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Brousse V.,Hopital University Necker Enfants Malades | Brousse V.,University of Paris Descartes | Brousse V.,Laboratory of Excellence GR Ex | Buffet P.,Laboratory of Excellence GR Ex | And 2 more authors.
British Journal of Haematology | Year: 2014

The spleen has a combined function of immune defence and quality control of senescent or altered red cells. It is the first organ injured in sickle cell anaemia (SCA) with evidence of hyposplenism present before 12 months in the majority of children. Repeated splenic vaso-occlusion leads to fibrosis and progressive atrophy of the organ (autosplenectomy), which is generally complete by 5 years in SCA. The precise sequence of pathogenic events leading to hyposplenism is unknown. Splenic injury is generally silent and progressive. It can be clinically overt with acute splenic sequestration of red cells, an unpredictable and life-threatening complication in infants. Splenomegaly, with or without hypersplenism, can also occur and can coexist with loss of function. Hyposplenism increases the susceptibility of SCA children to infection with encapsulated bacteria, which is notably reduced by penicillin prophylaxis and immunization. Whether hyposplenism indirectly increases the risk of vaso-occlusion or other circulatory complications remains to be determined. © 2014 John Wiley & Sons Ltd.


Aiuti A.,San Raffaele Scientific Institute | Aiuti A.,University of Rome Tor Vergata | Bacchetta R.,San Raffaele Scientific Institute | Seger R.,University of Zürich | And 5 more authors.
Current Opinion in Immunology | Year: 2012

Gene therapy has become an attractive alternative therapeutic strategy to allogeneic transplant for primary immunodeficiencies (PIDs) owing to known genetic defects. Clinical trials using gammaretroviral vectors have demonstrated the proof of principle of gene therapy for Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD), but have also highlighted limitations of the technology. New strategies based on vectors that can achieve more robust correction with less risk of insertional mutagenesis are being developed. In this review we present the status of gene therapy for WAS and CGD, and discuss the emerging application of similar strategies to a broader range of PIDs, such as IPEX syndrome. © 2012.


Cavazzana-Calvo M.,Hopital University Necker Enfants Malades | Cavazzana-Calvo M.,French Institute of Health and Medical Research | Cavazzana-Calvo M.,University of Paris Descartes | Andre-Schmutz I.,French Institute of Health and Medical Research | And 4 more authors.
British Journal of Haematology | Year: 2013

Severe combined immunodeficiencies (SCIDs) correspond to the most severe form of primary immunodeficiency. The extreme severity of the clinical presentation in SCID has legitimately led physicians to consider these conditions as medical emergencies. Hundreds of patients worldwide have undergone allogeneic haematopoietic stem cell transplantation (HCST) in the last 40 years. The complete absence of the T cell compartment in SCID prompted the development (starting in the early 1980s) of haploidentical, parental HSCT for the many patients who do not have a human leucocyte antigen (HLA)-identical sibling. Despite the undeniable progress made in this field over recent years, the long-lasting immunodeficiency that follows partially HLA-incompatible transplantation is still responsible for a mortality rate of 30% at one year post-transplantation. New approaches for reconstituting T cell compartments more rapidly are under intense preclinical development and are discussed herein. © 2012 Blackwell Publishing Ltd.


Cottart C.-H.,University of Paris Descartes | Cottart C.-H.,Hopital University Necker Enfants malades | Nivet-Antoine V.,University of Paris Descartes | Beaudeux J.-L.,University of Paris Descartes | Beaudeux J.-L.,Hopital University Necker Enfants malades
Molecular Nutrition and Food Research | Year: 2014

Several recently published clinical trials have extended our knowledge on the use of resveratrol (RVT) to treat several human pathological and metabolic disorders. Herein, we present insights into the metabolism, biological effects, and toxicity of RVT in humans. Recent data show that RVT exhibits antioxidant and anti-inflammatory activities. It can also improve glucose and lipid metabolism, it acts on cardiovascular parameters, and can modify some pathways involved in carcinogenesis. However, these effects are mostly tiny and the results are sometimes controversial as they depend on the protocols (i.e. dose, form of administration, patients' characteristics, adjuvant therapy, etc.). Toxicological data confirm that RVT is well tolerated. Any adverse effects (mainly concerning the abdomen), at doses of ≥0.5 g/day for long periods, remain moderate and reversible. Nevertheless, the efficacy and safety of RVT need to be further investigated. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Cavazzana-Calvo M.,French Institute of Health and Medical Research | Cavazzana-Calvo M.,Hopital University Necker Enfants Malades | Cavazzana-Calvo M.,University of Paris Descartes | Fischer A.,French Institute of Health and Medical Research | And 7 more authors.
Current Opinion in Immunology | Year: 2012

Over 60 patients affected by SCID due to IL2RG deficiency (SCID-X1) or adenosine deaminase (ADA)-SCID have received hematopoietic stem cell gene therapy in the past 15 years using gammaretroviral vectors, resulting in immune reconstitution and clinical benefit in the majority of them. However, the occurrence of insertional oncogenesis in the SCID-X1 trials has led to the development of new clinical trials based on integrating vectors with improved safety design as well as investigation on new technologies for highly efficient gene targeting and site-specific gene editing. Here we will present the experience and perspectives of gene therapy for SCID-X1 and ADA-SCID and discuss the pros and cons of gene therapy in comparison to allogeneic transplantation. © 2012 Elsevier Ltd.


More than 30 years ago, G. Curranino described a rare congenital malformations association, as three main clinical features, all sharing a common embryological origin: typical scimitar sacral malformation, hindgut anomaly, and presacral tumor. To date, more than 300 Currarino syndrome cases have been reported in literature. They clearly show that Currarino syndrome often displays a broad inter- and intra-familial phenotypic variability, leading to diagnosis divergences or late discoveries, when severe complications have already occurred. In 1998, heterozygous mutations of the HLXB9 gene–which is now the MNX1 gene since 2008 - located at the 7q36 locus, were identified as disease-causing in half of cases, with an autosomal dominant mode of inheritance. The MNX1 gene encodes the HB9 homeobox transcription factor. Considering the reported series and the phenotypic analysis, Currarino syndrome appears actually as a wide clinical spectrum due to a malformative sequence, which has started early in embryological development. It has a wide variability of expressivity, and could be revealed by four major clinical signs with terminal spinal cord anomalies in 70% of cases. Therefore, the syndrome should always be considered even when only a partial phenotype is present. The major complication is infection of the pre sacral mass, linked to the chronic intractable constipation, with a risk of diffusion to cerebro-spinal fluid. A second complication is the malignant degenerescence of the pre sacral teratoma, which is rare, but not exceptionnal. © 2015, Springer-Verlag France.


Valayannopoulos V.,Hopital University Necker Enfants Malades
Handbook of Clinical Neurology | Year: 2013

Lysosomal storage diseases (LSD) are inborn errors of metabolism secondary to lysosomal enzyme defects and are characterized by a progressive accumulation of nondigested macromolecules provoking cellular dysfunction and clinical manifestations. The diagnosis of these diseases can be confirmed easily in most cases by immuno-enzymatic techniques and molecular biology. Even though these enzymatic deficits result in an accumulation of pathological substrates, the underlying mechanisms responsible for the pathogenesis of the disease are not entirely known. Nevertheless, the distribution of the accumulated material determines the affected organs. More particularly in the central nervous system (CNS), neurons are often involved due to the accumulation of storage material and their incapacity of renewal. LSD can be responsible for mental retardation or for a neurodegenerative course in the central nervous system. The peripheral nervous system and the muscle can also be severely impaired. Hematopoietic stem cell transplantation was the first therapy, demonstrating efficacy especially on the neurological involvement of various LSD. Enzyme replacement therapy is now available for Gaucher disease, Fabry disease, mucopolysaccharidoses type I, type II, and type VI, and Pompe disease. Inhibition of the synthesis of the accumulated substrate by small molecules which also have the capacity to diffuse through the blood-brain barrier is another treatment option. New therapeutic strategies using the properties of molecular chaperones and of read-through molecules for nonsense mutations have been studied in vitro and hopefully will soon find clinical applications while intrathecal enzymes are currently studies in clinical trials for MPSII, MPS IIIA and MLD. © 2013 Elsevier B.V.


Vouhe P.,Hopital University Necker Enfants Malades
Bulletin de l'Academie Nationale de Medecine | Year: 2015

The first pediatric heart transplant was performed more than 25 years ago. The results, in terms of mortality and morbidity, have gradually improved over the years, and quality of life and development are thus becoming increasingly important issues. Functional capacity is considered excellent by most recipients: 90 % have few if any symptoms. Objective exercise capacity is usually subnormal, however, mainly owing to the inability of the heart rate to increase with exercise. Early cardiac rehabilitation should be encouraged in order to optimize the capacity for physical activity. Recipients can be expected to have neurodevelopmental outcomes in the low-to-normal range, with a 10- to 15-point deficit compared with normal children. Global cognitive abilities and school performance can be affected, particularly in mathematics. Moreover, 20 % to 30% of these patients have behavioral and psychological disorders, which are relatively stable over time. Neurodevelopmental outcome is poorer in patients grafted because of a congenital heart defect and is consistent with that of other children with complex congenital heart diseases requiring surgical intervention. This suggests that these problems may be related more to the underlying heart disease than to transplantation itself Neurodevelopmental outcome is better in families with good intellectual and socioeconomic status. A global, multidisciplinary approach is needed to manage these problems, both early after transplantation and later during follow-up, particularly during the transition from childhood and adulthood.


Lacaille F.,Hopital University Necker Enfants Malades
Archives de Pediatrie | Year: 2016

"Cholestasis" means abnormal synthesis or secretion of bile. The main symptom in a neonate or infant is jaundice. Urine is dark, staining diapers, and stools are variably pale or white. Vitamin K should be injected (to prevent coagulation disorders due to malabsorption). The two diagnoses requiring urgent treatment are urinary tract infection and biliary atresia. If stools are permanently white, biliary atresia is highly probable. A few genetic causes of intrahepatic cholestasis should be screened and corrective surgery organized. The diseases responsible for cholestasis in this age group are described as well as the investigations and treatments, including the management of non-specific complications of cholestasis. A delay in the diagnosis of biliary atresia can have such severe consequences that consultation with a hepatology unit or transfer should be easy and rapid. © 2016 Elsevier Masson SAS.


Leboulanger N.,Hopital University Necker Enfants Malades
European Annals of Otorhinolaryngology, Head and Neck Diseases | Year: 2016

Nasal obstruction is a very frequent symptom in children, with numerous etiologies. Clinical diagnosis is straightforward, but general impact and rare etiologies should be explored for. Complementary examinations are guided by diagnostic orientation. Although not usually a severe condition, nasal obstruction may be life-threatening in neonates and infants. An exhaustive list of etiologies is impossible and would not be useful, but it is worth distinguishing infantile nasal obstruction and nasal obstruction in older children, as causes differ greatly. This is the topic of the present update. © 2015 Elsevier Masson SAS. All rights reserved.

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