Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056.

Fragile X syndrome (FXS) is an X-linked condition associated with intellectual disability and behavioral problems. It is caused by expansion of a CGG repeat in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. This mutation is associated with hypermethylation at the FMR1 promoter and resultant transcriptional silencing. FMR1 silencing has many consequences, including up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling. mGluR5 receptor antagonists have shown promise in preclinical FXS models and in one small open-label study of FXS. We examined whether a receptor subtype-selective inhibitor of mGluR5, AFQ056, improves the behavioral symptoms of FXS in a randomized, double-blind, two-treatment, two-period, crossover study of 30 male FXS patients aged 18 to 35 years. We detected no significant effects of treatment on the primary outcome measure, the Aberrant Behavior Checklist-Community Edition (ABC-C) score, at day 19 or 20 of treatment. In an exploratory analysis, however, seven patients with full FMR1 promoter methylation and no detectable FMR1 messenger RNA improved, as measured with the ABC-C, significantly more after AFQ056 treatment than with placebo (P < 0.001). We detected no response in 18 patients with partial promoter methylation. Twenty-four patients experienced an adverse event, which was mostly mild to moderately severe fatigue or headache. If confirmed in larger and longer-term studies, these results suggest that blockade of the mGluR5 receptor in patients with full methylation at the FMR1 promoter may show improvement in the behavioral attributes of FXS.

Améliorer la prescription d'un traitement hypolipémiant lors d'un syndrome coronarien aigu: absence de benefice d'une alerte automatique.

Introduction: Seulement 25-30% des patients avec syndrome coronarien aigu (SCA) atteignent les valeurs cibles de LDL-cholestérol (LDL-C) dans leur suivi. L'objectif de cette étude pré/post est de tester une alerte automatique centralisée pour améliorer les pratiques. L'alerte apparaît sur les feuilles de laboratoire pour tous les patients ayant une troponine >= 0,1 microg/l; elle précise notamment les recommandations en matière de profil lipidique (LDL-C cible) à atteindre. Méthode: Tout patient admis au CHUV pour un SCA avec troponine >= 0,1 microg/l était éligible. Durant les 2 phases de l'étude (du 23.11.2008 au 15.08.201), un bilan lipidique complet a été dosé à l'admission et à 3 mois. La phase 1 (pré) était observationnelle et le message d'alerte a été introduit pour la phase 2 (post). Résultats: Phase 1: 157 patients dont 56 (35%) étaient déjà traités par une statine: 114 hommes (âge moyen 62 ans) et 43 femmes (73 ans). LDL-C moyen: 3,4 ± 1,0 mmol/l à l'admission et 2,4 ± 0,8 mmol/l à 3 mois (p <0,001). Phase 2: 140 patients dont 42 (30%) étaient déjà traités par une statine: 116 hommes (62 ans) et 24 femmes (67 ans). LDL-C moyen: 3,4 ± 1,1 mmol/l à l'admission et 2,2 ± 1,0 mmol/l à 3 mois (p <0,001). 66 % (104 patients) atteignent un LDL-C cible < = 2,6 mmol/l à 3 mois lors de la phase 1, versus 78% (110 patients) lors de la phase 2 (p = 0,2). Les patients déjà sous statine à l'admission ont une faible diminution du LDL-C à 3 mois (de 2,8 à 2,5 mmol/l phase 1, p <0,05; de 2,5 à 2,6 mmol/l phase 2, p = 0.2), alors que les patients chez qui une statine est introduite à l'admission ont une baisse significative et plus importante du LDL-C à 3 mois (de 3,8 à 2,3 mmol/l phase 1, p <0,001; de 3,7 à 2,1 mmol/l phase 2, p <0,001) que les patients déjà sous statine au préalable. Conclusion: La phase observationnelle montre un taux élevé de patients atteignant un LDL-C cible à 3 mois. L'introduction d'une alarme automatique centralisée n'a pas permis d'améliorer ces résultats. Par contre, les patients arrivant à l'hôpital avec un SCA et étant déjà sous statine devraient avoir une intensification de leur traitement.

Syndrome des ovaires polykystiques et résistance a l'insuline [Polycystic ovary syndrome and insulin resistance]

Polycystic ovary syndrome is the most common endocrinopathy in women of reproductive age. Insulin resistance is frequently found in affected patients, and probably plays an important physiopathological role. In this paper, we will review the well recognized association between polycystic ovary syndrome and insulin resistance, and discuss the increased risk of glucose intolerance, type 2 diabetes and metabolic syndrome carried by patients diagnosed with this syndrome. We will also suggest a practical strategy for the screening and follow up of the various metabolic complications associated with polycystic ovary syndrome, in light of the rare existing recommendations of the current literature.

