Caroline Ingre

A yeast functional screen predicts new candidate ALS disease genes

Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.

Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease primarily affecting motor neurons. We recently identified intermediate-length polyglutamine (polyQ) expansions (27-33 Qs) in ataxin 2 as a genetic risk factor for sporadic ALS in North American ALS patients. To extend these findings, we assessed the ataxin 2 polyQ repeat length in 1294 European ALS patients and 679 matched healthy controls. We observed a significant association between polyQ expansions and ALS (>30 Qs; P= 6.2 × 10(-3)). Thus, intermediate-length ataxin 2 polyQ repeat expansions are associated with increased risk for ALS also in the European cohort. The specific polyQ length cutoff, however, appears to vary between different populations, with longer repeat lengths showing a clear association. Our findings support the hypothesis that ataxin 2 plays an important role in predisposing to ALS and that polyQ expansions in ataxin 2 are a significant risk factor for the disease.

Risk factors for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. It is typically fatal within 2–5 years of symptom onset. The incidence of ALS is largely uniform across most parts of the world, but an increasing ALS incidence during the last decades has been suggested. Although recent genetic studies have substantially improved our understanding of the causes of ALS, especially familial ALS, an important role of non-genetic factors in ALS is recognized and needs further study. In this review, we briefly discuss several major genetic contributors to ALS identified to date, followed by a more focused discussion on the most commonly examined non-genetic risk factors for ALS. We first review factors related to lifestyle choices, including smoking, intake of antioxidants, physical fitness, body mass index, and physical exercise, followed by factors related to occupational and environmental exposures, including electromagnetic fields, metals, pesticides, β-methylamino-L-alanine, and viral infection. Potential links between ALS and other medical conditions, including head trauma, metabolic diseases, cancer, and inflammatory diseases, are also discussed. Finally, we outline several future directions aiming to more efficiently examine the role of non-genetic risk factors in ALS.

Homozygous SMN2 deletion is a protective factor in the Swedish ALS population.

Abnormal survival motor neuron 1 (SMN1)-copy number has been associated with an increased risk of amyotrophic lateral sclerosis (ALS) in French and Dutch population studies. The aim of this study was to determine whether SMN gene copy number increases the risk of ALS or modulates its phenotype in a cohort of Swedish sporadic ALS (SALS) patients. In all, 502 Swedes with SALS and 502 Swedish controls matched for gender and age were enrolled. SMN1 and SMN2 gene copy numbers were studied by a semi-quantitative PCR method. A genotype–phenotype comparison was performed in order to determine whether SMN genes modulate the phenotype of ALS. The results were also compared with our previously reported French cohort of ALS patients. There was no difference between Swedish patients and controls in the frequency of SMN1 and SMN2 copy numbers. The frequency of SMN1 gene copies differed significantly between the French and Swedish ALS populations. The duration of the disease was significantly longer in the Swedish cohort with homozygous deletions of SMN2 when compared with the French cohort. Abnormal SMN1 gene copy number cannot be considered as a universal genetic susceptibility factor for SALS and this result underlines the importance of reproducing association gene studies in groups from different origins. We also suggest that SMN2 gene copy number might have different effects on ALS progression in disparate human populations.

July 2017 ENCALS statement on edaravone

Neurologists of the ENCALS centers throughout Europe have discussed the potential of edaravone as a new therapy for amyotrophic lateral sclerosis (ALS, Motor Neuron Disease, MND) at the ENCALS meeting, 18–20 May 2017, in Ljubljana, Slovenia. In May 2017, the US Food and Drug Administration (FDA) granted a license for the drug known as edaravone (licensed in Japan in 2015 as Radicut®) for the treatment of ALS in the United States (to be marketed as Radicava®). We are not aware of any official request from Mitsubishi Tanabe Pharma, the manufacturer of edaravone, to the European Medicines Agency (EMA) to register the drug for use in ALS in Europe. However, edaravone can be imported to Europe from Japan or the United States. The FDA approval of edaravone is based on a single positive clinical trial. The ENCALS neurologists were of the view that the outcome of this trial requires a balanced and considered interpretation when considering how best to advise those with ALS and their families. This study showed that edaravone may slow disease progression in ALS, but the disease-modifying effect was limited to a subgroup of ALS patients with distinct clinical characteristics. For ALS patients without those characteristics there is currently no evidence for a therapeutic benefit of edaravone.

Blood biomarkers of carbohydrate, lipid, and apolipoprotein metabolisms and risk of amyotrophic lateral sclerosis: A more than 20-year follow-up of the Swedish AMORIS cohort

To assess the associations of blood biomarkers of carbohydrate, lipid, and apolipoprotein metabolisms with the future risk of amyotrophic lateral sclerosis (ALS).

