PRRT2 links infantile convulsions and paroxysmal dyskinesia with migraine.

OBJECTIVE: Whole genome sequencing and the screening of 103 families recently led us to identify PRRT2 (proline-rich-transmembrane protein) as the gene causing infantile convulsions (IC) with paroxysmal kinesigenic dyskinesia (PKD) (PKD/IC syndrome, formerly ICCA). There is interfamilial and intrafamilial variability and the patients may have IC or PKD. Association of IC with hemiplegic migraine (HM) has also been reported. In order to explore the mutational and clinical spectra, we analyzed 34 additional families with either typical PKD/IC or PKD/IC with migraine. METHODS: We performed Sanger sequencing of all PRRT2 coding exons and of exon-intron boundaries in the probands and in their relatives whenever appropriate. RESULTS: Two known and 2 novel PRRT2 mutations were detected in 18 families. The p.R217Pfs*8 recurrent mutation was found in ≈50% of typical PKD/IC, and the unreported p.R145Gfs*31 in one more typical family. PRRT2 mutations were also found in PKD/IC with migraine: p.R217Pfs*8 cosegregated with PKD associated with HM in one family, and was also detected in one IC patient having migraine with aura, in related PKD/IC familial patients having migraine without aura, and in one sporadic migraineur with abnormal MRI. Previously reported p.R240X was found in one patient with PKD with migraine without aura. The novel frameshift p.S248Afs*65 was identified in a PKD/IC family member with IC and migraine with aura. CONCLUSIONS: We extend the spectrum of PRRT2 mutations and phenotypes to HM and to other types of migraine in the context of PKD/IC, and emphasize the phenotypic pleiotropy seen in patients with PRRT2 mutationsjournal articleresearch support, non-u.s. gov't2012 Nov 202012 10 17importedComment in : Paroxysmal disorders associated with PRRT2 mutations shake up expectations on ion channel genes. [Neurology. 2012

Diabète insulino-dépendant (conseil du pharmacien)

DIJON-BU Médecine Pharmacie (212312103) / SudocSudocFranceF

Lessons from CADASIL

International audienceVascular dementia (VaD) includes several different vascular mechanisms and changes in the brain. Among VaD, CADASIL is an inherited angiopathy caused by mutations in the Notch3 gene. The pathological hallmark of CADASIL is a granular osmiophilic material deposit (GOM) that is not only found in the brain, but also in the peripheral vascular tree. Consequently, a window into the brain was opened from a strictly neurological disease with tremendous consequences thanks to a skin biopsy. The latter was and continues to be used as a diagnostic tool for CADASIL, despite an immunohistochemical test that is now available. The skin biopsy first used as a diagnostic tool revealed the existence of numerous other VaDs presenting systemic vascular changes. Later, skin biopsy became a research tool, and a morphological skin vessel change classification was proposed on 300 patients. Interestingly, similar skin vessel lesions appear to be related to the same biological modifications. In addition, an early destruction of the medial muscle cells was noticed in 74% of cases. Because vascular smooth muscle cells secrete a powerful endothelial permeability factor (VEGF), their destruction could lead to a decrease in vascular permeability. Cocultures of endothelial cells with vascular muscle cells showed that their presence doubled vascular permeability. Thus, alteration or the loss of vascular muscle cells likely results in hypopermeability, in addition to vessel wall hypotonia and a watershed hypoperfusion. The wealth of information brought forth by knowledge of CADASIL provided new tools for research and clues for understanding the consequences of vascular impairments in dementia

Leaching of trace metals (Pb, Zn) from contaminated tailings: a multicomponent reactive transport model of a pilot-scale experiment

International audienceUnreclaimed mine tailings are a worldwide problem, these deposits presenting a source of contamination which can result in health and/or environmental issues. Metal and metalloid contaminants can be present in tailings in different geochemical forms and are likely to be transported under the action of leaching from surface to underlying groundwater. Unfortunately, water flow and mass balance related to leaching in the vadose zone are still difficult to measure at field scale, hence they are poorly known. To address this problem a recent pilot-scale experiment was set up, i.e a one m3 column experiment ran over a period of 6 months. This experiment is suitable to control many parameters (water saturation, water flow, mass balance, etc.) while having a spatial and temporal scale closer to field conditions than standard laboratory experiments. A 70 cm high column was filled with highly Pb contaminated tailings, then regularly watered. The most reactive Pb-bearing phases are anglesite (PbSO4) and plumbojarosite Pb0.5Fe3(SO4)2(OH)6. The top half was unsaturated while the bottom half was kept saturated. Continuous measurements of water flows and water saturation have been done and geochemical properties of soil solutions were weekly monitored at different levels in the column. HPx software was used to build a 1D multicomponent reactive transport model to simulate fate and transport of Pb as well as other metal contaminants. Variably saturated water flow was simulated using the Richards equation and the van Genuchten analytic form was used to describe the unsaturated soil hydraulic properties. The main processes considered to simulate reactive transport were: advection-dispersion, thermodynamic equilibrium and kinetically-controlled dissolution/precipitation reactions as well as multicomponent competitive surface complexation reactions. The simulations reproduced accurately the drop of two pH units measured in pore solution during the experiment. This trend resulted from the dissolution of plumbojarosite followed by ferrihydrite precipitation. The increase of Pb concentration in pore solution induced by dissolution of Pb-bearing phases was partially counterbalanced by Pb-sorption onto newly formed iron-oxide and precipitation of secondary mineral phases. The modelling results could be used to assess potential risk of groundwater contamination by mine tailings

