Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1

Subarachnoid hemorrhage (SAH) carries a 50% mortality rate. The extravasated erythrocytes that surround the brain contain heme, which, when released from damaged red blood cells, functions as a potent danger molecule that induces sterile tissue injury and organ dysfunction. Free heme is metabolized by heme oxygenase (HO), resulting in the generation of carbon monoxide (CO), a bioactive gas with potent immunomodulatory capabilities. Here, using a murine model of SAH, we demonstrated that expression of the inducible HO isoform (HO-1, encoded by Hmox1) in microglia is necessary to attenuate neuronal cell death, vasospasm, impaired cognitive function, and clearance of cerebral blood burden. Initiation of CO inhalation after SAH rescued the absence of microglial HO-1 and reduced injury by enhancing erythrophagocytosis. Evaluation of correlative human data revealed that patients with SAH have markedly higher HO-1 activity in cerebrospinal fluid (CSF) compared with that in patients with unruptured cerebral aneurysms. Furthermore, cisternal hematoma volume correlated with HO-1 activity and cytokine expression in the CSF of these patients. Collectively, we found that microglial HO-1 and the generation of CO are essential for effective elimination of blood and heme after SAH that otherwise leads to neuronal injury and cognitive dysfunction. Administration of CO may have potential as a therapeutic modality in patients with ruptured cerebral aneurysms

Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals

FINCA syndrome [MIM: 618278] is an autosomal recessive multisystem disorder characterized by fibrosis, neurodegeneration and cerebral angiomatosis. To date, 13 patients from nine families with biallelic NHLRC2 variants have been published. In all of them, the recurrent missense variant p.(Asp148Tyr) was detected on at least one allele. Common manifestations included lung or muscle fibrosis, respiratory distress, developmental delay, neuromuscular symptoms and seizures often followed by early death due to rapid disease progression.Here, we present 15 individuals from 12 families with an overlapping phenotype associated with nine novel NHLRC2 variants identified by exome analysis. All patients described here presented with moderate to severe global developmental delay and variable disease progression. Seizures, truncal hypotonia and movement disorders were frequently observed. Notably, we also present the first eight cases in which the recurrent p.(Asp148Tyr) variant was not detected in either homozygous or compound heterozygous state.We cloned and expressed all novel and most previously published non-truncating variants in HEK293-cells. From the results of these functional studies, we propose a potential genotype-phenotype correlation, with a greater reduction in protein expression being associated with a more severe phenotype.Taken together, our findings broaden the known phenotypic and molecular spectrum and emphasize that NHLRC2-related disease should be considered in patients presenting with intellectual disability, movement disorders, neuroregression and epilepsy with or without pulmonary involvement

Psychometric properties of the KoCoN-V. A questionnaire on the quality of care of children and adolescents with complex chronic neurological impairments

