Monogenic diabetes in adults: A multi-ancestry study reveals strong disparities in diagnosis rates and clinical presentation.

AIM: Identification of monogenic diabetes (MgD) conveys benefits for patients' care. Algorithms for selecting the patients to be genetically tested have been established in EuroCaucasians, but not in non-EuroCaucasian individuals. We assessed the diagnosis rate, the phenotype of MgD, and the relevance of selection criteria, according to ancestry in patients referred for a suspected MgD. METHODS: Seven genes (GCK, HNF1A, HNF4A, HNF1B, ABCC8, KCNJ11, INS) were analyzed in 1975 adult probands (42% non-EuroCaucasians), selected on the absence of diabetes autoantibodies and ≥2 of the following criteria: age ≤40 years and body mass index <30 kg/m2 at diagnosis, and a family history of diabetes in ≥2 generations. RESULTS: Pathogenic/likely pathogenic variants were identified in 6.2% of non-EuroCaucasian and 23.6% of EuroCaucasian patients (OR 0.21, [0.16-0.29]). Diagnosis rate was low in all non-EuroCaucasian subgroups (4.1-11.8%). Common causes of MgD (GCK, HNF1A, HNF4A), but not rare causes, were less frequent in non-EuroCaucasians than in EuroCaucasians (4.1%, vs. 21.1%, OR 0.16 [0.11-0.23]). Using ethnicity-specific body mass index cutoffs increased the diagnosis rate in several non-EuroCaucasian subgroups. CONCLUSION: The diagnosis rate of MgD is low in non-EuroCaucasian patients, but may be improved by tailoring selection criteria according to patients'ancestry.

Unusual severe radiation-induced toxicity in a patient with discoid lupus erythematosus: A case report and critical review of the literature.

Data on the incidence and severity of radiation-induced toxicity in patients with systemic and/or cutaneous lupus erythematosus (SLE/CLE) are very limited. After reporting the case of a patient who experienced major toxicity and CLE flare in the irradiated area following breast irradiation, we conducted a comprehensive literature review of available data in this setting. The few retrospectives studies which have evaluated both the risk of toxicity in SLE/CLE patients and/or the potential induction or reactivation of SLE/CLE with radiotherapy have not shown differences between SLE/CLE patients and controls. Several other factors such as concurrent chemotherapy, a particular genetic background, or lupus treatments (essentially hydroxychloroquine) can explain severe radiation-induced toxicity. Therefore, patients with SLE/CLE should be irradiated like patients without SLE/CLE, with close monitoring during radiotherapy if other risk factors exist. Further studies examining a larger number of patients would probably allow a better understanding of the radiosensitivity of these patients.

Characterizing the Subcortical Structures in Youth with Congenital Heart Disease.

BACKGROUND AND PURPOSE: Congenital heart disease is a leading cause of neurocognitive impairment. Many subcortical structures are known to play a crucial role in higher-order cognitive processing. However, comprehensive anatomic characterization of these structures is currently lacking in the congenital heart disease population. Therefore, this study aimed to compare the morphometry and volume of the globus pallidus, striatum, and thalamus between youth born with congenital heart disease and healthy peers. MATERIALS AND METHODS: We recruited youth between 16 and 24 years of age born with congenital heart disease who underwent cardiopulmonary bypass surgery before 2 years of age (n = 48) and healthy controls of the same age (n = 48). All participants underwent a brain MR imaging to acquire high-resolution 3D T1-weighted images. RESULTS: Smaller surface area and inward bilateral displacement across the lateral surfaces of the globus pallidus were concentrated anteriorly in the congenital heart disease group compared with controls (q < 0.15). On the lateral surfaces of bilateral thalami, we found regions of both larger and smaller surface areas, as well as inward and outward displacement in the congenital heart disease group compared with controls (q < 0.15). We did not find any morphometric differences between groups for the striatum. For the volumetric analyses, only the right globus pallidus showed a significant volume reduction (q < 0.05) in the congenital heart disease group compared with controls. CONCLUSIONS: This study reports morphometric alterations in youth with congenital heart disease in the absence of volume reductions, suggesting that volume alone is not sufficient to detect and explain subtle neuroanatomic differences in this clinical population.

