p.L1612P, a novel voltage-gated sodium channel Nav1.7 mutation inducing a cold sensitive paroxysmal extreme pain disorder.

BACKGROUND: Mutations in the SCN9A gene cause chronic pain and pain insensitivity syndromes. We aimed to study clinical, genetic, and electrophysiological features of paroxysmal extreme pain disorder (PEPD) caused by a novel SCN9A mutation. METHODS: Description of a 4-generation family suffering from PEPD with clinical, genetic and electrophysiological studies including patch clamp experiments assessing response to drug and temperature. RESULTS: The family was clinically comparable to those reported previously with the exception of a favorable effect of cold exposure and a lack of drug efficacy including with carbamazepine, a proposed treatment for PEPD. A novel p.L1612P mutation in the Nav1.7 voltage-gated sodium channel was found in the four affected family members tested. Electrophysiologically the mutation substantially depolarized the steady-state inactivation curve (V1/2 from -61.8 ± 4.5 mV to -30.9 ± 2.2 mV, n = 4 and 7, P < 0.001), significantly increased ramp current (from 1.8% to 3.4%, n = 10 and 12) and shortened recovery from inactivation (from 7.2 ± 5.6 ms to 2.2 ± 1.5 ms, n = 11 and 10). However, there was no persistent current. Cold exposure reduced peak current and prolonged recovery from inactivation in wild-type and mutated channels. Amitriptyline only slightly corrected the steady-state inactivation shift of the mutated channel, which is consistent with the lack of clinical benefit. CONCLUSIONS: The novel p.L1612P Nav1.7 mutation expands the PEPD spectrum with a unique combination of clinical symptoms and electrophysiological properties. Symptoms are partially responsive to temperature but not to drug therapy. In vitro trials of sodium channel blockers or temperature dependence might help predict treatment efficacy in PEPD.

Mutations in CNNM4 cause recessive cone-rod dystrophy with amelogenesis imperfecta.

Cone-rod dystrophies are inherited dystrophies of the retina characterized by the accumulation of deposits mainly localized to the cone-rich macular region of the eye. Dystrophy can be limited to the retina or be part of a syndrome. Unlike nonsyndromic cone-rod dystrophies, syndromic cone-rod dystrophies are genetically heterogeneous with mutations in genes encoding structural, cell-adhesion, and transporter proteins. Using a genome-wide single-nucleotide polymorphism (SNP) haplotype analysis to fine map the locus and a gene-candidate approach, we identified homozygous mutations in the ancient conserved domain protein 4 gene (CNNM4) that either generate a truncated protein or occur in highly conserved regions of the protein. Given that CNNM4 is implicated in metal ion transport, cone-rod dystrophy and amelogenesis imperfecta may originate from abnormal ion homeostasis.

Quality of Web-based information on obsessive compulsive disorder.

BACKGROUND: The Internet is increasingly used as a source of information for mental health issues. The burden of obsessive compulsive disorder (OCD) may lead persons with diagnosed or undiagnosed OCD, and their relatives, to search for good quality information on the Web. This study aimed to evaluate the quality of Web-based information on English-language sites dealing with OCD and to compare the quality of websites found through a general and a medically specialized search engine. METHODS: Keywords related to OCD were entered into Google and OmniMedicalSearch. Websites were assessed on the basis of accountability, interactivity, readability, and content quality. The "Health on the Net" (HON) quality label and the Brief DISCERN scale score were used as possible content quality indicators. Of the 235 links identified, 53 websites were analyzed. RESULTS: The content quality of the OCD websites examined was relatively good. The use of a specialized search engine did not offer an advantage in finding websites with better content quality. A score ≥16 on the Brief DISCERN scale is associated with better content quality. CONCLUSION: This study shows the acceptability of the content quality of OCD websites. There is no advantage in searching for information with a specialized search engine rather than a general one. Practical implications: The Internet offers a number of high quality OCD websites. It remains critical, however, to have a provider-patient talk about the information found on the Web.

