Population genetics of wild-type CAG repeats in the Machado-Joseph disease gene in Portugal

To gain insights on the molecular mechanisms of mutation that led to the emergence of expanded alleles in the MJD gene, by studying the behavior of wild-type alleles and testing the association of its distribution with the representation of the disease. Methods: The number of CAG motifs in the MJD gene was determined in a representative sample of 1000 unrelated individuals. Associations between the repeat size and the epidemiological representation of MJD were tested. Results: The allelic profi le of the total sample was in the normal range (13–41 repeats), with mode (CAG) 23 . No intermediate alleles were present. Allelic size distribution showed a negative skew. The correlation between the epidemiological representation of MJD in each district and the frequency of small, medium and large normal alleles was not signifi cant. Further correlations performed grouping the districts also failed to produce signifi cant results. Conclusions: The absence of association between the size of the repeats and the representation of MJD demonstrates that prevalence is not an indirect refl ection of the frequency of large normal alleles. Globally the results obtained are in accordance with a model that postulates the occurrence of a few mutations on the basis of most of the MJD cases worldwide

Global and regional estimates of the morbidity due to type I diabetes among children aged 0-4 years:a systematic review and analysis

Background: Epidemiology of type 1 diabetes mellitus (T1DM) among children aged 0-4 years globally is not well understood. We aim to assess the incidence of T1DM in low- and middle-income countries (LMIC) by conducting a systematic review of previous reports. We also aim to address possible contribution to child mortality and to identify any temporal trends. Methods: A systematic review was performed using a carefully designed search strategy to explore MEDLINE, EMBASE and Global Health databases. Data was extracted from all studies that satisfied the inclusion criteria -a total of 83 records extracted from 26 830 sources that were analysed. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process to assess quality of evidence and applied meta-analysis approaches to assess global and regional incidence and time trends. Results: The overall pooled incidence of T1DM in children aged 0-4 years globally is 11.2 (95% CI = 10.0-12.3) per 100 000 child years. The regional incidence were the highest for European Region A (EUR A) at 15.5 (95% CI = 13.5-17.5) per 100 000 child years. EUR C had the incidence of 10.0 (95% CI = 6.5-13.6) and EUR B 5.8 (95% CI = 4.7-7.0), Region of the Americas A (AMR A) 11.4 (95% CI = 7.8-14.9), AMR B of 2.5 (95% CI = 0.2-4.8), Eastern Mediterranean Region (EMR B) 7.1 (95% CI = 4.2-10.0) and Western Pacific Region (WPR A) 7.0 (95% CI = 2.9-11.0) per 100 000 child years, while other regions had very low rates or no data. When data points were categorised in the study periods and re-analysed, an increasing trend of the T1DM incidence was observed, with the incidence of 20.9 (95% CI = 7.8-34.1) per 100 000 child years in the years 2010-2015, preceded by 13.2 (95% CI = 11.0-15.5) in 2000-2009 study period, 10.0 (95% CI = 8.4-11.7) in 1990-1999 and 8.3 (95% CI = 5.1-11.6) in 1980-1989, respectively. Although the data are scarce, and variation and uncertainty are large, we estimated that the number of new cases of T1DM among children aged 0-4 years in the world each year is between 100 000 and 150 000. Conclusions: The identified large variation in incidence estimates for different parts of the world, along with scarcity of information and the identified strong temporal increase in T1DM incidence suggest a clear need for further research into this subject