Objectives To determine the incidence of pathogenic SCN8A variants in a cohort of epilepsy patients referred for clinical genetic testing. We also investigated the contribution of SCN8A to autism spectrum disorder, intellectual disability, and neuromuscular disorders in individuals referred for clinical genetic testing at the same testing laboratory. Methods Sequence data from 275 epilepsy panels screened by Emory Genetics Laboratory were reviewed for variants in SCN8A. Additional cases with variants in SCN8A were ascertained from other testing laboratories. Parental samples were tested for variant segregation and clinical histories were examined. SCN8A variants detected from gene panel analyses for autism spectrum disorder, intellectual disability, and neuromuscular disorders were also examined. Results Five variants in SCN8A were identified in five individuals with epilepsy. Three variants were de novo, one was inherited from an affected parent, and one was inherited from an unaffected parent. Four of the individuals have epilepsy and developmental delay/intellectual disability. The remaining individual has a milder epilepsy presentation without cognitive impairment. We also identified an amino acid substitution at an evolutionarily conserved SCN8A residue in a patient who was screened on the autism spectrum disorder panel. Additionally, we examined the distribution of pathogenic SCN8A variants across the Nav1.6 channel and identified four distinct clusters of variants. These clusters are primarily located in regions of the channel that are important for the kinetics of channel inactivation. Conclusions Variants in SCN8A may be responsible for a spectrum of epilepsies as well as other neurodevelopmental disorders without seizures. The predominant pathogenic mechanism appears to involve disruption of channel inactivation, leading to gain-of-function effects.
Background: The prognosis of patients with untreated cardiac implantable electronic device (CIED) infection is poor. Whether removal of all leads by a successful transvenous lead extraction (TLE) procedure changes the prognosis is unclear.Objective: To identify predictors of mortality in patients with CIED infection despite successful TLE.Methods: Retrospective single-center analysis of prospectively collected database from consecutive patients undergoing TLE at our center. Predictors for mortality were identified and a score predicting high mortality rate was calculated.Results: A total of 371 consecutive patients underwent TLE, of whom 337 (90.8%) had complete hardware removal. Most were extracted due to infectious causes (81.3%).Approximately one-third (35%) died during a mean follow-up of 1056 ± 868 days. There was significantly higher mortality observed in the infectious group. Multivariate logistic regression models for infectious group only identified creatinine and albumin measurements as risk markers for 30 days mortality (odds ratio [OR], 1.68; 95% confidence interval [CI], 1.19-2.38; P = .003 and OR, 0.4; 95% CI, 0.16-0.97; P = .039, respectively).A risk score was created based on cutoff values of creatinine ≥2md/dL (1 point) and albumin ≤3.5 g/dL (1 point). A value of 2 points predicted a 50% chance of 30-day mortality and a 75% chance of 1-year mortality (P < .0001 for both).Conclusions: Creatinine and albumin can be used as a combined risk score to successfully identify patients at risk of death despite undergoing a successful TLE procedure for infectious reasons. This score could help decision making when contemplating on conservative antibiotic treatment vs TLE. K E Y W O R D S albumin, creatinine, infection, lead extraction, mortality, risk score
5-oxoprolinemia (pyroglutamic acid, PGA) in the absence of acetaminophen use has been rarely reported as a cause for high anion gap metabolic acidosis. We investigated the prevalence and risk factors for elevated PGA concentrations among hospitalized patients with high anion gap metabolic acidosis: We prospectively enrolled patients with high anion gap metabolic acidosis hospitalized in the department of medicine. For each patient we collected the main diagnosis, concurrent medications and laboratory parameters. Spot urine samples were tested for PGA concentration. Levels ≥63 µmol/mmol creatinine were considered elevated. Overall, forty patients were prospectively followed. Mean age was 66.9 (17.9) years. Four (6.3%) patients had a high urine PGA level and demonstrated also lower blood pH (7.2 vs 7.3, p = 0.05) and lower serum lactate concentration (17.5 mg/dl vs 23.0 mg/dl, p = 0.04). Additionally, the high PGA level group consisted of more patients with septic shock [2/4 (50%) vs 3/36 (8.3%)] with a trend towards significance (p = 0.07). In conclusion, PGA might have a role in patients with septic shock and acidosis. Being a treatable condition, PGA should be taken into consideration particularly when no other cause for high anion gap is identified.
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