Cardiac Screening of Young Athletes: a Practical Approach to Sudden Cardiac Death Prevention.

PURPOSE OF REVIEW: We aim to report on the current status of cardiovascular screening of athletes worldwide and review the up-to-date evidence for its efficacy in reducing sudden cardiac death in young athletes. RECENT FINDINGS: A large proportion of sudden cardiac death in young individuals and athletes occurs during rest with sudden arrhythmic death syndrome being recognised as the leading cause. The international recommendations for ECG interpretation have reduced the false-positive ECG rate to 3% and reduced the cost of screening by 25% without compromising the sensitivity to identify serious disease. There are some quality control issues that have been recently identified including the necessity for further training to guide physicians involved in screening young athletes. Improvements in our understanding of young sudden cardiac death and ECG interpretation guideline modification to further differentiate physiological ECG patterns from those that may represent underlying disease have significantly improved the efficacy of screening to levels that may make screening more attractive and feasible to sporting organisations as a complementary strategy to increased availability of automated external defibrillators to reduce the overall burden of young sudden cardiac death

Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases.

Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies