Autosomal dominant spondylocarpotarsal synostosis syndrome: phenotypic homogeneity and genetic heterogeneity.

Spondylocarpotarsal synostosis syndrome (SCT) (OMIM 272460), originally thought to be a failure of normal spine segmentation, is characterized by progressive fusion of vertebras and associates unsegmented bars, scoliosis, short stature, carpal and tarsal synostosis. Cleft palate, sensorineural or mixed hearing loss, joint limitation, clinodactyly, and dental enamel hypoplasia are variable manifestations. Twenty-five patients have been reported. Thirteen affected individuals were siblings from six families and four of these families were consanguineous. In four of those families, Krakow et al. [Krakow et al. (2004) Nat Genet 36:405-410] found homozygosity or compound heterozygosity for mutations in the gene encoding FLNB. This confirmed autosomal recessive inheritance of the disorder. We report on two new patients (a mother and her son) representing the first case of autosomal dominant inheritance. These patients met the clinical and radiological criteria for SCT and did not present any features which could exclude this diagnosis. Molecular analysis failed to identify mutations in NOG and FLNB. SCT is therefore, genetically heterogeneous. Both dominant and autosomal recessive forms of inheritance should be considered during genetic counseling.

A structural MRI study of motor conversion disorder: evidence of reduction in thalamic volume.

OBJECTIVE: To investigate potential abnormalities in subcortical brain structures in conversion disorder (CD) compared with controls using a region of interest (ROI) approach. METHODS: Fourteen patients with motor CD were compared with 31 healthy controls using high-resolution MRI scans with an ROI approach focusing on the basal ganglia, thalamus and amygdala. Brain volumes were measured using Freesurfer, a validated segmentation algorithm. RESULTS: Significantly smaller left thalamic volumes were found in patients compared with controls when corrected for intracranial volume. These reductions did not vary with handedness, laterality, duration or severity of symptoms. CONCLUSIONS: These differences may reflect a primary disease process in this area or be secondary effects of the disorder, for example, resulting from limb disuse. Larger, longitudinal structural imaging studies will be required to confirm the findings and explore whether they are primary or secondary to CD.

Differentiating schizoaffective and bipolar I disorder in first-episode psychotic mania.

OBJECTIVE: This study aims to differentiate schizoaffective disorder (SAD) and bipolar-I-disorder (BD) in first-episode psychotic mania (FEPM). METHODS: All 134 patients from an epidemiological first-episode psychosis cohort (N=786) with FEPM and an 18-month follow-up final diagnosis of SAD (n=36) or BD (n=98) were assessed with respect to pre-treatment, baseline and outcome differences. Second, patients with baseline BD who shifted (shifted BD) or did not shift to SAD (stable BD) over the follow-up period were compared regarding pre-treatment and baseline differences. RESULTS: SAD patients displayed a significantly longer duration of untreated psychosis (DUP; effect size r=0.35), a higher illness-severity at baseline (r=0.20) and more traumatic events (Cramer-V=0.19). SAD patients displayed a significantly higher non-adherence rate (Cramer-V=0.19); controlling for time in treatment and respective baseline scores, SAD patients had significantly worse illness severity (CGI-S; partial η(2)=0.12) and psychosocial functioning (GAF; partial η(2)=0.07) at 18-months, while BD patients were more likely to achieve remission of positive symptoms (OR=4.9, 95% CI=1.8-13.3; p=0.002) and to be employed/occupied (OR=7.7, 95% CI=2.4-24.4, p=0.001). The main discriminator of stable and shifted BD was a longer DUP in patients shifting from BD to SAD. CONCLUSIONS: It is difficult to distinguish BD with psychotic symptoms and SAD in patients presenting with FEPM. Longer DUP is related to SAD and to a shift from BD to SAD. Compared to BD, SAD had worse outcomes and higher rates of non-adherence with medication. Despite these differences, both diagnostic groups need careful dimensional assessment and monitoring of symptoms and functioning in order to choose the right treatment.

Budd-Chiari syndrome due to prothrombotic disorder: mid-term patency and efficacy of endovascular stents.

