Aberrant salience relationship with first rank symptoms.

BACKGROUND: Aberrant salience is the incorrect assignment of salience, significance, or value to different innocuous stimuli that might precede the onset of psychotic symptoms. The present study aimed to perform a preliminary evaluation of potentially different correlations between the Aberrant Salience Inventory (ASI) score and dimensional or categorical diagnostic approaches. METHODS: 168 adult outpatients with a current psychiatric diagnosis were consecutively enrolled. Patients were evaluated using different psychometric scales. ASI was used to evaluate aberrant salience, and to evaluate the association between ASI scores and first rank symptoms (FRS), and/or with a psychiatric diagnosis. Principal dichotomic clusters of ASI were identified using the Chi-square automatic interaction detection (CHAID) method. RESULTS: Current (16.76 ± 6.02 vs 13.37 ± 5.76; p = 0.001), lifetime (15.74 ± 6.08 vs 13.16 ± 5.74; p = 0.005) and past (15.75 ± 6.01 vs 13.33 ± 5.80; p = 0.009) FRS were the main clusters dichotomizing ASI. The average ASI score did not significantly differ among patients with different diagnoses. CONCLUSIONS: ASI could be used as a tool to identify psychopathological dimensions, rather than the categorical diagnoses, in the schizophrenic spectrum.

Substitution treatment for opioid dependence with slow-release oral morphine: Retention rate, health status, and substance use after switching to morphine.

INTRODUCTION: Since April 2015, slow-release oral morphine (SROM) has been approved for opioid agonist treatment (OAT) in Germany. Experimental studies show that benefits of SROM over methadone include less heroin craving, better tolerability, and higher patient satisfaction and mental stability. The SROMOS study (Efficacy and Tolerability of Slow-Release Oral Morphine in Opioid Substitution Treatment) aims to investigate the long-term effects (effectiveness and safety) of morphine substitution under routine care in Germany. MATERIAL AND METHODS: This is a prospective, noninterventional, naturalistic, observational study. Between July 2016 and November 2017, this study recruited patients in OAT who decided to switch to SROM from 23 outpatient addiction treatment centers in Germany. The study collected data on mental health (Brief Symptom Inventory - BSI-18), substance use, somatic health (Opiate Treatment Index Health-Symptoms-Scale - OTI-HSS), opioid craving (visual analogue scale), and withdrawal symptoms (Short Opiate Withdrawal Scale) at baseline (t0) and after 3 (t3), 6 (t6) and 12 (t12) months. Physicians documented side effects as adverse events (AEs) and adverse drug reactions (ADRs). RESULTS: Three-quarters of the enrolled study participants (N = 180) were male. The average age was 44.4 years. Patients were opioid-dependent for 23 years and had been in OAT for almost seven years on average. After 12 months, 60.6% were still being treated with SROM. Mental health improved significantly under SROM treatment between t0 and t12. The intention-to-treat (ITT), as well as the per-protocol (PP) analysis, shows a statistically significant improvement of the mean Global Severity Index (GSI) of the BSI-18 value of 20% (ITT) and 24% (PP). Physical health also improved significantly under SROM treatment. There were no statistically significant changes in the use of cannabis, cocaine, amphetamines, and tranquillizers in the past 30 days, but heroin use, intravenous consumption, and the number of drinking days significantly decreased. CONCLUSIONS: This study provides some of the first long-term data on OAT with SROM under routine care conditions. SROM treatment is an effective alternative for a subgroup of opioid-dependent patients with an unsatisfactory course of OAT or in cases where undesirable side effects due to alternative substances have occurred. ETHICAL STATEMENT: The study protocol was approved by the Ethics Committee of the Chamber of Physicians in Hamburg in March 2016 (No. PV5222). The study was conducted by following the Declaration of Helsinki and is registered with the German Register of Clinical Trials (DRKS, ID: DRKS00010712).

Switching opioid-dependent patients in substitution treatment from racemic methadone, levomethadone and buprenorphine to slow-release oral morphine: Analysis of the switching process in routine care.