Sense of time in children with Attention-Deficit/Hyperactivity Disorder (ADHD) : a comparative study

Parents of children with attention-deficit/hyperactivity disorder (ADHD) frequently report that their children have a poor sense of time. Several studies looking at the perception of time mentioned a form of temporal myopia. The present study investigates the sense of time in children with ADHD. Twenty-two French-speaking Swiss children with ADHD and 22 controls between the ages of 6 and 13 years were tested using a conventional time knowledge questionnaire and two Piagetian time conservation tasks. Parents were asked to complete the "It's about time" questionnaire. Better performance was observed in matched control group children than in children with ADHD on a conventional time knowledge questionnaire. For children under 10 years of age, the two Piagetian time conservation tasks were able to differentiate children with and without ADHD. Parents of ADHD children reported more frequently that their children had time-related difficulties in daily activities. This study suggests that children with ADHD take longer to develop several time-related abilities.

Absence of mTOR Inhibitor Effect on Hepatic Cyst Growth: A Case Report of a Kidney Transplant Recipient with Autosomal Dominant Polycystic Kidney Disease.

Some experimental studies have suggested a beneficial effect of the mammalian target of rapamycin (mTOR) inhibitor use on hepatic and renal cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the results of clinical studies are conflicting and the role of mTOR inhibitors is still uncertain. We report the case of a patient with ADPKD who underwent deceased kidney transplantation because of an end-stage renal disease. The evolution was uneventful with an excellent graft function under cyclosporine (CsA) monotherapy. Some years later, the patient developed a symptomatic hepatomegaly due to growth of cysts. CsA was replaced by sirolimus, an mTOR inhibitor, in order to reduce or control the increase in the cyst and liver volume. Despite the switch, the hepatic volume increased by 25% in two years. Finally sirolimus was stopped because of the lack of effect on hepatic cyst growth and the presence of sirolimus side effects. The interest of our case resides in the followup by MRI imaging during the mTOR inhibitor treatment and 15 months after the restart of the initial immunosuppressive therapy. This observation indicates that mTOR inhibitors did not have significant effect on cyst-associated hepatic growth in our patient, which is consistent with some results of recent large clinical studies.

Naevus Lentiginosus Linearis: A Distinct Skin Disorder

Congenital naevi of the melanocytic system include numerous types, which differ in their clinical appearance, pattern of distribution, and histopathological features (1). Examples are large congenital melanocytic naevus, macular naevus spilus, papular naevus spilus, café-au-lait macules of neurofibromatosis 1, café-au-lait macules arranged in broad bands as noted in McCune-Albright syndrome, partial unilateral lentiginosis, naevus achromicus (naevus depigmentosus), phylloid hypermelanosis, and phylloid hypomelanosis (1–3). We describe here two patients with a systematized pigmentary naevus that differed from all naevi reported so far.

Neuroanatomical and neuropsychological features of euthymic patients with bipolar disorder.

OBJECTIVE: Previous studies reported that the severity of cognitive deficits in euthymic patients with bipolar disorder (BD) increases with the duration of illness and postulated that progressive neuronal loss or shrinkage and white matter changes may be at the origin of this phenomenon. To explore this issue, the authors performed a case-control study including detailed neuropsychological and magnetic resonance imaging analyses in 17 euthymic elderly patients with BD and 17 healthy individuals. METHODS: Neuropsychological evaluation concerned working memory, episodic memory, processing speed, and executive functions. Volumetric estimates of the amygdala, hippocampus, entorhinal cortex, and anterior cingulate cortex were obtained using both voxel-based and region of interest morphometric methods. Periventricular and deep white matter were assessed semiquantitatively. Differences in cognitive performances and structural data between BD and comparison groups were analyzed using paired t-test or analysis of variance. Wilcoxon test was used in the absence of normal distribution. RESULTS: Compared with healthy individuals, patients with BD obtained significantly lower performances in processing speed, working memory, and episodic memory but not in executive functions. Morphometric analyses did not show significant volumetric or white matter differences between the two groups. CONCLUSIONS: Our results revealed impairment in verbal memory, working memory, and processing speed in euthymic older adults with BD. These cognitive deficits are comparable both in terms of affected functions and size effects to those previously reported in younger cohorts with BD. Both this observation and the absence of structural brain abnormalities in our cohort do not support a progressively evolving neurotoxic effect in BD.