Our objective was to evaluate efficacy and patency of metallic stent placement for symptomatic Budd-Chiari syndrome (BCS) due to prothrombotic disorders. Eleven patients with proved BCS due to prothrombotic disorders were referred for endovascular treatment because of refractory ascites (n=9), abdominal pain (n=8), jaundice (n=6), and/or gastrointestinal bleeding (n=4). Stents were inserted for stenosed hepatic vein (n=7), inferior vena cava (n=2), or mesenterico-caval shunt (n=2). Clinical efficacy and stent patency was evaluated by clinical and Doppler follow-up. After a mean follow-up of 21 months, 6 patients had fully patent stents without reintervention (primary stent patency: 55%). Two patients with hepatic vein stenosis had stent thrombosis and died 4 months after procedure. Restenosis occurred in 3 cases (2 hepatic vein and 1 mesenterico-caval shunt stenosis) and were successfully treated by balloon angioplasty (n=2) and addition of new stents (n=1) leading to a 82% secondary stent patency. Of 9 patients with patent stent, 7 were asymptomatic (77%) at the end of the study. Stent placement is a safe and effective procedure to control of symptomatic BCS. Prothrombotic disorder does not seem to jeopardize patency in anticoagulated patients.

Treating tobacco use and dependence in clinical practice.

Physicians are in a unique position to advise smokers to quit by the ability to integrate the various aspects of nicotine dependence. This review provides an overview of the intervention strategies for smokers presented in a primary care setting. The strategies that are used for smoking cessation counselling differ according to the patient's readiness to quit. For smokers who do not intend to give up smoking, physicians should inform about tobacco use and the benefits of cessation. For smokers who are dissonant, physicians should use motivational strategies, such as discussing the barriers to successful cessation and their solutions. For smokers who are ready to quit, the physician should show strong support, help set a date to quit, prescribe pharmaceutical therapies for nicotine dependence, such as nicotine replacement therapy (i.e., gum, transdermal patch, nasal spray, mouth inhaler, lozenges, and micro and sublingual tablets) and/or bupropion (an atypical antidepressant thought to work by blocking the neural re-uptake of dopamine and/or noradrenaline), with instructions for use, and suggest behavioural strategies to prevent relapse. The efficacy of all of these pharmacotherapies is comparable, roughly doubling the cessation rates over control conditions.

Life events in conversion disorder: Role of timing and nature of events

Aims: To compare the frequency of life events in the year preceding illness onset in a series of Conversion Disorder (CD) patients, with those of a matched control group and to characterize the nature of those events in terms of "escape" potential. Traditional models of CD hypothesise that relevant stressful experiences are "converted" into physical symptoms to relieve psychological pressure, and that the resultant disability allows "escape" from the stressor, providing some advantage to the individual. Methods: The Life Events and Difficulties Schedule (LEDS) is a validated semi-structured interview designed to minimise recall and interviewer bias through rigorous assessment and independent rating of events. An additional "escape" rating was developed. Results: In the year preceding onset in 25 CD patients (mean age 38.9 years ± 8) and a similar matched period in 13 controls (mean age 36.2 years ± 10), no significant difference was found in the proportion of subjects having ≥ 1 severe event (CD 64%, controls 38%; p=0.2). In the last month preceding onset, a higher number of patients experienced ≥1 severe events than controls (52% vs 15%, odds ratio 5.95 (CI: 1.09-32.57)). Patients were twice as much more likely to have a severe escape events than controls, in the month preceding onset (44% vs 7%, odds ratio 9.43 (CI: 1.06-84.04). Conclusion: Preliminary data from this ongoing study suggest that the time frame (preceding month) and the nature ("escape") of the events may play an important role in identifying key events related to CD onset.

Extreme self-monitoring, fear of hypoglycemia and obsessive-compulsive disorder in type 1 diabetes mellitus: when less is better

Background: Pre-existing psychological factors can strongly influence coping with type 1 diabetes mellitus and interfere with self-monitoring. Psychiatric disorders seem to be positively associated with poor metabolic control. We present a case of extreme compulsive blood testing due to obsessive fear of hypoglycemia in an adolescent with type 1 diabetes mellitus. Case report: Type 1 diabetes mellitus (anti GAD-antibodies 2624 U/l, norm < 9.5) was diagnosed in a boy aged 14.3 years [170 cm (+ 0.93 SDS), weight 50.5 kg (+ 0.05 SDS)]. Laboratory work-up showed no evidence for other autoimmune disease. Family and past medical history were unremarkable. Growth and developmental milestones were normal. Insulin-analog based basal-bolus regime was initiated, associated to standard diabetic education. Routine psychological evaluation performed at the onset of diabetes revealed intermittent anxiety and obsessivecompulsive traits. Accordingly, a close psychiatric follow-up was initiated for the patient and his family. An adequate metabolic control (HbA1c drop from >14 to 8%) was achieved within 3 months, attributed to residual -cell function. In the following 6 months, HbA1c rose unexpectedly despite seemingly adequate adaptations of insulin doses. Obsessive fear of hypoglycemia leading to a severe compulsive behavior developed progressively with as many as 68 glycemia measurements per day (mean over 1 week). The patient reported that he could not bear leaving home with glycemia < 15 mmol/l, ending up with school eviction and severe intra-familial conflict. Despite intensive psychiatric outpatient support, HbA1c rose rapidly to >14% with glycemia-testing reaching peaks of 120 tests/day. The situation could only be discontinued through psychiatric hospitalization with intensive behavioral training. As a result, adequate metabolic balance was restored (HbA1c value: 7.1 %) with acceptable 10-15 daily glycemia measurements. Discussion: The association of overt psychiatric disorders to type 1 diabetes mellitus is very rare in the pediatric age group. It can lead to a pathological behavior with uncontrolled diabetes. Such exceptional situations require long-term admissions with specialized psychiatric care. Slow acceptation of a "less is better" principle in glycemia testing and amelioration of metabolic control are difficult to achieve.

Stage managing bipolar disorder.

OBJECTIVES: Clinical staging is widespread in medicine - it informs prognosis, clinical course, and treatment, and assists individualized care. Staging places an individual on a probabilistic continuum of increasing potential disease severity, ranging from clinically at-risk or latency stage through first threshold episode of illness or recurrence, and, finally, to late or end-stage disease. The aim of the present paper was to examine and update the evidence regarding staging in bipolar disorder, and how this might inform targeted and individualized intervention approaches. METHODS: We provide a narrative review of the relevant information. RESULTS: In bipolar disorder, the validity of staging is informed by a range of findings that accompany illness progression, including neuroimaging data suggesting incremental volume loss, cognitive changes, and a declining likelihood of response to pharmacological and psychosocial treatments. Staging informs the adoption of a number of approaches, including the active promotion of both indicated prevention for at-risk individuals and early intervention strategies for newly diagnosed individuals, and the tailored implementation of treatments according to the stage of illness. CONCLUSIONS: The nature of bipolar disorder implies the presence of an active process of neuroprogression that is considered to be at least partly mediated by inflammation, oxidative stress, apoptosis, and changes in neurogenesis. It further supports the concept of neuroprotection, in that a diversity of agents have putative effects against these molecular targets. Clinically, staging suggests that the at-risk state or first episode is a period that requires particularly active and broad-based treatment, consistent with the hope that the temporal trajectory of the illness can be altered. Prompt treatment may be potentially neuroprotective and attenuate the neurostructural and neurocognitive changes that emerge with chronicity. Staging highlights the need for interventions at a service delivery level and implementing treatments at the earliest stage of illness possible.

Genome-wide association study of recurrent major depressive disorder in two European case-control cohorts.

Major depressive disorder (MDD) is a highly prevalent disorder with substantial heritability. Heritability has been shown to be substantial and higher in the variant of MDD characterized by recurrent episodes of depression. Genetic studies have thus far failed to identify clear and consistent evidence of genetic risk factors for MDD. We conducted a genome-wide association study (GWAS) in two independent datasets. The first GWAS was performed on 1022 recurrent MDD patients and 1000 controls genotyped on the Illumina 550 platform. The second was conducted on 492 recurrent MDD patients and 1052 controls selected from a population-based collection, genotyped on the Affymetrix 5.0 platform. Neither GWAS identified any SNP that achieved GWAS significance. We obtained imputed genotypes at the Illumina loci for the individuals genotyped on the Affymetrix platform, and performed a meta-analysis of the two GWASs for this common set of approximately half a million SNPs. The meta-analysis did not yield genome-wide significant results either. The results from our study suggest that SNPs with substantial odds ratio are unlikely to exist for MDD, at least in our datasets and among the relatively common SNPs genotyped or tagged by the half-million-loci arrays. Meta-analysis of larger datasets is warranted to identify SNPs with smaller effects or with rarer allele frequencies that contribute to the risk of MDD.