Leaching of trace metals (Pb, Zn) from contaminated tailings: a multicomponent reactive transport model of a pilot-scale experiment

International audienceUnreclaimed mine tailings are a worldwide problem, these deposits presenting a source of contamination which can result in health and/or environmental issues. Metal and metalloid contaminants can be present in tailings in different geochemical forms and are likely to be transported under the action of leaching from surface to underlying groundwater. Unfortunately, water flow and mass balance related to leaching in the vadose zone are still difficult to measure at field scale, hence they are poorly known. To address this problem a recent pilot-scale experiment was set up, i.e a one m3 column experiment ran over a period of 6 months. This experiment is suitable to control many parameters (water saturation, water flow, mass balance, etc.) while having a spatial and temporal scale closer to field conditions than standard laboratory experiments. A 70 cm high column was filled with highly Pb contaminated tailings, then regularly watered. The most reactive Pb-bearing phases are anglesite (PbSO4) and plumbojarosite Pb0.5Fe3(SO4)2(OH)6. The top half was unsaturated while the bottom half was kept saturated. Continuous measurements of water flows and water saturation have been done and geochemical properties of soil solutions were weekly monitored at different levels in the column. HPx software was used to build a 1D multicomponent reactive transport model to simulate fate and transport of Pb as well as other metal contaminants. Variably saturated water flow was simulated using the Richards equation and the van Genuchten analytic form was used to describe the unsaturated soil hydraulic properties. The main processes considered to simulate reactive transport were: advection-dispersion, thermodynamic equilibrium and kinetically-controlled dissolution/precipitation reactions as well as multicomponent competitive surface complexation reactions. The simulations reproduced accurately the drop of two pH units measured in pore solution during the experiment. This trend resulted from the dissolution of plumbojarosite followed by ferrihydrite precipitation. The increase of Pb concentration in pore solution induced by dissolution of Pb-bearing phases was partially counterbalanced by Pb-sorption onto newly formed iron-oxide and precipitation of secondary mineral phases. The modelling results could be used to assess potential risk of groundwater contamination by mine tailings

PRRT2 links infantile convulsions and paroxysmal dyskinesia with migraine.

ObjectiveWhole genome sequencing and the screening of 103 families recently led us to identify PRRT2 (proline-rich-transmembrane protein) as the gene causing infantile convulsions (IC) with paroxysmal kinesigenic dyskinesia (PKD) (PKD/IC syndrome, formerly ICCA). There is interfamilial and intrafamilial variability and the patients may have IC or PKD. Association of IC with hemiplegic migraine (HM) has also been reported. In order to explore the mutational and clinical spectra, we analyzed 34 additional families with either typical PKD/IC or PKD/IC with migraine.MethodsWe performed Sanger sequencing of all PRRT2 coding exons and of exon-intron boundaries in the probands and in their relatives whenever appropriate.ResultsTwo known and 2 novel PRRT2 mutations were detected in 18 families. The p.R217Pfs*8 recurrent mutation was found in ≈50% of typical PKD/IC, and the unreported p.R145Gfs*31 in one more typical family. PRRT2 mutations were also found in PKD/IC with migraine: p.R217Pfs*8 cosegregated with PKD associated with HM in one family, and was also detected in one IC patient having migraine with aura, in related PKD/IC familial patients having migraine without aura, and in one sporadic migraineur with abnormal MRI. Previously reported p.R240X was found in one patient with PKD with migraine without aura. The novel frameshift p.S248Afs*65 was identified in a PKD/IC family member with IC and migraine with aura.ConclusionsWe extend the spectrum of PRRT2 mutations and phenotypes to HM and to other types of migraine in the context of PKD/IC, and emphasize the phenotypic pleiotropy seen in patients with PRRT2 mutations