CLINICAL AND GENETIC FEATURES OF PERSONALIZED ANTIPSYCHOTIC THERAPY OF PATIENTS WITH PARANOID SCHIZOPHRENIA OF THE KAZAKH ETHNIC GROUP IN THE REPUBLIC OF KAZAKHSTAN.

The problems of schizophrenia therapy occupy a leading place in both foreign and domestic clinical psychiatry. The paper presents the results of a study to identify reliable biomarkers for predicting antipsychotic therapy of patients with paranoid schizophrenia of the Kazakh ethnic group in the Republic of Kazakhstan, conducted within the framework of the project: "National program for the introduction of personalized and preventive medicine in the Republic of Kazakhstan" IRN ОР12165486. The effectiveness and tolerability of antipsychotic drugs used in the treatment of paranoid schizophrenia in the Republic of Kazakhstan according to clinical treatment protocols are analyzed. Gender and age-specific dynamics in the clinic of paranoid schizophrenia in antipsychotic therapy in persons of Kazakh ethnicity are described. Certain genetic features of representatives of the Kazakh ethnic group have been identified, which can influence the effectiveness and tolerability of antipsychotic drugs, which determines the basis of an innovative approach to personalized therapy of paranoid schizophrenia in patients of the Kazakh ethnic group in the Republic of Kazakhstan.

A genome-wide association study identifies a gene network associated with paranoid schizophrenia and antipsychotics-induced tardive dyskinesia.

In the present study we conducted a genome-wide association study (GWAS) in a cohort of 505 patients with paranoid schizophrenia (SCZ), of which 95 had tardive dyskinesia (TD), and 503 healthy controls. Using data generated by the PsychENCODE Consortium (PEC) and other bioinformatic databases, we revealed a gene network, implicated in neurodevelopment and brain function, associated with both these disorders. Almost all these genes are in gene or isoform co-expression PEC network modules important for the functioning of the brain; the activity of these networks is also altered in SCZ, bipolar disorder and autism spectrum disorders. The associated PEC network modules are enriched for gene ontology terms relevant to the brain development and function (CNS development, neuron development, axon ensheathment, synapse, synaptic vesicle cycle, and signaling receptor activity) and to the immune system (inflammatory response). Results of the present study suggest that orofacial and limbtruncal types of TD seem to share the molecular network with SCZ. Paranoid SCZ and abnormal involuntary movements that indicate the orofacial type of TD are associated with the same genomic loci on chromosomes 3p22.2, 8q21.13, and 13q14.2. The limbtruncal type of TD is associated with a locus on chromosome 3p13 where the best functional candidate is FOXP1, a high-confidence SCZ gene. The results of this study shed light on common pathogenic mechanisms for SCZ and TD, and indicate that the pathogenesis of the orofacial and limbtruncal types of TD might be driven by interacting genes implicated in neurodevelopment.

Association of the genetic polymorphisms of metabolizing enzymes, transporters, target receptors and their interactions with treatment response to olanzapine in chinese han schizophrenia patients.

Olanzapine is an atypical antipsychotic drug that has been increasingly used for treatment in schizophrenia. It has been observed that olanzapine responses in schizophrenia patients vary individually, but the reason has not been elucidated. In the study, we aimed to comprehensively explore the relationships between olanzapine responses and genetic polymorphisms of drug metabolizing enzymes, transporters and target receptors, and so as to interpret the reason of good and poor responses of olanzapine. A total of 241 Chinese Han paranoid schizophrenia who treated with olanzapine alone for 4 weeks were recruited. The positive and negative symptom scale (PANSS) was used to evaluate the efficacy of olanzapine. The genetic polymorphisms were detected by improved multiple ligase detection reaction (iMLDR). Multivariate logistic regression analysis suggested that the genetic polymorphisms of CYP1A2 rs762551, UGT1A4 rs2011425, ABCB1 rs1045642, DRD2 rs1799732 and rs1799978, 5-HTR2A rs6311 were significantly associated with olanzapine response. Multifactor dimensionality reduction (MDR) analysis showed that there was a negative interaction between CYP1A2 rs762551, ABCB1 rs1045642, DRD2 rs1799978, 5-HTR2A rs6311 and the interaction model was the optimal model. Our findings could partially explain the different olanzapine outcome and provided evidence for clarifying the predictive indicators of olanzapine response in further.