Since 2015 slow-release oral morphine (SROM) is approved for opioid substitution treatment (OST) in Germany. The SROMOS study (efficacy and tolerability of slow-release oral morphine in opioid substitution treatment) evaluates the efficacy and safety of SROM in routine care. This article describes the switching process from racemic methadone, levomethadone and buprenorphine to SROM. Between July 2016 and November 2017 180 patients in 23 study centers in Germany were included in the prospective, non-interventional, naturalistic observational study. Patients were already in OST and switched from a previous medication to SROM. The switching process was analyzed during a period of fourteen days. Data were available for 169 participants. The switching process had a different progression depending on premedication and pre dosage. On the fourteenth day of SROM treatment patients switched from racemic methadone took an average dosage of 922.2 mg/day, from levomethadone 801.0 mg/day and from buprenorphine 626.7 mg/day. Average conversion ratio racemic methadone to SROM was 1:11.8, levomethadone to SROM 1:17.4 and buprenorphine to SROM 1:58.0. This study provides the first data on the switching process from buprenorphine to SROM. Average dose ratio racemic methadone to SROM on the fourteenth day of treatment was considerably higher than recommended in the prescribing information.

Brain malformations and mutations in α- and ß-tubulin genes: a review of the literature and description of two new cases.

AIM: The aim of this study was to determine the frequency of mutations in tubulin genes (TUBB2B, TUBA1A, and TUBB3) in patients with malformations of cortical development (MCDs) of unknown origin. METHOD: In total, 79 out of 156 patients (41 males, 38 females; age range 8mo-55y (mean age 13y 3mo, SD 11y 2mo) with a neuroradiological diagnosis of MCDs were enrolled in the study. The 77 excluded patients were excluded for the following reasons: suspected or proven diagnosis of pre- or perinatal ischaemic insult (n=13); syndromic disease (n=10); congenital infection (n=14); pregnancy complicated by twin-to-twin transfusion syndrome (n=2); proven mutations in known genes (n=13); poor magnetic resonance imaging (MRI) quality, or lack of informed consent (n=25). A genetic analysis of the TUBA1A, TUBB2B and TUBB3 genes was carried out by direct sequencing of the coding regions of the relevant genes for each participant. Previously described patients with mutations in the TUBB2B and TUBA1A genes were reviewed; clinical and neuroradiological findings were compared and discussed. RESULTS: Two novel heterozygous mutations were detected: a heterozygous mutation in exon 4 of the TUBA1A gene (c.1160C>T) in a 5-year-old female with microcephaly, severe intellectual disability, and absence of language, and a c.1080 _1084del CCTGAinsACATCTTC in exon 4 of the TUBB2B gene in a 31-year-old female with microcephaly, spastic tetraparesis, severe intellectual disability, and scoliosis. Different types of cortical abnormalities, cerebellar vermis hypoplasia, and optic nerve hypoplasia/atrophy were detected on MRI. Dysmorphisms of the basal ganglia and the hippocampi with abnormalities of the midline commissural structures were present in both cases. INTERPRETATION: The consistent presence of hypoplastic and disorganized white matter tracts suggests that, in addition to defects in neuronal migration, disruption of axon growth and guidance is a peculiar feature of tubulin-related disorders.

A novel mutation in the ß-tubulin gene TUBB2B associated with complex malformation of cortical development and deficits in axonal guidance.

Neurological disorders characterized by abnormal neuronal migration, organization, axon guidance, and maintenance have recently been associated with missense and splice-site mutations in the genes encoding α- and ß-tubulin isotypes TUBA1A, TUBB2B, TUBB3, and TUBA8. We found a novel heterozygous mutation c.419G > C in exon 4 of the gene encoding TUBB2B in a female with microcephaly, agenesis of the corpus callosum, open-lip schizencephaly of the left parietal lobe, extensive polymicrogyria, basal ganglia and thalami dysmorphisms, and vermis and right third nerve hypoplasia. The missense change results in a glycine to alanine substitution; the mutated residue falls within an invariant glycine-rich region and therefore is likely to result in impaired protein function and possibly microtubule formation. This study expands the spectrum of brain malformations associated with mutations in the ß-tubulin gene TUBB2B, supporting its critical role in migration/organization and axon guidance processes. In addition, it suggests a possible genetic aetiology of schizencephaly, thus strengthening the hypothesis that there is a common pathophysiological base in polymicrogyria and schizencephaly.

