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Publications des Services du site Necker :
4ème semaine 2012
(mise à jour du lundi 30 janvier 2012)

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(ordre alphabétique du 1er auteur)

BANDIERA S., BARREY E., ERNOULT-LANGE M., GIDROL X., HENRION-CAUDE A., HUANG L., SAINT-AURET G., WEIL D.
La mitochondrie. Un nouvel acteur de la régulation par ARN interférence.
M S-Méd. Sci., 28 (1), 23-26, 2012
(Services cités :U781, IMAGINE)
Les mitochondries assurent deuxfonctions vitales de la cellule : la productiond’énergie sous forme d’ATP parla voie aérobie et le déclenchement del’apoptose en cas de dysfonctionnementgrave de la cellule. Ces fonctionsmitochondriales doivent être moduléesavec l’ensemble de la machinerie cellulaireselon un mode de communicationconcertée. De récentes publications,réalisées indépendamment par troiséquipes françaises [1-3], indiquentun rôle probable de la mitochondriedans la régulation des gènes par ARNinterférence. Cette nouvelle fonctionmitochondriale découverte dans descellules humaines semble être un processusgénéral, avec des spécificitésliées au tissu et à l’état cellulaire. Ellemet en jeu la protéineArgonaute 2 localiséedans les P-bodies jusquedans la mitochondrie oùdes microARN (miR) ontaussi été mis en évidence. La découvertede ces miR mitochondriaux présenteun intérêt biologique particulierdu fait de leurs rôles multiples dansle développement, dans l’entretiendes tissus mais aussi dans l’étiologiedes pathologies humaines comme lescancers ou les maladies dégénérativesdu système nerveux. Cette Nouvelleexpose les dernières connaissancesacquises sur la localisation mitochondrialedes miR et leur activation aucontact des P-bodies dans la cellulehumaine.
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BEGHETTI M., GALIE N., BONNET D.
Can "Inoperable" Congenital Heart Defects Become Operable in Patients with Pulmonary Arterial Hypertension? Dream or Reality ?
Congenit. Heart Dis., 7 (1), 3-11, 2012
(Services cités : Cardiologie Pédiatrique)
The decision whether to repair congenital heart defects in patients with raised pulmonary vascular resistance to alleviate pulmonary hypertension is a complex one. The degree of pulmonary vascular disease is of paramount importance. Operating on patients with pulmonary vascular resistance above a certain threshold runs the risk of postoperative persistent pulmonary hypertension and a worse long-term prognosis. This review focuses on patients deemed "borderline inoperable" or "inoperable" due to pulmonary vascular disease and asks whether they can be "converted to an operable status" with pulmonary arterial hypertension-specific drugs that potentially modify the pulmonary vascular lesions and resistance.

BELTRAND J., CAQUARD M., ARNOUX J.B., LABORDE K., VELHO G., VERKARRE V., RAHIER J., BRUNELLE F., NIHOUL-FEKETE C., SAUDUBRAY J.M., ROBERT J.J., de LONLAY P.
Glucose Metabolism in 105 Children and Adolescents After Pancreatectomy for Congenital Hyperinsulinism.
Diabetes Care, 35 (2), 198-203, 2012
(Services cités : Anatomie Pathologique, Chirurgie Viscérale Pédiatrique, Endocrinologie Pédiatrique et Gynécologie, Explorations Fonctionnelles, Métabolisme, Radiologie Pédiatrique)
OBJECTIVETo describe the long-term metabolic outcome of children with congenital hyperinsulinism after near-total or partial elective pancreatectomy.RESEARCH DESIGN AND METHODSPatients (n = 105: 58 diffuse and 47 focal congenital hyperinsulinism) received operations between 1984 and 2006. Follow-up consisted of periodic measurements of pre- and postprandial plasma glucose over 24 h, OGTT, and IVGTT. Cumulative incidence of hypo- or hyperglycemia/insulin treatment was estimated by Kaplan-Meier analysis.RESULTSAfter near-total pancreatectomy, 59% of children with diffuse congenital hyperinsulinism still presented mild or asymptomatic hypoglycemia that responded to medical treatments and disappeared within 5 years. One-third of the patients had both preprandial hypoglycemia and postprandial hyperglycemia. Hyperglycemia was found in 53% of the patients immediately after surgery; its incidence increased regularly to 100% at 13 years. The cumulative incidence of insulin-treated patients was 42% at 8 years and reached 91% at 14 years, but the progression to insulin dependence was very variable among the patients. Plasma insulin responses to IVGTT and OGTT correlated well with glycemic alterations. In focal congenital hyperinsulinism, hypoglycemia or hyperglycemia were rare, mild, and transient.CONCLUSIONSPatients with focal congenital hyperinsulinism are cured of hypoglycemia after limited surgery, while the outcome of diffuse congenital hyperinsulinism is very variable after near-total pancreatectomy. The incidence of insulin-dependent diabetes is very high in early adolescence.
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BERTI C., BIESALSKI H.K., GARTNER R., LAPILLONNE A., PIETRZIK K., POSTON L., REDMAN C., KOLETZKO B., CETIN I.
Micronutrients in pregnancy: current knowledge and unresolved questions.
