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Objective: To investigate the prevalence and natural history of POLG disease in the Norwegian population. Methods: A national, population‐based, retrospective study using demographic, clinical, and genetic data of patients with genetically confirmed POLG disease. The patients were diagnosed between 2002 and 2022, and were included into the Norwegian POLG Patient Registry. Patients were stratified according to age at disease onset (early <12 years, juvenile to adult 12–40 years, late ≥40 years) and resident region. Results: Ninety‐one patients were included. The point prevalence of POLG disease was 1:149,253. Birth prevalence was 1:48,780. Median age at clinical onset was 16 years (range: 2 months to 70 years). Onset occurred early in 35% (32 out of 91), juvenile‐adult in 55% (50 out of 91) and late in 10% (9 out of 91). A distinct seasonal pattern in disease onset was observed, with 57% (52 out of 91) presenting between May and August. Forty‐five patients (49%) had acute exacerbations that required intensive care, and this affected 72% of those in the early‐onset group. The mortality rate was 54% (49 out of 91), with a median time from disease onset to death of 3 years (range: 1 month to 36 years). Interpretation: We provide the point prevalence and birth prevalence of POLG disease in the first nationwide study in which epidemiological and clinical data were integrated. Seasonal variations in clinical onset may offer valuable insights into disease mechanisms and modifying factors. The findings from this study are crucial for quantifying the disease burden, and contribute to evidence‐based healthcare planning. [ABSTRACT FROM AUTHOR]

Mitochondria are the primary generators of ATP in eukaryotic cells through the process of oxidative phosphorylation. Mitochondria are also involved in several other important cellular functions including regulation of intracellular Ca2+, cell signaling and apoptosis. Mitochondrial dysfunction causes disease and since it is not possible to perform repeated studies in humans, models are essential to enable us to investigate the mechanisms involved. Recently, the discovery of induced pluripotent stem cells (iPSCs), made by reprogramming adult somatic cells (Takahashi and Yamanaka 2006; Yamanaka and Blau 2010), has provided a unique opportunity for studying aspects of disease mechanisms in patient-specific cells and tissues. Reprogramming cells to neuronal lineage such as neural progenitor cells (NPCs) generated from the neural induction of reprogrammed iPSCs can thus provide a useful model for investigating neurological disease mechanisms including those caused by mitochondrial dysfunction. In addition, NPCs display a huge clinical potential in drug screening and therapeutics. [ABSTRACT FROM AUTHOR]

Genetic matching potentially provides a means to alleviate the effects of incomplete Mendelian randomization in population-based gene–disease association studies. We therefore evaluated the genetic-matched pair study design on the basis of genome-wide SNP data (309 790 markers; Affymetrix GeneChip Human Mapping 500K Array) from 2457 individuals, sampled at 23 different recruitment sites across Europe. Using pair-wise identity-by-state (IBS) as a matching criterion, we tried to derive a subset of markers that would allow identification of the best overall matching (BOM) partner for a given individual, based on the IBS status for the subset alone. However, our results suggest that, by following this approach, the prediction accuracy is only notably improved by the first 20 markers selected, and increases proportionally to the marker number thereafter. Furthermore, in a considerable proportion of cases (76.0%), the BOM of a given individual, based on the complete marker set, came from a different recruitment site than the individual itself. A second marker set, specifically selected for ancestry sensitivity using singular value decomposition, performed even more poorly and was no more capable of predicting the BOM than randomly chosen subsets. This leads us to conclude that, at least in Europe, the utility of the genetic-matched pair study design depends critically on the availability of comprehensive genotype information for both cases and controls.European Journal of Human Genetics (2009) 17, 967–975; doi:10.1038/ejhg.2008.266; published online 21 January 2009 [ABSTRACT FROM AUTHOR]