Long-term survival in HER2-positive metastatic breast cancer treated with first-line trastuzumab: results from the french real-life curie database.

BACKGROUND: Outcome of HER2-positive metastatic breast cancer (MBC) patients has improved since the use of trastuzumab. However, most HER2-positive MBC patients will progress within 1 year of trastuzumab-based therapy. Only limited data are available concerning long-term responders. METHODS: The primary objective of this study was to compare overall survival (OS) of HER2+ MBC patients with long-term response to first-line trastuzumab with overall survival of those with non-long-term response, based on two institutional databases: the French Epidemiological Strategy and Medical Economics program and the Breast Database. Long-term responders (LTR) were defined as patients with non-progressive disease for ≥ 2 years on first-line trastuzumab. Secondary objectives included progression-free survival (PFS), and predictive factors for LTR status. RESULTS: From 2004 to 2014, 422 HER2-positive MBC patients received first-line trastuzumab. With a median follow-up of 48 months, median OS and PFS were 63 months (CI95%, 50-71), and 18 months (CI95%, 15-21) respectively. In 111 patients (26.3%) classified as LTR, median OS was 110 months (CI95%, 95-not reached) versus 56 months in non-LTR patients (CI95%, 47-68). In multivariate logistic regressions, the following factors were independently associated with LTR status: number of metastatic sites (≤ 2 versus > 2, p = 0.01); endocrine therapy for metastatic disease (p = 0.001) and taxane-based first-line chemotherapy (p = 0.003). CONCLUSION: Several features are associated with long-term response to trastuzumab: few metastatic sites, taxane-based chemotherapy and maintenance endocrine therapy in HR+ patients. Further studies are needed to identify patients in whom trastuzumab can be stopped after several years of sustained response.

[Misdiagnosis of hidradenitis suppurativa continues to be a major issue. The R-ENS Verneuil study]. / Errance médicale des patients atteints d'hidradénite suppurée : un problème majeur et persistant. Étude « R-ENS Verneuil ¼.

OBJECTIVE: To provide physicians with an understanding of the factors behind significant delays in the diagnosis of hidradenitis suppurativa (HS) in France. PATIENTS AND METHODS: This prospective multicentre national study conducted from October 2015 to March 2016 included all patients consulting for HS. Patient data were collected by means of a standardized questionnaire. Univariate and multivariate analyses were conducted to collect factors associated with a significant time to diagnosis of at least 5.5years, defined as the period between the onset of initial clinical signs and the time of formal diagnosis. RESULTS: The 16 participating centres enrolled 312 patients (62% women), of average age 35years. The average age at onset of HS was 22years. Before formal diagnosis by a dermatologist (64% of cases), 170 (54%), 114 (37%) and 45 (15%) patients had previously consulted at least 3, 5 and 10 general physicians, respectively. The average time between the initial clinical signs of HS, the first dermatology visit and the definitive diagnosis was 6.2 and 8.4 years, respectively. Active smoking (OR adjusted 1.85; P=0.027) and disease onset at a younger age (adjusted OR 0.92; P<0.001) were both associated with significant delays in diagnosis. CONCLUSION: These results emphasized misdiagnosis among HS patients but did not evidence any association between either sociodemographic or economic characteristics and the existence of significant times to diagnosis.

Brain Temperature Is Increased During the First Days of Life in Asphyxiated Newborns: Developing Brain Injury Despite Hypothermia Treatment.

BACKGROUND AND PURPOSE: Therapeutic hypothermia is the current treatment for neonates with hypoxic-ischemic encephalopathy. It is believed to work by decreasing the brain temperature and reducing the baseline metabolism and energy demand of the brain. This study aimed to noninvasively assess brain temperature during the first month of life in neonates with hypoxic-ischemic encephalopathy treated with hypothermia. MATERIALS AND METHODS: Neonates with hypoxic-ischemic encephalopathy treated with hypothermia and healthy neonates were enrolled prospectively. MR imaging was used to identify the presence and extent of brain injury. MR imaging multivoxel spectroscopy was used to derive brain temperatures in the basal ganglia and white matter at different time points during the first month of life. Brain temperature measurements were compared between neonates with hypoxic-ischemic encephalopathy and healthy neonates. RESULTS: Forty-three term neonates with hypoxic-ischemic encephalopathy treated with hypothermia had a total of 74 spectroscopy scans, and 3 healthy term neonates had a total of 9 spectroscopy scans during the first month of life. Brain temperatures were lower in neonates with hypoxic-ischemic encephalopathy during hypothermia, compared with the healthy neonates (respectively, on day 1 of life: basal ganglia, 38.81°C ± 2.08°C, and white matter, 39.11°C ± 1.99°C; and on days 2-3 of life: basal ganglia, 38.25°C ± 0.91°C, and white matter, 38.54°C ± 2.79°C). However, neonates with hypoxic-ischemic encephalopathy who developed brain injury had higher brain temperatures during hypothermia (respectively, on day 1 of life: basal ganglia, 35.55°C ± 1.31°C, and white matter, 37.35°C ± 2.55°C; and on days 2-3 of life: basal ganglia, 35.20°C ± 1.15°C, and white matter, 35.44°C ± 1.90°C) compared with neonates who did not develop brain injury (respectively, on day 1 of life: basal ganglia, 34.46°C ± 1.09°C, and white matter, 33.97°C ± 1.42°C; and on days 2-3 of life: basal ganglia, 33.90°C ± 1.34°C, and white matter, 33.07°C ± 1.71°C). Also, brain temperatures tended to remain slightly higher in the neonates who developed brain injury around day 10 of life and around 1 month of age. CONCLUSIONS: Therapeutic hypothermia using current guidelines decreased the brain temperature of neonates with hypoxic-ischemic encephalopathy during the first days of life but did not prevent an early increase of brain temperature in neonates with hypoxic-ischemic encephalopathy who developed brain injury despite this treatment.

High-sensitivity C-reactive protein does not improve the differential diagnosis of HNF1A-MODY and familial young-onset type 2 diabetes: A grey zone analysis.

AIM: Low plasma levels of high-sensitivity C-reactive protein (hs-CRP) have been suggested to differentiate hepatocyte nuclear factor 1 alpha-maturity-onset diabetes of the young (HNF1A-MODY) from type 2 diabetes (T2D). Yet, differential diagnosis of HNF1A-MODY and familial young-onset type 2 diabetes (F-YT2D) remains a difficult challenge. Thus, this study assessed the added value of hs-CRP to distinguish between the two conditions. METHODS: This prospective multicentre study included 143 HNF1A-MODY patients, 310 patients with a clinical history suggestive of HNF1A-MODY, but not confirmed genetically (F-YT2D), and 215 patients with T2D. The ability of models, including clinical characteristics and hs-CRP to predict HNF1A-MODY was analyzed, using the area of the receiver operating characteristic (AUROC) curve, and a grey zone approach was used to evaluate these models in clinical practice. RESULTS: Median hs-CRP values were lower in HNF1A-MODY (0.25mg/L) than in F-YT2D (1.14mg/L) and T2D (1.70mg/L) patients. Clinical parameters were sufficient to differentiate HNF1A-MODY from classical T2D (AUROC: 0.99). AUROC analyses to distinguish HNF1A-MODY from F-YT2D were 0.82 for clinical features and 0.87 after including hs-CRP. For the grey zone analysis, the lower boundary was set to miss<1.5% of true positives in non-tested subjects, while the upper boundary was set to perform 50% of genetic tests in individuals with no HNF1A mutation. On comparing HNF1A-MODY with F-YT2D, 65% of patients were classified in between these categories - in the zone of diagnostic uncertainty - even after adding hs-CRP to clinical parameters. CONCLUSION: hs-CRP does not improve the differential diagnosis of HNF1A-MODY and F-YT2D.

