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Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients who had undergone exome sequencing and were partially analyzed with next-generation phenotyping approaches. Molecular genetic diagnoses were established in 32% of the patients totaling 370 distinct molecular genetic causes, most with prevalence below 1:50,000. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were identified, mainly in individuals with neurodevelopmental disorders. Sequencing data of the subcohort that consented to computer-assisted analysis of their facial images with GestaltMatcher could be prioritized more efficiently compared with approaches based solely on clinical features and molecular scores. Our study demonstrates the synergy of using next-generation sequencing and phenotyping for diagnosing ultrarare diseases in routine healthcare and discovering novel etiologies by multidisciplinary teams., (© 2024. The Author(s).)

Background The rapid emergence of the Omicron variant and its large number of mutations led to its classification as a variant of concern (VOC) by the World Health Organization. Subsequently, Omicron evolved into distinct sublineages (eg, BA.1 and BA.2), which currently represent the majority of global infections. Initial studies of the neutralizing response toward BA.1 in convalescent and vaccinated individuals showed a substantial reduction. Methods We assessed antibody (immunoglobulin G [IgG]) binding, ACE2 (angiotensin-converting enzyme 2) binding inhibition, and IgG binding dynamics for the Omicron BA.1 and BA.2 variants compared to a panel of VOCs/variants of interest, in a large cohort (N = 352) of convalescent, vaccinated, and infected and subsequently vaccinated individuals. Results While Omicron was capable of efficiently binding to ACE2, antibodies elicited by infection or immunization showed reduced binding capacities and ACE2 binding inhibition compared to wild type. Whereas BA.1 exhibited less IgG binding compared to BA.2, BA.2 showed reduced inhibition of ACE2 binding. Among vaccinated samples, antibody binding to Omicron only improved after administration of a third dose. Conclusions Omicron BA.1 and BA.2 can still efficiently bind to ACE2, while vaccine/infection-derived antibodies can bind to Omicron. The extent of the mutations within both variants prevents a strong inhibitory binding response. As a result, both Omicron variants are able to evade control by preexisting antibodies. [ABSTRACT FROM AUTHOR]

Introduction: Telemetric intracranial pressure measurement (tICPM) offers new opportunities to acquire objective information in shunted and non-shunted patients. The sensor reservoir (SR) provides tICPM modality at a decent sampling rate as an integrated component of the CSF shunt system. The aim of this study is to perform tICPM during a defined protocol of maneuvers in an outpatient setting as feasibility study including either shunt-dependent patients or candidates for possible shunt therapy. Methods: A total of 17 patients received a SR and were investigated within a protocol of maneuver measurements involving different body postures (90°, 10°, 0°, and − 10°), breathing patterns (hypo- and hyperventilation), and mild venous congestion (Valsalva, Jugular vein compression), while the latter two were performed in lying postures (10° and 0°). The cohort included 11 shunted and 6 non-shunted (stand-alone-SR) patients. All measurements were evaluated using an ICP-analysis software (ICPicture, Miethke, Germany) looking at ICP changes and amplitude (AMP) characteristics. Results: The shunted patient group consisted of 11 patients (median age: 15.8 years; range: 4–35.2 years) with either a primary shunt (n=9) and 2 patients received a shunt after stand-alone-SR tICPM. Six patients were enrolled with a stand-alone SR (median age 11.9 years, range 3.6–17.7 years). In the stand-alone SR group, maneuver related ICP and AMP changes were more sensitive compared to shunted patients. Postural maneuvers caused significant ICP changes in all body positions in both groups. The highest ICP values were seen during Valsalva maneuver, provoked by the patients themselves. In the stand-alone group, significant higher ICP values during hyperventilation were observed compared to shunted individuals. In shunted patients, a significant correlation between ICP and AMP was observed only during hyperventilation maneuver, while this correlation was additionally seen in Valsalva and jugular vein compression in stand-alone patients. Conclusion: SR-related tICPM is helpful to objectify diagnostic evaluation in patients with CSF dynamic disturbances. The defined protocol did result in a wide range of ICP changes with promising potential for effective outpatient tICPM investigation. Since the correlation of ICP and AMP was observed during mild venous congestion maneuvers it appears to be specifically helpful for the evaluation of intracranial compliance. Further investigations of maneuver-related tICPM in a larger population, including variable pathologies, are needed to further establish the protocol in the clinical practice. [ABSTRACT FROM AUTHOR]

The quality and persistence of children's humoral immune response following SARS-CoV-2 infection remains largely unknown but will be crucial to guide pediatric SARS-CoV-2 vaccination programs. Here, we examine 548 children and 717 adults within 328 households with at least one member with a previous laboratory-confirmed SARS-CoV-2 infection. We assess serological response at 3–4 months and 11–12 months after infection using a bead-based multiplex immunoassay for 23 human coronavirus antigens including SARS-CoV-2 and its Variants of Concern (VOC) and endemic human coronaviruses (HCoVs), and additionally by three commercial SARS-CoV-2 antibody assays. Neutralization against wild type SARS-CoV-2 and the Delta VOC are analysed in a pseudotyped virus assay. Children, compared to adults, are five times more likely to be asymptomatic, and have higher specific antibody levels which persist longer (96.2% versus 82.9% still seropositive 11–12 months post infection). Of note, symptomatic and asymptomatic infections induce similar humoral responses in all age groups. SARS-CoV-2 infection occurs independent of HCoV serostatus. Neutralization responses of children and adults are similar, although neutralization is reduced for both against the Delta VOC. Overall, the long-term humoral immune response to SARS-CoV-2 infection in children is of longer duration than in adults even after asymptomatic infection. In this prospective cohort study, authors follow 328 households in Germany with at least one confirmed SARS-CoV-2 infection and find that children are more likely to seroconvert without symptoms and have higher specific antibody levels that persist longer than in adults. [ABSTRACT FROM AUTHOR]

