FRA2A is a CGG repeat expansion associated with silencing of AFF3

Folate-sensitive fragile sites (FSFS) are a rare cytogenetically visible subset of dynamic mutations. Of the eight molecularly characterized FSFS, four are associated with intellectual disability (ID). Cytogenetic expression results from CGG tri-nucleotide-repeat expansion mutation associated with local CpG hypermethylation and transcriptional silencing. The best studied is the FRAXA site in the FMR1 gene, where large expansions cause fragile X syndrome, the most common inherited ID syndrome. Here we studied three families with FRA2A expression at 2q11 associated with a wide spectrum of neurodevelopmental phenotypes. We identified a polymorphic CGG repeat in a conserved, brain-active alternative promoter of the AFF3 gene, an autosomal homolog of the X-linked AFF2/FMR2 gene: Expansion of the AFF2 CGG repeat causes FRAXE ID. We found that FRA2A-expressing individuals have mosaic expansions of the AFF3 CGG repeat in the range of several hundred repeat units. Moreover, bisulfite sequencing and pyrosequencing both suggest AFF3 promoter hypermethylation. cSNP-analysis demonstrates monoallelic expression of the AFF3 gene in FRA2A carriers thus predicting that FRA2A expression results in functional haploinsufficiency for AFF3 at least in a subset of tissues. By whole-mount in situ hybridization the mouse AFF3 ortholog shows strong regional expression in the developing brain, somites and limb buds in 9.5-12.5dpc mouse embryos. Our data suggest that there may be an association between FRA2A and a delay in the acquisition of motor and language skills in the families studied here. However, additional cases are required to firmly establish a causal relationship

Choroid plexus tumours

Choroid plexus tumours are rare epithelial brain tumours and limited information is available regarding their biology and the best treatment. A meta-analysis was done to determine prognostic factors and the influence of various treatment modalities. A thorough review of the medical literature (1966–1998) revealed 566 well-documented choroid plexus tumours. These were entered into a database, which was analysed to determine prognostic factors and treatment modalities. Most patients with a supratentorial tumour were children, while the most common sites in adults were the fourth ventricle and the cerebellar pontine angle. Cerebellar pontine angle tumours were more frequently benign. Histology was the most important prognostic factor, as one, five, and 10-year projected survival rates were 90, 81, and 77% in choroid plexus-papilloma (n=353) compared to only 71, 41, and 35% in choroid plexus-carcinoma respectively (P<0.0005). Surgery was prognostically relevant for both choroid plexus-papilloma (P=0.0005) and choroid plexus-carcinoma (P=0.0001). Radiotherapy was associated with significantly better survival in choroid plexus-carcinomas. Eight of 22 documented choroid plexus-carcinomas responded to chemotherapy. Relapse after primary treatment was a poor prognostic factor in choroid plexus-carcinoma patients but not in choroid plexus-papilloma patients. Treatment of choroid plexus tumours should start with radical surgical resection. This should be followed by adjuvant treatment in case of choroid plexus-carcinoma, and a ‘wait and see’ approach in choroid plexus-papilloma

Impact of Optimized Breastfeeding on the Costs of Necrotizing Enterocolitis in Extremely Low Birthweight Infants

To estimate risk of NEC for ELBW infants as a function of preterm formula and maternal milk (MM) intake and calculate the impact of suboptimal feeding on NEC incidence and costs

Hypertension artérielle : qui traiter, jusqu’où et comment ?

International audienceHypertension is the modifiable risk factor causing the largest loss in healthy life-years. The risk of cardiovascular events increases exponentially with the level of blood pressure (BP), starting from 115mmHg for systolic BP. Out-of-office BP measurements (self-measurements or ambulatory BP measurements) are now preferred for the diagnosis and follow up. In the absence of a preferred indication, antihypertensive treatment is based on thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. These treatments are associated with a significant reduction in morbidity and mortality in people with office BP ≥ 140/90mmHg (self-measurements ≥ 135/85mmHg). For people at high cardiovascular risk, especially those with a history of cardiovascular disease, starting the treatment for an office BP ≥ 130/80mmHg is also beneficial (self-measurements ≥ 130/80mmHg as well). It is now common to start treatment with half-dose dual therapy, which is more effective and better tolerated than full-dose monotherapy. The clinical effect is assessed at 4 weeks and intensification, if required, is then usually done by switching to the same dual therapy at full-dose for both components.L’hypertension artérielle (HTA) est le facteur de risque modifiable responsable du plus d’années de vie en bonne santé perdues dans le monde. Le risque d’événement cardiovasculaire augmente de façon exponentielle avec le niveau de pression artérielle (PA) dès 115 mmHg pour la PA systolique. Le diagnostic de l’HTA et l’évaluation de l’efficacité du traitement se font idéalement avec des mesures de la PA hors du cabinet : automesures ou mesures ambulatoires de la PA. En l’absence d’indication préférentielle, le traitement pharmacologique repose sur les diurétiques thiazidiques, les inhibiteurs calciques, les inhibiteurs de l’enzyme de conversion et les antagonistes des récepteurs de l’angiotensine II. Ces traitements sont associés à une réduction importante de la morbimortalité chez les personnes dont la PA est ≥ 140/90 mmHg en mesure clinique (automesures ≥ 135/85 mmHg). Pour les personnes à haut risque cardiovasculaire, notamment en situation de prévention secondaire, l’initiation du traitement pour une PA ≥ 130/80 mmHg en mesure clinique est également profitable (automesures ≥ 130/80 mmHg également). On débute désormais volontiers le traitement par une bithérapie fixe à demi-dose, plus efficace et mieux tolérée qu'une monothérapie à pleine dose. L'évaluation de l'effet clinique a lieu à 4 semaines et l'intensification, si elle est nécessaire, se fait alors généralement en passant à la bithérapie fixe pleine dose pour les deux composantes