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Clinical and molecular characterization of SLC31A1-related developmental and epileptic encephalopathy: insights from 13 new cases
Get PDFCopper is indispensable for various metabolic processes, notably mitochondrial respiration. In humans, copper homeostasis hinges on transporters such as copper transporter 1 (CTR1), encoded by the SLC31A1 gene. Recently, bi-allelic mutations in SLC31A1 have been associated with a new neurodevelopmental disorder. This study presents clinical, genetic, and biochemical findings from 13 new cases across 10 families worldwide. RNA sequencing evaluated gene expression, and Western blotting assessed copper transporter 1 protein levels. Additionally, mitochondrial respiratory capacity was measured via high-resolution respirometry. Affected individuals exhibited a distinct clinical phenotype characterized by early-onset epileptic encephalopathy, severe neurodevelopmental delay and hypotonia, with high mortality. Neuroimaging revealed significant brain atrophy and white matter abnormalities. Genetic analysis identified bi-allelic SLC31A1 variants, predominantly p.His120Gln in six cases and p.(Arg102Cys/His) in three cases. Functional studies in patient fibroblasts demonstrated impaired mitochondrial respiration. This study significantly broadens the clinical spectrum of this recently described syndrome, presenting as a severe developmental encephalopathy with high mortality risk, and suggests mitochondrial dysfunction as a potential pathomechanism. These findings contribute to the mounting evidence linking copper transporter 1 dysfunction to neurodegeneration, underscoring the urgency for further therapeutic investigations
Neuropsychiatric involvement in epilepsy surgery pathways in the UK
Get PDFBACKGROUND: Epilepsy surgery is an effective treatment for drug-refractory epilepsy. Epilepsy surgery multidisciplinary team involves a number of professionals, yet the role of neuropsychiatric care in surgical programs remains inconsistent. Despite the known psychiatric risks associated with epilepsy and its surgical interventions, there is no standardised approach to neuropsychiatric care in epilepsy surgery. This study evaluates the current level of neuropsychiatric involvement in epilepsy surgery centres across the UK, identifying current gaps and makes the consensus recommendation for optimal neuropsychiatric input. METHODS: A self-administered questionnaire was developed by the Royal College of Psychiatrists (RCPsych) Neuropsychiatry Faculty epilepsy surgery working group. It was distributed to all epilepsy surgical centres in the UK both in 2013 and 2021-22. The survey focused on service provision, available resources, operational aspects, and clinicians' perspectives on neuropsychiatric involvement in epilepsy surgery. Data from the two surveys were analysed to assess the prevalent practice and identify barriers to the provision of neuropsychiatric care. RESULTS: A total of 12 responses were received in each survey out of a total of 15 centres. Findings indicate considerable variability in neuropsychiatric involvement, with inconsistent preoperative and postoperative assessments across centres. While most centres acknowledged the importance of neuropsychiatric input, resource constraints and a lack of formalised pathways result in fragmented service provision. CONCLUSION: The findings emphasise the need for standardised neuropsychiatric care in epilepsy surgery programs. Routine pre-operative and post-operative assessments should be integrated into epilepsy surgery pathways. Establishing national guidelines and increasing funding for neuropsychiatric services are crucial steps toward ensuring consistent and equitable care for epilepsy surgery patients across the UK
Effectiveness and safety of upadacitinib in a real-world cohort of patients with Crohn’s disease in the UK: a multicentre retrospective cohort study
Get PDFObjective
Upadacitinib is the first Janus kinase inhibitor and oral advanced therapy licensed for Crohn’s disease (CD). Following NICE approval in 2023, real-world data on outcomes are limited. The effectiveness and safety of upadacitinib in a cohort of patients with CD was assessed.
Methods
A multicentre retrospective cohort analysis across 19 UK hospitals. Adult patients with active CD who started upadacitinib between April 2023 and October 2023 were included. Outcomes were reviewed over 24 weeks. The primary endpoint was clinical remission (Harvey Bradshaw Index (HBI) <4) at 12 and 24 weeks. Biochemical remission (faecal calprotectin <200 μg/g and C-reactive protein ≤5) and endoscopic remission (Simple Endoscopic Score for Crohn’s Disease ≤3) were assessed at the same intervals. Adverse events (AEs) were recorded until 24 weeks or drug withdrawal.
Results
312 patients were included, with a minimum follow-up of 12 weeks. The cohort had difficult-to-treat disease; 64% failing 3 or more biologics, 51% exhibiting penetrating or stricturing disease and 41% requiring prior resection. 50% (113/227) of patients achieved clinical remission at 12 weeks and 45% (77/172) at 24 weeks. Patients with colonic disease had higher remission rates at 24 weeks compared with other disease locations. At 24 weeks, 51 patients (16%) had discontinued upadacitinib. Treatment persistence was 90.3% at 12 weeks and 84.1% at 24 weeks. 28% had AEs, with 18% experiencing serious AEs and 16.6% requiring hospitalisation.
Conclusion
This is a large real-world study reporting outcomes in patients with CD treated with upadacitinib. Our data demonstrated good short-term effectiveness and tolerance in a clinically refractory population
Risk Stratification of Acute Chest Pain in Patients With High‐Sensitivity Troponin T Below the 99th Percentile: A Long‐Term Cohort Study Assessing the Incremental Value of Necrosis and Non‐necrosis Biomarkers to Clinical Risk Scores
Get PDFBackground
Approximately 90% of patients presenting to the emergency department with suspected acute coronary syndrome have acute myocardial infarction excluded, but they remain at risk of major adverse cardiovascular events. This study assessed the long‐term outcomes of such patients, focusing on the incremental value of multiple biomarkers combined with clinical risk scores for risk stratification.
Methods
In this prospective observational study, 487 patients with suspected acute coronary syndrome but excluded acute myocardial infarction were recruited from a large urban hospital, with a median follow‐up of 5.8 years. The primary end point was major adverse cardiovascular events, including adjudicated type 1 myocardial infarction, unstable angina requiring urgent revascularization, and cardiovascular death. Biomarkers assessed were hs‐cTnT (high‐sensitivity cardiac troponin T), hs‐cTnI (high‐sensitivity cardiac troponin I), HFABP (heart‐type fatty acid binding protein), GDF‐15 (growth differentiation factor 15), NT‐proBNP (N‐terminal prohormone of brain naturetic peptide), galectin‐3, and hs‐CRP (high‐sensitivity C‐reactive protein (). Statistical methods included receiver operating characteristic analysis, Kaplan–Meier curves, net reclassification index, and Cox proportional hazards models to evaluate biomarker utility independently and combined with Thrombolysis in Myocardial Infarction and History, ECG, Age, Risk Factors, Troponin scores.
Results
Of the 487 patients (median age 56 years; 44% female), 9.9% experienced major adverse cardiovascular events. Annualized major adverse cardiovascular events rates for patients with troponin levels below the limit of detection were 0.5% (hs‐cTnT) and 0.7% (hs‐cTnI), with no cardiovascular deaths over 5 years. Both hs‐cTnT and hs‐cTnI levels modestly enhanced risk stratification when added to Thrombolysis in Myocardial Infarction or History, ECG, Age, Risk Factors, Troponinscores. Of the non‐necrosis biomarkers, only GDF‐15 demonstrated independent prognostic value in multivariable models.
Conclusions
Hs‐cTnT, hs‐cTnI, and GDF‐15 improve the long‐term risk stratification of the History, ECG, Age, Risk Factors, Troponinand Thrombolysis in Myocardial Infarction scores in patients with suspected acute coronary syndrome and acute myocardial infarction excluded. Hs‐cTn of either type at or below limit of detection was associated with excellent short‐ and long‐term outcomes.
Registration
URL: https://clinicaltrials.gov; Unique identifier: NCT03628586
Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy
Get PDFCharcot-Marie-Tooth Disease is a clinically and genetically heterogeneous group of hereditary neuropathies. Despite progress in genetic sequencing, around a quarter of patients remain unsolved. Here, we identify 16 recessive variants in the RhoGTPase activating protein 19 gene (ARHGAP19) causing motor-predominant neuropathy in 25 individuals from 20 unrelated families. The ARHGAP19 protein acts as a negative regulator of the RhoA GTPase. In vitro biochemical and cellular assays revealed that patient variants impair the GTPase-activating protein (GAP) activity of ARHGAP19 and reduce ARHGAP19 protein levels. Combined in vitro and in vivo studies reveal that human ARHGAP19, and conserved ARHGAP19 orthologs in Drosophila and Zebrafish, influence motoneuron morphology and promote locomotor capacity. Transcriptomic studies further demonstrate that ARHGAP19 regulates cellular pathways associated with motor proteins and the cell cycle. Taken together, our findings establish ARHGAP19 variants as a cause of inherited neuropathy acting through a loss-of-function mechanism
Is skull fracture associated with post-traumatic benign paroxysmal positional vertigo? An observational study
No full textBackground
Vestibular dysfunction (resulting in dizziness and imbalance) is common in acute traumatic brain injury (aTBI). The most frequently diagnosed cause of peripheral vestibular dysfunction in aTBI is benign paroxysmal positional vertigo (BPPV). However, post-traumatic BPPV is often undiagnosed and left untreated in these patients.
Objectives
To investigate clinical risk factors for BPPV in patients experiencing aTBI.
Methods
Patients were recruited from three Major Trauma Centres in London. Logistic regression was used to derive the adjusted odds ratio (aOR) of diagnosed BPPV for sex, categorised age, severity of traumatic brain injury (TBI), and site of skull fracture.
Results
166 patients with aTBI were included. Approximately a third (n = 55; 33.1 %) tested positive for BPPV. Compared to patients aged less than or equal to 40 years, those aged 41 to 64 years were more likely to experience BPPV (aOR=3.86; 95 % CI: 1.47 to 10.16; p = 0.006), as were those aged 65 years and above (4.41; 1.52 to 12.81; p = 0.006). Patients that experienced both facial and cranial skull fracture were more likely to experience BPPV than those that didn’t have a skull fracture (23.64; 6.36 to 87.89; p < 0.001).