Association of HSPA1B Polymorphisms with Paranoid Schizophrenia in a Polish Population.

This study aimed to find the potential association between HSPA1B polymorphisms and risk of paranoid schizophrenia, clinical variables of the disease, and suicidal behavior. A total of 901 unrelated Polish subjects of Caucasian origin (377 schizophrenia patients and 524 controls) were recruited. Four single-nucleotide polymorphisms (SNP) were genotyped using PCR-RFLP (rs539689, rs9281590) and TaqMan assays (rs263979, rs6547452). A strong tendency towards statistical significance (p = 0.051) was observed in rs539689 allele distribution between patients and controls in overall study subjects. After stratification according to gender, we found that rs539689 was significantly associated with schizophrenia in males, but not in females. The minor allele C had a protective effect in males [OR 0.73 (95% CI 0.61-0.88, p < 0.05)]. In addition, two SNPs (rs539689, rs9281590) were significantly associated with PANSS scores. Another important finding was a strong significant association between the HSPA1B rs539689 polymorphism and attempted suicide in schizophrenic patients. The C/C genotype and C allele were protective against suicidal behavior in entire sample (p < 0.001), in males (p < 001), and in females (p < 0.05), although associations were weaker than in males. Our findings support that HSPA1B gene may be involved in susceptibility to schizophrenia and clinical presentation of the disease in a sex-dependent manner, and may play a role in suicidal behavior in the Polish population of schizophrenic patients. Further independent analyses in different populations should be performed to clarify the role of HSPA1B in the pathogenesis of schizophrenia.

Schizophrenia Patient Shows a Rare Interleukin 15 Receptor alpha Variant Disrupting Signal Transduction.

BACKGROUND: Schizophrenia is a complex and debilitating mental disorder with strong heritability. Its pathogenesis involves immune dysregulation. Interleukin 15 and interleukin 15 receptor alpha(IL-15Rα) are classical immune molecules. They also help maintain normal brain function, leading to our hypothesis that IL-15Rα gene(IL- 15RA) variants contribute to the pathogenesis of schizophrenia. OBJECTIVE: We determine whether the genetic variants of IL-15RA are associated with the development and progression of schizophrenia and whether IL-15RA single nucleotide polymorphism(SNP) plays a key role in downstream signaling transduction. METHODS AND RESULTS: We sequenced IL-15RA exon from 132 Chinese schizophrenic patients and identified a rare variant(rs528238821) in a patient diagnosed with catatonic schizophrenia and ankylosing spondylitis(AS). We overexpressed this missense variant in cells driven by pBI-CMV vector. The cells showed attenuated STAT3 phosphorylation in response to interleukin15. CONCLUSION: IL-15RA mutation is rare in schizophrenic patients but interfered with IL- 15Rα intracellular signal transduction. Given the similarity of symptoms of catatonic schizophrenia and the known phenotype of IL-15Rα knockout mice, gene variation might offer diagnostic value for sub-types of schizophrenia.

Paranoid schizophrenia and methamphetamine-induced paranoia are both characterized by a similar LINE-1 partial methylation profile, which is more pronounced in paranoid schizophrenia.

