C Saint-Martin

Hôpitaux Universitaires La Pitié salpêtrière - Charles Foix, Lutetia Parisorum, Île-de-France, France

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Publications (42)119.72 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: 18fluorine-fluorodihydroxyphenylalanine (FDOPA) PET/CT is currently the first-line imaging technique to distinguish between focal and diffuse forms of congenital hyperinsulinism (CHI) and to accurately localize focal forms. However, this technique has a number of limitations, mainly the very small size of focal forms or inversely a very large focal form mimicking a diffuse form, and misinterpretation of physiologic uptake masking hot spots or inversely mimicking focal forms. The other limitation is the limited availability of the radiopharmaceutical. FDOPA PET/CT has no recognized competitor to date among the available morphologic and functional imaging techniques. Other potential approaches using specific tracers for positron emission tomography (PET) are discussed, using radiopharmaceuticals specific for β cell mass or targeting somatostatin receptors. These radiopharmaceuticals can be labeled with gallium-68, a PET emitter readily available in PET centers equipped with 68Ge/68Ga generators.
    Expert Review of Endocrinology &amp Metabolism 08/2014;
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    European journal of human genetics: EJHG 02/2014; · 3.56 Impact Factor
  • Transfusion Clinique et Biologique 06/2013; 20(3):280. · 0.64 Impact Factor
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    Diabetes care 11/2012; 35(11):e76. · 7.74 Impact Factor
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    ABSTRACT: The long-term evolution of familial myeloproliferative neoplasms was studied in 93 families with 227 subjects including 97 with polycythemia vera (PV), 105 essential thrombocythemia (ET), 14 primary myelofibrosis (PMF) and 11 chronic myeloid leukemia (CML). In PV patients, with 12years of median follow-up, overall survival was 83% at 10years and 37% at 20years. A high JAK2(V617F) allele burden was correlated with the transformation to myelofibrosis (p<0.0001), but not with the transformation to acute leukemia. Among the 105 ET, with 8years of median follow-up, overall survival was 83% at 10years and 57% at 20years. Progression to acute leukemia and progression to myelofibrosis were 10% and 13%. There was a trend toward a more frequent evolution to myelofibrosis when the JAK2(V617F) mutated allele burden was >50% (p=0.09), but not to AML. Hematologic transformation of the MPN was responsible for 69% of the deaths, cerebral stroke for 7% and 4% died of myocardial infarction. Eleven JAK2(V617F) mutated patients developed 13 deep splanchnic thromboses in PV and ET. Finally whereas patients with familial PV and ET have a comparable prognosis to non-familial MPN, the JAK2(V617F) mutation was associated with a more frequent occurrence of thrombosis in the entire population.
    Blood Cells Molecules and Diseases 07/2012; 49(3-4):170-176. · 2.26 Impact Factor
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    ABSTRACT: Congenital hyperinsulinism (HI) is a common cause of hypoglycemia in infancy. The medical treatment of diazoxide-unresponsive HI is based on a somatostatin analogue. This study aims at replacing three daily s.c. octreotide (Sandostatin, Novartis) injections by a single and monthly i.m. injection of long-acting release (LAR) octreotide (Sandostatin LP, Novartis) in HI patients. LAR octreotide was injected every 4 weeks during 6 months and s.c. octreotide injections were stopped after the third injection of LAR octreotide. After this 6-month study, LAR octreotide was continued, with an average follow-up of 17 months. Ten HI pediatric patients unresponsive to diazoxide and currently treated with s.c. octreotide were included in the trial. Glycemias and other parameters (HbA1c, IGF1, height, weight, quality of life (QoL), and satisfaction) were monitored at each monthly visit. For all ten patients, glycemias were maintained in the usual range, HbAlc (mean 5.5%; 95% CI: 4.6-6.2) and IGF1 (mean 89.7 ng/ml; 95% CI: 26-153) were unchanged. Patients gained height significantly (mean 2.7 cm; 95% CI: 1.9-3.4) and no side effect was noted during the study and the later follow-up. Plasma octreotide levels were stable under LAR octreotide. Parents' questionnaires of general satisfaction were highly positive whereas children's QoL evaluation remained unchanged. In these diazoxide-unresponsive HI patients, LAR octreotide was efficient, well tolerated and contributed to a clear simplification of the medical care.
    European Journal of Endocrinology 11/2011; 166(2):333-9. · 3.14 Impact Factor
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    ABSTRACT: Congenital hyperinsulinism (HI) is an inappropriate insulin secretion by the pancreatic β-cells secondary to various genetic disorders. The incidence is estimated at 1/50, 000 live births, but it may be as high as 1/2, 500 in countries with substantial consanguinity. Recurrent episodes of hyperinsulinemic hypoglycemia may expose to high risk of brain damage. Hypoglycemias are diagnosed because of seizures, a faint, or any other neurological symptom, in the neonatal period or later, usually within the first two years of life. After the neonatal period, the patient can present the typical clinical features of a hypoglycemia: pallor, sweat and tachycardia. HI is a heterogeneous disorder with two main clinically indistinguishable histopathological lesions: diffuse and focal. Atypical lesions are under characterization. Recessive ABCC8 mutations (encoding SUR1, subunit of a potassium channel) and, more rarely, recessive KCNJ11 (encoding Kir6.2, subunit of the same potassium channel) mutations, are responsible for most severe diazoxide-unresponsive HI. Focal HI, also diazoxide-unresponsive, is due to the combination of a paternally-inherited ABCC8 or KCNJ11 mutation and a paternal isodisomy of the 11p15 region, which is specific to the islets cells within the focal lesion. Genetics and 18F-fluoro-L-DOPA positron emission tomography (PET) help to diagnose diffuse or focal forms of HI. Hypoglycemias must be rapidly and intensively treated to prevent severe and irreversible brain damage. This includes a glucose load and/or a glucagon injection, at the time of hypoglycemia, to correct it. Then a treatment to prevent the recurrence of hypoglycemia must be set, which may include frequent and glucose-enriched feeding, diazoxide and octreotide. When medical and dietary therapies are ineffective, or when a focal HI is suspected, surgical treatment is required. Focal HI may be definitively cured when the partial pancreatectomy removes the whole lesion. By contrast, the long-term outcome of diffuse HI after subtotal pancreatectomy is characterized by a high risk of diabetes, but the time of its onset is hardly predictable.
    Orphanet Journal of Rare Diseases 10/2011; 6:63. · 4.32 Impact Factor
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    ABSTRACT: Monogenic diabetes resulting from mutations that reduce β-cell insulin secretion accounts for 1-2% of diabetes cases. Knowledge of the genetic etiology of diabetes has practical consequences for patients. It enables better prediction of disease progression, more appropriate treatment, screening of extrapancreatic features and family member predictive genetic screening. Genetic testing is routinely available for the most frequent monogenic diabetes. However, due to the genetic heterogeneity and the clinical variability of phenotypes, it requires detailed description of diabetes in the proband and its diabetic relatives. Indeed monogenic diabetes is often misdiagnosed as type 1 or type 2 diabetes. Different clinical situations of monogenic diabetes (MODY, Maturity-Onset Diabetes of the Young; diabetes resulting from mutations in the ATP-sensitive potassium channel; diabetes with extrapancreatic features) are here reported to illustrate the clinical approach in the identification of monogenic diabetes. The practical and legal rules of molecular testing as well as the interpretation of results are presented. Both are essential and should be known by the clinician before requesting genetic testing, before taking medical decisions for patient treatment according to genetic results or requesting genetic screening of family members.
    Médecine des Maladies Métaboliques 10/2011; 5(5):497–505.
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    ABSTRACT: The diagnosis of maturity-onset diabetes of the young type 3 (MODY3), associated with HNF1A molecular abnormalities, is often missed. The objective of the study was to describe the phenotypes of a large series of MODY3 patients and to reassess parameters that may improve its diagnosis. This retrospective multicenter study included 487 unrelated patients referred because of suspicion of MODY3. Genetic analysis identified 196 MODY3 and 283 non-MODY3 cases. Criteria associated with MODY3 were assessed by multivariate analysis. The capacity of the model to predict MODY3 diagnosis was assessed by the area under the receiver-operating characteristic curve and was further validated in an independent sample of 851 patients (165 MODY3 and 686 non-MODY3). In the MODY3 patients, diabetes was revealed by clinical symptoms in 25% of the cases and was diagnosed by screening in the others. Age at diagnosis of diabetes was more than 25 yr in 40% of the MODY3 patients. There was considerable variability and overlap of all assessed parameters in MODY3 and non-MODY3 patients. The best predictive model was based on criteria available at diagnosis of diabetes, including age, body mass index, number of affected generations, presence of diabetes symptoms, and geographical origin. The area under the curve of the receiver-operating characteristic analysis was 0.81. When sensitivity was set to 90%, specificity was 49%. Differential diagnosis between MODY3 and early-onset type 2 diabetes remains difficult. Whether the proposed model will improve the pick-up rate of MODY3 diagnosis needs to be confirmed in independent populations.
    The Journal of Clinical Endocrinology and Metabolism 06/2011; 96(8):E1346-51. · 6.31 Impact Factor
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    ABSTRACT: Adenosine triphosphate (ATP)-sensitive potassium channels (K(ATP) channels) have a central role in the regulation of insulin secretion in pancreatic β cells. They are octameric complexes organized around the central core constituted by the Kir6.2 subunits. The regulation of the channel itself takes place on the sulfonylurea receptor-1 subunit. The channel opens and closes according to the balance between adenine nucleotide ATP and adenosine diphosphate. Hyperinsulinemic hypoglycemia (also named congenital hyperinsulinism, or CHI) is associated with loss-of-function K(ATP) channel mutations. Their frequency depends on the histopathological form and the responsiveness of CHI patients to diazoxide. ABCC8/KCNJ11 defects are identified in approximately 80% of patients with CHI refractory to diazoxide. Within this group, focal forms are related to a paternally inherited KCNJ11 or ABCC8 mutation and the loss of the corresponding maternal allele in some pancreatic β cells leading to a focal lesion. Diffuse forms are mostly associated with recessively inherited mutations. Some patients with diffuse forms also carried a single K(ATP) channel mutation. In contrast, K(ATP) mutations are involved in 15% of diazoxide-responsive CHI cases that are either sporadic or dominantly inherited.
    Seminars in Pediatric Surgery 02/2011; 20(1):18-22. · 2.40 Impact Factor
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    ABSTRACT: TET2 mutations are found in polycythemia vera and it was initially reported that there is a greater TET2 mutational burden than JAK2(V617F) in polycythemia vera stem cells and that TET2 mutations precede JAK2(V617F). We quantified the proportion of TET2, JAK2(V617F) mutations and X-chromosome allelic usage in polycythemia vera cells, BFU-Es and in vitro expanded erythroid progenitors and found clonal reticulocytes, granulocytes, platelets and CD34(+) cells. We found that TET2 mutations may also follow rather than precede JAK2(V617F) as recently reported by others. Only a fraction of clonal early hematopoietic precursors and largely polyclonal T cells carry the TET2 mutation. We showed that in vitro the concomitant presence of JAK2(V617F) and TET2 mutations favors clonal polycythemia vera erythroid progenitors in contrast with non-TET2 mutated progenitors. We conclude that loss-of-function TET2 mutations are not the polycythemia vera initiating events and that the acquisition of TET2 somatic mutations may increase the aggressivity of the polycythemia vera clone.
    Haematologica 01/2011; 96(5):775-8. · 5.94 Impact Factor
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    ABSTRACT: We have dissected the rare molecular anomalies that may affect hepatocyte nuclear factor-1a (HNF1A) and hepatocyte nuclear factor-4a (HNF4A) in patients with familial young-onset diabetes for whom HNF1A mutations have been excluded by sequence analysis. Eighty-four unrelatedHNF1A-negative patients with diabetes diagnosed before the age of 40 years, a family history of diabetes and the absence of features suggestive of Type 2 diabetes were included. We analysed by sequencing the HNF4A promoter and coding regions, the HNF1A promoter region and specific regions of HNF1A(B) and HNF1A(C) isoforms and searched for large deletions of HNF1A and HNF4A by multiplex ligation-dependent probe amplification (MLPA). We identified five novel HNF4A mutations (5 ⁄ 84, 6%), including four missense and one in-frame deletion, and one mutation of the HNF1A promoter (1 ⁄ 84). Sequence analysis of isoform-specific coding regions of HNF1A did not reveal any mutation. We next identified two whole gene deletions of HNF1A and HNF4A, respectively (2 ⁄ 84, 2.4%). Altogether, the search for rare molecular events in HNF1A and HNF4A led us to elucidate 8 ⁄ 84 (9.5%) of our HNF1A-negative cases.This study shows that genetic aetiologies remain to be elucidated in familial young-onset diabetes. It also highlights the difficulty of the differential diagnosis with Type 2 diabetes because of the wide clinical expression of monogenic young-onset diabetes and the absence of specific biomarkers.
