Pyridoxine‐dependent epilepsy (PDE‐ALDH7A1) is an autosomal recessive condition due to a deficiency of α‐aminoadipic semialdehyde dehydrogenase, which is a key enzyme in lysine oxidation. PDE‐ALDH7A1 is a developmental and epileptic encephalopathy that was historically and empirically treated with pharmacologic doses of pyridoxine. Despite adequate seizure control, most patients with PDE‐ALDH7A1 were reported to have developmental delay and intellectual disability. To improve outcome, a lysine‐restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy. These lysine‐reduction therapies have resulted in improved biochemical parameters and cognitive development in many but not all patients. The goal of these consensus guidelines is to re‐evaluate and update the two previously published recommendations for diagnosis, treatment, and follow‐up of patients with PDE‐ALDH7A1. Members of the International PDE Consortium initiated evidence and consensus‐based process to review previous recommendations, new research findings, and relevant clinical aspects of PDE‐ALDH7A1. The guideline development group included pediatric neurologists, biochemical geneticists, clinical geneticists, laboratory scientists, and metabolic dieticians representing 29 institutions from 16 countries. Consensus guidelines for the diagnosis and management of patients with PDE‐ALDH7A1 are provided.
We report the clinical, biochemical, and molecular findings in two brothers with encephalopathy and multi-systemic disease. Abnormal transferrin glycoforms were suggestive of a type I congenital disorder of glycosylation (CDG). While exome sequencing was negative for CDG related candidate genes, the testing revealed compound heterozygous mutations in the mitochondrial elongation factor G gene (GFM1). One of the mutations had been reported previously while the second, novel variant was found deep in intron 6, activating a cryptic splice site. Functional studies demonstrated decreased GFM1 protein levels, suggested disrupted assembly of mitochondrial complexes III and V and decreased activities of mitochondrial complexes I and IV, all indicating combined OXPHOS deficiency.
Insecticide and fungicide seed treatments are commonly used to control pests and pathogens in conventional maize and soybean culture, but little is known about their effects on the communities of non-target microbes that inhabit the rhizospheres or leaves of these crops. Because rhizosphere bacterial and fungal communities influence carbon and nutrient turnover, nutrient transformation, nutrient uptake and disease suppression, and because leaf endophyte fungal communities influence many aspects of stress tolerance in plants, any effect of a pesticide seed treatment on these microbial communities could have unintended and possibly adverse effects on seedling performance. We conducted a three-year field experiment in which maize (2013, 2015) and soybean (2014) were grown in rotation from seeds that were either coated or not coated with common pesticide treatments, which included contact and systemic fungicides and systemic insecticides. We sampled seedling rhizosphere soil (maize in 2013, soybean in 2014) and seedling leaves (soybean in 2014, maize in 2015) and characterized their microbial communities. For maize, the rhizosphere fungal and bacterial communities were significantly affected by the seed treatment, but leaf endophytic fungal communities were not. For soybean, the rhizosphere fungal community was significantly affected, as was the leaf endophytic fungal community, but not the rhizosphere bacterial community. These results show that pesticide seed treatments may affect rhizosphere soil microbial communities and endophytic leaf fungal communities more than one month after planting and, therefore, may have significant, unintended effects on non-target organisms. Additional research must determine the consequences of these effects and the nature of their context dependency.
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