BACKGROUND: There is evidence that schizophrenia is a neuro-immune disorder. Genes linked to intragenic LINE-1 methylation show a strong association with immune-associated disorders including psychosis. The aim of this study was to examine LINE-1 methylation patterns in paranoid schizophrenia and methamphetamine-induced paranoia, a model for schizophrenia. METHODS: This study recruited 31 patients with paranoid schizophrenia, 94 with methamphetamine-induced paranoia (MIP) and 163 normal controls. LINE-1 methylation patterns were assayed in peripheral blood mononuclear cells and a combined bisulphite restriction analysis and COBRA were used to estimate LINE1 methylation (mC) and CpG dinucleotide methylation patterns, namely 2 methylated (mCmC) and 2 unmethylated (uCuC) CpGs and the partially methylated loci mCuC (5'm with 3'u) and uCmC (5'u with 3'm). RESULTS: Patients with paranoid schizophrenia show highly significant changes in LINE-1 partial methylation patterns, namely a higher percentage of mCuC and lower percentage of uCmC as compared with controls and MIP patients, while the latter show a higher percentage of mCuC but lower percentage of uCmC as compared with controls. Higher mCuC significantly predicts paranoid schizophrenia with a sensitivity of 51.6%, specificity of 97.5% and an area under the ROC curve of 0.895. CONCLUSIONS: The results indicate that a common dysfunction in LINE-1 partial methylation may underpin both paranoid schizophrenia and MIP and that this methylation pattern is significantly more expressed in paranoid schizophrenia than MIP. Reciprocal links between impairments in LINE-1 methylation and neuro-immune and neuro-oxidative pathways may underpin the pathophysiology of both MIP and paranoid schizophrenia.

Haplotypes of TNFα/ß Genes Associated with Sex-Specific Paranoid Schizophrenic Risk in Tunisian Population.

Several medical research findings have announced a strong association between the biology of cytokines and various brain activities. Since growing evidences suggest the crucial and complex role of the tumor necrosis factor in the CNS, we have hypothesized that functional genetic variants of the LTA and TNFA genes (LTA +252A/G (rs909253) and TNFA -857C/T (rs1799724) and TNFA -238G/A (rs361525)) may be involved in the predisposition to schizophrenia. This research is based on a case-control study. The RFLP-PCR genotyping was conducted on a Tunisian population composed of 208 patients and 208 controls. We found a strong significant overrepresentation of the minor alleles (G, T, and A, respectively) in all patients compared with controls (p = 0.003, OR = 1.55; p = 0.005, OR = 1.78; and p = 0.0001, OR = 1.74, respectively). This correlation was confirmed for male but not for female patients. Interestingly, the frequencies of the minor alleles were significantly more common among patients with paranoid schizophrenia when compared with controls (p = 0.003, OR = 1.75; p = 5 · 10-6, OR = 3.04; and p = 4 · 10-6, OR = 2.35, respectively). This potential association was confirmed by a logistic binary regression analysis only for the development of the paranoid form of schizophrenia (p = 0.001/OR = 2.6; p = 0.0002/OR = 3.2; and p = 0.0004/OR = 3.1, respectively) and remained not significant for the other subtypes. Moreover, our study showed an important association between GCA haplotype and the development of this pathological form (p = 10-4, OR = 3.71). In conclusion, our results proved a significant association between the three polymorphisms and paranoid schizophrenia, at least in the Tunisian population, suggesting a substantially increased risk for paranoid schizophrenia with dominant inheritance of these three minor alleles.

Negative and paranoid symptoms are associated with negative performance beliefs and social cognition in 22q11.2 deletion syndrome.

AIMS: 22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic condition associated with an increased risk of developing schizophrenia. Previous studies have shown that negative symptoms represent the most specific clinical characteristic of psychosis in 22q11.2DS and are strongly associated with outcome. However, the psychological mechanisms associated with these symptoms in this population are poorly understood. In accordance with recent conceptualizations in the field of schizophrenia, the present study aims at investigating whether negative symptoms are associated with the presence of negative performance beliefs and cognitive deficits. METHODS: Thirty-five participants with 22q11.2DS and 24 typically developing individuals aged between 11 and 24 years were included in the study. Self-reported schizotypal symptoms (cognitive-perceptual, paranoid, negative and disorganization symptoms) and dysfunctional beliefs (negative performance beliefs and need for approval) were assessed. Measures of processing speed, verbal memory, working memory, executive functioning and face recognition were also extracted from a broad cognitive evaluation protocol. RESULTS: Adolescents with 22q11.2DS reported significantly higher score on the negative dimension of the Schizotypal Personality Questionnaire than controls, even when controlling for the influence of anxiety/depression and intellectual functioning. Negative and paranoid symptoms were associated with the severity of negative performance beliefs and lower face recognition abilities. Mediation analyses revealed that negative performance beliefs significantly mediated the association between face recognition and negative/paranoid symptoms. CONCLUSIONS: These findings suggest that negative performance beliefs and basic social cognitive mechanisms are associated with negative and paranoid symptoms in individuals with 22q11.2DS. Implications for intervention are discussed in this article.