Clin. Nutr., 30 (6), 689-701, 2011
(Services cités : Médecine d'Urgence)
Micronutrient status is increasingly recognized to play an important role in the health and well-being of pregnant women and in the development and long-term health of the offspring. On 26th - 28th February 2009, The Child Health Foundation invited leading experts in this area to a scientific workshop at Obergurgl, Austria to review and critically discuss current knowledge, to identify issues that may need to be addressed in future recommendations, and to highlight priorities and opportunities for future research. This report summarizes updated key conclusions of the workshop with regards to micronutrients' intake and physiological role related to mother, placenta and fetus, as well as relevance for adverse pregnancy and long-term outcomes.
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BRASME J.F., CHALUMEAU M., DOZ F., LACOUR B., VALTEAU-COUANET D., GAILLARD S., DELALANDE O., AGHAKHANI N., SAINTE-ROSE C., PUGET S., GRILL J.
Interval between onset of symptoms and diagnosis of medulloblastoma in children: distribution and determinants in a population-based study.
Eur. J. Pediat., 171 (1), 25-32, 2012
(Services cités : Neurochirurgie Pédiatrique, Pédiatrie Générale)
Hospital-based studies have reported long delays in the diagnosis of paediatric brain tumours. Our objective was to describe the duration between onset of symptoms and diagnosis of medulloblastoma in children and study their clinical determinants in a population-based study. This retrospective cohort study included all paediatric medulloblastoma from a region of France from 1990 to 2005. The median interval from symptom onset until diagnosis for these 166 patients was 65 days and did not decrease during the study period. The most frequent manifestations were: vomiting (88%), headaches (79%), psychomotor regression (60% of children under 3 years), psychological symptoms (27%), strabismus (26%), and asthenia (25%). For one third of the children under 3 years, the diagnosis was made only after life-threatening signs of intracranial hypertension appeared. The prediagnosis interval was significantly longer (median 91 vs. 60 days, p = 0.001) in children with psychological symptoms (27%). Causes for intervals that exceeded the median (65 days) included inconsistent (25%) or late (36%) combination of headaches and vomiting, a period of spontaneous symptom remission (14%-20%), no (24%) or late (57%) neurological signs, psychological symptoms (35%), and a normal neurological examination (27%). Time to medulloblastoma diagnosis in children remains fairly long, despite advances in imaging. Primary-care physicians must be suspicious not only of suggestive neurological signs, but also of non-specific symptoms that persist or are multiple. A meticulous neurological examination and cerebral imaging for such patients might facilitate earlier diagnosis.
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CARSIN A., PHAM-THI N.
Asthmatic exacerbations: specific features in children.
Rev. Mal. Resp., 28 (10), 1322-1328, 2011
(Services cités : Pneumologie et Asthmologie Pédiatriques)
Asthma concerns more than 10% of 10-year-old children. Despite the similarities between adult and childhood asthma, the pediatric population presents some specific characteristics, notably in relation to exacerbations. Asthma in the newborn infant is a specific entity, the definition of which has recently been officially recognized. In exacerbations, the most important trigger factors are respiratory virus infections, the strain having prognostic importance. The indoor and outdoor environments are risk factors, particularly high levels of atmospheric pollution. Nutrients seem to play a prognostic role through vitamin D or food allergy. Measurement of exhaled nitric oxide and examination of induced sputum may help in diagnosis and adjustment of treatment but these tools are not yet effective as predictive factors in asthma exacerbations. Prevention, early management and continued education of children and their families remain the best methods to improve asthma control.
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CHASSOUX F., LANDRE E., MELLERIO C., TURAK B., MANN M.W., DAUMAS-DUPORT C., CHIRON C., DEVAUX B.
Type II focal cortical dysplasia: Electroclinical phenotype and surgical outcome related to imaging.
Epilepsia, 53 (2), 349-358, 2012
(Services cités : Neurologie, U663)
Purpose: Type II focal cortical dysplasia (TTFCD), a highly epileptogenic lesion with severe epilepsy curable by surgery, is missed by magnetic resonance imaging (MRI) in about one third of cases. Little is known about the electroclinical presentation in these MRI-negative patients and a poor surgical outcome is frequently reported. We compared the clinical and neurophysiologic features in MRI-negative and MRI-positive cases in order to better identify candidates for surgery. Methods: Among 62 consecutive TTFCD patients (38 male, 24 female; 7-52 years old; 22 children) operated for intractable epilepsy, 25 (40%) presented negative MRI findings. We compared the history of epilepsy; the type, frequency, and distribution of seizures; neurologic examination cognitive and psychiatric impairment; interictal-ictal electroencephalography (EEG) and stereo-EEG (SEEG) data, fluorodeoxyglucose positron emission tomography (FDG-PET) data, neuropathologic findings; and surgical outcome in the MRI-negative and the MRI-positive groups. Key Findings: Severe partial epilepsy beginning in childhood, high seizure frequency including status epilepticus, stereotyped seizures suggestive of precise brain localization, extratemporal location and functional area involvement were characteristic and similarly found in both groups. On EEG, pseudorhythmic activity was found in about 40% of patients in each group. SEEG recordings demonstrated the typical pattern characterizing TTFCD in both groups. FDG-PET had a localization value in 84% of the MRI-negative cases and helped to delineate the dysplastic cortex in 65% of the MRI-positive cases. The combination of imaging and neurophysiologic data allowed us to perform safe and restricted resections, limited to a single gyrus in more than half of all cases. In addition, we were able to avoid invasive monitoring in most MRI-positive cases and even in some selected MRI-negative cases. The proportion of patients with a favorable surgical outcome was comparable in both groups (88% in MRI-negative and 94% in MRI-positive cases). The main difference between the groups was a significantly higher frequency of sleep-related epilepsy in the MRI-negative group (p = 0.028). This phenotypic characteristic provides a new argument for TTFCD in MRI-negative extratemporal epilepsy. Significance: These results lead us to consider that children or adult patients in whom electroclinical data suggest TTFCD, are highly suitable for surgery, especially for cryptogenic sleep-related epilepsy.