Depression in amyotrophic lateral sclerosis

Objective: To examine the relative risk of depression among patients with amyotrophic lateral sclerosis (ALS), both in terms of depression diagnosis and use of antidepressant drugs, before and after diagnosis. Methods: We conducted a nested case-control study including 1,752 patients with ALS diagnosed from July 2005 to December 2010 and 8,760 controls based on the Swedish national health and population registers, to assess the associations of depression diagnosis and use of antidepressant drugs with a subsequent risk of ALS. We further followed the patients with ALS after diagnosis to estimate the association of an ALS diagnosis with the subsequent risk of depression and use of antidepressant drugs. Results: Before diagnosis, patients with ALS were at higher risk of receiving a clinical diagnosis of depression compared to controls (odds ratio [OR] 1.7, 95% confidence interval [CI] 1.3–2.3), and the highest risk increase was noted during the year before diagnosis (OR 3.5, 95% CI 2.1–5.6). Patients with ALS also had a highly increased risk of depression within the first year after diagnosis (hazard ratio 7.9, 95% CI 4.4–14.3). Antidepressant use was more common in patients with ALS than in controls, especially during the year before (OR 5.8, 95% CI 4.5–7.5) and the year after (hazard ratio 16.1, 95% CI 11.5–22.6) diagnosis. Conclusions: Patients with ALS are at higher risk of depression diagnosis and use of antidepressant drugs both immediately before and after diagnosis.

No association between VAPB mutations and familial or sporadic ALS in Sweden, Portugal and Iceland

Abstract Linkage analysis in Brazilian families with amyotrophic lateral sclerosis (ALS) revealed that a missense mutation p.Pro56Ser in a conserved gene VAMP-associated protein type B and C (VAPB) cosegregates with disease. Blood samples were studied from 973 Swedish, 126 Portuguese and 19 Icelandic ALS patients, and from 644 control subjects. We identified five VAPB mutations, two of which are novel, in 14 Swedish ALS patients and in nine control individuals from Sweden and Portugal. The 14 patients with VAPB mutations all carried a diagnosis of sporadic ALS. Mutations were also found in healthy adult relatives. The p.Asp130Glu VAPB mutation was also found in two patients from an Icelandic ALS family, but the mutation did not cosegregate with disease. All patients were instead found to be heterozygous for a p.Gly93Ser SOD1 mutation. There were no clinical differences between them, suggesting that the p.Asp130Glu VAPB mutation is unrelated to the disease process. In conclusion, the VAPB mutations were as frequent in control individuals as in patients. This observation, in combination with the finding of several healthy relatives carrying the VAPB mutations and no ancestors with ALS disease, suggests that it is unlikely that these VAPB mutations are pathogenic.

Predictors of health-related quality of life in people with amyotrophic lateral sclerosis

BACKGROUND Knowledge of factors influencing health-related quality of life (HRQL) in people with amyotrophic lateral sclerosis (ALS) is important because some factors might be amenable to intervention. OBJECTIVES The aim was to describe and explore the effects of disease severity, fatigue, anxiety, depression, frequency of social and lifestyle activities, coping capacity and mechanical ventilator use on HRQL in people with ALS. METHODS Sixty people with ALS were enrolled in this cross-sectional study. Data were collected with questionnaires during home visits. The Sickness Impact Profile and the EuroQol Visual Analogue Scale were used to assess HRQL. Multivariate regression analyses explored associations between HRQL and independent factors. RESULTS Low frequency of social and lifestyle activities, and severe disease, were associated with worse HRQL, explaining 57% of total variance in the Sickness Impact Profile physical score. Severe disease, weak coping capacity and anxiety and/or depression were associated with worse HRQL, explaining 33% of total variance in Sickness Impact Profile psychosocial score. Fatigue and mechanical ventilator use were associated with worse HRQL, explaining 17% of variance in the EuroQol Visual Analogue Scale. CONCLUSION Knowledge and understanding of how frequency of social and lifestyle activities, disease severity, coping capacity, anxiety and/or depression, fatigue and ventilator use contribute to and predict self-rated HRQL can optimize person-centred care and support.

Neurodegenerative and psychiatric diseases among families with amyotrophic lateral sclerosis

Objective: To estimate risks of neurodegenerative and psychiatric diseases among patients with amyotrophic lateral sclerosis (ALS) and their families. Methods: We conducted a register-based nested case-control study during 1990–2013 in Sweden to assess whether patients with ALS had higher risks of other neurodegenerative and psychiatric diseases before diagnosis. We included 3,648 patients with ALS and 36,480 age-, sex-, and county of birth–matched population controls. We further conducted a follow-up study of the cases and controls to assess the risks of other neurodegenerative and psychiatric diseases after ALS diagnosis. To assess the potential contribution of familial factors, we conducted similar studies for the relatives of patients with ALS and their controls. Results: Individuals with previous neurodegenerative or psychiatric diseases had a 49% increased risk of ALS (odds ratio 1.49, 95% confidence interval 1.35–1.66) compared to individuals without these diseases. After diagnosis, patients with ALS had increased risks of other neurodegenerative or psychiatric diseases (hazard ratio 2.90, 95% confidence interval 2.46–3.43) compared to individuals without ALS. The strongest associations were noted for frontotemporal dementia, Parkinson disease, other dementia, Alzheimer disease, neurotic disorders, depression, stress-related disorders, and drug abuse/dependence. First-degree relatives of patients with ALS had higher risk of neurodegenerative diseases, whereas only children of patients with ALS had higher risk of psychiatric disorders, compared to relatives of the controls. Conclusions: Familial aggregation of ALS and other neurodegenerative diseases implies a shared etiopathogenesis among all neurodegenerative diseases. The increased risk of psychiatric disorders among patients with ALS and their children might be attributable to nonmotor symptoms of ALS and severe stress response toward the diagnosis.