IFNGR2 genetic polymorphism associated with sex-specific paranoid schizophrenia risk.

BACKGROUND: Considering current scientific evidence about the significant role of chronic low grade inflammation in the physiopathology of schizophrenia, it has been hypothesized that changes in pro-inflammatory cytokines such as interferon gamma may have a significant role in the predisposition to schizophrenia. AIM: This study focuses on identifying whether the functional polymorphism of interferon gamma receptor 2 (IFNGR2) is a risk factor for the development of schizophrenia. METHODS: This study was conducted by the RFLP-PCR on a Tunisian population composed of 225 patients with different sub-types of schizophrenia and 166 controls. RESULTS: The IFNGR2 (Q64R) polymorphism analysis showed higher frequencies of minor homozygous genotype (RR) and allele (R) in all patients compared to controls (21.8% vs 10.2%; p = .006, OR = 2.54) and (44% vs 34.9%; p = .01; OR = 1.46), respectively. This correlation was confirmed only for males. This study also noted a significant increase of the mutated homozygous (RR) genotype and (R) allele frequencies of IFNGR2 in paranoid schizophrenics compared to controls (31.4% vs 10.2%; p = .001; OR = 3.34 and 47.2% vs 34.9%; p = .009; OR = 1.66, respectively). This increase remains significant after using binary logistic regression to eliminate confounding factors such as age and sex. Additionally, carriers of RR genotype have significant lower scores on the Scale of Assessment of Positive (SAPS) and negative (SANS) symptoms comparatively to the carrier of the QQ + QR genotypes, suggesting that the R recessive allele carriers could have milder symptoms. CONCLUSION: The IFNGR2Q64R polymorphism is correlated with male sex and paranoid schizophrenia. It is suggested that a chronic neuroinflammation may predispose to the paranoid schizophrenia development in men.

Association of the IFN-γ (+874A/T) Genetic Polymorphism with Paranoid Schizophrenia in Tunisian Population.

Since growing evidence suggests a significant role of chronic low-grade inflammation in the physiopathology of schizophrenia, we have hypothesized that functional genetic variant of the IFN gamma (IFN-γ; +874A/T; rs2430561) gene may be involved in the predisposition to schizophrenia. This research is based on a case-control study which aims to identify whether polymorphism of the IFN-γ gene is a risk factor for the development of schizophrenia. The RFLP-PCR genotyping of the IFN-γ gene was conducted on a Tunisian population composed of 218 patients and 162 controls. The IFN-γ (+874A/T) polymorphism analysis showed higher frequencies of minor homozygous genotype (TT) and allele (T) in all patients compared with controls (11.5 vs. 4.9%; p = 0.03, OR = 2.64 and 30.7 vs. 24.1%, p = 0.04, OR = 1.4, respectively). This correlation was confirmed for male but not for female patients. Also, the T allele was significantly more common among patients with paranoid schizophrenia when compared with controls (25.8 vs. 4.9%, p = 0.0001; OR = 6.7). Using the binary regression analysis to eliminate confounding factors as age and sex, only this last association remained significant (p = 0.03; OR = 1.76, CI = 1.05-2.93). In conclusion, our results showed a significant association between +874A/T polymorphism of IFN-γ and paranoid schizophrenia, suggesting that this single nucleotide polymorphism (SNP) or another at proximity could predispose to paranoid schizophrenia. Since the minor allele of this polymorphism was correlated with an increased expression of their product, our study validates the hypothesis of excessive pro-inflammatory cytokine in the physiopathology of paranoid schizophrenia.

Familial Aggregation and Heritability of Schizophrenia and Co-aggregation of Psychiatric Illnesses in Affected Families.