Conclusion
The risk of post-traumatic BPPV increased with increasing age, plus in those with combined skull and facial fractures when compared to those without a skull fracture. We advocate routine BPPV screening of those with aTBI, especially in older adults and those with combined facial and skull fractures
A novel cause of type 1 Von Willebrand Disease: impaired exocytosis of Weibel-Palade bodies due to biallelic MADD variants
Get PDFThe regulated secretion of von Willebrand factor (VWF) from Weibel-Palade bodies (WPBs) in endothelial cells is fundamental to hemostasis. This process relies on recruiting Rab GTPases and their effectors to the WPB membrane, with the guanine nucleotide exchange factor MAPK-activating death domain (MADD) playing a central role. Biallelic variants in MADD lead to a pleiotropic neurological and developmental disorder that can include bleeding abnormalities. This study investigates the impact of pathogenic MADD variants on VWF secretion using patient-derived endothelial cells. We isolated endothelial colony-forming cells (ECFCs) from 3 pediatric patients with biallelic MADD variants and unaffected heterozygous family members. All patients exhibited low VWF plasma levels (22-30 IU/dL). Proteomic analysis of patient-derived ECFCs revealed an absence of MADD peptides, reduced VWF, and downregulation of proteins involved in the exocytotic machinery, including Rab3D and the Rab3/27 effector Slp4-a. Functional assays demonstrated diminished Rab27A and Rab3D activity and their failure to localize to WPBs in patient cells. Biochemical and live-imaging studies showed that histamine-induced VWF and VWF propeptide secretion were significantly reduced in patient cells due to delayed and reduced degranulation of WPBs. Our findings demonstrate the critical role of MADD in maintaining the secretion competence of WPBs and the magnitude of VWF secretion by regulating the recruitment of the endothelial exocytotic machinery. This study highlights the in vivo significance of WPB exocytosis in maintaining plasma VWF levels and establishes MADD as the first causal gene for quantitative von Willebrand disease in patients without pathogenic VWF variants
Lymphocytic myocarditis: A histopathologic definition and classification from the society for cardiovascular pathology and association for European cardiovascular pathology. II: Surgical and autopsy specimens
Get PDFBackground and aim
Lymphocytic myocarditis, characterized by lymphocyte-predominant myocardial inflammation with associated myocyte injury, is a term that has decades-old histopathologic criteria when encountered on endomyocardial biopsy. However, the interpretation of non-biopsy specimens such as surgical resections and autopsy samples has lacked standardized histopathologic criteria, despite their growing clinical and forensic relevance. The aim was to develop and establish criteria for the diagnosis and classification of lymphocytic myocarditis in non-biopsy ventricular myocardial specimens.
Methods and results
An international panel of cardiovascular pathologists representing the Society for Cardiovascular Pathology (SCVP) and the Association for European Cardiovascular Pathology (AECVP) developed a new classification system, which was completed at a final meeting in the Seaport area of Boston. These “Seaport” criteria for non-biopsy specimens formally define lymphocytic myocarditis as myocardial inflammation predominantly composed of lymphocytes, accompanied by myocyte injury not attributable to other causes. Recommendations address specimen type, technical handling, diagnostic thresholds, and qualifiers of chronicity. Diagnostic categories include active myocarditis and lymphocytic infiltrate of uncertain significance (LIUS). The document also outlines the interpretive challenges in attributing causality in autopsy settings, provides guidance on the use of ancillary techniques, and highlights the limitations of current histopathologic approaches.
Conclusion
These consensus-based criteria offer a standardized framework for diagnosing lymphocytic myocarditis in non-biopsy specimens. Adoption of these guidelines is expected to improve diagnostic consistency, enhance research comparability, and inform clinical and forensic evaluations. Future efforts should aim to refine definitions of myocyte injury, validate ancillary techniques, and elucidate the clinical significance of inflammation in the absence of injury
The indirect effects of cytomegalovirus infection—mechanisms and consequences
Get PDFIn this introduction, we summarize the research papers, review articles, opinion pieces and important aspects of the facilitated discussion from the meeting ‘The indirect effects of cytomegalovirus infection: mechanisms and consequences’ held at the Royal Society, London, on 14–15 October 2024. The term ‘indirect effects’ describes a statistical excess of pathologies seen in people with human cytomegalovirus (CMV) in the absence of histopathological hallmarks of direct CMV tissue damage. This meeting brought together laboratory scientists, paediatric and adult clinical academics, epidemiologists, and trialists, to discuss the latest research on indirect effects, from biological mechanisms to potential clinical consequences. Important questions regarding the impact of CMV remain unanswered in areas important to human health, such as preterm birth and fetal growth restriction, asymptomatic congenital infection, susceptibility to non-CMV infections, cardiovascular and respiratory disease, transplant, cancer and mental health. Further research is needed to better describe the biology and, critically, to robustly quantify its clinical impact and develop interventions to mitigate any harms.
This article is part of the discussion meeting issue ‘The indirect effects of cytomegalovirus infection: mechanisms and consequences’
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