A wide spectrum of clinical, neurophysiological and neuroradiological abnormalities in a family with a novel CACNA1A mutation.

BACKGROUND: Mutations in the calcium channel voltage dependent P/Q-type alpha-1A subunit (CACNA1A) can cause different neurological disorders which share a wide range of symptoms, including episodic ataxia type 2 (EA2), familial hemiplegic migraine (FHM1) and progressive spinocerebellar ataxia (SCA6). OBJECTIVE: To describe a three generations family in which a spectrum of different phenotypes, ranging from SCA6 (proband), to EA2 (proband's mother) to FHM1 (proband's mother and proband's aunt) was found. All of the family members carried a novel CACNA1A missense mutation. PATIENTS AND METHODS: A clinical, molecular, neuroradiological and neurophysiological study was carried out in all subjects. RESULTS: A single heterozygous base change in exon 9, c1213G-->A, leading to the amino acid substitution pAla405Thr was found to segregate within the family. Brain MRI showed cerebellar and cerebral atrophy signs in all but one mutation carriers. Neurophysiological findings (electroencephalography and evoked potentials) confirmed possible cerebral cortex and white matter involvement regardless of the clinical symptoms displayed. CONCLUSIONS: This novel CACNA1A mutation adds to the number of mutations associated with a heterogeneous clinical picture in family members. This mutation might affect the interaction between the intracellular loops and the beta subunit, leading to a relatively rapid cell death. In order to explain the wide phenotypic variability observed in this family, it is hypothesised that additional genetic and environmental (hormonal) factors play a role in the pathophysiology of the disease.

Cryptogenic epileptic syndromes related to SCN1A: twelve novel mutations identified.

BACKGROUND: Sodium channel alpha 1 subunit gene, SCN1A, is the gene encoding the neuronal voltage-gated sodium channel alpha 1 subunit (Na(v)1.1) and is mutated in different forms of epilepsy. Mutations in this gene were observed in more than 70% of patients with severe myoclonic epilepsy of infancy (SMEI) and were also found in different types of infantile epileptic encephalopathy. OBJECTIVE: To search for disease-causing mutations in SCN1A in patients with cryptogenic epileptic syndromes (ie, syndromes with an unknown cause). DESIGN: Clinical characterization and molecular genetic analysis of a cohort of patients. SETTING: University hospitals, rehabilitation centers, and molecular biology laboratories. PATIENTS: Sixty unrelated patients with cryptogenic epileptic syndromes. MAIN OUTCOME MEASURES: Samples of DNA were analyzed for mutations and for large heterozygous deletions encompassing the SCN1A gene. A search for microdeletions in the SCN1A gene was also performed in the subset of patients with SMEI/SMEI-borderland who had negative results at the point mutation screening. RESULTS: No large deletions at the SCN1A locus were found in any of the patients analyzed. In contrast, 13 different point mutations were identified in 12 patients: 10 with SMEI, 1 with generalized epilepsy with febrile seizures plus, and 1 with cryptogenic focal epilepsy. An additional search for SCN1A intragenic microdeletions in the remaining patients with SMEI/SMEI-borderland and no point mutations was also negative. CONCLUSIONS: These results confirm the role of the SCN1A gene in different types of epilepsy, including cryptogenic epileptic syndromes. However, large deletions encompassing SCN1A were not common disease-causing rearrangements in this group of epilepsies.

Eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia.