Strong familial aggregation of schizophrenia has been reported but there is uncertainty concerning the degree of genetic contribution to the phenotypic variance of the disease. This study aimed to examine the familial aggregation and heritability of schizophrenia, and the relative risks (RRs) of other psychiatric diseases, in relatives of people with schizophrenia using the Taiwan National Health Insurance Database. The study population included individuals with affected first-degree or second-degree relatives identified from all beneficiaries (n = 23 422 955) registered in 2013. Diagnoses of schizophrenia made by psychiatrists were ascertained between January 1, 1996 and December 31, 2013. Having an affected co-twin, first-degree relative, second-degree relative, or spouse was associated with an adjusted RR (95% CI) of 37.86 (30.55-46.92), 6.30 (6.09-6.53), 2.44 (1.91-3.12), and 1.88 (1.64-2.15), respectively. Compared with the general population, individuals with one affected first-degree relative had a RR (95% CI) of 6.00 (5.79-6.22) and those with 2 or more had a RR (95% CI) of 14.66 (13.00-16.53) for schizophrenia. The accountability for the phenotypic variance of schizophrenia was 47.3% for genetic factors, 15.5% for shared environmental factors, and 37.2% for non-shared environmental factors. The RR (95% CI) in individuals with a first-degree relative with schizophrenia was 3.49 (3.34-3.64) for mood disorders and 3.91 (3.35-4.57) for delusional disorders. A family history of schizophrenia is therefore associated with a higher risk of developing schizophrenia, mood disorders, and delusional disorders. Heritability and environmental factors each account for half of the phenotypic variance of schizophrenia.

Association Study of Tumor Necrosis Factor Receptor 1 (TNFR1) Gene Polymorphisms with Schizophrenia in the Polish Population.

Schizophrenia is a devastating mental disorder with undetermined aetiology. Previous research has suggested that dysregulation of proinflammatory cytokines and their receptors plays a role in developing schizophrenia. We examined the association of the three single nucleotide polymorphisms (SNPs; rs4149576, rs4149577, and rs1860545) in the tumor necrosis factor receptor 1 (TNFR1) gene with the development and psychopathology of paranoid schizophrenia in the Polish Caucasian sample consisting of 388 patients and 657 control subjects. The psychopathology was assessed using a five-factor model of the Positive and Negative Syndrome Scale (PANSS). SNPs were genotyped using the TaqMan 5'-exonuclease allelic discrimination assay. The SNPs tested were not associated with a predisposition to paranoid schizophrenia in either the entire sample or after stratification according to gender. However, rs4149577 and rs1860545 SNPs were associated with the intensity of the PANSS excitement symptoms in men, which may contribute to the risk of violent behavior. Polymorphisms in the TNFR1 gene may have an impact on the symptomatology of schizophrenia in men.

Variants in TERT influencing telomere length are associated with paranoid schizophrenia risk.

Schizophrenia is one of the most severe psychiatric disorders, with a high heritability of up to 80%. Several studies have reported telomere dysfunction in schizophrenia, and common variants in the telomerase reverse transcriptase (TERT) gene. TERT is a key component of the telomerase complex that maintains telomere length by addition of telomere repeats to telomere ends, and has repeatedly shown association with mean lymphocyte telomere length (LTL). Thus, we hypothesized that TERT may be a novel susceptibility gene for schizophrenia. Using a Taqman protocol, we genotyped eight tag SNPs from the TERT locus in 1,072 patients with paranoid schizophrenia and 1,284 control subjects from a Chinese Han population. We also measured mean LTL in 98 cases and 109 controls using a quantitative PCR-based technique. Chi-square tests showed that two SNPs, rs2075786 (P = 0.0009, OR = 0.76, 95%CI = 0.65-0.90) and rs4975605 (P = 0.0026, OR = 0.73, 95%CI = 0.60-0.90), were associated with a protective effect, while rs10069690 was associated with risk of paranoid schizophrenia (P = 0.0044, OR = 1.23, 95%CI = 1.07-1.42). Additionally, the rs2736118-rs2075786 haplotype showed significant association with paranoid schizophrenia (P = 0.0013). Moreover, mean LTL correlated with rs2075786 genotypes was significantly shorter in the patient group than the control group. The present results suggest that the TERT gene may be a novel candidate involved in the development of paranoid schizophrenia.