Biased thinking assessed by external observers in borderline personality disorder

Objectives. Biased thinking (to some extent overlapping with the concepts of cognitive distortions and cognitive errors) is a key concept in cognitive therapy of Borderline Personality Disorder (BPD). Specific contents and cognitive processes related to BPD functioning are known. However, most studies are based on self-report measures which present a number of important limitations, in particular the difficulty in assessing non-conscious processes infused by affect. So far, no studies were conducted using valid observer-rated methodology addressing the question of biased thinking in BPD as it unfolds spontaneously in session. Design. This is a controlled interview study comparing two matched groups, BPD patients and healthy controls. Methods. A total of N= 25 clinical dynamic interviews with patients presenting with BPD were transcribed and rated using the Cognitive Errors Rating Scale (Drapeau, Perry, & Dunkley, 2008); their cognitive profiles were compared to those of N= 25 healthy controls who underwent the same procedure. Results. Overall, results indicated that no between-group difference in the frequency of specific biases was found. However, heightened levels of negative cognitive biases, in particular over-generalizing and fortune-telling, were associated with BPD. Furthermore, negative over-generalizing was associated with the number of BPD symptoms. Conclusions. These results have high levels of ecological validity and are promising for the refinement of cognitive theory of BPD. Clinical implications for assessment and intervention are discussed.

Genetic polymorphisms in folate pathway enzymes, DRD4 and GSTM1 are related to temporomandibular disorder

BACKGROUND Temporomandibular disorder (TMD) is a multifactorial syndrome related to a critical period of human life. TMD has been associated with psychological dysfunctions, oxidative state and sexual dimorphism with coincidental occurrence along the pubertal development. In this work we study the association between TMD and genetic polymorphisms of folate metabolism, neurotransmission, oxidative and hormonal metabolism. Folate metabolism, which depends on genes variations and diet, is directly involved in genetic and epigenetic variations that can influence the changes of last growing period of development in human and the appearance of the TMD. METHODS A case-control study was designed to evaluate the impact of genetic polymorphisms above described on TMD. A total of 229 individuals (69% women) were included at the study; 86 were patients with TMD and 143 were healthy control subjects. Subjects underwent to a clinical examination following the guidelines by the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Genotyping of 20 Single Nucleotide Polymorphisms (SNPs), divided in two groups, was performed by multiplex minisequencing preceded by multiplex PCR. Other seven genetic polymorphisms different from SNPs (deletions, insertions, tandem repeat, null genotype) were achieved by a multiplex-PCR. A chi-square test was performed to determine the differences in genotype and allelic frequencies between TMD patients and healthy subjects. To estimate TMD risk, in those polymorphisms that shown significant differences, odds ratio (OR) with a 95% of confidence interval were calculated. RESULTS Six of the polymorphisms showed statistical associations with TMD. Four of them are related to enzymes of folates metabolism: Allele G of Serine Hydoxymethyltransferase 1 (SHMT1) rs1979277 (OR = 3.99; 95%CI 1.72, 9.25; p = 0.002), allele G of SHMT1 rs638416 (OR = 2.80; 95%CI 1.51, 5.21; p = 0.013), allele T of Methylentetrahydrofolate Dehydrogenase (MTHFD) rs2236225 (OR = 3.09; 95%CI 1.27, 7.50; p = 0.016) and allele A of Methionine Synthase Reductase (MTRR) rs1801394 (OR = 2.35; 95CI 1.10, 5.00; p = 0.037). An inflammatory oxidative stress enzyme, Gluthatione S-Tranferase Mu-1(GSTM1), null allele (OR = 2.21; 95%CI 1.24, 4.36; p = 0.030) and a neurotransmission receptor, Dopamine Receptor D4 (DRD4), long allele of 48 bp-repeat (OR = 3.62; 95%CI 0.76, 17.26; p = 0.161). CONCLUSIONS Some genetic polymorphisms related to folates metabolism, inflammatory oxidative stress, and neurotransmission responses to pain, has been significantly associated to TMD syndrome.

Effects of motive-oriented therapeutic relationship in early-phase treatment of borderline personality disorder: a pilot study of a randomized trial.

