Genetic epidemiology of amyotrophic lateral sclerosis in Norway - a 2-year population based study

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons. In Europe, disease-causing genetic variants have been identified in 40-70% of familial ALS patients and approximately in 5% of sporadic ALS patients. In Norway, the contribution of genetic variants to ALS has not yet been studied. In light of the potential development of personalized medicine, knowledge of genetic causes of ALS in a population is becoming increasingly important. The present study provides clinical and genetic data on familial and sporadic ALS patients in a Norwegian population-based cohort. Methods: Blood samples and clinical information from ALS patients were obtained at all 17 neurological departments throughout Norway during a 2-year period. Genetic analysis of the samples involved expansion analysis of C9orf72 and exome sequencing targeting 30 known ALS-linked genes. The variants were classified using genotype-phenotype correlations and bioinformatics tools. Results: A total of 279 ALS patients were included in the study. Of these, 11.5% had one or several family members affected with ALS, whereas 88.5% had no known family history of ALS. A genetic cause of ALS was identified in 31 individuals (11.1%), among which 18 (58.1%) were familial and 13 (41.9%) were sporadic. The most common genetic cause was the C9orf72 expansion (6.8%), which was identified in 8 familial and 11 sporadic ALS patients. Pathogenic or likely pathogenic variants of SOD1 and TBK1 were identified in 10 familial and 2 sporadic cases. C9orf72 expansions dominated in patients from the Northern and Central regions, whereas SOD1 variants dominated in patients from the South-Eastern region. Conclusion: In the present study, we identified several pathogenic gene variants in both familial and sporadic ALS patients. Restricting genetic analysis to only familial cases would miss more than 40 percent of those with a disease-causing genetic variant, indicating the need for genetic analysis in sporadic cases as well.publishedVersio

Moderately Prolonged QTc in Computer-Assessed ECG, Random Variation or Significant Risk Factor? A Literature Review

Most ECGs in European hospitals are recorded with equipment giving computer measured intervals and interpretation of the recording. In addition to measurements of interval and QRS axis, this interpretation frequently provides the Bazett’s-corrected QTc time. The introduction of computer-corrected QTc revealed QTc prolongation to be a frequent condition among medical patients. Nevertheless, the finding is frequently overlooked by the treating physician. The authors combine experience from a local hospital with a review of the current literature in this field in order to elucidate the importance of this risk factor both as congenital long QT syndrome and as acquired QT prolongation

Genetic and phenotypic characterization of community hospital patients with QT prolongation

Background: Congenital long‐QT syndrome (LQTS) is a genetic disorder characterized by prolongation of the corrected QT interval (QTc) on an ECG. The aim of the present study was to estimate the prevalence of pathogenic and likely pathogenic sequence variants in patients who had at least 1 ECG with a QTc ≥500 ms. Methods and Results: Telemark Hospital Trust is a community hospital within the Norwegian national health system, serving ≈173 000 inhabitants. We searched the ECG database at Telemark Hospital Trust, Norway, from January 2004 to December 2014, and identified 1531 patients with at least 1 ECG with a QTc ≥500 ms. At the time of inclusion in this study (2015), 766 patients were alive. A total of 733 patients were invited to participate, and 475 accepted. The 17 genes that have been reported to cause monogenic LQTS were sequenced among the patients. Pro‐QTc score was calculated for each patient. A molecular genetic cause of LQTS was detected in 31 (6.5%) of 475 patients. These patients had a lower pro‐QTc score than those without pathogenic or likely pathogenic variants (1.7±1.0 versus 2.8±1.6; P<0.001). Conclusions: Compared with the general population, hospitalized patients with a QTc ≥500 ms in at least 1 ECG recording had an increased likelihood for pathogenic and likely pathogenic variants in LQTS genes. We recommend increased awareness of the possibility of LQTS in patients with at least 1 ECG with a QTc ≥500 ms

Influence of asthma and obesity on respiratory symptoms, work ability and lung function: findings from a cross-sectional Norwegian population study

Background: Although asthma and obesity are each associated with adverse respiratory outcomes, a possible interaction between them is less studied. This study assessed the extent to which asthma and overweight/obese status were independently associated with respiratory symptoms, lung function, Work Ability Score (WAS) and sick leave; and whether there was an interaction between asthma and body mass index (BMI) ≥25 kg/m2 regarding these outcomes. Methods: In a cross-sectional study, 626 participants with physician-diagnosed asthma and 691 without asthma were examined. All participants completed a questionnaire and performed spirometry. The association of outcome variables with asthma and BMI category were assessed using regression models adjusted for age, sex, smoking status and education. Results: Asthma was associated with reduced WAS (OR=1.9 (95% CI 1.4 to 2.5)), increased sick leave in the last 12 months (OR=1.4 (95% CI 1.1 to 1.8)) and increased symptom score (OR=7.3 (95% CI 5.5 to 9.7)). Obesity was associated with an increased symptom score (OR=1.7 (95% CI 1.2 to 2.4)). Asthma was associated with reduced prebronchodilator and postbronchodilator forced expiratory volume in 1 s (FEV1) (β=-6.6 (95% CI -8.2 to -5.1) and -5.2 (95% CI -6.7 to -3.4), respectively) and prebronchodilator forced vital capacity (FVC) (β=-2.3 (95% CI -3.6 to -0.96)). Obesity was associated with reduced prebronchodilator and postbronchodilator FEV1 (β=-2.9 (95% CI -5.1 to -0.7) and -2.8 (95% CI -4.9 to -0.7), respectively) and FVC (-5.2 (95% CI -7.0 to -3.4) and -4.2 (95% CI -6.1 to -2.3), respectively). The only significant interaction was between asthma and overweight status for prebronchodilator FVC (β=-3.6 (95% CI -6.6 to -0.6)). Conclusions: Asthma and obesity had independent associations with increased symptom scores, reduced prebronchodilator and postbronchodilator FEV1 and reduced prebronchodilator FVC. Reduced WAS and higher odds of sick leave in the last 12 months were associated with asthma, but not with increased BMI. Besides a possible association with reduced FVC, we found no interactions between asthma and increased BMI