LncRNA MIAT: Myocardial infarction associated and more.

Non-coding RNAs are emerging as regulatory RNAs that participate in the regulation of gene expression and play vital roles in various biological and pathological processes. Long non-coding (lncRNA) is a novel class of non-coding RNAs that regulates gene expression by binding to chromatin regulators and interfering RNAs to affect cellular response. Myocardial infarction associated transcript (MIAT) is identified as lncRNAs, which is involved in various diseases, pathological and physiological processes, such as myocardial infarction, diabetic retinopathy, paranoid schizophrenia, microvascular dysfunction and formation of nuclear bodies, and neurogenic commitment. Here we review the growing understanding and potential utilization of MIAT.

[The Role of Neurotrophins and Neurexins Genes in the Risk of Paranoid Schizophrenia in Russians and Tatars].

Schizophrenia affects about 1% of the population. Its etiology is not fully understood. Environmental conditions certainly contribute to the development of schizophrenia, but the determining factor is genetic predisposition: the coefficient of heritability of schizophrenia is about 80%, which is typical for the most highly heritable multifactorial diseases. Polymorphic loci of genes of enzymes and receptors involved in the processes of neuroprotection and neurotrophia play significant role in the development of this disease. In this paper we investigated 48 polymorphic variants of genes of the neurotrophins and neurexins family (BDNF, NTRK2, NTRK3, NGF, NXPH1, and NRXN1) in Russian and Tatar cases and in a control group living in the Republic of Bashkortostan. The results of this study confirm the important role of neurotrophin and neurexin genes in paranoid schizophrenia development.

2q37.3 Deletion Syndrome: Two Cases with Highly Distinctive Facial Phenotype, Discordant Association with Schizophrenic Psychosis, and Shared Deletion Breakpoint Region on 2q37.3.

2q37.3 deletion syndrome belongs to the chromosomal 2q37 deletion spectrum which clinically resembles Albright hereditary osteodystrophy (AHO) syndrome. It is is mainly characterized by short stature, obesity, round face, brachydactyly type E, intellectual disability, behavioral problems, and variable intellectual deficits. Different from classical AHO syndrome, patients with 2q37 deletion syndrome lack renal parathyroid hormone resistance (pseudohypoparathyroidism) and soft tissue ossification. So far, deletion mapping or molecular breakpoint analyses of 2q37 have been performed in only few patients. Here, we report on 2 patients with 2q37.3 deletion syndrome. In both patients the breakpoint of the 5.5-Mb terminal microdeletion could be narrowed down to the same ∼ 200-kb interval on 2q37.3 by BAC-FISH and/or array-CGH. Flanking low-copy repeats may indicate a classical microdeletion syndrome genesis for the 2q37.3 microdeletion subgroup. Clinical evaluation revealed intellectual deficits and type E brachydactyly typical for classical AHO syndrome together with distinctive facial dysmorphisms not present in the former. Furthermore, one patient presented with schizophrenic psychosis, an observation that would be in accordance with previous reports about an association between schizophrenia susceptibility and an unknown gene within the chromosomal region 2q37.

Genetic variants in long non-coding RNA MIAT contribute to risk of paranoid schizophrenia in a Chinese Han population.

The heritability of schizophrenia has been reported to be as high as ~80%, but the contribution of genetic variants identified to this heritability remains to be estimated. Long non-coding RNAs (LncRNAs) are involved in multiple processes critical to normal cellular function and dysfunction of lncRNA MIAT may contribute to the pathophysiology of schizophrenia. However, the genetic evidence of lncRNAs involved in schizophrenia has not been documented. Here, we conducted a two-stage association analysis on 8 tag SNPs that cover the whole MIAT locus in two independent Han Chinese schizophrenia case-control cohorts (discovery sample from Shanxi Province: 1093 patients with paranoid schizophrenia and 1180 control subjects; replication cohort from Jilin Province: 1255 cases and 1209 healthy controls). In discovery stage, significant genetic association with paranoid schizophrenia was observed for rs1894720 (χ(2)=74.20, P=7.1E-18), of which minor allele (T) had an OR of 1.70 (95% CI=1.50-1.91). This association was confirmed in the replication cohort (χ(2)=22.66, P=1.9E-06, OR=1.32, 95%CI 1.18-1.49). Besides, a weak genotypic association was detected for rs4274 (χ(2)=4.96, df=2, P=0.03); the AA carriers showed increased disease risk (OR=1.30, 95%CI=1.03-1.64). No significant association was found between any haplotype and paranoid schizophrenia. The present studies showed that lncRNA MIAT was a novel susceptibility gene for paranoid schizophrenia in the Chinese Han population. Considering that most lncRNAs locate in non-coding regions, our result may explain why most susceptibility loci for schizophrenia identified by genome wide association studies were out of coding regions.