Motive-oriented therapeutic relationship (MOTR, also called complementary therapeutic relationship) was postulated to be a particularly helpful therapeutic ingredient in the early-phase treatment of patients with personality disorders, in particular borderline personality disorder (BPD). The present pilot study of randomized controlled trial using an add-on design aims to investigate the effects of MOTR in early-phase treatment (up to session 10), with BPD patients on therapeutic alliance, session impact, and outcome. In total, N = 25 patients participated in the study. BPD patients were randomly allocated to a manual-based investigation process in 10 sessions or to the same investigation process infused with MOTR. Adherence ratings were performed and yielded satisfactory results. The results suggested a specific effectiveness of MOTR on the interpersonal problem area, on the quality of the therapeutic alliance and the quality of the therapeutic relationship, as rated by the patient. These results may have important clinical implications for the early-phase treatment of patients presenting with BPD.

Phenotype of two Consanguineous Autosomic Recessive Retinitis Pigmentosa Families Caused by PDE6A and PDE6B Mutations

Purpose: To assess the clinical phenotype in two consanguineous Tunisian families with non syndromic autosomic recessive retinitis Pigmentosa (RP) caused by a PDE6A and PDE6B mutations.Methods: All accessible familiy members were included. Affected members from each family underwent full ophthalmic examination with best corrected Snellen visual acuity, fundus photography, optical coherence tomography and full field electroretinography. Haplotype analyses were used to test linkage in the family to 20 arRP loci, including ABCA4, LRAT, USH2A, RP29, CERKL, CNGA1, CNGB1, CRB1, EYS, RP28, MERTK, NR2E3, PDE6A, PDE6B, RGR, RHO, RLBP1, TULP1. All exons and intron-exon junctions of candidate genes not excluded by haplotype analysis were PCR amplified and directly sequenced.Results: Two family members were clinically affected with arRP in each pedigree. Age range at baseline was 43 to 54 years (mean age at baseline was 48 years). For all affected members, night blindness appeared since early childhood (at 4-5 years old) without nystagmus but with a severe progression and mild to severe loss of central vision at the second decade. Visual acuity at baseline ranged from 20/500 to 20/63. Kinetic visual field was severely constricted for one patient and unrealizable for the others. Funduscopic examination revealed bone spicule-shaped pigment deposits in the mid periphery along with atrophy of the retina, narrowing of the vessels and waxy optic discs. Tomograms showed macular atrophy in both cases of family A, and macular edema in the patients of family B. ERG showed a loss of both rod and cone responses. Haplotype analysis revealed homozygosity for microsatellites markers flanking PDE6A and PDE6B in family A and B, respectively. Sequencing of PDE6A in family A showed a homozygous R102S mutation. In family B, sequencing identified a D600N homozygous mutation. Both mutations cosegregated within each respective pedigree.Conclusions: For these families, affected members developed a severe form of non syndromic arRP. The two reported mutations have already been described. Our data further contribute to our understanding of genotype-phenotype correlations.

Non-invasive prenatal diagnosis of multiple endocrine neoplasia type 2A using COLD-PCR combined with HRM genotyping analysis from maternal serum.

The multiple endocrine neoplasia type 2A (MEN2A) is a monogenic disorder characterized by an autosomal dominant pattern of inheritance which is characterized by high risk of medullary thyroid carcinoma in all mutation carriers. Although this disorder is classified as a rare disease, the patients affected have a low life quality and a very expensive and continuous treatment. At present, MEN2A is diagnosed by gene sequencing after birth, thus trying to start an early treatment and by reduction of morbidity and mortality. We first evaluated the presence of MEN2A mutation (C634Y) in serum of 25 patients, previously diagnosed by sequencing in peripheral blood leucocytes, using HRM genotyping analysis. In a second step, we used a COLD-PCR approach followed by HRM genotyping analysis for non-invasive prenatal diagnosis of a pregnant woman carrying a fetus with a C634Y mutation. HRM analysis revealed differences in melting curve shapes that correlated with patients diagnosed for MEN2A by gene sequencing analysis with 100% accuracy. Moreover, the pregnant woman carrying the fetus with the C634Y mutation revealed a melting curve shape in agreement with the positive controls in the COLD-PCR study. The mutation was confirmed by sequencing of the COLD-PCR amplification product. In conclusion, we have established a HRM analysis in serum samples as a new primary diagnosis method suitable for the detection of C634Y mutations in MEN2A patients. Simultaneously, we have applied the increase of sensitivity of COLD-PCR assay approach combined with HRM analysis for the non-invasive prenatal diagnosis of C634Y fetal mutations using pregnant women serum.