Injury to the Cerebellum in Term Asphyxiated Newborns Treated with Hypothermia.

BACKGROUND AND PURPOSE: Until now, most studies of brain injury related to term neonatal encephalopathy have focused on the cerebrum and ignored the cerebellum. We sought to evaluate whether cerebellar injury occurs in term asphyxiated neonates. MATERIALS AND METHODS: Asphyxiated neonates treated with hypothermia were enrolled prospectively. Severity of brain injury in the cerebrum was scored on each MR imaging obtained during the first month of life; cerebellar injury was recorded when mentioned in the imaging or autopsy report. In addition, for some of the neonates, the ADC and fractional anisotropy were measured in 4 regions of interest in the cerebellum. RESULTS: One hundred seventy-two asphyxiated neonates met the criteria for hypothermia. Cerebellar injury was visible only on conventional imaging of 4% of the neonates for whom brain imaging was available, but it was reported in the autopsy report of 72% of the neonates who died. In addition, 41 of the asphyxiated neonates had a total of 84 ADC and fractional anisotropy maps. Neonates with brain injury described only in the cerebrum demonstrated ADC and fractional anisotropy changes similar to those of the neonates with brain injury in the cerebrum and cerebellum--increased ADC around day 10 of life and decreased fractional anisotropy on day 2-3 of life, around day 10 of life, and around 1 month of age. CONCLUSIONS: The cerebellum may be injured in term neonates after birth asphyxia. These cerebellar injuries are only rarely visible on conventional imaging, but advanced neuroimaging techniques may help to identify them.

Monoallelic ABCC8 mutations are a common cause of diazoxide-unresponsive diffuse form of congenital hyperinsulinism.

ABCC8 encodes a subunit of the ß-cell potassium channel (KATP ) whose loss of function is responsible for congenital hyperinsulinism (CHI). Patients with two recessive mutations of ABCC8 typically have severe diffuse forms of CHI unresponsive to diazoxide. Some dominant ABCC8 mutations are responsible for a subset of diffuse diazoxide-unresponsive forms of CHI. We report the analysis of 21 different ABCC8 mutations identified in 25 probands with diazoxide-unresponsive diffuse CHI and carrying a single mutation in ABCC8. Nine missense ABCC8 mutations were subjected to in vitro expression studies testing traffic efficiency and responses of mutant channels to activation by MgADP and diazoxide. Eight of the 9 missense mutations exhibited normal trafficking. Seven of the 8 mutants reaching the plasma membrane had dramatically reduced response to MgADP or to diazoxide (<10% of wild-type response). In our cohort, dominant KATP mutations account for 22% of the children with diffuse unresponsive-diazoxide CHI. Their clinical phenotype being indistinguishable from that of children with focal CHI and diffuse CHI forms due to two recessive KATP mutations, we show that functional testing is essential to make the most reliable diagnosis and offer appropriate genetic counseling.

Risk factors and impact of orthopaedic monitoring on the outcome of avascular necrosis of the femoral head in adults with sickle cell disease: 215 patients case study with control group.