Development and validation of a clinical prediction rule for chest wall syndrome in primary care

Le "Chest wall syndrome" (CWS) est défini comme étant une source bénigne de douleurs thoraciques, localisées sur la paroi thoracique antérieure et provoquées par une affection musculosquelettique. Le CWS représente la cause la plus fréquente de douleurs thoraciques en médecine de premier recours. Le but de cette étude est de développer et valider un score de prédiction clinique pour le CWS. Une revue de la littérature a d'abord été effectuée, d'une part pour savoir si un tel score existait déjà, et d'autre part pour retrouver les variables décrites comme étant prédictives d'un CWS. Le travail d'analyse statistique a été effectué avec les données issues d'une cohorte clinique multicentrique de patients qui avaient consulté en médecine de premier recours en Suisse romande avec une douleur thoracique (59 cabinets, 672 patients). Un diagnostic définitif avait été posé à 12 mois de suivi. Les variables pertinentes ont été sélectionnées par analyses bivariées, et le score de prédiction clinique a été développé par régression logistique multivariée. Une validation externe de ce score a été faite en utilisant les données d'une cohorte allemande (n= 1212). Les analyses bivariées ont permis d'identifier 6 variables caractérisant le CWS : douleur thoracique (ni rétrosternale ni oppressive), douleur en lancées, douleur bien localisée, absence d'antécédent de maladie coronarienne, absence d'inquiétude du médecin et douleur reproductible à la palpation. Cette dernière variable compte pour 2 points dans le score, les autres comptent pour 1 point chacune; le score total s'étend donc de 0 à 7 points. Dans la cohorte de dérivation, l'aire sous la courbe sensibilité/spécificité (courbe ROC) est de 0.80 (95% de l'intervalle de confiance : 0.76-0.83). Avec un seuil diagnostic de > 6 points, le score présente 89% de spécificité et 45% de sensibilité. Parmi tous les patients qui présentaient un CWS (n = 284), 71% (n = 201) avaient une douleur reproductible à la palpation et 45% (n= 127) sont correctement diagnostiqués par le score. Pour une partie (n = 43) de ces patients souffrant de CWS et correctement classifiés, 65 investigations complémentaires (30 électrocardiogrammes, 16 radiographies du thorax, 10 analyses de laboratoire, 8 consultations spécialisées, et une tomodensitométrie thoracique) avaient été réalisées pour parvenir au diagnostic. Parmi les faux positifs (n = 41), on compte trois angors stables (1.8% de tous les positifs). Les résultats de la validation externe sont les suivants : une aire sous la courbe ROC de 0.76 (95% de l'intervalle de confiance : 0.73-0.79) avec une sensibilité de 22% et une spécificité de 93%. Ce score de prédiction clinique pour le CWS constitue un complément utile à son diagnostic, habituellement obtenu par exclusion. En effet, pour les 127 patients présentant un CWS et correctement classifiés par notre score, 65 investigations complémentaires auraient pu être évitées. Par ailleurs, la présence d'une douleur thoracique reproductible à la palpation, bien qu'étant sa plus importante caractéristique, n'est pas pathognomonique du CWS.

Prescription d'un traitement hypolipémiant lors d'un syndrome coronarien aigu en fonction du profil lipidique

