A rare case of uncharacterized autoinflammatory disease: Patient carrying variations in NLRP3 and TNFRSF1A genes.

Tumor necrosis factor type 1A receptor-associated periodic syndrome (TRAPS) and cryopyrin-associated autoinflammatory syndrome (CAPS) are rare monogenic autoinflammatory diseases (AIDs) mainly caused by pathogenic variations in the TNFRSF1A and NLRP3 genes, respectively. Here, we describe a unique patient presenting with symptoms overlapping both TRAPS and CAPS, without known pathogenic variants in the respective genes. The patient harbored the p.Val200Met variation in NLRP3 and the p.Ser226Cys variation in TNFRSF1A, prompting us to delve deeper into the functional analysis due to conflicting or inconclusive pathogenicity interpretations of the variants across various databases. Molecular dynamics analysis of the p.Val200Met variation in NLRP3 revealed a rigid conformation in the helical domain 2 subdomain of the NACHT domain. This increased rigidity suggests a potential mechanism by which this variation supports the assembly of the NLRP3 inflammasome. Notably, the patient's peripheral mononuclear blood cells demonstrated an elevated IL-1ß response upon lipopolysaccharides (LPS) induction. Subsequent initiation of anti-IL-1ß therapy resulted in a significant alleviation of the patient's symptoms, further supporting our hypothesis. We interpret these findings as suggestive of a potential pathophysiological role for the NLPR3 p.Val200Met variation in shaping the patient's clinical phenotype, which was also supported by clinical and genetic analysis of the family. This case underscores the complexity of the genetic landscape in AIDs and highlights the value of combining family genetic and functional data to refine the understanding and management of such challenging cases.

Prospective outcome analysis of multiple sclerosis cases reveals candidate prognostic cerebrospinal fluid markers.

BACKGROUND: Predicting the long-term disability outcomes of multiple sclerosis (MS) cases is challenging. OBJECTIVE: We prospectively analysed our previous MS cohort with initial cerebrospinal fluid (CSF) proteomics data to reveal disability markers after 8.2±2.2 years of follow-up. METHODS: Patients with regular follow-up visits were assigned into two groups: those with an age-related MS severity (ARMSS) score ≥5 (unfavourable course group, N = 27) and ARMSS score <5 (favourable course group, N = 67). A machine learning-based algorithm was applied to reveal candidate poor prognosis-associated initial CSF proteins, which were measured in an independent MS cohort (verification group, N = 40) by ELISA. Additionally, the correlation of initial clinical and radiological parameters with long-term disability was analysed. RESULTS: CSF alpha-2-macroglobulin (P = 0.0015), apo-A1 (P = 0.0016), and haptoglobin (P = 0.0003) protein levels, as well as cerebral lesion load (>9 lesions) on magnetic resonance imaging, gait disturbance (P = 0.04), and bladder/bowel symptoms (P = 0.01) were significantly higher in the unfavourable course group than in the favourable course group. Optic nerve involvement evident on initial magnetic resonance imaging (P = 0.002) and optic neuritis (P = 0.01) were more frequent in the favourable course group. CONCLUSION: The herein identified initial CSF protein levels, in addition to the clinical and radiological parameters at disease onset, have predictive value for long-term disability in MS cases.

Investigating the role of common and rare variants in multiplex multiple sclerosis families reveals an increased burden of common risk variation.

Many multiple sclerosis (MS)-associated common risk variants as well as candidate low-frequency and rare variants have been identified; however, approximately half of MS heritability remains unexplained. We studied seven multiplex MS families, six of which with parental consanguinity, to identify genetic factors that increase MS risk. Candidate genomic regions were identified through linkage analysis and homozygosity mapping, and fully penetrant, rare, and low-frequency variants were detected by exome sequencing. Weighted sum score and polygenic risk score (PRS) analyses were conducted in MS families (24 affected, 17 unaffected), 23 sporadic MS cases, 63 individuals in 19 non-MS control families, and 1272 independent, ancestry-matched controls. We found that familial MS cases had a significantly higher common risk variation burden compared with population controls and control families. Sporadic MS cases tended to have a higher PRS compared with familial MS cases, suggesting the presence of a higher rare risk variation burden in the families. In line with this, score distributions among affected and unaffected family members within individual families showed that known susceptibility alleles can explain disease development in some high-risk multiplex families, while in others, additional genetic contributors increase MS risk.

Characteristics and Outcomes of Psychiatric Inpatients With Severe Mental Illness and COVID-19: Experience From a COVID-19-Specific Acute Psychiatric Ward in Istanbul.

ABSTRACT: Recent studies indicated that psychiatric inpatients with severe mental illness (SMI) are at a greater risk of morbidity and mortality from COVID-19. However, there is still little data about the impact of comorbid COVID-19 infection on the course and outcome of acute exacerbations in this population. We conducted a prospective historically matched case control study. The sociodemographic and clinical characteristics of acute psychiatric inpatients with SMI and comorbid COVID-19 (n = 21) were compared with those of historically-matched non-COVID-19 controls with SMI (n = 42). The outcomes for acute inpatients with SMI and COVID-19 were also investigated. The new-onset SMI rate was relatively higher (23.8%) in the COVID-19 group, which has characteristics similar to those of the non-COVID-19 group except for working status (p < 0.05). The COVID-19 group had a high rate of relapse (47.6%) within 6 months of discharge. Our study suggests that patients with SMI who contracted SARS-CoV-2 may have a higher rate of new-onset mental disorder. Considering the high rate of relapse during the pandemic, chronically ill patients with SMI and COVID-19 should be closely monitored after discharge.

Adverse drug reactions associated with concurrent acute psychiatric treatment and Covid-19 drug therapy.

OBJECTIVE: Psychiatric patients are at increased risk of contamination, morbidity, and mortality associated with COVID-19, together with potentially more pronounced adverse effects. We present and discuss the adverse effects observed in an acute psychiatric clinic that has admitted COVID-19 patients during the first three months of the pandemic in Turkey. METHODS: The COVID-19 treatment schemes were formed in accordance with the national and regional guidelines at the time of admittance, which were mainly based on the use of hydroxychloroquine and other drugs. The sample consisted exclusively of inpatients, and all patients were enrolled in the study regardless of their specific diagnosis or treatment schemes. RESULTS: 4 out of 23 patients (17.4%) had experienced adverse effects, two of which had mild hepatic enzyme elevation and one had mild sinus bradycardia. Of note is that we haven't encountered any serious complications or life-threatening events during inpatient treatment. The most emphasised adverse effect in the literature, namely QTc prolongation and ECG changes, were not observed in our sample. The adverse effects were not found to be significantly associated with patient-related factors nor dose of antipsychotic medication. CONCLUSIONS: From our point of view, non-cardiac adverse effects should not be overlooked while treating comorbid psychiatric and COVID-19 patients.KEY POINTSAcute inpatient psychiatric treatment of patients who have comorbid COVID-19 is a complex situation requiring multidisciplinary action.Adverse drug reactions, which may or not result from the interaction of psychiatric and COVID-19 treatment, should be of concern for this patient group.While there is controversy over the benefits of some of the off-label COVID-19 medications, there should also be discussion over safety and concomitant medication use.In order to be adequately prepared for future escalations of COVID-19 pandemic, psychiatric services should thoroughly evaluate their initial experience with COVID-19, including from the point of drug effectiveness and safety.