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COLOMB V., BOURDON-LANNOY E., LAMBE C., SAUVAT F., HADJ-RABIA S., TEILLAC D., de PROST Y., BODEMER C.
Nutritional outcome in children with severe generalized recessive dystrophic epidermolysis bullosa: a short and long-term evaluation of gastrostomy and enteral feeding.
Br. J. Dermatol., 166 (2), 354-361, 2012
(Services cités : Chirurgie Viscérale Pédiatrique, Dermatologie, Gastro-Hépatologie et Nutrition Pédiatriques)
Background: Generalized RDEB is often complicated by high nutritional difficulties with risks of malnutrition. Objectives: To provide information regarding the benefits of enteral feeding by gastrostomy (GTF), energy and protein requirements, tolerance, growth and pubertal development in RDEB children. Methods: Retrospective study. 24 patients were referred over a 7 year-period of time. GT placement was decided in patients unable to oral feeding and/or presenting a loss of at least 1 standard deviation in weight and height as compared to their best growth level, despite regular nutritional advices. Weight and height were expressed as Z-scores. Catch-up growth following GTF onset was studied. Results: Gastrostomies were performed in 11 children (9.0 +/- 5.8 years), and 1 young man aged 18 years. The body weight Z-score was -2.3+/- 1.0, height Z-score 1.1+/-1.1, weight-for-height was 81+/-11% and height-for-age 95+/-4%. At onset, GTF provided 74 +/- 21% and 180 +/- 81% of the recommended dietary allowance (RDA), for energy and proteins respectively. At study update (53 +/- 20 months), GTF provided 91 +/- 29% and 205 +/- 100% of RDA, for energy and proteins respectively. Weight-for-height reached 92 +/- 15% and height-for-age 98 +/- 5%. A normal puberty was obtained when GT was performed before the age of 10 years. Skin was not improved. Conclusion: Malnutrition was observed in 50% of generalized RDEB children. Protein-energy needs are particularly high. GTF is well tolerated and helps for catch-up growth and puberty. It has to be considered before malnutrition onset, and, if necessary, before the puberty.
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CORREAS J.M., POL S.
New developments in ultrasound imaging for chronic liver diseases: From anatomic imaging to structural and functional imaging.
Presse Médicale, 41 (2), 153-168, 2012
(Services cités : Radiologie Adulte)
Conventional US imaging is playing a key role for the diagnosis and the therapeutic management of chronic liver diseases. Nevertheless, conventional US imaging is facing many limitations: operator-dependency, subjective assessment, variable detectability of nodules depending on accessibility to the US beam and spontaneous contrast to surrounding normal parenchyma, limited characterization capabilities. Conventional US imaging is taking advantage of major technological improvements including contrast-enhanced US (CEUS), elastography and volume and fusion imaging techniques. CEUS allows real-time detection of contrast enhancement and improves identification of the hypervascular pattern, major diagnostic criteria of hepatocellular carcinoma. Its kinetics is different from those of benign lesions (regenerative nodules, hemangioma..). CEUS is an excellent technique for focal liver lesion characterization (lesion detected previously at either conventional US or any imaging modality) while its performance remains limited for HCC detection. US contrast agent tolerance is excellent is routine clinical practise with no contraindication related to liver or renal dysfunction. US elastography is a non invasive technique that allows detection and quantification of liver fibrosis and is extending its application toward characterization of focal liver diseases. Volumetric and fusion imaging should improve the therapeutic management of malignant liver lesions and particularly percutaneous guidance of thermo-ablation procedures.
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DEVUYST O., ANTIGNAC C., BINDELS R.J.M., CHAUVEAU D., EMMA F., GANSEVOORT R., MAXWELL P.H., ONG A.C.M., REMUZZI G., RONCO P., SCHAEFER F.
The ERA-EDTA Working Group on inherited kidney disorders.
Nephrol. Dialysis Transplant., 27 (1), 67-69, 2012
(Services cités : U983)
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FLAMEIN F., RIFFAULT L., MUSELET-CHARLIER C., PERNELLE J., FELDMANN D., JONARD L., DURAND-SCHNEIDER A.M., COULOMB A., MAURICE M., NOGEE L.M., INAGAKI N., AMSELEM S., DUBUS J.C., RIGOURD V., BREMONT F., MARGUET C., BROUARD J., de BLIC J., CLEMENT A., EPAUD R., GUILLOT L.
Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children.