Introduction: Les données épidémiologiques montrent que seuls25-30% des patients avec syndrome coronarien aigu (SCA) atteignentles valeurs cibles de LDL-cholestérol (LDL-C). Les recommandationsexistantes précisent le choix et le dosage des statines à utiliser enfonction du LDL-C cible souhaité. Le but de cette étude observationnelleétait de connaître les pratiques actuelles au CHUV avant d'introduireune étude d'intervention.Méthode: Pour être inclus, les patients devaient être admis au CHUVpour un SCA avec troponine positive (>= 0.1 microg/l) entre le23.11.2008 et le 29.05.2010. Un bilan lipidique complet (CT, HDL-C,LDL-C, TG) a été dosé à leur admission et un nouveau contrôle desparamètres lipidiques a été effectué à 3 mois. Les hypolipémiantsutilisés durant cette période ont été analysés pour chaque patient.Résultats: 141 patients, 101 hommes (âge moyen 63 ± 13 ans) et 40femmes (âge moyen 73 ± 13 ans) admis aux urgences pour un SCAavec troponine positive ont été inclus. La valeur moyenne du LDL-C àl'admission était de 3,4 ± 1,1 mmol/l (hommes 3,5 ± 1,1; femmes 3,3 ±1,1) et de 2,4 ± 0,8 mmol/l (hommes 2,4 ± 0,8; femmes 2,2 ± 0,7) aucontrôle de 3 mois. Parmi ces 141 patients, 52 (37%) étaient déjàtraités par une statine (36 hommes et 16 femmes). Leur valeur deLDL-C à l'admission était de 2,8 ± 0,9 mmol/l et de 2,5 ± 0,6 mmol/l aucontrôle de 3 mois. 7 patients (13%) ont eu une augmentation dudosage de leur statine, 14 patients (27%) ont eu un changement destatine et 31 patients (60%) n'ont eu aucune modification de leurtraitement. 89 patients n'avaient pas de statine (65 hommes et 24femmes) à leur admission mais ont quitté l'hôpital sous une statine.Leur valeur de LDL-C à l'entrée s'élevait à 3,8 ± 1 mmol/l et à 2,3 ± 0,8mmol/l au contrôle de 3 mois.Conclusion: Chez les patients hospitalisés pour un SCA mais sanstraitement par statine préalable, les résultats montrent une bonneadéquation (peut-être liée au hasard au vu d'une prescriptionstandardisée) entre le traitement prescrit et l'obtention d'un LDL-C ciblesouhaitable à 3 mois. Chez les patients déjà sous traitement de statine,les résultats montrent une faible baisse du LDL-C à 3 mois malgré leurrisque cardio-vasculaire plus élevé. Une prise en charge individualiséesemble d'autant plus nécessaire que le risque est élevé.

Descriptive epidemiology of Cornelia de Lange syndrome in Europe.

Cornelia de Lange syndrome (CdLS) is a multiple congenital anomaly/mental retardation syndrome consisting of characteristic dysmorphic features, microcephaly, hypertrichosis, upper limb defects, growth retardation, developmental delay, and a variety of associated malformations. We present a population-based epidemiological study of the classical form of CdLS. The data were extracted from the database of European Surveillance of Congenital Anomalies (EUROCAT) database, a European network of birth defect registries which follow a standard methodology. Based on 23 years of epidemiologic monitoring (8,558,346 births in the 1980-2002 period), we found the prevalence of the classical form of CdLS to be 1.24/100,000 births or 1:81,000 births and estimated the overall CdLS prevalence at 1.6-2.2/100,000. Live born children accounted for 91.5% (97/106) of cases, fetal deaths 2.8% (3/106), and terminations of pregnancy following prenatal diagnosis 5.7% (6/106). The most frequent associated congenital malformations were limb defects (73.1%), congenital heart defects (45.6%), central nervous system malformations (40.2%), and cleft palate (21.7%). In the last 11 years, as much as 68% of cases with major malformations were not detected by routine prenatal US. Live born infants with CdLS have a high first week survival (91.4%). All patients were sporadic. Maternal and paternal age did not seem to be risk factors for CdLS. Almost 70% of patients, born after the 37th week of gestation, weighed <or=2,500 g. Low birth weight correlated with a more severe phenotype. Severe limb anomalies were significantly more often present in males.

Syndrome métabolique, une maladie mitochondriale? [Metabolic syndrome, a mitochondrial disease?]

Le syndrome métabolique (SM) associe dyslipidémie, hypertension, intolérance au glucose, état pro-inflammatoire/prothrombotique et surpoids, dont nous vous présentons une hypothèse physiopathologique émergente. Des recherches récentes ont montré que des dysfonctions mitochondriales induisent l'accumulation intracellulaire d'acylCoA et de diacylglycérol, inactivant la signalisation de l'insuline par un effet direct sur les transporteurs du glucose insulino-dépendants. Un défaut de la phosphorylation oxydative conduirait à l'insulino-résistance. Des atteintes de la fonction mitochondriale sont présentes dans le muscle, le foie, le pancréas et les vaisseaux sanguins et contribuent aux manifestations cliniques. Ces observations des atteintes mitochondriales nous montrent un lien entre la clinique et la physiopathologie du SM. The metabolic syndrome is a cluster of metabolic risk factors including: atherogenic dyslipidemia, elevated blood pressure, high plasma glucose and a prothrombotic and proinflammatory state, frequently associated to overweight. Impaired cell metabolism has been suggested as a relevant pathophysiological process. Indeed, the accumulation of intracellular fatty acylCoA and diacylglycerol, which then activate critical signal transduction pathways that ultimatly lead to suppression of insulin signalisation. Therefore a defect in mitochondrial function may be responsible for insulin resistance. Moreover, mitochondrial dysfunction has been found to take place in organs such as skeletal muscle, liver, pancreas and smoth vascular cells suggesting that mitochondrial defect could play a critical role in the occurence of cardiovascular diseases.