    Diabetic Medicine 12/2010; 27(12):1454-8. · 3.24 Impact Factor
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    ABSTRACT: Congenital hyperinsulinism (CHI) is characterised by an over secretion of insulin by the pancreatic β-cells. This condition is mostly caused by mutations in ABCC8 or KCNJ11 genes encoding the SUR1 and KIR6.2 subunits of the ATP-sensitive potassium (K(ATP)) channel. CHI patients are classified according to their responsiveness to diazoxide and to their histopathological diagnosis (either focal, diffuse or atypical forms). Here, we raise the benefits/limits of the genetic diagnosis in the clinical management of CHI patients. ABCC8/KCNJ11 mutational spectrum was established in 109 diazoxide-unresponsive CHI patients for whom an appropriate clinical management is essential to prevent brain damage. Relationships between genotype and radiopathological diagnosis were analysed. ABCC8 or KCNJ11 defects were found in 82% of the CHI cases. All patients with a focal form were associated with a single K(ATP) channel molecular event. In contrast, patients with diffuse forms were genetically more heterogeneous: 47% were associated with recessively inherited mutations, 34% carried a single heterozygous mutation and 19% had no mutation. There appeared to be a predominance of paternally inherited mutations in patients diagnosed with a diffuse form and carrying a sole K(ATP) channel mutation. The identification of recessively inherited mutations related to severe and diffuse forms of CHI provides an informative genetic diagnosis and allows prenatal diagnosis. In contrast, in patients carrying a single K(ATP) channel mutation, genetic analysis should be confronted with the PET imaging to categorise patients as focal or diffuse forms in order to get the appropriate therapeutic management.
    Journal of Medical Genetics 11/2010; 47(11):752-9. · 5.70 Impact Factor
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    ABSTRACT: Familial cortical myoclonic tremor with epilepsy (FCMTE) is defined by autosomal dominant adult-onset cortical myoclonus (CM) and seizures in 40% of patients. Two loci, 8q23.3-q24.11 (FAME1/FCMTE1) and 2p11.1-q12.2 (FAME2/FCMTE2), were previously reported without an identified gene. Unlinked families argue for a third mutated gene. A genome-wide scan was performed in a large FCMTE family using Linkage-12 microarrays (Illumina). Refinement of the locus on 5p was performed by genotyping 13 polymorphic microsatellite markers in the 45 available family members. This large French FCMTE family included 16 affected relatives. The first symptoms were CM in 5 patients (31.2%), seizures in 5 patients (31.2%), and both at the same time in 6 patients (37.5%). A total of 12.5% (2/16) had only CM without seizures. The genome-wide scan identified a single region on 5p15.31-p15, with a multipoint lod score of 3.66. Further genotyping of all family members confirmed that the region spans 9.31 Mb between D5S580 and D5S2096, 2-point lod scores reaching 6.3 at theta = 0 for D5S486. Sequencing of the SEMA5A and CTNND2 genes failed to detect mutations. We report the clinical and genetic characteristics of a large familial cortical myoclonic tremor with epilepsy family. The third gene maps to 5p15.31-p15. Identification of the mutated gene is ongoing.
    Neurology 06/2010; 74(24):2000-3. · 8.25 Impact Factor
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    ABSTRACT: BACKGROUND Mutations in SCN1A can cause genetic epilepsy with febrile seizures plus (GEFS+, inherited missense mutations) or Dravet syndrome (DS, de novo mutations of all types). Although the mutational spectra are distinct, these disorders share major features and 10% of DS patients have an inherited SCN1A mutation. OBJECTIVES AND PATIENTS 19 selected families with at least one DS patient were studied to describe the mechanisms accounting for inherited SCN1A mutations in DS. The mutation identified in the DS probands was searched in available parents and relatives and quantified in the blood cells of the transmitting parent using quantitative allele specific assays. RESULTS Mosaicism in the blood cells of the transmitting parent was demonstrated in 12 cases and suspected in another case. The proportion of mutated allele in the blood varied from 0.04-85%. In the six remaining families, six novel missense mutations were associated with autosomal dominant variable GEFS+ phenotypes including DS as the more severe clinical picture. CONCLUSION The results indicate that mosaicism is found in at least 7% of families with DS. In the remaining cases (6/19, 32%), the patients were part of multiplex GEFS+ families and seemed to represent the extreme end of the GEFS+ clinical spectrum. In this latter case, additional genetic or environmental factors likely modulate the severity of the expression of the mutation.
    Journal of Medical Genetics 06/2010; 47(6):404-10. · 5.70 Impact Factor
  • Revue Neurologique - REV NEUROL. 01/2010; 166.