Hum. Mol. Genet., 21 (4), 765-775, 2012
(Services cités : Pneumologie et Asthmologie Pédiatriques)
ABCA3 (ATP-binding cassette subfamily A, member 3) is expressed in the lamellar bodies of alveolar type II cells and is crucial to pulmonary surfactant storage and homeostasis. ABCA3 gene mutations have been associated with neonatal respiratory distress (NRD) and pediatric interstitial lung disease (ILD). The objective of this study was to look for ABCA3 gene mutations in patients with severe NRD and/or ILD. The 30 ABCA3 coding exons were screened in 47 patients with severe NRD and/or ILD. ABCA3 mutations were identified in 10 out of 47 patients, including 2 homozygous, 5 compound heterozygous and 3 heterozygous patients. SP-B and SP-C expression patterns varied across patients. Among patients with ABCA3 mutations, five died shortly after birth and five developed ILD (including one without NRD). Functional studies of p.D253H and p.T1173R mutations revealed that p.D253H and p.T1173R induced abnormal lamellar bodies. Additionally, p.T1173R increased IL-8 secretion in vitro. In conclusion, we identified new ABCA3 mutations in patients with life-threatening NRD and/or ILD. Two mutations associated with ILD acted via different pathophysiological mechanisms despite similar clinical phenotypes.
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FOUGERAY S., LORIOT M.A., NICAUD V., LEGENDRE C., THERVET E., PALLET N.
Increased body mass index after kidney transplantation in activating transcription factor 6 single polymorphism gene carriers.
Transplant. Proc., 43 (9), 3418-3422, 2011
(Services cités : Transplantation Adulte)
OBJECTIVES: Endoplasmic reticulum stress has been implicated in the pathogenesis of new-onset diabetes after transplantation (NODAT) and of metabolic disorders. Activated Transcription Factor 6 (ATF6), which is activated during endoplasmic reticulum stress, is involved in lipogenesis and gluconeogenesis. Tacrolimus may induce endoplasmic reticulum stress in pancreatic beta cells. Since studies have demonstrated that single nucleotide polymorphisms (SNPs) of ATF6 are associated with type 2 diabetes, we sought to determine whether their mutations were associated with NODAT among renal transplant recipients treated with tacrolimus. METHODS: We genotyped 269 renal transplant recipients using TaqMan assays for allelic discrimination for 6 ATF6 gene polymorphisms: rs10918215, rs7514053, rs1058405, rs4479731, rs2340721, and rs13401. All patients received an immunosuppressive regimen including tacrolimus. We analyzed all previously known risk factors for NODAT. RESULTS: We could not confirm are association between ATF6 SNP and NODAT. We observed a significant association between ATF6 SNP rs2340721 and increased body weight and body mass index (BMI) both upon univariate and multivariate analyses. The average BMI was higher among patients with 2 mutant SNP2 (rs2340721) alleles (CC) than those with 2 wild-type alleles (AA): 23.8 +/- 3.7 versus 25.5 +/- 4.4 kg/m2 (P =.02). The odds ratio (95% confidence interval [CI]) for BMI associated with the CC genotype was 2.43 (1.16-5.09; P =.02). CONCLUSION: ATF6 polymorphisms were not associated with NODAT among our population of renal transplant recipients treated with tacrolimus. However, these data underscore the role of ATF6 and endoplasmic reticulum stress in the regulation of metabolic flux among patients treated with tacrolimus, suggesting that inherited disturbances of endoplasmic reticulum stress signaling could predispose people to obesity.
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GREFF B., FAIVRE J., CARLI P.A., NIAUDET P., ORLIAGUET G.A.
Intra- and postoperative adverse events in children with nephrotic syndrome requiring surgery under general anesthesia.
Paediatr. Anaesth., 22 (3), 244-249, 2012
(Services cités : Médecine d'Urgence, Néphrologie Pédiatrique)
Background: There are few data regarding perioperative adverse events in children with nephrotic syndrome. Objectives: The aim of this study was to describe the nature and frequency of perioperative adverse events in children with nephrotic syndrome. Materials and Methods: This is a retrospective study from a large university pediatric hospital. All procedures under general anesthesia in children with nephrotic syndrome between January 1995 and May 2007 were included, with the exception of renal transplantation. Data were collected on demographics, etiology of nephrotic syndrome and related treatments, surgical procedures and anesthetic techniques, and pre- and postoperative treatments. Adverse events occurring during the intraoperative period and up to the fifth postoperative day were recorded. Results: Data on eight patients who underwent 24 surgical or interventional procedures under general anesthesia over the study period were reviewed. Three patients had steroid-resistant nephrotic syndrome and five patients had congenital or infantile nephrotic syndrome. Five patients had progressed to end-stage renal failure requiring dialysis. General anesthesia was performed for: nephrectomy (n = 9), central venous catheter insertion (n = 8), peritoneal dialysis catheter insertion (n = 5), and emergency surgery in two cases (acute intestinal intussusception and hemodialysis catheter insertion). Three patients were receiving aspirin and one anticoagulant therapy. No postoperative thrombosis or infections, bleeding, peripheral edema or ascites, and increase in kalemia were noted. There was no significant postoperative increase in median serum creatinine level. Conclusions: Surgical procedures were seldom associated with the occurrence of perioperative adverse events. However, larger studies are needed to confirm these results.
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JONQUOY A., MUGNIERY E., BENOIST-LASSELIN C., KACI N., LE CORRE L., BARBAULT F., GIRARD A.L., LE MERRER Y., BUSCA P., SCHIBLER L., MUNNICH A., LEGEAI-MALLET L.