Identification of the first nonsense CDSN mutation with expression of a truncated protein causing peeling skin syndrome type B.

BACKGROUND: Peeling skin disease (PSD), a generalized inflammatory form of peeling skin syndrome, is caused by autosomal recessive nonsense mutations in the corneodesmosin gene (CDSN). OBJECTIVES: To investigate a novel mutation in CDSN. METHODS: A 50-year-old white woman showed widespread peeling with erythema and elevated serum IgE. DNA sequencing, immunohistochemistry, Western blot and real-time polymerase chain reaction analyses of skin biopsies were performed in order to study the genetics and to characterize the molecular profile of the disease. RESULTS: Histology showed hyperkeratosis and acanthosis of the epidermis, and inflammatory infiltrates in the dermis. DNA sequencing revealed a homozygous mutation leading to a premature termination codon in CDSN: p.Gly142*. Protein analyses showed reduced expression of a 16-kDa corneodesmosin mutant in the upper epidermal layers, whereas the full-length protein was absent. CONCLUSIONS: These results are interesting regarding the genotype-phenotype correlations in diseases caused by CDSN mutations. The PSD-causing CDSN mutations identified heretofore result in total corneodesmosin loss, suggesting that PSD is due to full corneodesmosin deficiency. Here, we show for the first time that a mutant corneodesmosin can be stably expressed in some patients with PSD, and that this truncated protein is very probably nonfunctional.

Hyperferritinémie associée au syndrome métabolique: une nouvelle cible thérapeutique [Dysmetabolic hyperferritinemia: a new target for treatment?].

Dysmetabolic hyperferritinemia is currently the most frequent cause of elevated ferritin levels in the general population. Whether dysmetabolic hyperferritinemia is a cause or an effect of insulin resistance is still a matter of debate. Still, several findings have been well established: increased iron intake or elevated ferritin levels are individual risk factors for diabetes, metabolic syndrome or gestational diabetes. When in presence of dysmetabolic hyperferritinemia, a small number of randomized controlled trials have suggested that therapeutic measures aimed at reducing ferritin levels such as low red meat consumption, deferoxamin or therapeutic phlebotomies have shown a beneficial effect on glucose homeostasis, lipid profile and impaired hepatic markers observed in non-alcoholic steatohepatitis.

Circulating matrix γ-carboxyglutamate protein (MGP) species are refractory to vitamin K treatment in a new case of Keutel syndrome.

Summary.  Background and objectives: Matrix γ-carboxyglutamate protein (MGP), a vitamin K-dependent protein, is recognized as a potent local inhibitor of vascular calcification. Studying patients with Keutel syndrome (KS), a rare autosomal recessive disorder resulting from MGP mutations, provides an opportunity to investigate the functions of MGP. The purpose of this study was (i) to investigate the phenotype and the underlying MGP mutation of a newly identified KS patient, and (ii) to investigate MGP species and the effect of vitamin K supplements in KS patients. Methods: The phenotype of a newly identified KS patient was characterized with specific attention to signs of vascular calcification. Genetic analysis of the MGP gene was performed. Circulating MGP species were quantified and the effect of vitamin K supplements on MGP carboxylation was studied. Finally, we performed immunohistochemical staining of tissues of the first KS patient originally described focusing on MGP species. Results: We describe a novel homozygous MGP mutation (c.61+1G>A) in a newly identified KS patient. No signs of arterial calcification were found, in contrast to findings in MGP knockout mice. This patient is the first in whom circulating MGP species have been characterized, showing a high level of phosphorylated MGP and a low level of carboxylated MGP. Contrary to expectations, vitamin K supplements did not improve the circulating carboxylated MGP levels. Phosphorylated MGP was also found to be present in the first KS patient originally described. Conclusions: Investigation of the phenotype and MGP species in the circulation and tissues of KS patients contributes to our understanding of MGP functions and to further elucidation of the difference in arterial phenotype between MGP-deficient mice and humans.

