A novel homozygous KCNQ3 loss-of-function variant causes non-syndromic intellectual disability and neonatal-onset pharmacodependent epilepsy

OBJECTIVE: Heterozygous variants in KCNQ2 or, more rarely, KCNQ3 genes are responsible for early-onset developmental/epileptic disorders characterized by heterogeneous clinical presentation and course, genetic transmission, and prognosis. While familial forms mostly include benign epilepsies with seizures starting in the neonatal or early-infantile period, de novo variants in KCNQ2 or KCNQ3 have been described in sporadic cases of early-onset encephalopathy (EOEE) with pharmacoresistant seizures, various age-related pathological EEG patterns, and moderate/severe developmental impairment. All pathogenic variants in KCNQ2 or KCNQ3 occur in heterozygosity. The aim of this work was to report the clinical, molecular, and functional properties of a new KCNQ3 variant found in homozygous configuration in a 9-year-old girl with pharmacodependent neonatal-onset epilepsy and non-syndromic intellectual disability. METHODS: Exome sequencing was used for genetic investigation. KCNQ3 transcript and subunit expression in fibroblasts was analyzed with quantitative real-time PCR and Western blotting or immunofluorescence, respectively. Whole-cell patch-clamp electrophysiology was used for functional characterization of mutant subunits. RESULTS: A novel single-base duplication in exon 12 of KCNQ3 (NM_004519.3:c.1599dup) was found in homozygous configuration in the proband born to consanguineous healthy parents; this frameshift variant introduced a premature termination codon (PTC), thus deleting a large part of the C-terminal region. Mutant KCNQ3 transcript and protein abundance was markedly reduced in primary fibroblasts from the proband, consistent with nonsense-mediated mRNA decay. The variant fully abolished the ability of KCNQ3 subunits to assemble into functional homomeric or heteromeric channels with KCNQ2 subunits. SIGNIFICANCE: The present results indicate that a homozygous KCNQ3 loss-of-function variant is responsible for a severe phenotype characterized by neonatal-onset pharmacodependent seizures, with developmental delay and intellectual disability. They also reveal difference in genetic and pathogenetic mechanisms between KCNQ2- and KCNQ3-related epilepsies, a crucial observation for patients affected with EOEE and/or developmental disabilities

Prolonged NCX activation prevents SOD1 accumulation, reduces neuroinflammation, ameliorates motor behavior and prolongs survival in a ALS mouse model

Imbalance in cellular ionic homeostasis is a hallmark of several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). Sodium-calcium exchanger (NCX) is a membrane antiporter that, operating in a bidirectional way, couples the exchange of Ca2+ and Na + ions in neurons and glial cells, thus controlling the intracellular homeostasis of these ions. Among the three NCX genes, NCX1 and NCX2 are widely expressed within the CNS, while NCX3 is present only in skeletal muscles and at lower levels of expression in selected brain regions. ALS mice showed a reduction in the expression and activity of NCX1 and NCX2 consistent with disease progression, therefore we aimed to investigate their role in ALS pathophysiology. Notably, we demonstrated that the pharmacological activation of NCX1 and NCX2 by the prolonged treatment of SOD1G93A mice with the newly synthesized compound neurounina: (1) prevented the reduction in NCX activity observed in spinal cord; (2) preserved motor neurons survival in the ventral spinal horn of SOD1G93A mice; (3) prevented the spinal cord accumulation of misfolded SOD1; (4) reduced astroglia and microglia activation and spared the resident microglia cells in the spinal cord; (5) improved the lifespan and mitigated motor symptoms of ALS mice. The present study highlights the significant role of NCX1 and NCX2 in the pathophysiology of this neurodegenerative disorder and paves the way for the design of a new pharmacological approach for ALS

Military business and the business of the military

Contrary to dominant approaches that locate the causes for military entrepreneurialism in eastern Democratic Republic of the Congo predominantly in criminal military elites, this article highlights the importance of the Congolese military’s (FARDC) civilian context for understanding military revenue-generation. It analyses how the latter is shaped by structures of domination, signification and legitimisation that drive and are driven by the FARDC’s governance, private protection and security practices. It argues that these practices contribute to bestowing a degree of legitimacy on both the FARDC’s position of power and some of its revenue-generation activities. Furthermore, by emphasising that the FARDC’s regulatory and protection practices are partly the product of popular demands and the routine actions of civilians, the article contends that the causes of military revenue-generation are co-located in the military’s civilian environment. In this manner, it offers a more nuanced conceptualisation of military entrepreneurialism, thus opening up new perspectives on policy interventions in this area

[Combined or coadministred Measles, Mumps, Rubella and Varicella Vaccines? That is the question!]

In November 2011, the Medicine's Italian Agency published the Pediatric Working Group's recommendation; that is do not use the quadruple vaccine against measles, rubella, mumps and varicella as first dosage in children from 12 to 23 months, because it involves an increase of febrile convulsions risks. It caused a big discussion between international and national Scientific and Institutional Bodies. In Italy, varicella is the most common vaccine preventable disease and preventive measures are not uniform. Clear and universally accepted indication is needed

[Combined or coadministred Measles, Mumps, Rubella and Varicella Vaccines? That is the question!]

In November 2011, the Medicine's Italian Agency published the Pediatric Working Group's recommendation; that is do not use the quadruple vaccine against measles, rubella, mumps and varicella as first dosage in children from 12 to 23 months, because it involves an increase of febrile convulsions risks. It caused a big discussion between international and national Scientific and Institutional Bodies. In Italy, varicella is the most common vaccine preventable disease and preventive measures are not uniform. Clear and universally accepted indication is needed

Analysis of energy wood supply chain in thinning operations: a case study in a pine stand of Central Italy

Thinning is an essential practice in Mediterranean pine forests management but is rarely applied because of the high harvesting costs. The new market of bioenergy products could give a profit to wood biomass harvesting activities, though the drawbacks of elevated supply chain costs, related to technical problems and lack of knowledge about the wood quality have to be overcome in advance. This study analyzed technical, economic, energy and environmental factors of a pine stand thinning in Central Italy, where collected biomass was directed to energy, in order to give a decisional support to reach economical profitability and environmental sustainability in thinning practices. The introduction of Full Tree System maximized the recovery of available biomass, full tree chipping produced material with Heating Value superior than single tree components. The use of a felling frame in motor-manual felling in comparison with the traditional chainsaw reduced operator effort, increasing the number of felled trees per hour, when the stump diameter remained under 15 cm. The energy wood supply chain is not sustainable from an economic point of view, the profitability could be reached only acting on suggested technical levers and particularly reducing costs of hauling operation. The estimation of output/input energy ratio in the supply chain underlined the feasibility of thinning practices for energy. The assessment of CO2 emissions confirmed the environmental sustainability of biomass supply chain in energy when compared to traditional fossil fuels. Study conclusions provide the guidelines for thinning treatment in Mediterranean pine stands, in order to reach environmental and economic sustainability of these practices