BACKGROUND: Hereditary spastic paraplegia (HSP) is a group of genetically heterogeneous disorders characterized by progressive spasticity of the lower limbs. Mutations in the SPG4 gene, which encodes spastin protein, are responsible for up to 45% of autosomal dominant cases. OBJECTIVE: To search for disease-causing mutations in a large series of Italian patients with HSP. DESIGN: Samples of DNA were analyzed by direct sequencing of all exons in SPG4. Samples from a subset of patients were also analyzed by direct sequencing of all exons in SPG3A, SPG6, SPG10, and SPG13. SETTING: Molecular testing facility in Italy. PATIENTS: Sixty unrelated Italian patients with pure (n = 50) and complicated (n = 10) HSP. MAIN OUTCOME MEASURES: Mutations in SPG4, SPG3A, SPG6, SPG10, and SPG13. RESULTS: We identified 12 different mutations, 8 of which were novel, in 13 patients. No mutations of any of the other HSP genes tested were found in 15 patients with sporadic pure HSP who did not have mutations in the SPG4 gene. CONCLUSIONS: The overall rate of mutation in the SPG4 gene within our sample was 22%, rising to 26% when only patients with pure HSP were considered. The negative result obtained in 15 patients without mutations in SPG4 in whom 4 other genes were analyzed (SPG3A, SPG6, SPG10, and SPG13) indicate that these genes are not frequently mutated in sporadic pure HSP.

A case-control and family-based association study of the 5-HTTLPR in pediatric-onset depressive disorders.

BACKGROUND: Pediatric depression can be particularly informative for clarification of the causes of mood disorders. The aim of this work was to explore the possible association between childhood- and early-adolescent-onset DSM-IV depressive disorders (DD; including major depression and dysthymia) and the serotonin transporter-linked promoter polymorphism (5-HTTLPR) locus. METHODS: The case-control sample consisted of 68 unrelated patients with DD, and 68 unrelated age- and gender-matched healthy control subjects. The same patients were included in the family-based study, which consisted of 41 triads and 11 dyads. RESULTS: An excess of the SS-genotype (p =.025) and of the S-allele (p =.021) was found among DD children (odds ratio = 1.81; 95% confidence interval = 1.12-2.94). The family-based results suggested that the S-allele was preferentially transmitted to depressed children (haplotype-based haplotype relative risk: chi(2) = 7.231 df = 1, p =.007; transmission disequilibrium test: chi(2) = 5.233, df = 1, p =.022). CONCLUSIONS: A role for the 5-HTTLPR locus that needs replication in larger samples is suggested in childhood DD.

Effective retrovirus-mediated gene transfer in normal and mutant human melanocytes.

Melanocytes represent the second most important cell type in the skin and are primarily responsible for the pigmentation of skin, hair, and eyes. Their function may be affected in a number of inherited and acquired disorders, characterized by hyperpigmentation or hypopigmentation, consequent aesthetic problems, and increased susceptibility to sun-mediated skin damage and photocarcinogenesis. Nevertheless, the possibility of genetically manipulating human melanocytes has been hampered so far by a number of limitations, including their resistance to retroviral infection. To address the problem of human melanocyte transduction, we generated a melanocyte culture from a patient affected with ocular albinism type 1 (OA1), an X-linked pigmentation disorder, characterized by severe reduction of visual acuity, retinal hypopigmentation, and the presence of macromelanosomes in skin melanocytes and retinal pigment epithelium (RPE). The cultured patient melanocytes displayed a significant impairment in replication ability and showed complete absence of endogenous OA1 protein, thus representing a suitable model for setting up an efficient gene transfer procedure. To correct the genetic defect in these cells, we used a retroviral vector carrying the OA1 cDNA and exploited a melanocyte-keratinocyte coculturing approach. Despite their lower replication rate with respect to wildtype cells, the patient melanocytes were efficiently transduced and readily selected in vitro, and were found to express, process, and properly sort large amounts of recombinant OA1 protein. These results indicate the feasibility of efficiently and stably transducing in vitro not only normal neonatal, but also mutant adult, human melanocytes with nonmitogenic genes.