.

Some evidence supports the involvement of the hypothalamic-pituitary-adrenal axis (HPA axis) with multiple sclerosis (MS)-related fatigue. In this study, we determined the relation of HPA-axis function with primary fatigue in MS patients in the longitudinal treating fatigue in a MS cohort. MS patients from the TREeating FAtigue in MS (TREFAMS) research program that consists of three randomized controlled trials to study the effects of aerobic training, energy conservation management, and cognitive behavioral therapy on MS-related fatigue were included. The HPA-axis functioning was determined at baseline, the end of treatment (16 weeks) and after 52 weeks. The cortisol awakening response (CAR) and night-time cortisol levels were analyzed. Fatigue was measured with the fatigue subscale of the Checklist Individual Strength (CIS20r fatigue). There was no relationship between CAR and night-time cortisol parameters with CIS20r fatigue scores. Neither of the treatments influenced CAR and night-time cortisol parameters, with the exception of an effect in the energy conservation management treatment group on the CAR surge increase over 52 weeks (β = -114.8, p = 0.007, 95% CI = -197.6, -31.9). Our data suggest that the diurnal cortisol secretion is not associated with MS-related fatigue. This indicates that MS-related fatigue is not attributed to diurnal cortisol secretion and is likely caused by other disease mechanisms., (Copyright © 2020 Malekzadeh, Bader, van Dieteren, Heijboer, Beckerman, Twisk, de Groot and Teunissen.)

Autosomal recessive (AR) gene defects are the leading genetic cause of intellectual disability (ID) in countries with frequent parental consanguinity, which account for about 1/7th of the world population. Yet, compared to autosomal dominant de novo mutations, which are the predominant cause of ID in Western countries, the identification of AR-ID genes has lagged behind. Here, we report on whole exome and whole genome sequencing in 404 consanguineous predominantly Iranian families with two or more affected offspring. In 219 of these, we found likely causative variants, involving 77 known and 77 novel AR-ID (candidate) genes, 21 X-linked genes, as well as 9 genes previously implicated in diseases other than ID. This study, the largest of its kind published to date, illustrates that high-throughput DNA sequencing in consanguineous families is a superior strategy for elucidating the thousands of hitherto unknown gene defects underlying AR-ID, and it sheds light on their prevalence.

The original version of this Article contained an error in the spelling of the author Laurence Faivre, which was incorrectly given as Laurence Faive. This has now been corrected in both the PDF and HTML versions of the Article.

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.

Aspiration pneumonia has a high incidence in hospitalized patients with community-acquired pneumonia and results in high mortality rates. We aimed to evaluate microbiology and assess prognostic factors of aspiration pneumonia in the setting of a tertiary hospital pulmonology department. Community-acquired (CAAP) and healthcare-associated aspiration pneumonia (HCAAP) cases hospitalized over a period of a year were prospectively followed. Demographic, clinical, biological and radiological data were recorded at admission, while sputum, tracheal aspirates or bronchial washing samples were collected within 48 hours of admission. During hospital stay, therapeutic and supportive measures and resulting complications were recorded. Regression analysis was applied to find statistically significant prognostic factors. The sample consisted of 70 patients (67.1% men); 55.7% of them presented as HCAAP; 94.3% had positive culture of lower respiratory tract specimens with isolation of 115 pathogens, 47 of which were multidrug- or extensively drug-resistant. The most common pathogens were Pseudomonas aeruginosa (37.1%), Klebsiella pneumoniae (27.1%), Staphylococcus aureus (25.7%) and Acinetobacter baumannii (20%). Empiric antimicrobial therapy was combination therapy in 70% and included antipseudomonal and MRSA-targeted antibiotics in 61.4% and 11.4%, respectively. Patients in the HCAAP group had a higher rate of antibiotics usage in the previous trimester, more frequent isolation of resistant strains and were more likely to receive inadequate empiric treatment than those in the CAAP group. In-hospital mortality was 52.2%; no difference between groups was noted. Independent factors of increased mortality were older age (p=0.004), low serum albumin levels (p=0.039), increased radiological involvement (p=0.050) and ineffective initial therapy (p=0.001). We concluded that patients hospitalized for aspiration pneumonia have frequent contact with healthcare services and acquire multidrug-resistant Gram-negative bacteria. Empiric therapy should target these specific microorganisms as its success determines the prognosis.

SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes., (© 2017 Wiley Periodicals, Inc.)

The coordinated tissue-specific regulation of gene expression is essential for the proper development of all organisms. Mutations in multiple transcriptional regulators cause a group of neurodevelopmental disorders termed "transcriptomopathies" that share core phenotypical features including growth retardation, developmental delay, intellectual disability and facial dysmorphism. Cornelia de Lange syndrome (CdLS) belongs to this class of disorders and is caused by mutations in different subunits or regulators of the cohesin complex. Herein, we report on the clinical and molecular characterization of seven patients with features overlapping with CdLS who were found to carry mutations in chromatin regulators previously associated to other neurodevelopmental disorders that are frequently considered in the differential diagnosis of CdLS. The identified mutations affect the methyltransferase-encoding genes KMT2A and SETD5 and different subunits of the SWI/SNF chromatin-remodeling complex. Complementary to this, a patient with Coffin-Siris syndrome was found to carry a missense substitution in NIPBL. Our findings indicate that mutations in a variety of chromatin-associated factors result in overlapping clinical phenotypes, underscoring the genetic heterogeneity that should be considered when assessing the clinical and molecular diagnosis of neurodevelopmental syndromes. It is clear that emerging molecular mechanisms of chromatin dysregulation are central to understanding the pathogenesis of these clinically overlapping genetic disorders.

Truncating ASXL3 mutations were first identified in 2013 by Bainbridge et al. as a cause of syndromic intellectual disability in four children with similar phenotypes using whole-exome sequencing. The clinical features - postulated by Bainbridge et al. to be overlapping with Bohring-Opitz syndrome - were developmental delay, severe feeding difficulties, failure to thrive and neurological abnormalities. This condition was included in OMIM as 'Bainbridge-Ropers syndrome' (BRPS, #615485). To date, a total of nine individuals with BRPS have been published in the literature in four reports (Bainbridge et al., Dinwiddie et al, Srivastava et al. and Hori et al.). In this report, we describe six unrelated patients with newly diagnosed heterozygous de novo loss-of-function variants in ASXL3 and concordant clinical features: severe muscular hypotonia with feeding difficulties in infancy, significant motor delay, profound speech impairment, intellectual disability and a characteristic craniofacial phenotype (long face, arched eyebrows with mild synophrys, downslanting palpebral fissures, prominent columella, small alae nasi, high, narrow palate and relatively little facial expression). The majority of key features characteristic for Bohring-Opitz syndrome were absent in our patients (eg, the typical posture of arms, intrauterine growth retardation, microcephaly, trigonocephaly, typical facial gestalt with nevus flammeus of the forehead and exophthalmos). Therefore we emphasize that BRPS syndrome, caused by ASXL3 loss-of-function variants, is a clinically distinct intellectual disability syndrome with a recognizable phenotype distinguishable from that of Bohring-Opitz syndrome.