[Evoked potentials N200/P300 disorders and clinical phenotype in Cuban families with paranoid schizophrenia: a family-based association study]. / Estudio de asociación familiar entre las alteraciones de los potenciales evocados N200/P300 y el fenotipo clínico en familias cubanas con esquizofrenia paranoide.

INTRODUCTION: N200 and P300 event-related evoked potentials provide sensitive measurements of sensory and cognitive function and have been used to study information processing in patients with schizophrenia and their unaffected first-degree relatives. Reduced amplitude and increased latency of N200 and P300 potentials have been consistently reported in schizophrenia. Thus, event-related evoked potentials abnormalities are promising possible biological markers for genetic vulnerability to schizophrenia. OBJECTIVE: To assess the association of changes in latency, amplitude and topographic distribution of potentials N200 and P300 of patients with paranoid schizophrenia and their healthy first-degree relatives, in families with schizophrenia multiplex. METHODOLOGY: We measured latency and amplitude of the N200 and P300 component of evoked potentials using an auditory odd-ball paradigm in 25 schizophrenic patients (probands) from 60 families multiply affected with paranoid schizophrenia, 23 of their non-schizophrenic first-degree relatives and 25 unrelated healthy controls, through a study of family association. RESULTS: Schizophrenic patients and their relatives showed significant latency prolongation and amplitude reduction of the N200 and P300 waves compared to controls. Left-temporal as compared to right-temporal N200 and P300 were significantly smaller in schizophrenic patients and their non-schizophrenic first-degree relatives than in controls. Our results suggest that event-related evoked potentials abnormalities may serve as markers of genetic vulnerability in schizophrenia. CONCLUSIONS: Confirming results of other researchers, this present study suggests that latency prolongation and amplitude reduction of the N200 and P300 waves and an altered topography at temporal sites may be a trait “marker” of paranoid schizophrenia.

INTRODUCCIÓN: Los potenciales relacionados a eventos N200 y P300 son herramientas sensibles para evaluar el funcionamiento sensorial y cognitivo. Debido a que, frecuentemente se reporta una prolongación de la latencia y una disminución de la amplitud de los componentes N200 y P300 en pacientes con esquizofrenia, estos potenciales constituyen marcadores biológicos de vulnerabilidad genética para este trastorno mental. OBJETIVO: Precisar la asociación de las alteraciones en la latencia, la amplitud y la distribución topográfica de los potenciales N200 y P300 de pacientes con esquizofrenia paranoide y sus familiares sanos de primer grado, pertenecientes a familias con esquizofrenia multiplex. MÉTODOS: Se utilizó un paradigma “odd-ball” auditivo para evaluar la latencia, la amplitud y la distribución topográfica de los componentes N200 y P300 en 25 pacientes con esquizofrenia paranoide (probandos), 23 familiares sanos de primer grado y 25 sujetos controles, mediante un estudio de asociación familiar en 60 familias afectadas con esquizofrenia multiplex. RESULTADOS: Los probandos y sus familiares mostraron una prolongación significativa de la latencia y una disminución de amplitud de las ondas N200 y P300 cuando se compararon con los sujetos sanos. De igual forma, la amplitud de los potenciales N200 y P300 resultó significativamente disminuida en regiones temporales del hemisferio izquierdo de los probandos y sus familiares con respecto al grupo control. CONCLUSIONES: En concordancia con resultados de otros investigadores, este estudio sugiere que, la prolongación de latencia, la disminución de amplitud y las alteraciones en la distribución topográficas detectadas en regiones temporales de los potenciales N200 y P300, pueden constituir por su elevada asociación familiar, marcadores de rasgo para la esquizofrenia paranoide.