Schmidt P, Zernikow B, Hartenstein-Pinter A, et al. Psychometrische Eigenschaften des KoCoN-V. Ein Fragebogen zur Versorgungsqualität von Kindern und Jugendlichen mit komplex-chronisch neurologischen Erkrankungen. Monatsschrift Kinderheilkunde . 2023.Background: Complex chronic conditions in children and adolescents very often affect the nervous system. These children are frequently dependent on a wide variety of medical aids including home respiration or respiratory devices. They are often unable to communicate verbally. Frequent hospital stays as well as the use of various outpatient support services characterize their everyday life. Despite the complex care needs there has been little research on parents' perceptions of the quality of care for these children and adolescents.Aim: The present study aimed to validate a questionnaire to assess the quality of care of children and adolescents with complex chronic neurological diseases (KoCoN-V).Methods: A prospective multicenter study was conducted. Study participants were recruited from March 2022 to October 2022 in six pediatric neurology departments. Principal component analysis as well as reliability and item analyses were employed.Results: Data from 342 patients were collected. The questionnaire was rated as appropriate by the participants in terms of its length, comprehensibility and relevance of the questions. Within the principal component analysis, a single factor structure was revealed. High correlation (Spearman's p= -0.678, p < 0.001.) of the sum scores of the KoCoN-V with a global measure of quality of care confirmed convergent validity. Internal consistency of the KoCoN-V was excellent (Cronbach's alpha= 0.905).Conclusion: The KoCoN-V is a validated measure to assess the quality of care for children and adolescents with complex chronic neurological disorders.Hintergrund Komplex-chronische Krankheiten bei Kindern und Jugendlichen betreffen sehr häufig das Nervensystem. Nicht selten sind die Kinder abhängig von unterschiedlichsten medizinischen Hilfsmitteln bis hin zur Heimbeatmung und sind oft nicht in der Lage, verbal zu kommunizieren. Der Alltag der betroffenen Familien ist geprägt von häufigen Krankenhausaufenthalten sowie der Inanspruchnahme vielfältiger ambulanter Unterstützungsangebote. Trotz des komplexen Versorgungsbedarfs ist die Einschätzung der Eltern zur Versorgungsqualität dieser Kinder und Jugendlichen kaum untersucht. Ziel Die vorliegende Studie zielte darauf ab, einen Fragebogen zur Erfassung der Versorgungsqualität von Kindern und Jugendlichen mit komplex-chronisch neurologischen Erkrankungen zu entwickeln und zu validieren. Methodik Zur Validierung wurde eine prospektive multizentrische Studie durchgeführt. Die Rekrutierung der Studienteilnehmer:innen erfolgte von März 2022 bis Oktober 2022 in 6 kinderneurologischen Abteilungen verschiedener Kliniken. Der neu entwickelte Fragebogen (KoCoN-Versorgung, KoCoN-V) richtet sich an Eltern von Kindern und Jugendlichen mit komplex-chronisch neurologischen Erkrankungen und besteht aus 17 Items zur Einschätzung der Versorgungsqualität. Für die Validierung des KoCoN‑V wurde im Rahmen einer Hauptkomponentenanalyse eine verlässliche Messgröße ermittelt. Zudem wurden die Messgenauigkeit (interne Konsistenz) des KoCoN‑V berechnet und die Übereinstimmung des KoCoN‑V mit einem globalen Maß zur Zufriedenheit mit der Versorgungsqualität (konvergente Validität) berechnet. Ergebnisse Es konnten Daten von insgesamt 342 Patient:innen erfasst werden. Der Fragebogen wurde von den Teilnehmenden in Bezug auf seine Länge, Verständlichkeit und Relevanz der Fragen als angemessen bewertet. Die Analysen zur Validierung ergaben eine einfaktorielle Struktur; im klinischen Alltag ist somit lediglich ein einzelner Summenwert zu bilden, um die Zufriedenheit der Sorgeberechtigten mit der Versorgung ihres chronisch-komplex neurologisch erkrankten Kindes abbilden zu können. Die hohe Korrelation (Spearmans p = −0,678, p < 0,001) der Summenwerte des KoCoN‑V mit dem globalen Maß zur Versorgungsqualität bestätigt die konvergente Validität des Fragebogens. Die Messgenauigkeit (interne Konsistenz) des KoCoN‑V ist exzellent (Cronbachs α = 0,905). Diskussion Mit dem KoCoN‑V liegt ein validiertes Maß der elterlichen Bewertung der Versorgungsqualität von Kindern und Jugendlichen mit komplex-chronisch neurologischen Erkrankungen vor

Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability

First published June 28, 2021. Online issue publication April 22, 2022.Purpose: Binding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. A de novo missense variant in GNB2 was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm GNB2 as a neurodevelopmental disease gene, and elucidate the GNB2-associated neurodevelopmental phenotype in a patient cohort. Methods: We discovered a GNB2 variant in the index case via exome sequencing and sought individuals with GNB2 variants via international data-sharing initiatives. In silico modelling of the variants was assessed, along with multiple lines of evidence in keeping with American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants. Results: We identified 12 unrelated individuals with five de novo missense variants in GNB2, four of which are recurrent: p.(Ala73Thr), p.(Gly77Arg), p.(Lys89Glu) and p.(Lys89Thr). All individuals have DD/ID with variable dysmorphism and extraneurologic features. The variants are located at the universally conserved shared interface with the Gα subunit, which modelling suggests weaken this interaction. Conclusion: Missense variants in GNB2 cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins.Natalie B Tan ... Christopher P Barnett ... Hamish S Scott ... et al

Characteristic brain magnetic resonance imaging pattern in patients with macrocephaly and PTEN mutations

We describe an MRI phenotype seen in a series of patients with mutations in PTEN who have clinical features consistent with PTEN hamartoma tumor syndrome (PHTS). Retrospective review of clinical data and MRI was performed in 23 subjects evaluated in four different tertiary care centers with clinical programs in inherited disorders of the white matter. Patients were referred due to abnormal MRI features and abnormal PTEN sequencing was identified. All subjects had significant macrocephaly (on average >4 SD above the mean), developmental delay with or without autism spectrum disorder and uniform MRI features of enlarged perivascular spaces and multifocal periventricular white matter abnormalities. The phenotype of PHTS may include MRI abnormalities such as multifocal periventricular white matter abnormalities and enlarged perivascular spaces. These neuroimaging findings, in association with macrocephaly and developmental delay, should prompt consideration of PTEN as a diagnostic possibility