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BackgroundNext-generation sequencing, combined with international pooling of cases, has impressively enhanced the discovery of genes responsible for Mendelian neurodevelopmental disorders, particularly in individuals affected by clinically undiagnosed diseases. To date, biallelic missense variants in ZNF526 gene, encoding a Krüppel-type zinc-finger protein, have been reported in three families with non-syndromic intellectual disability.MethodsHere, we describe five individuals from four unrelated families with an undiagnosed neurodevelopmental disorder in which we performed exome sequencing, on a combination of trio-based (4 subjects) or single probands (1 subject).ResultsWe identified five patients from four unrelated families with homozygous ZNF526 variants by whole exome sequencing. Four had variants resulting in truncation of ZNF526; they were affected by severe prenatal and postnatal microcephaly (ranging from −4 SD to −8 SD), profound psychomotor delay, hypertonic–dystonic movements, epilepsy and simplified gyral pattern on MRI. All of them also displayed bilateral progressive cataracts. A fifth patient had a homozygous missense variant and a slightly less severe disorder, with postnatal microcephaly (−2 SD), progressive bilateral cataracts, severe intellectual disability and unremarkable brain MRI.Mutant znf526 zebrafish larvae had notable malformations of the eye and central nervous system, resembling findings seen in the human holoprosencephaly spectrum.ConclusionOur findings support the role of ZNF526 biallelic variants in a complex neurodevelopmental disorder, primarily affecting brain and eyes, resulting in severe microcephaly, simplified gyral pattern, epileptic encephalopathy and bilateral cataracts.

PurposeWhile intra-abdominal hypertension (IAH) has been associated with adverse outcomes in multiple settings, the epidemiology and clinical implications of IAH in the context of cardiac surgery are less known. In this study, we aimed to describe the prevalence of IAH in patients undergoing cardiac surgery and determine its association with patient characteristics and postoperative outcomes. MethodsWe conducted a single-centre prospective cohort study in which intra-abdominal pressure was measured in the operating room after general anesthesia (T1), after the surgical procedure (T2), and two hours after intensive care unit (ICU) admission (T3) in a subset of patients. Intra-abdominal hypertension was defined as intra-abdominal pressure (IAP) ≥ 12 mm Hg. Postoperative outcomes included death, acute kidney injury (AKI), and length of stay in the ICU and hospital.ResultsA total of 513 IAP measurements were obtained from 191 participants in the operating room and 131 participants in the ICU. Intra-abdominal hypertension was present in 105/191 (55%) at T1, 115/191 (60%) at T2, and 31/131 (24%) at T3. Intra-abdominal pressure was independently associated with body mass index, central venous pressure, and mean pulmonary artery pressure but was not associated with cumulative fluid balance. Intraoperative IAH was not associated with adverse outcomes including AKI.ConclusionsIntra-abdominal hypertension is very common during cardiac surgery but its clinical implications are uncertain.

Tuberous sclerosis complex (TSC) is a genetic and multisystemic disorder that affects between 1/6'000 and 1/10'000 of newborns. Clinical criteria and/or genetic analysis establish the diagnosis. The mechanistic target of rapamycin (mTOR) inhibitors everolimus or sirolimus reduce the severity of several TSC-related clinical traits. We report here on the epidemiology and management of TSC patients in a large Swiss canton: the canton of Vaud. We extracted patient files containing the diagnostic code TSC in 2015 at the Lausanne University hospital (tertiary reference center for a population of about 755'000 people) and in specialized neurological institutions of the same region. We identified 52 patients with a diagnosis of TSC. The majority of the patients with a pathologic result in genetic testing were positive for a pathogenic variant in the gene, including five cases of contiguous gene deletion syndrome of and causing both polycystic kidney disease and TSC. The most frequent clinical manifestations encountered were affecting the skin (87% of patients), the brain (83%), the heart (46%) and the kidneys (46%). Neuropsychiatric disorders were described in 56% of cases. At the time of data collection (2015), there were 2 patients using systemic mTOR inhibitors and 16 patients using topical mTOR inhibitors for dermatological features. Next, we compared this data with those of large published cohorts. While we found fewer cases than expected for the screened population, demographic as well as genetic data were overall similar to the literature. However, we observed that some clinical manifestations (renal, lung and neuropsychiatric disorders) were less frequently described in our cohort. This work indicates that TSC and some of its clinical manifestations is under-reported. It raises concern that patients with mild manifestations are often not referred to reference centers with dedicated multidisciplinary group. The follow-up by expert board is instrumental in offering systematic screening of all putatively affected organs and to assess the eligibility for targeted treatment.