A novel tyrosine kinase inhibitor restores chondrocyte differentiation and promotes bone growth in a gain-of-function Fgfr3 mouse model.
Hum. Mol. Genet., 21 (4), 841-851, 2012
(Services cités : U781)
Activating germline fibroblast growth factor receptor 3 (FGFR3) mutations cause achondroplasia (ACH), the most common form of human dwarfism and a spectrum of skeletal dysplasias. FGFR3 is a tyrosine kinase receptor and constitutive FGFR3 activation impairs endochondral ossification and triggers severe disorganization of the cartilage with shortening of long bones. To decipher the role of FGFR3 in endochondral ossification, we analyzed the impact of a novel tyrosine kinase inhibitor (TKI), A31, on both human and mouse mutant FGFR3-expressing cells and on the skeleton of Fgfr3(Y367C/+) dwarf mice. We found that A31 inhibited constitutive FGFR3 phosphorylation and restored the size of embryonic dwarf femurs using an ex vivo culture system. The increase in length of the treated mutant femurs was 2.6 times more than for the wild-type. Premature cell cycle exit and defective chondrocyte differentiation were observed in the Fgfr3(Y367C/+) growth plate. A31 restored normal expression of cell cycle regulators (proliferating cell nuclear antigen, KI67, cyclin D1 and p57) and allowed pre-hypertrophic chondrocytes to properly differentiate into hypertrophic chondocytes. Our data reveal a specific role for FGFR3 in the cell cycle and chondrocyte differentiation and support the development of TKIs for the treatment of FGFR3-related chondrodysplasias.
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LECUYER H., NASSIF X., COUREUIL M.
Two Strikingly Different Signaling Pathways Are Induced by Meningococcal Type IV Pili on Endothelial and Epithelial Cells.
Infect. Immun., 80 (1), 175-186, 2012
(Services cités : Laboratoire de Microbiologie, U1002)
Following adhesion on brain microvasculature, Neisseria meningitidis is able to cross the blood-brain barrier (BBB) by recruiting the polarity complex and the cell junction proteins, thus allowing the opening of the paracellular route. This feature is the consequence of the activation by the type IV pili of the beta(2)-adrenergic receptor/beta-arrestin signaling pathway. Here, we have extended this observation to primary peripheral endothelial cells, and we report that the interaction of N. meningitidis with the epithelium is strikingly different. The recruitment of the junctional components by N. meningitidis is indeed restricted to endothelial cell lines, and no alteration of the cell-cell junctions can be seen in epithelial monolayers following meningococcal type IV pilus-mediated colonization. Consistently, the beta(2)-adrenergic receptor/beta-arrestin pathway was not hijacked by bacteria adhering on epithelial cells. In addition, we showed that the consequences of the bacterial signaling on epithelial cells is different from that of endothelial cells, since N. meningitidis-induced signaling which protects the microcolonies from shear stress on endothelial cells is unable to do so on epithelial cells. Finally, we report that the minor pilin PilV, which has been shown to be essential for endothelial cell response, is not a required bacterial determinant to induce an epithelial cell response. These data demonstrate that even though pilus-mediated signaling induces an apparently similar cortical plaque, in epithelial and endothelial cell lineages, the signaling pathways are strikingly different in both models.
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LEE J.E., SILHAVY J.L., ZAKI M.S., SCHROTH J., BIELAS S.L., MARSH S.E., OLVERA J., BRANCATI F., IANNICELLI M., IKEGAMI K., SCHLOSSMAN A.M., MERRIMAN B., ATTIE-BITACH T., LOGAN C.V., GLASS I.A., CLUCKEY A., LOUIE C.M., LEE J.H., RAYNES H.R., RAPIN I., CASTROVIEJO I.P., SETOU M., BARBOT C., BOLTSHAUSER E., NELSON S.F., HILDEBRANDT F., JOHNSON C.A., DOHERTY D.A., VALENTE E.M., GLEESON J.G.
CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium.
Nat. Genet., 44 (2), 193-199, 2012
(Services cités : Centre de Génétique Médicale Jean Frézal, U781)
Tubulin glutamylation is a post-translational modification that occurs predominantly in the ciliary axoneme and has been suggested to be important for ciliary function. However, its relationship to disorders of the primary cilium, termed ciliopathies, has not been explored. Here we mapped a new locus for Joubert syndrome (JBTS), which we have designated as JBTS15, and identified causative mutations in CEP41, which encodes a 41-kDa centrosomal protein. We show that CEP41 is localized to the basal body and primary cilia, and regulates ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme. Depletion of CEP41 causes ciliopathy-related phenotypes in zebrafish and mice and results in glutamylation defects in the ciliary axoneme. Our data identify CEP41 mutations as a cause of JBTS and implicate tubulin post-translational modification in the pathogenesis of human ciliary dysfunction.
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LEU C., de KOVEL C.G., ZARA F., STRIANO P., PEZZELLA M., ROBBIANO A., BIANCHI A., BISULLI F., COPPOLA A., GIALLONARDO A.T., BECCARIA F., TRENITE D.K., LINDHOUT D., GAUS V., SCHMITZ B., JANZ D., WEBER Y.G., BECKER F., LERCHE H., KLEEFUSS-LIE A.A., HALLMAN K., KUNZ W.S., ELGER C.E., MUHLE H., STEPHANI U., MOLLER R.S., HJALGRIM H., MULLEN S., SCHEFFER I.E., BERKOVIC S.F., EVERETT K.V., GARDINER M.R., MARINI C., GUERRINI R., LEHESJOKI A.E., SIREN A., NABBOUT R., BAULAC S., LEGUERN E., SERRATOSA J.M., ROSENOW F., FEUCHT M., UNTERBERGER I., COVANIS A., SULS A., WECKHUYSEN S., KANEVA R., CAGLAYAN H., TURKDOGAN D.
Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies.
Epilepsia, 53 (2), 308-318, 2012
(Services cités : Neurologie, U663)
Purpose: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. Methods: Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE-multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. Key Findings: For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). Significance: Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31.3 preferentially predispose to myoclonic seizures or absence seizures, respectively. Phenotype- genotype strategies applying narrow trait definitions in phenotypic homogeneous subgroups of families improve the prospects of disentangling the genetic basis of common familial GGE syndromes.
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MARIJON E., BOUGOUIN W., CARIOU A., JOST D., CARLI P., COMBES A., LEENHARDT A., JOUVEN X.
Sudden death expertise centre: a multi disciplinary approach for sudden death.
Arch. Cardiovasc. Dis., 104 (11), 555-557, 2011
(Services cités : Médecine d'Urgence)
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ORLIAGUET G.A., GALL O., SAVOLDELLI G.L., COULOIGNER V.
Case Scenario: Perianesthetic Management of Laryngospasm in Children.
Anesthesiology, 116 (2), 458-471, 2012
(Services cités : Médecine d'Urgence, ORL & Chirurgie Cervico-Faciale)
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PARK A.K., LEE S.J., PHI J.H., WANG K.C., KIM D.G., CHO B.K., HABERLER C., FATTET S., DUFOUR C., PUGET S., SAINTE-ROSE C., BOURDEAUT F., GRILL J., DELATTRE O., KIM S.K., PARK W.Y.
Prognostic classification of pediatric medulloblastoma based on chromosome 17p loss, expression of MYCC and MYCN, and Wnt pathway activation.
Neuro-Oncol., 14 (2), 203-214, 2012
(Services cités : Neurochirurgie Pédiatrique)
Pediatric medulloblastoma is considered a highly heterogeneous disease and a new strategy of risk stratification to optimize therapeutic outcomes is required. We aimed to investigate a new risk-stratification approach based on expression profiles of medulloblastoma cohorts. We analyzed gene expression profiles of 30 primary medulloblastomas and detected strong evidence that poor survival outcome was significantly associated with mRNA expression profiles of 17p loss. However, it was not supported in independent cohorts from previously published data (n = 100). We speculated that this discrepancy might come from complex conditions of two important prognostic determinants: loss of tumor suppressors (chromosome 17p) and high expression of oncogenes c-myc (MYCC) or N-myc (MYCN). When patients were stratified into 5 or 7 subgroups based on simultaneous consideration of these 2 factors while defining the Wnt group as independent, obviously different survival expectancies were detected between the subgroups. For instance, predicted 5-year survival probabilities ranged from 19% to 81% in the 5 subgroups. We also found that age became a significant prognostic marker after adjusting for 17p, MYCC, and MYCN status. Diminished survival in age <3 years was more substantial in subgroups with high expression of MYCC, MYCN, or 17p loss but not in other subgroups, indicating that poor survival outcome might be synergistically affected by these 3 factors. Here we suggest a more tailored subgrouping system based on expression profiles of chromosome 17p, MYCC, and MYCN, which could provide the basis for a novel risk-stratification strategy in pediatric medulloblastoma.

RACHDI L., AIELLO V., DUVILLIE B., SCHARFMANN R.
L-Leucine Alters Pancreatic beta-Cell Differentiation and Function via the mTor Signaling Pathway.
Diabetes, 61 (2), 409-417, 2012
(Services cités : U845 (RS))
Leucine (Leu) is an essential branched-chain amino acid, which activates the mammalian target of rapamycin (mTOR) signaling pathway. The effect of Leu on cell differentiation during embryonic development is unknown. Here, we show that Leu supplementation during pregnancy significantly increased fetal body weight, caused fetal hyperglycemia and hypoinsulinemia, and decreased the relative islet area. We also used rat embryonic pancreatic explant culture for elucidating the mechanism of Leu action on beta-cell development. We found that in the presence of Leu, differentiation of pancreatic duodenal homeobox-1-positive progenitor cells into neurogenin3-positive endocrine progenitor cells was inefficient and resulted in decreased beta-cell formation. Mechanistically, Leu increases the intracellular levels of hypoxia-inducible factor 1-alpha, a repressor of endocrine fate in the pancreas, by activating the mTOR complex 1 signaling pathway. Collectively, our findings indicate that Leu supplementation during pregnancy could potentially increase the risk of type 2 diabetes mellitus by inhibiting the differentiation of pancreatic endocrine progenitor cells during a susceptible period of fetal life.
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RAMMAERT B., LANTERNIER F., ZAHAR J.R., DANNAOUI E., BOUGNOUX M.E., LECUIT M., LORTHOLARY O.
Healthcare-associated mucormycosis.
Clin. Infect. Dis., 54 (Suppl.1), S44-S54, 2012
(Services cités : Laboratoire de Microbiologie, Maladies Infectieuses)
Mucormycosis is a severe emerging invasive fungal infection that occurs as a consequence of environmental exposure. We exhaustively reviewed all the cases of mucormycosis (European Organisation for Research and Treatment of Cancer/Mycoses Study Group 2008 criteria) attributed to healthcare procedures that occurred between 1970 and 2008. A total of 169 cases were studied (29% children, 61% male). Major underlying diseases were solid organ transplantation (24%), diabetes mellitus (22%), and severe prematurity (21%). Skin was the most common localization (57%), followed by gastrointestinal tract (15%). Culture results were available in 75% (92% positive), and results of histological examination were positive in 95%. Rhizopus was the most frequent genus (43%). Infection portal of entry included surgery and presence of medical devices such as catheters or adhesive tape. Outbreaks and clusters were related to adhesive bandages (19 cases), wooden tongue depressors (n = 5), ostomy bags (n = 2), water circuitry damage (n = 2), and adjacent building construction (n = 5). Thorough investigations are mandatory to identify healthcare-associated mucormycosis, notably in neonatology, hematological, and transplantation units.
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RIVELINE J.P., ROUSSEAU E., REZNIK Y., FETITA S., PHILIPPE J., DECHAUME A., HARTEMANN A., POLAK M., PETIT C., CHARPENTIER G., GAUTIER J.F., FROGUEL P., VAXILLAIRE M.
Clinical and Metabolic Features of Adult-Onset Diabetes Caused by ABCC8 Mutations.
Diabetes Care, 35 (2), 248-251, 2012
(Services cités : Endocrinologie Pédiatrique et Gynécologie, U845 (RS))
OBJECTIVEGain-of-function ABCC8/sulfonylurea (SU) receptor 1 mutations cause neonatal diabetes mellitus (NDM) or late-onset diabetes in adult relatives. Given the effectiveness of SU treatment in ABCC8-NDM patients, we further characterized late-onset ABCC8-associated diabetes.RESEARCH DESIGN AND METHODSSeven adult subjects from three NDM families and one family with type 2 diabetes were studied. Insulin secretion and insulin sensitivity were assessed using clamp techniques. We screened 139 type 2 diabetic patients who were well controlled by SU for ABCC8 mutations.RESULTSABCC8 mutation carriers exhibited glucose intolerance, frank diabetes, or insulin-requiring diabetes since diagnosis. HbA(1c) improved in five SU-treated patients. Insulin secretion capacity was impaired in three patients compared with adult control subjects but was restored after a 4-week SU trial in two patients. Cohort screening revealed four SU-treated patients with ABCC8 mutations, two of which are likely causal.CONCLUSIONSAlthough of rare occurrence, recognition of adult-onset ABCC8-associated diabetes may help in targeting patients for SU therapy.
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SCHOINDRE Y., TERRIER B., KAHN J.E., SAADOUN D., SOUBERBIELLE J.C., BENVENISTE O., AMOURA Z., PIETTE J.C., CACOUB P., COSTEDOAT-CHALUMEAU N.
Vitamin D and autoimmunity. First part: Fundamental aspects.
Rev. Méd. Interne, 33 (2), 80-86, 2012
(Services cités : Explorations Fonctionnelles)
The effects of vitamin D on calcium homeostasis and bone metabolism are well known. In recent years, suboptimal vitamin D status has been recognized as a pandemic. Meanwhile, extra-skeletal effects of vitamin D are becoming better documented, particularly its effects on immunity. The authors present their actions on myeloid dendritic cells, T cells, B cells, as well as on the synthesis of antimicrobial peptides and autophagy, and the potential beneficial effects in autoimmune and inflammatory diseases.
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SCHOINDRE Y., TERRIER B., KAHN J.E., SAADOUN D., SOUBERBIELLE J.C., BENVENISTE O., AMOURA Z., PIETTE J.C., CACOUB P., COSTEDOAT-CHALUMEAU N.
Vitamin D and autoimmunity. Second part: Clinical aspects.
Rev. Méd. Interne, 33 (2), 87-93, 2012
(Services cités : Explorations Fonctionnelles)
Vitamin D is often confined to its role in calcium homeostasis and bone metabolism. An exponential literature discusses its non-skeletal effects, especially its central role in the physiology of the immune system, where it acts at several levels to maintain self-tolerance. Here, the authors review the experimental, epidemiological and clinical studies, illustrating the potential role of vitamin D in the development and perpetuation of autoimmune diseases such as systemic lupus erythematosus, type 1 diabetes mellitus, multiple sclerosis, inflammatory bowel diseases or rheumatoid arthritis.
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TOUZOT F., GAILLARD L., VASQUEZ N., LE GUEN T., BERTRAND Y., BOURHIS J., LEBLANC T., FISCHER A., SOULIER J., de VILLARTAY J.P., REVY P.
Heterogeneous telomere defects in patients with severe forms of dyskeratosis congenita.
