The changing picture of amyotrophic lateral sclerosis: lessons from European registers

Prospective population based-registers of amyotrophic lateral sclerosis (ALS) have operated in Europe for over two decades, and have provided important insights into our understanding of ALS. Here, we review the benefits that population registers have brought to the understanding of the incidence, prevalence, phenotype and genetics of ALS and outline the core operating principles that underlie these registers and facilitate international collaboration. Going forward, we offer lessons learned from our collective experience of operating population-based ALS registers in Europe for over two decades, focusing on register design, maintenance, identification and management of bias and the value of cross-national harmonisation and integration.Please see the article for a full statement regarding funding

Sampling strategies to measure the prevalence of common recurrent infections in longitudinal studies

<p>Abstract</p> <p>Background</p> <p>Measuring recurrent infections such as diarrhoea or respiratory infections in epidemiological studies is a methodological challenge. Problems in measuring the incidence of recurrent infections include the episode definition, recall error, and the logistics of close follow up. Longitudinal prevalence (LP), the proportion-of-time-ill estimated by repeated prevalence measurements, is an alternative measure to incidence of recurrent infections. In contrast to incidence which usually requires continuous sampling, LP can be measured at intervals. This study explored how many more participants are needed for infrequent sampling to achieve the same study power as frequent sampling.</p> <p>Methods</p> <p>We developed a set of four empirical simulation models representing low and high risk settings with short or long episode durations. The model was used to evaluate different sampling strategies with different assumptions on recall period and recall error.</p> <p>Results</p> <p>The model identified three major factors that influence sampling strategies: (1) the clustering of episodes in individuals; (2) the duration of episodes; (3) the positive correlation between an individual's disease incidence and episode duration. Intermittent sampling (e.g. 12 times per year) often requires only a slightly larger sample size compared to continuous sampling, especially in cluster-randomized trials. The collection of period prevalence data can lead to highly biased effect estimates if the exposure variable is associated with episode duration. To maximize study power, recall periods of 3 to 7 days may be preferable over shorter periods, even if this leads to inaccuracy in the prevalence estimates.</p> <p>Conclusion</p> <p>Choosing the optimal approach to measure recurrent infections in epidemiological studies depends on the setting, the study objectives, study design and budget constraints. Sampling at intervals can contribute to making epidemiological studies and trials more efficient, valid and cost-effective.</p

Hereditary breast cancer in Middle Eastern and North African (MENA) populations: identification of novel, recurrent and founder BRCA1 mutations in the Tunisian population

Germ-line mutations in BRCA1 breast cancer susceptibility gene account for a large proportion of hereditary breast cancer families and show considerable ethnic and geographical variations. The contribution of BRCA1 mutations to hereditary breast cancer has not yet been thoroughly investigated in Middle Eastern and North African populations. In this study, 16 Tunisian high-risk breast cancer families were screened for germline mutations in the entire BRCA1 coding region and exon–intron boundaries using direct sequencing. Six families were found to carry BRCA1 mutations with a prevalence of 37.5%. Four different deleterious mutations were detected. Three truncating mutations were previously described: c.798_799delTT (916 delTT), c.3331_3334delCAAG (3450 delCAAG), c.5266dupC (5382 insC) and one splice site mutation which seems to be specific to the Tunisian population: c.212 + 2insG (IVS5 + 2insG). We also identified 15 variants of unknown clinical significance. The c.798_799delTT mutation occurred at an 18% frequency and was shared by three apparently unrelated families. Analyzing five microsatellite markers in and flanking the BRCA1 locus showed a common haplotype associated with this mutation. This suggests that the c.798_799delTT mutation is a Tunisian founder mutation. Our findings indicate that the Tunisian population has a spectrum of prevalent BRCA1 mutations, some of which appear as recurrent and founding mutations

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered