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International audience; In this retrospective study, we evaluate long-term complications in nearly all β-thalassemia-major patients who successfully received allogeneic hematopoietic stem cell transplantation in France. Ninety-nine patients were analyzed with a median age of 5.9 years at transplantation. The median duration of clinical follow up was 12 years. All conditioning regimens were myeloablative, most were based on busulfan combined with cyclophosphamide, and more than 90% of patients underwent a transplant from a matched sibling donor. After transplantation, 11% of patients developed thyroid dysfunction, 5% diabetes, and 2% heart failure. Hypogonadism was present in 56% of females and 14% of males. Female patients who went on to normal puberty after transplant were significantly younger at transplantation than those who experienced delayed puberty (median age 2.5 vs. 8.7 years). Fertility was preserved in 9 of 27 females aged 20 years or older and 2 other patients became pregnant following oocyte donation. In addition to patient’s age and higher serum ferritin levels at transplantation, time elapsed since transplant was significantly associated with decreased height growth in multivariate analysis. Weight growth increased after transplantation particularly in females, 36% of adults being overweight at last evaluation. A comprehensive long-term monitoring, especially of endocrine late effects, is required after hematopoietic stem cell transplantation for thalassemia.

Objective: Paroxysmal kinesigenic dyskinesia (PKD) is a rare disorder characterized by recurrent attacks of hyperkinetic movements. PKD can be isolated or associated with benign infantile seizures as part of the infantile convulsions with choreoathetosis (ICCA) syndrome. Mutations in the PRRT2 gene were recently identified in patients with PKD and ICCA. We studied the prevalence of PRRT2 mutations and characteristics of the patients in a European population of patients with PKD and ICCA. Methods: Patients were recruited through the 1996−2011 database of our DNA bank, to which physicians refer DNA with a putative diagnosis and clinical information. Two movement disorders experts reviewed the information on patients with a putative diagnosis of PKD. Patients who fulfilled the criteria for PKD and ICCA were included. The PRRT2 coding sequence was analyzed by direct sequencing. Results: Among 42 index cases of unrelated families referred with a putative diagnosis of PKD, a total of 34 patients, including 32 with isolated PKD and 2 with ICCA, were selected for genetic analysis. Mutations introducing premature termination codons were identified in 22 of 34 patients including 13 of 14 families and 9 of 20 patients with sporadic cases. The previously described c.649dupC/pArg217ProfsX8 and c.629dupC/pAla211SerfsX14 were present, respectively, in 17 patients and 1 patient; we also report 3 novel mutations: c.649delC/pArg217GlufsX12 in 2 patients, and c.562C>T/pGln188X and c.649C>T/pArg217X, each in 1 patient. The group with mutations was characterized by a younger age at onset (9 years) compared with the patients without mutations (15 years; p Conclusion: Mutations in PRRT2 are a major cause of PKD in familial and sporadic cases in the European population.

International audience; Mutations in PCDH19, encoding protocadherin 19 on chromosome X, cause familial epilepsy and mental retardation limited to females or Dravet-like syndrome. Heterozygous females are affected while hemizygous males are spared, this unusual mode of inheritance being probably due to a mechanism called cellular interference. To extend the mutational and clinical spectra associated with PCDH19, we screened 150 unrelated patients (113 females) with febrile and afebrile seizures for mutations or rearrangements in the gene. Fifteen novel point mutations were identified in 15 female patients (6 sporadic and 9 familial cases). In addition, qPCR revealed two whole gene deletions and one partial deletion in 3 sporadic female patients. Clinical features were highly variable but included almost constantly a high sensitivity to fever and clusters of brief seizures. Interestingly, cognitive functions were normal in several family members of 2 families: the familial condition in family 1 was suggestive of Generalized Epilepsy with Febrile Seizures Plus (GEFS+) whereas all three affected females had partial cryptogenic epilepsy. These results show that mutations in PCDH19 are a relatively frequent cause of epilepsy in females and should be considered even in absence of family history and/or mental retardation.

Hydroxyurea (HU) is approved in EU and USA for preventing vaso-occlusive crises (VOC) including acute chest syndromes (ACS) in adults, adolescents and children ≥2 years with sickle-cell disease (SCD). Further to the double blinded, randomized controlled Multicenter Study of Hydroxyurea administration (MSH) which provided the first data on clinical efficacy of HU (Charache 1995), a few follow-up studies suggested that long-term use of HU resulted in significant clinical benefit on patient outcome. This was reflected by lower mortality rates in HU-treated patients compared to conventionally treated patients (Steinberg 2003 & 2010, Voskaridou 2010, Lê 2015). Sustained hematological and clinical response after several years of follow-up at maximal tolerated dose was further shown in subsequent studies, especially the LaSHS study (Voskaridou 2010). Based on these data, the ESCORT-HU (European Sickle Cell Disease COhoRT - HydroxyUrea) study was launched aiming in the establishment of the safety and the sustainability of hematological and clinical benefits to HU administration in the prevention of sickle-cell vaso-occlusive crises in routine practice. We hereby present preliminary results from a large cohort of patients enrolled in the study between January 2009 and June 2017. 1920 patients were enrolled from 63 centers in France, Germany, Greece and Italy, For 147 of the 600 HU-naive patients (never treated with HU before enrolment) and started on HU for VOC or ACS, there was documented clinical outcome (number of VOC >48h and ACS episodes per year) over a 4-year follow-up period. These patients were selected for analysis to evaluate sustainability of clinical and hematological HU response in routine practice. Demographic data and Hb genotypes are displayed in table 1. The children group was mainly composed of βS/βS patients, while adults were mainly βS/βS and βS/β-thal patients. As shown in figure 1 and 2, there was a dramatic reduction in the number of VOC >48h and ACS episodes (-79%) from year 1 in adults and children, with results comparable to previous randomised clinical trials in adults (Charache et al., 1995) and children (Jain et al, 2012). Overall, the reduction in number of VOC (>48h) and ACS was stable over the 4 years of follow-up. This reduction is inversely proportional to the increase in HbF. There were however a moderate rebound in children from year 2 while adults remained stable. Similarly, there was reduction in the proportion of adults and children requiring transfusion (figure 3). The clinical benefit of HU was higher in severe forms of SCD, as displayed by the markedly reduced number of patients with ≥ 3 VOC episodes (>48h)/year at year 1 (figure 4). Hematological response to HU was evidenced as soon as year 1 with a marked increase in HbF% (+6-10) and were maintained over subsequent years of treatment (figure 1 and 2) as the dose of HU was further increased. While there was no striking differences in HbF% variation between age groups and genotypes, the requirement for increase in HU dose over the 4 years of follow-up was markedly higher in children, probably reflecting the different severity between the two population at entry (figure 5). The red cell red cell mean corpuscular volume (MCV) could be used as a measurement of compliance, showing differences between age group (figure 5). There was, as expected, an apparent negative correlation between induction of HbF synthesis and number of VOC >48h and ACS episodes at year 1, attesting to reduced effectiveness of treatment in some patients (figure 6). Improvement in blood parameters was accompanied by mild reduction of absolute neutrophil and platelet count although not to the point of myelosuppression (defined as ANC < 2 x 109/L), showing that MTD was not targeted in routine practice. Treatment-emergent adverse reactions occurring in the 147 patients of the cohort over the 4 years of follow-up were consistent with the known safety profile of hydroxyurea. The commonest effects included neutropenia and thrombocytopenia (25 events in 13 patients) and were easily manageable with temporary discontinuation of treatment. No tumorigenesis was reported. In conclusion, preliminary results from ESCORT-HU in 147 patients treated with HU showed sustained hematological and clinical response while MTD was not targeted, with differences between adults and children which may be attributed in part to reduced compliance in the latter group. Disclosures Voskaridou: Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron: Membership on an entity's Board of Directors or advisory committees, Research Funding. Oevermann:Addmedica: Membership on an entity's Board of Directors or advisory committees. Thuret:Addmedica: Research Funding; bluebird bio: Research Funding; Novartis: Research Funding. Steschenko:Novartis: Membership on an entity's Board of Directors or advisory committees.

Summary Purpose: Lafora disease (LD) is an autosomal recessive form of progressive myoclonus epilepsy with onset in childhood or adolescence and with fatal outcome caused by mutations in two genes: EPM2A and NHLRC1. The aim of this study was to characterize the mutation spectrum in a cohort of unrelated patients with presumed LD. Methods: Sequencing of the two genes and search for large rearrangements was performed in 46 unrelated patients with suspected LD, 33 originating from France and the others from different countries. Patients were classified into two groups according to the clinical presentation. Results: Mutations of various types were found in EPM2A in 10 patients and in NHLRC1 in 4 patients. Mutations were found in 14 (93%) of 15 patients with classical clinical and electroencephalography (EEG) presentation of LD and in no patients with an atypical presentation. Ten mutations were novel, including the first substitution reported in a donor splice site of EPM2A, leading to the deletion of exon 2 at the RNA level. Four large deletions, including two deletions of exon 2 with different sizes and breakpoints, were found in EPM2A, corresponding to 20% of the alleles of this gene. Discussion: We described several novel mutations of EPM2A and NHLRC1 and brought additional data to the genetic epidemiology of LD. This study emphasized the high mutation rate in patients with classical LD as well as the high negativity rate of skin biopsy.

Summary The level of circulating platelet-, erythrocyte-, leucocyte- and endothelial-derived microparticles detected by high-sensitivity flow cytometry was investigated in 37 β-thalassaemia major patients receiving a regular transfusion regimen. The phospholipid procoagulant potential of the circulating microparticles and the microparticle-dependent tissue factor activity were evaluated. A high level of circulating erythrocyte- and platelet-microparticles was found. In contrast, the number of endothelial microparticles was within the normal range. Platelet microparticles were significantly higher in splenectomized than in non-splenectomized patients, independent of platelet count (P

Lafora disease (LD) is an autosomal recessive form of progressive myoclonus epilepsy with onset in childhood or adolescence and with fatal outcome caused by mutations in two genes: EPM2A and NHLRC1. The aim of this study was to characterize the mutation spectrum in a cohort of unrelated patients with presumed LD.Sequencing of the two genes and search for large rearrangements was performed in 46 unrelated patients with suspected LD, 33 originating from France and the others from different countries. Patients were classified into two groups according to the clinical presentation.Mutations of various types were found in EPM2A in 10 patients and in NHLRC1 in 4 patients. Mutations were found in 14 (93%) of 15 patients with classical clinical and electroencephalography (EEG) presentation of LD and in no patients with an atypical presentation. Ten mutations were novel, including the first substitution reported in a donor splice site of EPM2A, leading to the deletion of exon 2 at the RNA level. Four large deletions, including two deletions of exon 2 with different sizes and breakpoints, were found in EPM2A, corresponding to 20% of the alleles of this gene.We described several novel mutations of EPM2A and NHLRC1 and brought additional data to the genetic epidemiology of LD. This study emphasized the high mutation rate in patients with classical LD as well as the high negativity rate of skin biopsy.

International audience; The congenital dyserythropoietic anemias (CDAs) are inherited red blood cell disorders whose hallmarks are ineffective erythropoiesis, hemolysis, and morphological abnormalities of erythroblasts in bone marrow. We have identified a missense mutation in KLF1 of patients with a hitherto unclassified CDA. KLF1 is an erythroid transcription factor, and extensive studies in mouse models have shown that it plays a critical role in the expression of globin genes, but also in the expression of a wide spectrum of genes potentially essential for erythropoiesis. The unique features of this CDA confirm the key role of KLF1 during human erythroid differentiation. Furthermore, we show that the mutation has a dominant-negative effect on KLF1 transcriptional activity and unexpectedly abolishes the expression of the water channel AQP1 and the adhesion molecule CD44. Thus, the study of this disease-causing mutation in KLF1 provides further insights into the roles of this transcription factor during erythropoiesis in humans.