Background Assessing fluid responsiveness is important in the management of patients with hemodynamic instability. Passive leg raising (PLR) is a validated dynamic method to induce a transient increase in cardiac preload and predict fluid responsiveness. Variations in end-tidal carbon dioxide (ETCO 2 ) obtained by capnography correlate closely with variations in cardiac output when alveolar ventilation and carbon dioxide production are kept constant. In this prospective observational study, we tested the hypothesis that variations in ETCO 2  induced by a simplified PLR maneuver can track changes in the cardiac index (CI) and thus predict fluid responsiveness. Method A five-minute standardized PLR maneuver was performed in 90 paralyzed hemodynamically stable cardiac surgical patients receiving mechanical ventilation. Cardiac index was measured by thermodilution before and one minute after PLR. End-tidal CO 2  measurements using capnography were obtained during the entire PLR maneuver. Fluid responsiveness was defined as a 15% increase in the CI. The Chi square test and Student’s t test were used to compare responders and non-responders. Logistic regression analyses were then performed to determine factors of responsiveness. Results There were no differences between responders and non-responders in demographic and baseline hemodynamic variables. Fluid responsiveness was associated with an ETCO 2 variation (ΔETCO 2 ) of ≥ 2 mmHg during PLR [odds ratio (OR), 7.3; 95% confidence interval (CI), 2.7 to 20.2; P < 0.01; sensitivity 75%]. A low positive predictive value (54%) and a high negative predictive value (NPV) (86%) were observed. No other clinical or hemodynamic predictors were associated with fluid responsiveness. A logistic regression model established that a combination of ΔETCO 2 ≥ 2 mmHg and a change in systolic blood pressure ≥ 10 mmHg induced by passive leg raising was predictive of fluid responsiveness (OR, 8.9; 95% CI, 2.5 to 32.2; P = 0.005). Conclusion Use of a passive leg raising maneuver to induce variation in ETCO 2  is a noninvasive and useful method to assess fluid responsiveness in paralyzed cardiac surgery patients receiving mechanical ventilation. Given its high NPV, fluid responsiveness is unlikely if a passive leg raising maneuver induces ΔETCO 2 of < 2 mmHg.

PurposeThe primary objective of this study was to define the ultrasound-derived anatomy of the axillary/subclavian vessels. As a secondary objective, we evaluated the relationship between the vascular anatomy and demographic, anthropometric, and hemodynamic data of patients.MethodsThis observational anatomical study used bedside ultrasound with 150 cardiac surgical patients in the operating room. Bilateral axillary and subclavian anatomy was determined using a high-frequency ultrasound probe with fixed reference points. Images were recorded and analyzed, and correlation with demographic, anthropometric, and hemodynamic data was performed.ResultsThe images were adequate to evaluate potential anatomical variations in 97.4% of patients with a body mass index as high as 46.4 kg·m−2. The mean (standard deviation) diameter of the axillary vein was 1.2 (0.3) cm on the right side and 1.1 (0.2) cm on the left side. The dimensions of the axillary vein were larger on the right side in 69% of patients. The vein was located directly over the artery in the mid-clavicular view in 67% of the patients and in lateral-clavicular view in only 7% of the patients. As we moved the probe laterally, the vein was lateralized in relation to the artery in 89% of patients. There was no significant correlation between the hemodynamic data and vessel size, although direct correlation was found between body mass index and the depth of the vessel (P < 0.001). The axillary vein area was smaller in females than in males (P < 0.002), and in 4% of patients, the axillary vein was in an aberrant position.ConclusionsIn patients undergoing cardiac surgery, axillary vessel anatomy varied considerably, and the patients’ hemodynamics could not predict the size of the axillary vessels. Only the patients’ weight correlated moderately with the depth of the vein.

Influenza is a viral infection presenting with general symptoms such as fever, headache, fatigue, and involvement of airways or the gastrointestinal tract. The nervous system may be involved, but less frequently. These neurological complications remain challenging to diagnose; moreover, no guidelines for management and treatment exist. Therefore, when presenting with neurological symptoms, patients undergo invasive diagnostic procedures and empirical treatments before making the correct diagnosis. During the winter of 2022–2023, four children between nine months and nine years of age were admitted to the Lausanne University Hospital, Switzerland, complaining of influenza and neurological complications. This report presents the symptoms of neurological manifestation and the treatment management of the four patients. All the legally authorized representatives gave their written informed consent before study inclusion.