Unexplained global developmental delay and epilepsy in childhood pose a major socioeconomic burden. Progress in defining the molecular bases does not often translate into effective treatment. Notable exceptions include certain inborn errors of metabolism amenable to dietary intervention. CAD encodes a multifunctional enzyme involved in de novo pyrimidine biosynthesis. Alternatively, pyrimidines can be recycled from uridine. Exome sequencing in three families identified biallelic CAD mutations in four children with global developmental delay, epileptic encephalopathy, and anaemia with anisopoikilocytosis. Two died aged 4 and 5 years after a neurodegenerative disease course. Supplementation of the two surviving children with oral uridine led to immediate cessation of seizures in both. A 4-year-old female, previously in a minimally conscious state, began to communicate and walk with assistance after 9 weeks of treatment. A 3-year-old female likewise showed developmental progress. Blood smears normalized and anaemia resolved. We establish CAD as a gene confidently implicated in this neurometabolic disorder, characterized by co-occurrence of global developmental delay, dyserythropoietic anaemia and seizures. While the natural disease course can be lethal in early childhood, our findings support the efficacy of uridine supplementation, rendering CAD deficiency a treatable neurometabolic disorder and therefore a potential condition for future (genetic) newborn screening., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Joubert syndrome (JS) is a clinically and genetically heterogeneous ciliopathy characterized by episodic hyperpnea and apnea, hypotonia, ataxia, cognitive impairment and ocular motor apraxia. The "molar tooth sign" is pathognomonic of this condition. Mutations in the MKS1 gene are a major cause of Meckel-Gruber syndrome (MKS), the most common form of syndromic neural tube defects, frequently resulting in perinatal lethality. We present the phenotype and genotype of a child with severe JS and agenesis of the corpus callosum (ACC). In our patient, a next generation sequencing (NGS) approach revealed the following two variants of the MKS1 gene: first, a novel missense variant [ c.240G > T (p.Trp80Cys)], which affects a residue that is evolutionarily highly conserved in mammals and ciliates; second, a 29 bp deletion in intron 15 [c.1408-35&#95;1408-7del29], a founder mutation, which in a homozygous state constitutes the major cause of MKS in Finland. We review the MKS1-variants in all of the eleven JS patients reported to date and compare these patients to our case. To our knowledge, this is the first patient with Joubert syndrome and agenesis of the corpus callosum where a potentially causal genotype is provided., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Littoral cell angioma (LCA) is a recently described rare generally benign primary vascular neoplasm of the spleen originating from the lining cells of the splenic red pulp sinuses that is usually discovered incidentally. LCA may be associated with epithelial malignancies and may itself also have malignant potential. We report the case of a 71-year-old woman who presented with intraoperative bleeding from the spleen during sigmoidectomy for colonic adenocarcinoma. Histopathological examination of the removed spleen revealed multiple haemorrhagic lesions diagnosed as littoral cell angioma. This case has been reported due to its rarity and to highlight how its accidental detection, unique and unexpected presentation complicated a case of colonic carcinoma. Individuals diagnosed with this tumour must be carefully evaluated to exclude primary, secondary and synchronous malignancies.

Background: Weight regain due to gastric pouch dilatation after Roux-en-Y gastric bypass (RYGB) is seen more frequently after long-term follow-up. We studied the feasibility and safety of laparoscopic pouch resizing (LPR) for dilated gastric pouch after RYGB associated with inadequate weight loss., Methods: From 1st June 2011 to 1st September 2013, patients who underwent LPR after failed RYGB were retrospectively compared and analyzed. Data included patient demographics, comorbidity, indication for revision, preoperative weight and BMI, operative time, hospital stay, conversion rate, mean follow-up, body mass index (BMI) loss, percentage excess weight loss (%EWL), reoperation rate, morbidity, and mortality., Results: Out of 170 revisional bariatric procedures, 32 LPR (27/5, F/M) were performed for dilated gastric pouch after RYGB. The mean age, preoperative weight, and BMI were 38.3 ± 9.3 years, 101.7 ± 22.8 kg, 38.8 ± 6.4 kg/m(2), respectively. The median operative time and hospital stay were 100 min and 2 days, respectively. All pouch resizing procedures were carried out laparoscopically, with none requiring conversion to open surgery. The overall complication and reoperation rates were 15.6 and 3.1 %, respectively. There were no deaths. The mean follow-up was 14.1 ± 6.2 months. The mean postoperative BMI was 32.8 ± 7.3 kg/m(2), and the median %EWL was 29.1 %., Conclusions: LPR is safe and can lead to adequate weight loss. However, long-term follow-up is needed to determine the efficiency and durability of this procedure.

