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 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 the 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 by 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.

De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability.

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.

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 (ß coefficient -4.5) and pre-bronchodilator forced expiratory volume in 1 s as a percentage of predicted (FEV1) (ß 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.

Predictors of mortality in high-risk patients with QT prolongation in a community hospital.

Aims: To determine predictors of mortality in patients with corrected QT interval (QTc) ≥ 500 ms in a community hospital. Methods and results: In this retrospective observational study, we searched the electrocardiogram (ECG) database at Telemark Hospital Trust, Norway, from January 2004 to December 2014. Medication, electrolyte abnormalities, and medical conditions known to prolong the QT interval were recorded. From the medical records, we assessed whether the prolonged QTc was noted by the health care providers. We identified 1531 patients (age = 70 ± 15 years, 59% female) with an ECG with QTc ≥ 500 ms. All-cause mortality during 952 (range 0-4161) days of follow-up was 50% (n = 765/1531). Main predictors of mortality were aborted cardiac arrest [hazard ratio (HR) 2.40, 95% confidence interval (CI) 1.44-4.01; P = 0.001], cerebral stroke/head trauma (HR 2.28, 95% CI 1.70-3.05; P < 0.001), and heart failure (HR 1.74, 95% CI 1.43-2.12; P< 0.001). Females with prolonged QTc had better survival compared with males (P = 0.006). We constructed a risk-weighted QTc mortality score. QT prolongation was acknowledged in the medical records in 12% of the cases. Conclusions: QTc ≥ 500 ms was associated with high all-cause mortality with increased mortality in males compared with females. A new QTc mortality score was constructed to predict mortality. Only a minority of cases with prolonged QTc ≥ 500 ms were acknowledged in the medical records.

Genetic overlap between ALS and other neurodegenerative or neuromuscular disorders.

OBJECTIVE: In Norway, 89% of patients with Amyotrophic lateral sclerosis (ALS) lacks a genetic diagnose. ALS genes and genes that cause other neuromuscular or neurodegenerative disorders extensively overlap. This population-based study examined whether patients with ALS have a family history of neurological disorders and explored the occurrence of rare genetic variants associated with other neurodegenerative or neuromuscular disorders. METHODS: During a two-year period, blood samples and clinical data from patients with ALS were collected from all 17 neurological departments in Norway. Our genetic analysis involved exome sequencing and bioinformatics filtering of 510 genes associated with neurodegenerative and neuromuscular disorders. The variants were interpreted using genotype-phenotype correlations and bioinformatics tools. RESULTS: A total of 279 patients from a Norwegian population-based ALS cohort participated in this study. Thirty-one percent of the patients had first- or second-degree relatives with other neurodegenerative disorders, most commonly dementia and Parkinson's disease. The genetic analysis identified 20 possible pathogenic variants, in ATL3, AFG3L2, ATP7A, BICD2, HARS1, KIF1A, LRRK2, MSTO1, NEK1, NEFH, and SORL1, in 25 patients. NEK1 risk variants were present in 2.5% of this ALS cohort. Only four of the 25 patients reported relatives with other neurodegenerative or neuromuscular disorders. CONCLUSION: Gene variants known to cause other neurodegenerative or neuromuscular disorders, most frequently in NEK1, were identified in 9% of the patients with ALS. Most of these patients had no family history of other neurodegenerative or neuromuscular disorders. Our findings indicated that AFG3L2, ATP7A, BICD2, KIF1A, and MSTO1 should be further explored as potential ALS-causing genes.

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) (ß=-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) (ß=-2.3 (95% CI -3.6 to -0.96)). Obesity was associated with reduced prebronchodilator and postbronchodilator FEV1 (ß=-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 (ß=-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.

Nonsense-mediated decay of human LDL receptor mRNA.

OBJECTIVE: The objective of this project was to determine whether nonsense mutation in the low density lipoprotein receptor (LDLR) induces nonsense-mediated mRNA decay (NMD). MATERIAL AND METHODS: Four known nonsense mutations (W23X, S78X, E207X and W541X) in the LDLR gene, which are found in Norwegian familial hypercholesterolaemia (FH) patients, were investigated. Epstein-Barr virus (EBV) transformed lymphocytes from patients heterozygous for these mutations in the LDLR gene were analysed. Flow cytometric analysis was used to determine the amount and function of the cell surface LDLRs. The expression of LDLR mRNA in lymphocytes was quantified by real-time polymerase chain reaction (PCR). The presence of NMD was tested using the inhibitors gentamicin, emetine or cycloheximide. RESULTS: Cells from heterozygous FH patients with nonsense mutations in the LDLR gene contained significantly less LDLR protein (p<0.05). In addition, flow cytometric analysis revealed that these patients had a reduced LDL-uptake compared to controls (p<0.005). Cells from heterozygous FH patients with nonsense mutations W23X, S78X or W541X in the LDLR gene showed significantly decreased levels of LDLR mRNA (p<0.005). LDLR mRNA was reduced in the mutant lymphocyte S78X prior to treatment with pharmacological inhibitors, and after treatment the level of LDLR mRNA increased to the same level as that of normal cells. CONCLUSION: In the present study, NMD was confirmed in the LDLR gene. Translation inhibitors showed reduced NMD caused by nonsense mutated LDLR transcripts. Knowledge of NMD might have an important impact in clinical medicine as genetic intervention develops.