INTRODUCTION: Sickle cell disease is a public health problem. The WHO has recommended that global management be implemented to reduce mortality and morbidity. Since no comprehensive care programme for bone and joint complications exists, the Caribbean Sickle Cell Disease Center added orthopaedic consultation to screen for and monitor these complications in 1992. HYPOTHESIS: Comprehensive medical and surgical care of patients with sickle cell disease will reduce the complications and disability associated with this disease. POPULATIONS AND METHODS: Two populations were compared to evaluate the impact of comprehensive disease management on the occurrence of avascular necrosis (AVN) of the femoral head (femoral head AVN). The case-control series, [E-1994], included 115 patients (58 SS and 57 S) without orthopaedic monitoring and was evaluated retrospectively. The other patient series, [E-2008], included 215 patients (94 SS and 121 SC) with systematic orthopaedic care and was followed prospectively. Age, gender, duration of follow-up, haemoglobin levels, genotype, pain before treatment, associated humerus AVN and leg ulcers were analysed. RESULTS: Femoral head AVN occurred in young adult patients (35.3 ± 4 years for [E-1994] and 29 ± 3.4 years for [E-2008]). Only elevated haemoglobin levels were associated with the occurrence of femoral head AVN, which suggests that increased blood viscosity contributes to the condition ([E-1994], P<0.0001; [E-2008], P=0.001). Treatment in [E-2008] patients reduced the number of femoral head AVN cases from 36.5% in [E-1994] to 14.4% in [E-2008] (P<0.0001). DISCUSSION: The prevention and management of femoral head AVN must include medical treatment of the disease to reduce the occurrence of painful vaso-occlusive crises, which are known to trigger femoral head AVN. The effectiveness of this programme hinged on identifying risk factors and using simple approaches (hydration, pain medication, rest and crutches) to manage painful joint crises before femoral head AVN appeared. These approaches could be implemented in disadvantaged countries where sickle cell disease is prevalent. CONCLUSION: By knowing the risk factors, symptomatic patients who are at risk for femoral head AVN can be identified and additional evaluations can be performed early on in cases of hip pain.

Treatment-related morbidity in atypical teratoid/rhabdoid tumor: multifocal necrotizing leukoencephalopathy.

BACKGROUND: Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive malignant brain tumor that, since it was first identified, has been treated with aggressive treatment regimens, e.g. high-dose chemotherapy with stem cell rescue and early radiotherapy. We reviewed our experience because of concerns with respect to treatment-related toxicity in our patients. METHODS: Seven patients with a median age at presentation of 18 months were diagnosed with AT/RT between 1996 and 2006. Tumor location was supratentorial in 2 patients, in the posterior fossa in 4 and spinal in 1. Gross total resection was performed in 1 patient, subtotal resection in 5 and biopsy only in 1. Adjuvant treatment consisted of chemotherapy and radiotherapy in 5 patients. RESULTS: Median progression-free survival was 4 months, and median overall survival was 7 months. Two children are alive at 44 and 102 months. Significant surgical and chemotherapy-related morbidity was seen. Biopsy-proven multifocal necrotizing leukoencephalopathy (MNL) was seen in one patient who is alive 44 months after diagnosis. Another patient who was thought to have recurrent tumor in the brainstem 9 months after diagnosis had imaging findings compatible with MNL. CONCLUSION: Although improving results are reported for AT/RT using intensive treatment regimens, treatment-related morbidity is considerable in this young patient population.

Familial young-onset forms of diabetes related to HNF4A and rare HNF1A molecular aetiologies.

OBJECTIVE: 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. METHODS: 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). RESULTS: 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%). CONCLUSIONS: 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.

ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism.

BACKGROUND: Congenital hyperinsulinism (CHI) is characterised by an over secretion of insulin by the pancreatic ß-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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Familial cortical myoclonic tremor with epilepsy: the third locus (FCMTE3) maps to 5p.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Contribution of psychopathic traits to delinquent behaviors in a sample of high-school male students]. / Contribution des traits psychopathiques aux comportements délinquants dans un échantillon de garçons adolescents scolarisés.