Recently, de novo aberrations in PHF6 were identified in females with intellectual disability and with a distinct phenotype including a characteristic facial gestalt with bitemporal narrowing, prominent supraorbital ridges, synophrys, a short nose and dental anomalies, tapering fingers with brachytelephalangy, clinodactyly and hypoplastic nails, short toes with hypoplastic nails, and linear skin hyperpigmentation. In adolescent or older patients, this phenotype overlaps but is not identical with Borjeson-Forssman-Lehmann syndrome in males, caused by X-linked recessive mutations in PHF6. In younger girls there seems to be a striking phenotypic overlap with Coffin-Siris syndrome, which is characterized by intellectual disability, sparse hair and hypoplastic nails. This review will summarize and characterize the female phenotype caused by de novo aberrations in PHF6 and will discuss the overlapping and distinguishing features with Coffin-Siris syndrome., (© 2014 Wiley Periodicals, Inc.)

Background: The aim of our study was to determine the therapeutic effect of low-molecular weight heparin after laparoscopic Roux-en-Y gastric bypass., Methods: We prospectively analyzed data of 39 patients who underwent Roux-en-Y gastric bypass from 1093 consecutive patients who underwent bariatric procedures from May 1999 to May 2012. All patients were given 40 mg enoxaparin subcutaneously once daily preoperatively and continued for 5 days., Results: There were 31 females. Mean age was 32.48 years and mean body mass index was 44.59 kg/m. Only 46.1% of patients reached the defined therapeutic dose on the second day and 41% on the fifth day. One fatal pulmonary embolism was recorded (1/1093, 0.09%) in the entire series., Conclusions: Anti-Xa surveillance did not correlate strongly with outcome. Further studies are required for proper dose adjustments of low-molecular weight heparin in these obese patients and whether anti-Xa monitoring should be continued.

Background: A considerable number of patients require revisional surgery after laparoscopic adjustable gastric banding (LAGB). Studies that compared the outcomes of revisional sleeve gastrectomy (r-SG) and revisional Roux-en-Y gastric bypass (r-RYGB) after failed LAGB are scarce in the literature. Our objective was to determine whether significant differences exist in outcomes between r-SG and r-RYGB after failed LAGB., Methods: From 2005 to 2012, patients who underwent laparoscopic r-SG and r-RYGB after failed LAGB were retrospectively compared and analyzed. Data included demographics, indication for revision, operative time, hospital stay, conversion rate, percentage excess weight loss (%EWL), and morbidity and mortality., Results: Out of 693 bariatric procedures, 42 r-SG and 53 r-RYGB were performed. The median preoperative weight (107.7 and 117.7 kg, respectively, p = 0.02) and body mass index (BMI) (38.5 vs. 43.2 kg/m(2), respectively, p = 0.01) were statistically significantly lower in r-SG than in r-RYGB. The mean operative time and median hospital stay were significantly shorter in r-SG than in r-RYGB (108.4 vs. 161.2 min, p < 0.01) (2 vs. 3 days, p = 0.02), respectively. One patient underwent conversion to open surgery after r-RYGB (p = 0.5). The reoperation rate was lower in r-SG than in r-RYGB (0.0 vs. 3.8 %, p = 0.5). There was one postoperative leak in the r-RYGB, and the overall complication rate was significantly lower in r-SG patients than in r-RYGB patients (7.1 vs. 20.8 %, p = 0.05). The mean follow-up was significantly shorter in the r-SG group (9.8 vs. 29.3 months, p < 0.01). However, the mean postoperative BMI was not different at 1 year (32.3 vs. 34.7, p = 0.29) as well as mean %EWL was (47.4 vs. 45.6 %, p = 0.77)., Conclusions: Both r-SG and r-RYGB are safe procedures with similar outcomes in terms of %EWL. As a result of the long-term potential nutritional complication of r-RYGB, r-SG may be a better option in this group of patients. Longer follow-up is needed.