Background Postnatally acquired cytomegalovirus (pCMV) infection through breast milk (BM) may cause severe illness and even death, yet BM is advantageous for preterm infants. Therefore, effective methods to prevent CMV transmission are needed. Methods To assess the effectiveness of short-term pasteurization (62°C for 5 seconds) in preventing CMV transmission via BM in preterm infants. Design: Prospective interventional bicentric cohort study with infant enrollment between 6/2010 and 1/2012. A cohort from the Tuebingen neonatal intensive care unit (NICU) from 1995–1998 served as historical controls. Differences in CMV transmission were compared with reference to the cumulative time at risk for CMV transmission. Setting: Two German level-3 NICUs. Eighty-seven preterm infants of 69 CMV immunoglobulin G-positive mothers with birth weight <1500 g or gestational age <32 weeks and 83 historical controls were included. Intervention: BM samples were short-term pasteurized from postnatal day 4 to discharge. Primary endpoint: CMV status at discharge, evaluated by polymerase chain reaction and short-term microculture from urine. Results Two of 87 (2.3%) study infants had a pCMV transmission. This compared to 17 of 83 (20.5%) controls. Total time under risk for infection was 9.6 years vs 10.0 years in controls, yielding an incidence of 0.21/year (95% confidence interval [CI], 0.03 to 0.75/year) vs 1.70/year (95% CI, 0.99 to 2.72/year), respectively. The risk ratio controls vs study infants was 8.3 (95% CI, 2.4 to 52.4) according to Cox proportional hazard model (P =.0003). Conclusions Short-term pasteurization significantly reduces the incidence of pCMV infection through BM in the NICU. Clinical Trials Registration NCT01178905. [ABSTRACT FROM AUTHOR]

In preterm infants with very low birth weight (VLBW) <1500 g the most important acquired intestinal diseases are necrotising enterocolitis (NEC) and focal intestinal perforation (FIP). We analyzed data of the neonatology module of national external comparative quality assurance for inpatients in the state of Baden-Württemberg, Germany. Between 2010 and 2012, 59 of 3549 VLBW infants developed FIP (1.7%), 128 of them NEC (3.6%). In approximately 3% of infants with BW<1000 g FIP was diagnosed, which was nearly 9 times more often than in infants with BW between 1250 and 1499 g (FIP frequency 0.36%). NEC frequency increased with decreasing BW and was more than 10 times higher in the smallest infants (BW<750 g: 7.87%) compared to those with BW between 1250 and 1499 g (0.72%). The BW limit of 1250 g differentiates between groups of patients with distinguished risks for NEC and FIP. [ABSTRACT FROM AUTHOR]

Background: Krabbe disease or globoid cell leukodystrophy is a severe neurodegenerative disorder caused by a defect in the GALC gene leading to a deficiency of the enzyme ß-galactocerebrosidase. The aim of this work was to describe the natural disease course covering the whole spectrum of the disease.Methods: Natural history data were collected with a standardized questionnaire, supplemented by medical record data. We defined different forms of the disease according to Abdelhalim et al. (2014). Developmental and disease trajectories were described based on the acquisition and loss of milestones as well as the time of first clearly identifiable symptoms and needs such as spasticity, seizures and tube feeding. MRI was assessed using the scoring system by Loes et al. (1999) and in addition a pattern recognition approach, based on Abdelhalim et al. (2014).Results: Thirty-eight patients were identified, from 27 of these patients 40 MRIs were available; 30 (79%) had an infantile onset, showing first symptoms in their first year of life, almost all (27 out of 30) starting in the first six months. A later onset after the first year of life was observed in 8 patients (21%, range 18 months to 60 years). Irritability, abnormalities in movement pattern as well as general developmental regression were the first symptoms in the infantile group; disease course was severe with rapid progression, e.g. loss of visual fixation, need for tube feeding and then an early death. Gait disorders were the first symptoms in all patients of the later onset groups; progression was variable. The different forms of the disease were characterized by different MRI patterns (infantile: diffuse white matter involvement and cerebellar structures specifically affected, later onset: parieto-occipital white matter and splenium affected, adult: motor tracts specifically affected).Conclusion: This is the first description of the natural history of Krabbe disease in a larger European cohort using developmental, clinical and MRI data. We would like to highlight the very different clinical and MRI characteristics of the later onset forms. These data are important for counselling affected patients and families and may serve as a basis for future treatment trials. [ABSTRACT FROM AUTHOR]