UNLABELLED: The aim of this study was to evaluate the contribution of psychopathic personality traits to delinquent behaviour after controlling for borderline personality traits, depressive symptomatology, dissociation and cannabis use in male adolescent delinquent behaviour. METHOD: A sample of 155 young male participants (mean age=17+/-1.5) completed self-report questionnaires. Delinquent behaviour was assessed with the Antisocial behavior scales (ABS, Schawb-Stone et al., 1999) which include three subscales assessing behavior problems of different severity: conduct problems, assessing relatively mild behavior problems; less severe delinquency, assessing non-violent antisocial behavior; severe antisocial behavior, exploring relatively serious aggressive and antisocial behavior. The respondents were asked to report on a 5-point scale how many times (ranging from "0 times" to "5 or more times") they were involved in the described behaviors during the past year. In this study, only the two subscales assessing less severe delinquency and severe antisocial behavior were used. Personality psychopathic traits were assessed with the Youth psychopathic traits inventory (YPI; Andershed et al., 2002). It consists in three scales assessing interpersonal, affective (with callousness, which is considered as the core dimension of a psychopathy) and lifestyle traits of the psychopathic personality (alpha=0.90, alpha=0.81 and alpha=0.77, respectively). Other questionnaires assessed borderline personality traits (Borderline personality features scale for children), depression (Center for epidemiological studies-depression scale), dissociation (Adolescent dissociative experience scale) (alpha=0.83, 0.88 and 0.92 respectively) and cannabis use. RESULTS: In the present study, the frequency of antisocial behaviour was important (55%): 7% of the adolescents had stolen a bike or a car at least once, 11% had committed a theft at least once, 36% had started a fight at least once, and 25% had threatened someone seriously or beaten up somebody at least once, 15% had had hurt someone badly in a physical fight so they had to be treated by a doctor or a nurse at least once, 21% had carried a blade, knife or gun at least once, 9% had been involved in a gang fight at least once, and 12% had carried a blade, knife or gun in school. A multiple regression analysis predicting antisocial behaviour in the total sample with the psychopathic and borderline traits, depressive and dissociative symptoms, alcohol and cannabis use, showed that delinquent behaviours were only predicted by alcohol and cannabis use and the psychopathic trait "callousness". DISCUSSION: This study suggests the importance of callousness in explaining adolescent delinquent behaviour. Other psychopathological variables did not appear to influence delinquent behaviour in this sample.

Familial cortical myoclonic tremor with epilepsy (FCMTE): Clinical characteristics and exclusion of linkages to 8q and 2p in a large French family.

INTRODUCTION: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

[Contribution of dissociative symptoms to antisocial behavior in a sample of high-school students]. / Contributions des symptômes dissociatifs aux comportements antisociaux dans un échantillon d'adolescents scolarisés.

