Bi-allelic loss-of-function CACNA1B mutations in progressive epilepsy-dyskinesia

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment

Toxicological evaluation of a saponin-rich standardized extract of fenugreek seeds (FenuSMART®): Acute, sub-chronic and genotoxicity studies

The present study investigated the safety of a saponin-rich standardized extract of fenugreek seeds (FenuSMART®; FHE), that has been clinically shown to be effective in ameliorating the postmenopausal discomforts and establishing hormonal balance. The safety was assessed by oral acute (2500 mg/kg b. wt. for 14 days) and subchronic (250, 500 and 1000 mg/kg b. wt. for 90 days) toxicity studies on Wistar rats and mutagenicity studies employing Salmonella typhimurium strains. Administration of FHE did not produce any toxicologically significant changes in clinical/behavioral observations, ophthalmic examinations, body weight, organ weight, feed consumption, urinalysis, hematology and clinical biochemistry parameters when compared to the untreated control group of animals. Highest dose recovery group (1000 mg/kg b. wt.) of animals also showed no mortality or adverse events; with hematological and biochemical parameters at par with those of controls. Terminal autopsy revealed no alterations in relative organ weight or any treatment-related histopathology changes. FHE also showed no mutagenicity upon Ames test employing TA-98, TA-100 and TA-102 Salmonella typhimurium strains with or without metabolic activation. Based on the results of the study, the no observed-adverse-effect level (NOAEL) of FHE was determined as 1000 mg/kg b. wt./day, the highest dose tested. Keywords: Fenugreek extract, Trigonella foenum graecum, Phytoestrogen, Menopause, Subchronic toxicity, Genotoxicit

Phenotypes of South Asian patients with atrial fibrillation and holistic integrated care management: cluster analysis of data from KERALA-AF RegistryResearch in context

Summary: Background: Patients with atrial fibrillation (AF) frequently experience multimorbidity. Cluster analysis, a machine learning method for classifying patients with similar phenotypes, has not yet been used in South Asian AF patients. Methods: The Kerala Atrial Fibrillation Registry is a prospective multicentre cohort study in Kerala, India, and the largest prospective AF registry in South Asia. Hierarchical clustering was used to identify different phenotypic clusters. Outcomes were all-cause mortality, major adverse cardiovascular events (MACE), and composite bleeding events within one-year follow-up. Findings: 3348 patients were included (median age 65.0 [56.0–74.0] years; 48.8% male; median CHA2DS2-VASc 3.0 [2.0–4.0]). Five clusters were identified. Cluster 1: patients aged ≤65 years with rheumatic conditions; Cluster 2: patients aged >65 years with multi-comorbidities, suggestive of cardiovascular-kidney-metabolic syndrome; Cluster 3: patients aged ≤65 years with fewer comorbidities; Cluster 4: heart failure patients with multiple comorbidities; Cluster 5: male patients with lifestyle-related risk factors. Cluster 1, 2 and 4 had significantly higher MACE risk compared to Cluster 3 (Cluster 1: OR 1.36, 95% CI 1.08–1.71; Cluster 2: OR 1.79, 95% CI 1.42–2.25; Cluster 4: OR 1.76, 95% CI 1.31–2.36). The results for other outcomes were similar. Atrial fibrillation Better Care (ABC) pathway in the whole cohort was low (10.1%), especially in Cluster 4 (1.9%). Overall adherence to the ABC pathway was associated with reduced all-cause mortality (OR 0.26, 95% CI 0.15–0.46) and MACE (OR 0.45, 95% CI 0.31–0.46), similar trends were evident in different clusters. Interpretation: Cluster analysis identified distinct phenotypes with implications for outcomes. There was poor ABC pathway adherence overall, but adherence to such integrated care was associated with improved outcomes. Funding: Kerala Chapter of Cardiological Society of India