False negative apraclonidine test in two patients with Horner syndrome

BACKGROUND: Because of denervation supersensitivity, a miotic pupil in a sympathetically-denervated eye dilates in response to a dilute or weak alpha-1-agonist drug. A reversal of anisocoria after topical apraclonidine is considered as a positive test result that diagnoses a unilateral Horner syndrome. HISTORY AND SIGNS: Two women aged 34 and 46 years with a cocaine-confirmed oculosympathetic defect (Horner syndrome) were tested with 1 % topical apraclonidine on separate days. THERAPY AND OUTCOME: In one patient, her miotic Horner pupil dilated marginally but not enough to reverse the baseline anisocoria. Additionally, the upper lid on the same side retracted. There was no discernable effect of apraclonidine on the normal, contralateral eye. In the second patient, there was no pupillary response to apraclonidine but there was resolution of her ptosis. CONCLUSIONS: Neither patient demonstrated a reversal of anisocoria, the current criterion for diagnosing a Horner syndrome using apraclonidine. Thus, these two patients with an established oculosympathetic defect were said to have a "negative test" for Horner syndrome. Yet both women showed subtle pupil and/or lid changes in response to apraclonidine that were consistent with sympathetic denervation supersensitivity. Reversal of anisocoria following topical apraclonidine does not occur in all patients with a unilateral oculosympathetic defect and more specific parameters for defining a positive test result might optimize apraclonidine's utility as a diagnostic test for Horner syndrome

Syndrome de Cogan : à propos d'un cas et brève revue de la littérature [Cogan's Syndrome]

We report the case of a 20-year-old woman, with no medical history, who in a short period of time developed the association of a bilateral vestibulocochlear deficit and a nonsyphilitic interstitial keratitis, the usual clinical presentation of Cogan's syndrome. This rare disease was named after David Cogan, the ophthalmologist to whom we owe the description of the first series of cases. The precise aetiology of Cogan's syndrome has yet to be defined, but clinical and biological evidence point toward an immunopathological process. Some authors distinguish between a typical and an atypical form of Cogan's syndrome, the former being associated with interstitial keratitis, the latter with other forms of ocular involvement. The diagnosis of Cogan's syndrome is mainly a clinical one, the association of a bilateral vestibulocochlear deficit and a non-syphilitic keratitis being almost specific. Cogan's syndrome is frequently associated with general signs and cardiovascular, neurological, rheumathological and digestive involvement. Laboratory data usually show nonspecific inflammatory signs (elevation of the white cell count and of the erythrocyte sedimentation rate). The mortality of the disease is essentially determined by its cardiovascular involvement, mostly aortic insufficiency, which should therefore actively be sought for in every patient. It is useful to emphasise that the typical form of Cogan's syndrome carries a higher risk regarding the development of aortic insufficiency, whereas the atypical form is more often associated with a systemic vasculitis. Treatment is mandatory, based upon corticosteroids, and must sometimes be intensified by the administration of a steroid-sparing immunosuppressive drug. Although our patient perfectly met the diagnostic criteria of Cogan's syndrome, the vestibular symptoms preceded the visual complaints, the reverse temporal sequence being more often reported in the literature. Systemic signs and cardiovascular involvement are frequently seen in Cogan's syndrome, but were notably absent in our patient. Blood samples showed inflammatory signs, whereas both lumbar puncture and cerebral MRI were normal, which is the usual pattern encountered in Cogan's syndrome. Following the rapid initiation of immunosuppressive therapy (Prednisone), the visual symptoms due to the bilateral keratitis resolved in a matter of days, whereas the vestibulocochlear deficit was only partly - but dramatically - reduced. This is in accordance with literature data, showing that a severe and permanent auditory deficit occurs at some time in the majority of patients suffering from Cogan's syndrome. Tapering off Prednisone unfortunately reactivated the audiovestibular and ocular symptoms of the disease in our patient so that a steroid-sparing immunosuppressive drug had to be added (azathioprine, followed by mycophenolate mofetil because the patient developed hepatic intolerance). Only after these therapeutic measures could the disease be stabilised. With this case report, we would like to emphasise the importance of rapidly identifying the clinical picture of Cogan's syndrome, so that immunosuppressive therapy can be started without delay, which may significantly reduce both morbidity and mortality of this disease.