[Niemann-Pick type C disease and psychosis: Two siblings]. / Maladie de Niemann-Pick de type C et troubles psychiatriques : le cas d'une fratrie.

INTRODUCTION: Niemann-Pick type C disease (NPC) is a rare, neurovisceral, autosomal recessive disease, with an extremely heterogeneous clinical presentation. The adult form of the disease is usually expressed as a neurological form. Non-specific psychiatric symptoms are often associated with NPC. For some cases, it can also be expressed as an isolated psychiatric disorder form. Since 2009, the launching of a medicine called miglustat has helped to improve the disease evolution. CASE HISTORIES: We report two siblings followed-up in the same department of psychiatry and with an atypical psychotic symptomatology. Case 1 is a 27-year-old French male. He was hospitalised several times due to disordered behaviour, psychomotor excitation, mood instability and wandering. He was originally diagnosed with schizophrenia. However, the patient's psychosis proved refractory to treatment. He also exhibited a number of neurological signs (pyramidal signs and abnormal movements of the hands, head and limbs), which were considered related to his antipsychotic medication. Three years later, a full physical, neurological and neuropsychological examination revealed various neurological and visceral symptoms. He was diagnosed with NPC based on a classical biochemical NPC-phenotype following filipin staining in cultured skin fibroblasts. NPC1 gene sequencing revealed that he was a compound heterozygote for the p.S954L and p.N1156S mutations. The patient's psychiatric and neurological symptoms are currently stabilized by miglustat, allowing the patient to cease antipsychotic medication. Case 2 is the elder sister of Case 1. She was hospitalised several times due to acute delirium, hallucinations and suicidal tendencies. She was diagnosed with paranoid schizophrenia at 22 years of age. She has received a variety of typical and atypical antipsychotics. Many of these drugs proved initially effective but the patient's symptoms repeatedly returned. The patient shows persistent and worsening gait disorder and abnormal arm movements. A follow-up neurological examination at age 29 did not detect any ataxia, cataplexy or vertical supra-nuclear gaze palsy. Direct NPC1 gene sequencing detected a mutant NPC1 allele held in common with her brother, but full sequencing of both the NPC1 and NPC2 genes and multiplex ligation-dependent probe amplification (MLPA) did not detect any other pathogenic mutation or other anomalies. DISCUSSION: Because NPC is an autosomal recessive condition, heterozygous individuals carrying only one causal gene mutation are usually asymptomatic. Thus, while the accepted wisdom would suggest that patient 2 is not affected by the disease, it is interesting to consider why she has developed neurological and psychiatric disorders like her brother. Several hypotheses are discussed: mental expression in heterozygous genetic factor predisposing to schizophrenia, comorbidity or fortuitous association. It is not currently known whether a patient with a single NPC gene mutation can express NPC in full, partially, or perhaps just to a minimal degree. This case of a patient with a heterozygous "carrier" NPC genotype and neuropsychiatric disorders suggestive of the disease raises the possibility that symptomatic heterozygous NPC patients may exist. On the other hand, if the heterozygous genotype of patient 2 does not give rise to symptomatic disease, it is pertinent to question whether it could be a predisposing factor for the development of psychiatric pathologies. There are currently no published data on the occurrence of heterozygous NPC1 or NPC2 mutations among patients with atypical psychiatric presentations combined with neurological symptoms. Conversely, there are no published data demonstrating an increased frequency of psychiatric disorders in families affected by NPC. Finally, in view of the history of psychiatric disorders in this family, it is possible that psychosis simply occurred concomitantly with symptomatic NPC in patient 1 by chance, and that schizophrenia occurred simultaneously with an asymptomatic NPC carrier genotype in patient 2. To investigate this further, NPC patients' carrier family members (parents and siblings) should be fully screened for signs suggestive of the disease.