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    ABSTRACT: Monogenic diabetes may account for 1-2% of diabetes cases. They constitute a group of heterogenous diseases as regards to their clinical presentation and genetics. Genetic screening may be guided by the phenotype of the patient. However, in some cases differential diagnosis with early-onset type 2 diabetes may be difficult. According to their clinical presentation, monogenic diabetes may be divided into three main groups: in the first one, corresponding to MODYs (Maturity onset diabetes of the young), diabetes is the main clinical symptom; in the second one, diabetes is associated with extrapancreatic features, such as renal involvement in the RCAD syndrome (Renal cysts and diabetes, or MODY5), or deafness and macular dystrophy in MIDD (Maternally inherited diabetes and deafness), due to a point mutation of mitochondrial DNA; the third group comprises neonatal or early infancy diabetes. The diagnosis of monogenic diabetes has clinical implications in terms of prognosis, treatment, screening for associated anomalies, and for genetic screening of relatives.
    Médecine des Maladies Métaboliques 09/2009; 3(4):448–453.
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    ABSTRACT: Glucokinase is a key regulatory enzyme in the pancreatic beta-cell. It plays a crucial role in the regulation of insulin secretion and has been termed the glucose sensor in pancreatic beta-cells. Given its central role in the regulation of insulin release it is understandable that mutations in the gene encoding glucokinase (GCK) can cause both hyper- and hypoglycemia. Heterozygous inactivating mutations in GCK cause maturity-onset diabetes of the young (MODY) subtype glucokinase (GCK), characterized by mild fasting hyperglycemia, which is present at birth but often only detected later in life during screening for other purposes. Homozygous inactivating GCK mutations result in a more severe phenotype presenting at birth as permanent neonatal diabetes mellitus (PNDM). A growing number of heterozygous activating GCK mutations that cause hypoglycemia have also been reported. A total of 620 mutations in the GCK gene have been described in a total of 1,441 families. There are no common mutations, and the mutations are distributed throughout the gene. The majority of activating mutations cluster in a discrete region of the protein termed the allosteric activator site. The identification of a GCK mutation in patients with both hyper- and hypoglycemia has implications for the clinical course and clinical management of their disorder.
    Human Mutation 09/2009; 30(11):1512-26. · 5.21 Impact Factor
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    ABSTRACT: Familial cortical myoclonic tremor with epilepsy (FCMTE) is defined by an autosomal-dominant inheritance, adult onset of myoclonus of the extremities, infrequent epileptic seizures, a non-progressive course, polyspikes on electroencephalography (EEG), photosensitivity, giant somatosensory-evoked potentials (SEP), enhancement of C-reflex and a premyoclonus spike detected by jerk-locked EEG back-averaging. Two genes yet to be identified are mapped to 8q23.3-q24.1 and 2p11.1-q12.2. The present study involved five generations of a French family presenting with FCMTE, including 76 family members. Clinical analyses were performed in 39 living subjects and electrophysiological studies in five patients. Altogether, 27 relatives (21 living and six deceased) had the clinical characteristics of FCMTE, 17 of whom were analyzed. Linkage analyses were performed with microsatellites encompassing the two known loci (8q 23.3-q24.1 and 2p11.1-q12.2). Mean age at onset in the 17 living patients was 28.8 years (range 24-41). All had myoclonus/cortical tremor, and 11/17 had generalized tonic-clonic seizures. Other clinical symptoms were photosensitivity (16 cases), partial seizures (five cases), sensitivity to starvation/exercise (six cases) and vibration (four cases), ophthalmic migraine (six cases) and gait disorders (10 cases). Electrophysiological studies confirmed the FCMTE diagnosis in the five studied patients. Of the remaining relatives, 14 were considered healthy (asymptomatic subjects aged more than 40years) and eight were of unknown status (asymptomatic aged lesser than 40years). The pattern of inheritance was consistent with autosomal-dominant inheritance, although the two loci responsible for FCMTE were excluded. This large family highlights some unusual clinical characteristics and suggests the presence of a third gene. Genetic research is ongoing to identify the mutated gene.
    Revue Neurologique 08/2009; 165(10):812-20. · 0.51 Impact Factor

Publication Stats

613 Citations
119.72 Total Impact Points

Institutions

  • 2009–2013
    • Hôpitaux Universitaires La Pitié salpêtrière - Charles Foix
      Lutetia Parisorum, Île-de-France, France
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • Université René Descartes - Paris 5
      • Faculté de Médecine
      Lutetia Parisorum, Île-de-France, France
  • 2009–2011
    • Pierre and Marie Curie University - Paris 6
      Lutetia Parisorum, Île-de-France, France
  • 2008–2009
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 1999
    • Cliniques Universitaires Saint-Luc
      • Department of Medical Imaging
      Brussels, BRU, Belgium
  • 1998
    • Catholic University of Louvain
      • Department of Radiology and Medical Imaging - RAIM
      Louvain-la-Neuve, WAL, Belgium