Unlabelled:  , Introduction: Hypertension (HT) is the most common modifiable risk factor for atrial fibrillation (AF), yet little is known of the atrial effects of chronic HT in humans. We aimed to characterize the electrophysiologic (EP) and electroanatomic (EA) remodeling of the right atrium (RA) in patients with chronically treated systemic HT and left ventricular hypertrophy (LVH) without a history of AF., Methods and Results: Twenty patients with (systolic BP 145 ± 10 mmHg) and without (BP 119 ± 11 mmHg, P < 0.01) systemic HT underwent detailed conventional EP and EA voltage and activation mapping. We measured RA refractoriness at the coronary sinus and high septum at cycle lengths (CLs) 600 and 450 ms, and RA conduction velocities, activation times, and voltages at a global and regional level at CLs 600 ms and 300 ms. HT was associated with slowing of global (73 ± 17 cm/s vs 96 ± 12 cm/s in controls, P < 0.01) and regional conduction velocity particularly in the posterior RA (70 ± 17 cm/s vs 96 ± 12 cm/s in controls, P < 0.01) at the crista terminalis (fractionation and double potentials in HT 72%± 4 vs 43%± 23 in controls, P = 0.04). Mean RA voltage was similar between the 2 groups, however HT was associated with an increase in areas of low voltage (<0.5 mV; HT 13% vs controls 9%, P = 0.04). Sustained AF was induced in 30% HT patients and no controls., Conclusion: Chronically treated systemic HT with LVH is accompanied by atrial remodeling characterized by: (i) global conduction slowing, (ii) regional conduction delay particularly at the crista terminalis, and (iii) increased AF inducibility. These changes may in part be responsible for the increased propensity to AF associated with systemic HT., (© 2011 Wiley Periodicals, Inc.)

Background: Heterozygous copy-number and missense variants in CNTNAP2 and NRXN1 have repeatedly been associated with a wide spectrum of neuropsychiatric disorders such as developmental language and autism spectrum disorders, epilepsy and schizophrenia. Recently, homozygous or compound heterozygous defects in either gene were reported as causative for severe intellectual disability., Methods: 99 patients with severe intellectual disability and resemblance to Pitt-Hopkins syndrome and/or suspected recessive inheritance were screened for mutations in CNTNAP2 and NRXN1. Molecular karyotyping was performed in 45 patients. In 8 further patients with variable intellectual disability and heterozygous deletions in either CNTNAP2 or NRXN1, the remaining allele was sequenced., Results: By molecular karyotyping and mutational screening of CNTNAP2 and NRXN1 in a group of severely intellectually disabled patients we identified a heterozygous deletion in NRXN1 in one patient and heterozygous splice-site, frameshift and stop mutations in CNTNAP2 in four patients, respectively. Neither in these patients nor in eight further patients with heterozygous deletions within NRXN1 or CNTNAP2 we could identify a defect on the second allele. One deletion in NRXN1 and one deletion in CNTNAP2 occurred de novo, in another family the deletion was also identified in the mother who had learning difficulties, and in all other tested families one parent was shown to be healthy carrier of the respective deletion or mutation., Conclusions: We report on patients with heterozygous defects in CNTNAP2 or NRXN1 associated with severe intellectual disability, which has only been reported for recessive defects before. These results expand the spectrum of phenotypic severity in patients with heterozygous defects in either gene. The large variability between severely affected patients and mildly affected or asymptomatic carrier parents might suggest the presence of a second hit, not necessarily located in the same gene., (© 2011 Gregor et al; licensee BioMed Central Ltd.)

Tubulolobular carcinoma (TLC) is a rare tumor of the breast in which histologic features of both tubular and lobular carcinoma are combined. We report a case of TLC, in which the specific subtype was missed at routine cytologic and histopathological examination. A 69-year-old woman presented with a right breast lump. Imaging studies indicated a malignant lesion in right upper quadrant. Routine fine needle aspiration (FNA) cytology diagnosis was a duct cell carcinoma (small cell type). In a setting of cystic thyroid lesions, presence of excessive nuclear grooves, and rare intranuclear cytoplasmic inclusion, metastatic papillary thyroid carcinoma was also considered. However, both these possibilities were not supported by immunocytochemical findings (estrogen receptor+, thyroglobulin-, and chromogranin-). The histopathology diagnosis was invasive duct cell carcinoma. Review of FNA smears and paraffin sections led to the diagnosis of TLC, which was supported by positive immunohistochemical stainings for markers like e-cadherin and β-catein., (Copyright © 2010 Wiley-Liss, Inc.)