Differences between first episode schizophrenia and schizoaffective disorder.

BACKGROUND: The diagnostic and clinical overlap between schizophrenia and schizoaffective disorder is an important nosological issue in psychiatry that is yet to be resolved. The aim of this study was to compare the clinical and functional characteristics of an epidemiological treated cohort of first episode patients with an 18-month discharge diagnosis of schizophrenia (FES) or schizoaffective disorder (FESA). METHODS: This study was part of the larger First Episode Psychosis Outcome Study (FEPOS) which involved a medical file audit study of all 786 patients treated at the Early Psychosis Prevention and Intervention Centre between 1998 and 2000. Of this cohort, 283 patients had an 18-month discharge diagnosis of FES and 64 had a diagnosis of FESA. DSM-IV diagnoses and clinical and functional ratings were derived and validated by two consultant psychiatrists. RESULTS: Compared to FES patients, those with FESA were significantly more likely to have a later age of onset (p=.004), longer prodrome (p=.020), and a longer duration of untreated psychosis (p<.001). At service entry, FESA patients presented with a higher illness severity (p=.020), largely due to the presence of more severe manic symptoms (p<.001). FESA patients also had a greater number of subsequent inpatient admissions (p=.017), had more severe depressive symptoms (p=.011), and higher levels of functioning at discharge. DISCUSSION: The findings support the notion that these might be considered two discernable disorders; however, further research is required to ascertain the ways and extent to which these disorders are discriminable at presentation and over time.

