LGI2 truncation causes a remitting focal epilepsy in dogs

One quadrillion synapses are laid in the first two years of postnatal construction of the human brain, which are then pruned until age 10 to 500 trillion synapses composing the final network. Genetic epilepsies are the most common neurological diseases with onset during pruning, affecting 0.5% of 2-10-year-old children, and these epilepsies are often characterized by spontaneous remission. We previously described a remitting epilepsy in the Lagotto romagnolo canine breed. Here, we identify the gene defect and affected neurochemical pathway. We reconstructed a large Lagotto pedigree of around 34 affected animals. Using genome-wide association in 11 discordant sib-pairs from this pedigree, we mapped the disease locus to a 1.7 Mb region of homozygosity in chromosome 3 where we identified a protein-truncating mutation in the Lgi2 gene, a homologue of the human epilepsy gene LGI1. We show that LGI2, like LGI1, is neuronally secreted and acts on metalloproteinase-lacking members of the ADAM family of neuronal receptors, which function in synapse remodeling, and that LGI2 truncation, like LGI1 truncations, prevents secretion and ADAM interaction. The resulting epilepsy onsets at around seven weeks (equivalent to human two years), and remits by four months (human eight years), versus onset after age eight in the majority of human patients with LGI1 mutations. Finally, we show that Lgi2 is expressed highly in the immediate post-natal period until halfway through pruning, unlike Lgi1, which is expressed in the latter part of pruning and beyond. LGI2 acts at least in part through the same ADAM receptors as LGI1, but earlier, ensuring electrical stability (absence of epilepsy) during pruning years, preceding this same function performed by LGI1 in later years. LGI2 should be considered a candidate gene for common remitting childhood epilepsies, and LGI2-to-LGI1 transition for mechanisms of childhood epilepsy remission.     

A realistic complication analysis of 70 sural artery flaps in a multimorbid patient group

The popularity of the sural artery flap has increased markedly throughout the years, and favorable results are reported almost uniformly. Previous publications have mainly presented results of small groups and of predominantly younger patients with posttraumatic defects, or they have reported technical modifications of the sural artery flap. The authors have increasingly used the reversed sural artery flap in a high-risk, critically multimorbid, and older patient population, and in contrast to the results of other authors, a considerable necrosis rate of 36 percent was seen. For the first time, a detailed, critical, retrospective complication analysis of 70 sural artery flaps is presented. The results reveal the following risk factors, which can potentially impair successful defect coverage and thus contribute to flap complications: concomitant diseases, particularly diabetes mellitus; peripheral arterial disease or venous insufficiency, which increase the risk of flap necrosis five-fold to six-fold; and patient age of over 40 years, because of an increased rate of comorbidity, underlying osteomyelitis, and the use of a tight subcutaneous tunnel. However, age alone did not seem to represent a risk factor by itself. Given the results of the analysis, the operative procedure was altered, as follows. In cases in which a lesser saphenous vein cannot be found, a delay procedure is recommended, or the flap is not utilized. In addition, an external fixation device seems to facilitate postoperative care markedly without adding specific complications; it is recommended in most patients. This analysis emphasizes specific risk factors that result in higher complication rates of the sural artery flap, and it leads to more realistic and appropriate expectations for this flap.     

The axon guidance receptor gene ROBO1 is a candidate gene for developmental dyslexia

Dyslexia, or specific reading disability, is the most common learning disorder with a complex, partially genetic basis, but its biochemical mechanisms remain poorly understood. A locus on Chromosome 3, DYX5, has been linked to dyslexia in one large family and speech-sound disorder in a subset of small families. We found that the axon guidance receptor gene ROBO1, orthologous to the Drosophila roundabout gene, is disrupted by a chromosome translocation in a dyslexic individual. In a large pedigree with 21 dyslexic individuals genetically linked to a specific haplotype of ROBO1 (not found in any other chromosomes in our samples), the expression of ROBO1 from this haplotype was absent or attenuated in affected individuals. Sequencing of ROBO1 in apes revealed multiple coding differences, and the selection pressure was significantly different between the human, chimpanzee, and gorilla branch as compared to orangutan. We also identified novel exons and splice variants of ROBO1 that may explain the apparent phenotypic differences between human and mouse in heterozygous loss of ROBO1. We conclude that dyslexia may be caused by partial haplo-insufficiency for ROBO1 in rare families. Thus, our data suggest that a slight disturbance in neuronal axon crossing across the midline between brain hemispheres, dendrite guidance, or another function of ROBO1 may manifest as a specific reading disability in humans.     

Environmental Product Declarations for plants and soils: how to quantify carbon uptake in landscape design and construction?

The International Journal of Life Cycle Assessment - Currently, no clear guidance exists for ISO and EN standards of calculating, verifying, and reporting the climate impacts of plants, mulches,...