Background β-thalassemia is a rare disease in France, encountered mainly in patients originating from Italy and North Africa. In the setting of the recent French plan for rare diseases, a National Registry for thalassemia has been developed since 2005. Epidemiological and clinical data have been collected on living patients with β-thalassemia major or intermedia, including those who underwent hematopoietic stem cell transplantation.Design and Methods A standardized questionnaire was sent to clinicians throughout the national professional networks involved in the management of thalassemic patients and data were updated every 18 months. A cross-sectional study was performed in February 2009.Results Data on 378 patients (267 with thalassemia major) with a median age of 20 were recorded. Hematopoietic stem cell transplantation was performed in 52 patients. Stature, rates of parenthood, splenectomy, and cholecystectomy were no different between non-transplanted thalassemia major and thalassemia intermedia patients, after adjustment for age. Among the 215 non-transplanted thalassemia major patients, the median serum ferritin level was 1240 ng/mL and the rates of iron-related complications were 10%, 6%, 10% and 48% for cardiac failure, diabetes, hypothyroidism, and hypogonadism, respectively. From 2005 to 2008, a dramatic switch in chelation treatment, from deferoxamine to deferasirox, was observed.Conclusions The rates of complications of iron overload in French thalassemia major patients appeared similar to those reported in other developed countries in which this condition is not endemic. There were no significant differences in height and parenthood rates between patients with the major and the intermedia forms of the disease, underlining the progress in clinical care. Future developments will focus on mortality and morbidity under oral chelation treatment.

A complete family history was obtained for 501 patients with Wilms' tumor, treated in departments of pediatric oncology in whole France. The information was collected by self-questionnaire and/or by interview of parents. The proportion of bilateral cases is 4.6% and there are 12 patients (2.4%) with a positive family history of Wilms' tumor. The affected relatives are most often distant and no first degree relative was affected. Apart from the well-known associations with aniridia, hemihypertrophy, genitourinary anomalies, Beckwith-Wiedeemann, and Drash syndromes, there is also a significant excess of congenital heart defects (P = .008) which remains to be explained. Several findings support the bimutational hypothesis such as earlier diagnosis and increased parental age in bilateral cases. No particular anomalies and no increased frequency of childhood cancer were found in patients' relatives. The frequency of Wilms' tumor in relatives was estimated to be less than 0.4% in sibs, 0.06% in unclesand aunts, and 0.04% in first cousins. These figures are very different from those found in retinoblastoma and suggest that the mechanism may be more complex in Wilms' tumor. This conclusion is in agreement with molecular biology studies in tumors and linkage analysis in multiple case families which suggest that more than one locus is involved. © 1992 Wiley-Liss, Inc.

Hematopoietic cell transplantation (HCT) is the only potentially curative treatment for sickle cell disease (SCD). The probability of event-free survival is currently between 85 and 90% after matched sibling-donor HCT. This intensive treatment conducts to a major change for patients and families. The purpose of the present study was to determine the psychological impact on individuals and their families of this recovery process after HCT. The hypothesis was that the recovery is a process with different aspects (medical, psychological, individual, familial and cultural) which could be discordant. This study was supported by the Etablissement Français des Greffes (EFG) and conducted by child and adolescent psychiatrists, psychologists and a medical anthropologist. The assessment consisted in two semi-structured interviews adressed to the patients and their families for studying their illness narratives and questionnaires for quality of life, post-traumatic stress disorder (PTSD), depression and anxiety. 28 patients (17 males, 11 females) with SCD treated in France by HCT (22 by bone marrow and 6 by cord blood transplantation) and their families were evaluated at least one year (median 5 years, range, 1–14 years) after HCT at the median age of 14 years (range, 4–24 years). Among these 28 patients, 7 had prior history of severe vasculopathy and 6 of stroke before the HCT. At evaluation, 27 patients were free from SCD symptoms (but 3 had moderate chronic GVHD), 1 had graft rejection. 9 patients (4 males, 5 females) (median age 16 years, range 7–23 years) presented psychiatric symptoms as inhibition, depression, hypomaniac symptoms, anxiety, stutter. A psychiatric care was indicated for these 9 subjects. No diagnosis of current PTSD was found. Psychological distress was reported by parents. 21 patients considered themselves as cured, 4 of them in an incomplete way (none with stroke before the HCT, 3 with moderate chronic GVHD), and 3 not cured at all (none with stroke before the HCT, 1 with graft rejection). The study of the narratives illustrated the major individual, familial and cultural changes after the HCT. The recovery needed complex adjustments. Patients had to cope with new potentialities and requirements: school and relationships with peers, identity issues (disease transmission, infertility) and family changes. This study underlies the importance of psychological interventions for improving the outcome of patients with SCD treated by HCT and their families.