QT prolongation predicts short-term mortality independent of comorbidity

A prolonged corrected QT interval (QTc) ≥500 ms is associated with high all-cause mortality in hospitalized patients. We aimed to explore any difference in short- and long-term mortality in patients with QTc ≥500 ms compared with patients with QTc &lt;500 ms after adjustment for comorbidity and main diagnosis. Methods and results Patients with QTc ≥500 ms who were hospitalized at Telemark Hospital Trust, Norway between January 2007 and April 2014 were identified. Thirty-day and 3-year all-cause mortality in 980 patients with QTc ≥500 ms were compared with 980 patients with QTc &lt;500 ms, matched for age and sex and adjusting for Charlson comorbidity index (CCI), previous admissions, and main diagnoses. QTc ≥500 ms was associated with increased 30-day all-cause mortality [hazard ratio (HR) 1.90, 95% confidence interval (CI) 1.38–2.62; P &lt; 0.001]. There was no significant difference in mortality between patients with QTc ≥500 ms and patients with QTc &lt;500 ms who died between 30 days and 3 years; 32% vs. 29%, P = 0.20. Graded CCI was associated with increased 3-year all-cause mortality (CCI 1–2: HR 1.62, 95% CI 1.34–1.96; P &lt; 0.001; CCI 3–4: HR 2.50, 95% CI 1.95–3.21; P &lt; 0.001; CCI ≥5: HR 3.76, 95% CI 2.85–4.96; P &lt; 0.001) but was not associated with 30-day all-cause mortality. QTc ≥500 ms is a powerful predictor of short-term mortality overruling comorbidities. QTc ≥500 ms also predicted long-term mortality, but this effect was mainly caused by the increased short-term mortality. For long-term mortality, comorbidity was more important

Influence of Obesity on Work ability, Respiratory Symptoms, and Lung Function in Adults with Asthma

BACKGROUND:Asthma is defined by variable respiratory symptoms and lung function, and may influence work ability. Similarly, obesity may contribute to respiratory symptoms, affect lung function, and reduce work ability. Thus, assessment of the influence of obesity on work ability, respiratory symptoms, and lung function in adults with asthma is needed. OBJECTIVES:We hypothesized that patients with obesity and asthma have more respiratory symptoms and reduced work ability and lung function compared with normal-weight patients with asthma. METHODS:We examined 626 participants with physician-diagnosed asthma, aged 18-52 years, recruited from a cross-sectional general population study using a comprehensive questionnaire including work ability score, the asthma control test (ACT), height and weight, and spirometry with reversibility testing. RESULTS:Participants with a body mass index (BMI) ≥30 kg/m2 (i.e., obese) had a higher symptom score (OR 1.78, 95% CI 1.14-2.80), current use of asthma medication (1.60, 1.05-2.46), and incidence of ACT scores ≤19 (poor asthma control) (1.81, 1.03-3.18) than participants with BMI ≤24.9 kg/m2 (i.e., normal weight). Post-bronchodilator forced vital capacity (FVC) as a percentage of predicted (β coefficient -4.5) and pre-bronchodilator forced expiratory volume in 1 s as a percentage of predicted (FEV1) (β coefficient -4.6) were negatively associated with BMI ≥30 kg/m2. We found no statistically significant association of BMI >30 kg/m2 (compared to BMI <24.9 kg/m2) with sick leave (1.21, 0.75-1.70) or reduced work ability (1.23, 0.74-2.04). CONCLUSIONS:There were indications that patients with obesity had a higher symptom burden, poorer asthma control, higher consumption of asthma medication, and reduced lung function, in particular for FVC, compared with normal-weight patients

QT prolongation predicts short-term mortality independent of comorbidity

A prolonged corrected QT interval (QTc) ≥500 ms is associated with high all-cause mortality in hospitalized patients. We aimed to explore any difference in short- and long-term mortality in patients with QTc ≥500 ms compared with patients with QTc &lt;500 ms after adjustment for comorbidity and main diagnosis. Methods and results Patients with QTc ≥500 ms who were hospitalized at Telemark Hospital Trust, Norway between January 2007 and April 2014 were identified. Thirty-day and 3-year all-cause mortality in 980 patients with QTc ≥500 ms were compared with 980 patients with QTc &lt;500 ms, matched for age and sex and adjusting for Charlson comorbidity index (CCI), previous admissions, and main diagnoses. QTc ≥500 ms was associated with increased 30-day all-cause mortality [hazard ratio (HR) 1.90, 95% confidence interval (CI) 1.38–2.62; P &lt; 0.001]. There was no significant difference in mortality between patients with QTc ≥500 ms and patients with QTc &lt;500 ms who died between 30 days and 3 years; 32% vs. 29%, P = 0.20. Graded CCI was associated with increased 3-year all-cause mortality (CCI 1–2: HR 1.62, 95% CI 1.34–1.96; P &lt; 0.001; CCI 3–4: HR 2.50, 95% CI 1.95–3.21; P &lt; 0.001; CCI ≥5: HR 3.76, 95% CI 2.85–4.96; P &lt; 0.001) but was not associated with 30-day all-cause mortality. QTc ≥500 ms is a powerful predictor of short-term mortality overruling comorbidities. QTc ≥500 ms also predicted long-term mortality, but this effect was mainly caused by the increased short-term mortality. For long-term mortality, comorbidity was more important