J. Allergy Clin. Immunol., 129 (3), 473-482, 2012
(Services cités : IMAGINE, Immunologie-Hématologie Pédiatriques, U768)
BACKGROUND: Telomeres represent the tips of linear chromosomes. In human subjects telomere maintenance deficiency leads to dyskeratosis congenita (DC), a rare genetic disorder characterized by progressive bone marrow failure, accelerated aging, and cancer predisposition. Hoyeraal-Hreidarsson syndrome (HH) is a severe variant of DC in which an early onset of bone marrow failure leading to combined immunodeficiency is associated with microcephaly, cerebellar hypoplasia, and growth retardation. OBJECTIVES: Limited information is available on the cellular and molecular phenotypes of cells from patients with HH. We analyzed fibroblasts and whole blood cells from 5 patients with HH, 3 of them of unknown molecular origin. METHODS: Telomere length, cellular senescence rate, telomerase activity, telomeric aberration, and DNA repair pathways were investigated. RESULTS: Although patients' cells exhibit dysfunctional telomeres, sharp differences in the telomeric aberrations and telomere lengths were noted among these patients. In some patients the dysfunctional telomere phenotype was unprecedented and associated with either normal telomere length or with telomeric aberrations akin to fragile telomeres. This result is of particular importance because the molecular diagnosis of these patients is primarily based on telomere length, which therefore misses a subset of patients with telomere dysfunction. CONCLUSION: These observations provide the notions that (1) various telomere defects can lead to similar clinical features, (2) telomere dysfunction in cells from patients with DC/HH is not always associated with short telomeres, and (3) additional factors, likely involved in telomere protection rather than in length regulation, are responsible for a subset of DC/HH.
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VALAYANNOPOULOS V., WIJBURG F.A.
Therapy for the mucopolysaccharidoses.
Rheumatology, 50 (Suppl.5), 49-59, 2011
(Services cités : Métabolisme)
Better understanding of disease pathophysiology, improved supportive care and availability of disease-specific treatments for some of the mucopolysaccharidosis (MPS) disorders have greatly improved the outlook for patients with MPS disorders. Optimal management of these multisystemic disorders involves a multidisciplinary team and regular, comprehensive follow-up. Enzyme replacement therapy (ERT) is now available for MPS I (Hurler, Hurler-Scheie and Scheie syndromes) (laronidase), MPS II (Hunter syndrome) (idursulfase) and MPS VI Maroteaux-Lamy (galsulfase), and is in development for MPS IV (Morquio syndrome) and MPS VII (Sly syndrome). Benefits of ERT can include improved walking ability, improved respiration and enhanced quality of life. Haematopoietic stem cell transplantation (HSCT) can preserve cognition and prolong survival in very young children with the most severe form of MPS I, and is under investigation for several other MPS disorders. Better tissue matching techniques, improved graft-vs-host prophylaxis and more targeted conditioning regimens have improved morbidity and mortality associated with HSCT.
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VINCENT-ROHFRITSCH A., ANSELEM O., GRANGE G., BENARD C., VIOT G., LALAU P., MILLISCHER-BELLAICHE A.E., HORNOY P., MITROFANOFF M., TSATSARIS V.
Prenatal diagnosis of a cleft of the tongue, lower lip and mandible.
Ultrasound Obstet. Gynecol., 39 (1), 110-112, 2012
(Services cités : Chirurgie Maxillo-Faciale - Stomatologie Pédiatrique)
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VUIBLET V., BIREMBAUT P., FRANCOIS A., CORDONNIER C., NOEL L.H., GOUJON J.M., PARAF F., MACHET M.C., GIRARDOT-SEGUIN S., LEBRANCHU Y., RIEU P.
Sirolimus-based regimen is associated with decreased expression of glomerular vascular endothelial growth factor.
Nephrol. Dialysis Transplant., 27 (1), 411-416, 2012
(Services cités : Anatomie Pathologique)
BACKGROUND: Sirolimus (SRL) is a potent immunosuppressant used in organ transplantation. It is known to decrease vascular endothelial growth factor (VEGF) synthesis, making it an interesting treatment option for transplant patients who develop Kaposi sarcoma or other malignant diseases. Because VEGF plays a key role in glomerular function and vascular remodelling, we determined the effect of SRL on renal VEGF expression. METHODS: Using immunohistochemistry and quantitative image analysis, we examined renal VEGF expression in routine kidney biopsies performed at 1 year post-transplant in the CONCEPT study, a prospective randomized study comparing a cyclosporine (CsA)-based regimen to a SRL-based regimen in association with mycophenolate mofetil (MMF). RESULTS: A total of 74 patients were included in this substudy; 35 were randomized to the CsA group and 39 to the SRL group. Using continuous variables, the mean percentage of glomerular VEGF expression at Week 52 was significantly lower in the SRL group (14.7 +/- 13%) compared to CsA group (21.2 +/- 14%: P = 0.02). The percentage of glomerular VEGF expression at Week 52 was not influenced by recipient or donor age, gender, renal function, CsA dose, CsA blood level, SRL dose or SRL blood level. It was significantly lower in patients with a proteinuria over versus below 0.5 g/day (11.58 +/- 7.9 versus 19.45 +/- 15.53; P = 0.036). CONCLUSIONS: There is emerging evidence that the VEGF system can play either a beneficial or a detrimental role depending on the specific pathologic situations. Therefore, modulating the renal VEGF axis by using an SRL-based regimen may influence the evolution of kidney injury associated with renal transplantation.
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