Heterotrimeric G proteins are immediate transducers of G protein-coupled receptors—the biggest receptor family in metazoans—and play innumerate functions in health and disease. A set of de novo point mutations in GNAO1 and GNAI1, the genes encoding the α-subunits (Gαo and Gαi1, respectively) of the heterotrimeric G proteins, have been described to cause pediatric encephalopathies represented by epileptic seizures, movement disorders, developmental delay, intellectual disability, and signs of neurodegeneration. Among such mutations, the Gln52Pro substitutions have been previously identified in GNAO1 and GNAI1. Here, we describe the case of an infant with another mutation in the same site, Gln52Arg. The patient manifested epileptic and movement disorders and a developmental delay, at the onset of 1.5 weeks after birth. We have analyzed biochemical and cellular properties of the three types of dominant pathogenic mutants in the Gln52 position described so far: Gαo[Gln52Pro], Gαi1[Gln52Pro], and the novel Gαo[Gln52Arg]. At the biochemical level, the three mutant proteins are deficient in binding and hydrolyzing GTP, which is the fundamental function of the healthy G proteins. At the cellular level, the mutants are defective in the interaction with partner proteins recognizing either the GDP-loaded or the GTP-loaded forms of Gαo. Further, of the two intracellular sites of Gαo localization, plasma membrane and Golgi, the former is strongly reduced for the mutant proteins. We conclude that the point mutations at Gln52 inactivate the Gαo and Gαi1 proteins leading to aberrant intracellular localization and partner protein interactions. These features likely lie at the core of the molecular etiology of pediatric encephalopathies associated with the codon 52 mutations in GNAO1/GNAI1.

Background A new monogenic neurodegenerative disease affecting ribosomal metabolism has recently been identified in association with a monoallelic UBTF putative gain of function variant (NM_001076683.1:c.628G>A, hg19). Phenotype is consistent among these probands with progressive motor, cognitive, and behavioural regression in early to middle childhood. Case presentation We report on a child with this monoallelic UBTF variant who presented with progressive disease including regression, episodes of subacute deterioration during febrile illnesses and a remarkable EEG pattern with a transient pattern of semi-periodic slow waves. Conclusions This case further supports the phenotype-genotype correlation of neurodegeneration associated with UBTF c.628G>A. Moreover, it brings new insights into the clinical features and EEG that could possibly serve as diagnostic markers of this otherwise nonspecific phenotype.

We studied a family in which the first-born child, a girl, had developmental delay, facial dysmorphism, and agenesis of the corpus callosum (ACC). The subsequent pregnancy was interrupted as the fetus was found to be also affected by ACC. Both cases were heterozygous for two KDM5B variants predicting p (Ala635Thr) and p (Ser1155AlafsTer4) that were shown to be in trans. KDM5B variants have been previously associated with moderate to severe developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and dysmorphism in a few individuals, but the pathogenetic mechanisms are not clear yet as patients with both monoallelic and biallelic variants have been observed. Interestingly, one individual has previously been reported with ACC and severe ID in association with biallelic KDM5B variants. Together with the observations in this family, this suggests that agenesis of the corpus callosum may be part of the phenotypic spectrum associated with KDM5B variants and that the KDM5B gene should be included in gene panels to clarify the etiology of ACC both in the prenatal and postnatal setting.

Background De novo variants in the voltage-gated calcium channel subunit α1 E gene ( CACNA1E ) have been described as causative of epileptic encephalopathy with contractures, macrocephaly and dyskinesias. Methods Following the observation of an index patient with developmental delay and autism spectrum disorder (ASD) without seizures who had a de novo deleterious CACNA1E variant, we screened GeneMatcher for other individuals with CACNA1E variants and neurodevelopmental phenotypes without epilepsy. The spectrum of pathogenic CACNA1E variants was compared to the mutational landscape of variants in the gnomAD control population database. Results We identified seven unrelated individuals with intellectual disability, developmental regression and ASD-like behavioral profile, and notably without epilepsy, who had de novo heterozygous putatively pathogenic variants in CACNA1E . Age of onset of clinical manifestation, presence or absence of regression and degree of severity were variable, and no clear-cut genotype–phenotype association could be recognized. The analysis of disease-associated variants and their comparison to benign variants from the control population allowed for the identification of regions in the CACNA1E protein that seem to be intolerant to substitutions and thus more likely to harbor pathogenic variants. As in a few reported cases with CACNA1E variants and epilepsy, one patient showed a positive clinical behavioral response to topiramate, a specific calcium channel modulator. Limitations The significance of our study is limited by the absence of functional experiments of the effect of identified variants, the small sample size and the lack of systematic ASD assessment in all participants. Moreover, topiramate was given to one patient only and for a short period of time. Conclusions Our results indicate that CACNA1E variants may result in neurodevelopmental disorders without epilepsy and expand the mutational and phenotypic spectrum of this gene. CACNA1E deserves to be included in gene panels for non-specific developmental disorders, including ASD, and not limited to patients with seizures, to improve diagnostic recognition and explore the possible efficacy of topiramate.