Molecular genetics of narcolepsy

1 Abstract Sleep is a vital necessity, yet its basic physiological function is still unknown, despite numerous studies both in healthy humans and animal models. The study of patients with sleep disorders may help uncover major biological pathways in sleep regulation and thus shed light on the actual function of sleep. Narcolepsy is a well defined but rare sleep disorder characterized by excessive daytime sleepiness and cataplexy, thought to be caused by a combination of genetic and environmental factors. The aim of this work was to identify genes or genetic variants, which contribute to the pathogenesis of sporadic and familial narcolepsy. Sporadic narcolepsy is the disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1 *1501-DQB1 *0602 haplotype is common in the general population (15-25%), it has been suggested that it is necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2. Further analysis revealed that the identified SNP is strongly linked to DRB1*03-DQB1*02 and DRBΠ 301-DQB1*0603. Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype. This unexpected protective HLA haplotype suggests a causal involvement of the HLA region in narcolepsy susceptibility. Familial cases of narcolepsy account for 10% of all narcolepsy cases. However, due to low number of affected family members, narcolepsy families are usually not eligible for genetic linkage studies. We identified and characterized a large Spanish family with 11 affected family members representing the largest ever reported narcolepsy family. We ran a genetic linkage analysis using DNA of 11 affected and 15 unaffected family members and hereby identified a chromosomal candidate region on chromosome 6 encompassing 163 kb with a maximum multipoint LOD score of 5.02. The coding sequences of 4 genes within this haplotype block as well as 2 neighboring genes were screened for pathogenetic mutations in 2 affected and 1 healthy family members. So far no pathogenic mutation could be identified. Further in-depth sequencing of our candidate region as well as whole genome exome sequencing are underway to identify the pathogenic mutation(s) in this family and will further improve our understanding of the genetic basis of narcolepsy. 2 Résumé Le sommeil est un processus vital, dont la fonction physiologique est encore inconnue, malgré de nombreuses études chez des sujets humains sains ainsi que dans des modèles animaux. L'étude de patients souffrant de troubles du sommeil peut permettre la découverte de voies biologiques jouant un rôle majeur dans la régulation du sommeil. L'un de ces troubles, la narcolepsie, est une maladie rare mais néanmoins bien définie, caractérisée par une somnolence diurne excessive accompagnée de cataplexies. Les connaissances actuelles suggèrent qu'une combinaison de facteurs génétiques et environnementaux en est à l'origine. Le but du présent travail était d'identifier !e(s) gène(s) ou les polymorphismes constituant des facteurs de risque dans les formes sporadique et familiale de narcolepsie. La narcolepsie sporadique est la maladie possédant la plus forte association avec le complexe majeur d'histocompatibilité humain (HLA) jamais reportée. La fréquence au sein de la population générale de l'haplotype associé HLA-DRB1*1501- DQB1*0602 (15-25%) suggère que ce dernier est nécessaire, mais pas suffisant, pour (e développement de la maladie. Nous avons voulu approfondir la recherche de facteurs génétiques augmentant le risque de la narcolepsie. A cette fin, nous avons entrepris une étude d'association à l'échelle du génome (genome-wide association study, GWAS) parmi 562 sujets narcoleptiques européens (cas) et 702 individus contrôle de même origine ethnique et nous avons trouvé une association avec un variant protecteur près du gène HLA- DQA2. Ce résultat a été répliqué indépendamment dans 370 cas et 495 contrôles, tous hétérozygotes au locus DRB1*1501-DQB1*0602. Une analyse plus fine montre que le polymorphisme identifié est fortement lié aux allèles DRB1*03-DQB1*02 et DRB1*1301-DQB1*0603. Nous notons que seul un cas était porteur d'un haplotype en trans DRB1*1301-DQBr0603. La découverte de cet allele HLA protecteur suggère que la région HLA joue un rôle causal dans la susceptibilité à la narcolepsie. Dix pourcents des cas de narcolepsie sont familiaux. Cependant, le faible nombre de membres affectés rend ces familles inéligibles pour des études de liaison génétique. Nous avons identifié et caractérisé une grande famille espagnole, dont 11 membres sont atteints par la maladie, ce qui représente la plus grande famille narcoleptique rapportée jusqu'à ce jour. A partir de l'ADN de 11 membres atteints et 15 non- atteints, nous avons identifié par étude de liaison une région candidate de 163 kîlobases (kb) sur le chromosome 6, correspondant à un LOD score multipoints de 5.02. Nous avons cherché, sans succès, des mutations pathogéniques dans la séquence codante de deux gènes situés à l'intérieur de ce segment, ainsi que 4 gènes adjacents. Un séquençage plus approfondi de la région ainsi que le séquençage des exons de tout le génome est en cours et doit s'avérer plus fructueux et révéler la ou tes mutation(s) pathogénique(s) dans cette famille, ce qui contribuerait à une meilleure compréhension des causes génétiques de la narcolepsie. 3 Résumé pour un large public Le sommeil est une nécessité vitale, dont le rôle physiologique exact reste inconnu malgré de nombreuses études sur des sujets humains sains ainsi que sur des modèles animaux. C'est pourquoi les troubles du sommeil intéressent les chercheurs, car l'élucidation des mécanismes responsables peut permettre de mieux comprendre le fonctionnement du sommeil normal. La narcolepsie est une maladie du sommeil caractérisée par une somnolence diurne excessive. Les personnes atteintes peuvent s'endormir involontairement à tout moment de la journée, et souffrent également de pertes du tonus musculaire (cataplexie) lors de fortes émotions, par exemple un fou rire. La narcolepsie est une maladie rare, apparaissant dans 1 personne sur 2000. Les connaissances actuelles suggèrent qu'une combinaison de facteurs génétiques et environnementaux en est à l'origine. Nous avons voulu identifier les facteurs génétiques influençant le déclenchement de la maladie, d'abord dans sa forme sporadique, puis dans une famille comptant de nombreux membres atteints. En comparant les variations génétiques de près de 1000 sujets narcoleptiques européens avec ceux de 1200 individus sains, nous avons trouvé chez 30% de ces derniers un variant protecteur, qui diminue de 50 fois le risque de développer la maladie, ce qui constitue le plus puissant facteur génétique protecteur décrit à ce jour. Nous avons ensuite étudié une grande famille espagnole comptant une trentaine de membres, dont 11 sont atteints de narcolepsie. De nouveau, nous avons comparé les variations génétiques des membres atteints avec ceux des membres sains. Nous avons ainsi pu identifier une région dans le génome où se trouverait le(s) gène(s) impliqué(s) dans la maladie dans cette famille, mais n'avons pas encore trouvé le(s) variant(s) exact(s). Une étude plus approfondie devrait permettre de P(les) identifier et ainsi contribuer à l'élucidation des mécanismes menant au développement de la narcolepsie.