INTRODUCTION: The link between dissociative disorders and delinquent behavior has been reported in forensic and clinical adolescents. Despite the frequency of dissociative symptoms in nonclinical adolescents, the relation between dissociative disorders and antisocial behavior has not been studied in community samples of adolescents. AIM OF THE STUDY: The aim of this study is to investigate the relative contribution of dissociative symptoms and other psychopathological variables (depressive symptoms, borderline and psychopathic personality traits often reported to be associated with behavioral problems) to antisocial behavior in a sample of high-school students. METHOD: A sample of 130 participants (84 girls, 46 boys; mean age=16.9+/-1.2) completed self-report questionnaires, the adolescent-dissociative experience scale (A-DES), the center for epidemiological studies-depression scale (CES-D), the Levenson self-report psychopathy scale (LSRP), the scale of the personality disorder questionnaire (PDQ-4+) assessing the borderline personality traits, and the scale of the PDQ-4+ assessing antisocial behavior and antecedent of conduct disorder (aggression to people and animals, destruction of property, deceitfulness or theft, serious violations of rules) for the diagnosis of antisocial personality disorder. In the present study, the internal consistency of these scales was satisfactory or excellent as assessed using Cronbach's alpha. Regarding the A-DES, the CES-D, the borderline traits scale, the antisocial behavior scale, alphas were 0.94, 0.76, 0.78, and 0.91, respectively. The consistency of the LSRP scale assessing callousness (a callous, selfish, and manipulative use of others), which is considered as the core dimension of psychopathy was satisfactory (alpha=0.83), whereas the consistency of the scale assessing impulsivity was poor (alpha=0.49). This scale was not used in the present study. RESULTS: The comparison between boys and girls revealed the differences usually reported in studies on community samples of adolescents. Girls displayed higher scores on dissociative and depressive symptoms, and borderline traits. Boys had higher score on callousness. Among girls, dissociative symptoms were positively and moderately related to depressive symptoms (r=0.62, p<0.05), borderline traits [(r=0.62, p<.05), callousness (r=0.41, p<0.05). Among boys, these associations were weaker (depressive symptoms, (r=0.45, p<0.05); borderline traits, (r=0.47, p<0.05); callousness, (r=.24, NS)]. A multiple regression analysis predicting antisocial behavior with the psychopathological variables showed that sex was a significant predictor (p<0.01). The analysis was repeated for males and females separately. Among boys, the model explained a negligible fraction of the variance in antisocial behaviors (R(2)=0.12). No predictors were significant, perhaps because of the lack of power of this analysis (dissociative symptoms, beta=0.07, p=0.71; CES-D, beta=0.20, p=0.22; borderline traits, beta=0.19, p=0.30; callousness, beta=0.17, p=0.27). Among girls, the model explained a modest part of the variance (R(2)=0.30). Dissociative symptoms were the strongest predictor of antisocial behavior (beta=0.54, p<0.001). Depressive symptoms were significantly and negatively related to antisocial predictor (CES-D, beta=-0.36, p=0.006). Borderline traits (beta=0.08, p=0.54) and callousness (beta=0.18, p=0.009) were not significant predictors. DISCUSSION: As in other studies, antisocial behavior appeared more linked to psychopathological variables in girls than in boys. The most salient result was the influence of dissociative symptoms on antisocial behavior in girls contrary to boys. Three hypotheses may explain this link: dissociative symptoms may facilitate antisocial acting-outs; dissociation may be a defense against anger and affect dysregulation; antisocial behavior and dissociative symptoms may be linked to a third variable such as trauma antecedents. Whereas depressive symptoms were positively linked to antisocial behavior among boys, depressive symptoms were negatively and significantly linked to antisocial behavior among girls. Depressive symptoms may inhibit antisocial behavior in girls. The association between dissociative and depressive symptoms and antisocial behavior in girls warrants further studies.

Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients.

INTRODUCTION: Mutations in the voltage-gated sodium channel SCN1A gene are the main genetic cause of Dravet syndrome (previously called severe myoclonic epilepsy of infancy or SMEI). OBJECTIVE: To characterise in more detail the mutation spectrum associated with Dravet syndrome. METHODS: A large series of 333 patients was screened using both direct sequencing and multiplex ligation-dependent probe amplification (MLPA). Non-coding regions of the gene that are usually not investigated were also screened. RESULTS: SCN1A point mutations were identified in 228 patients, 161 of which had not been previously reported. Missense mutations, either (1) altering a highly conserved amino acid of the protein, (2) transforming this conserved residue into a chemically dissimilar amino acid and/or (3) belonging to ion-transport sequences, were the most common mutation type. MLPA analysis of the 105 patients without point mutation detected a heterozygous microrearrangement of SCN1A in 14 additional patients; 8 were private, partial deletions and six corresponded to whole gene deletions, 0.15-2.9 Mb in size, deleting nearby genes. Finally, mutations in exon 5N and in untranslated regions of the SCN1A gene that were conserved during evolution were excluded in the remaining negative patients. CONCLUSION: These findings widely expand the SCN1A mutation spectrum identified and highlight the importance of screening the coding regions with both direct sequencing and a quantitative method. This mutation spectrum, including whole gene deletions, argues in favour of haploinsufficiency as the main mechanism responsible for Dravet syndrome.