Verbal working memory in individuals with schizophrenia and their first degree relatives: relationship with negative and disorganized symptoms.

OBJECTIVE: To determine whether there are differences in verbal working memory amongst subjects with schizophrenia, their first degree relatives and controls, and to evaluate the influence of symptoms on these differences, as an initial step to assess whether this cognitive function is an endophenotype. METHODS: We examined 197 cases with schizophrenia, 197 first degree relatives and 200 controls through psychiatric interviews and the Letters and Numbers Sequencing test (LNS). Performance was compared among the three groups adjusting for age, sex and education level. Adjustment for "negative symptoms" and "disorganization" was performed afterwards. RESULTS: Subjects with schizophrenia showed lower performance in the LNS than their first degree relatives and the healthy controls; the effect sizes were 0.75 and 1.18 respectively. There was a small difference between relatives and controls (effect size =0.38). These differences were significant after adjustment for negative and disorganized symptoms, but the effect sizes became smaller: 0.26 for relatives vs. subjects with schizophrenia, 0.56 for controls vs. subjects with schizophrenia and 0.33 for relatives vs. controls. Among individuals with schizophrenia, performance in the LNS was not associated with disorder duration, disease onset age, antipsychotics, history of depressive episodes or substance use disorders. CONCLUSION: Results suggest verbal working memory may be considered as an endophenotype in schizophrenia.

Cognitive mechanisms underlying disorganization of thought in a genetic syndrome (47,XXY).

Because of the risk for development of psychopathology such as psychotic symptoms, it has been suggested that studying men with the XXY karyotype may help in the search for underlying cognitive, neural and genetic mechanisms. The aim of this study was to identify cognitive mechanisms that may contribute to disorganization of thought in XXY men. A group of 24 XXY men and two non-clinical control groups (N=20, N=18) participated in the study. The level of disorganization of thought was measured using the Schizotypal Personality Questionnaire. We assessed IQ, lateralization of verbal information processing and executive functions including inhibition and mental flexibility. XXY men with high levels of disorganization showed more severe impairments in mental flexibility and inhibition as compared to non-clinical controls and other XXY men. This subgroup also showed a stronger reduction in lateralization of verbal information processing. IQ measures did not differentiate XXY men with high versus low levels of disorganization. These findings indicate that executive impairments in the domains of inhibition and mental flexibility might play a role in the increased vulnerability for disorganized thought in the XXY group. Reduced lateralization of verbal information processing points to non-optimal cerebral specialization in the XXY group, especially in XXY men with high levels of disorganization. This fits with deficits in brain functions most vulnerable to such maturational disruptions, i.e. executive dysfunctions. Our findings are in line with those reported for schizophrenia patients with thought disorder. We speculate that the underlying mechanisms of thought disorder probably are deficit specific rather than disorder specific.

The genetics of symptom dimensions of schizophrenia: review and meta-analysis.

BACKGROUND: The use of symptom dimensions of schizophrenia as quantitative phenotypes has been proposed as a mean to reduce the heterogeneity of schizophrenia and facilitate genetic research. However, the genetic background of symptom dimensions is not clear. AIM: We aim to investigate whether the symptom dimensions "reality distortion", "psychomotor poverty" and "disorganization" are heritable phenotypes. METHOD: We performed a Medline search including all papers from 1980 to August 2007. In addition to reviewing the articles, we performed meta-analyses on these studies where possible. RESULTS: We identified 18 relevant papers. Only the studies on affected sibling pairs were suitable for meta-analysis. Data from twin and affected sibling studies are consistent with a genetic contribution to the disorganization dimension. However these studies did not unequivocally support a large genetic contribution to neither the reality distortion symptom dimension nor to the psychomotor poverty symptom dimension. In contrast several molecular genetic studies did report associations of genes with psychomotor poverty. CONCLUSIONS: These data suggest that only the disorganization symptom dimension may provide an useful alternative phenotype for genetic research. More research is required to make any definitive conclusions.

A genetic variant of the serine racemase gene is associated with schizophrenia.

BACKGROUND: Serine racemase (SRR) is a brain-enriched enzyme that converts L-serine to D-serine, which acts as an endogenous ligand of N-methyl D-aspartate (NMDA) receptors. Dysfunction of SRR may reduce the function of NMDA receptors and susceptibility to schizophrenia. METHODS: We genotyped three single-nucleotide polymorphisms (SNPs) of the 5' region of the SRR gene in 525 patients with schizophrenia and 524 healthy controls. Effects of SNPs on the promoter activity and on serum levels of total and D-serine were examined. RESULTS: We found a significant excess of the IVS1a+465C allele of the SRR gene in schizophrenia, especially in the paranoid subtype (p = .0028). A reporter assay showed that the IVS1a+465C allele had 60% lower promoter activity than did the IVS1a+465G allele. CONCLUSIONS: The IVS1a+465C allele of the SRR gene, which reduces expression of the gene, is a risk factor for schizophrenia, especially the paranoid subtype.

Genome-wide linkage scan of schizophrenia: a cross-isolate study.

Genetic isolates are exceptional resources for the detection of susceptibility genes for complex diseases because of the potential reduction in genetic and clinical heterogeneity. However, the outcome of these mapping efforts is dependent upon the demographic history of a given isolated population, with the most significant factors being a constant population size, the number of generations since founding, and the pathogenic loci and their allele frequencies among founders. Here we employed a cross-isolate genome-wide multipoint linkage study design using uniform genetic and clinical methods in four Daghestan ethnically and demographically diverse isolates with an aggregation of schizophrenia. Our previous population-genetics study showed that Daghestan has an extremely high genetic diversity between ethnic populations and a low genetic diversity within them. The isolates selected for this study include some with more than 200 and some with fewer than 100 generations of demographical history since their founding. Updated clinical data using DSM-IV criteria showed between-isolate differences in aggregation of distinct types of schizophrenia: one of the isolates had a predominant aggregation of disorganized schizophrenia, while the other three had predominantly paranoid schizophrenia. The summarized cross-isolate results indicated prominent within and between-isolate differences in clinical and genetic heterogeneity: the most ancient isolates have roughly twofold fewer incidences of distinct clinical phenotypes and fewer linked genomic regions compared to the demographically younger isolates, which exhibit higher clinical and genetic heterogeneity. Affected individuals in the demographically ancient isolate of ethnic Dargins (No. 6022) who suffered from disorganized schizophrenia showed the highest linkage evidence at 17p11-p12 (LOD=3.73), while isolates with a predominant aggregation of paranoid schizophrenia (Nos. 6005, 6011, and 6034) showed the highest linkage evidence at 22q11 (LOD=3.0 and 4.4). The unified clinical, genomic, and statistical design we used enabled us to separate the linked and unlinked pedigrees in an unbiased fashion for each genomic location. Overall maximized heterogeneity lod scores for the combined pedigrees ranging from 3.5 to 8.7 were found at 2p24, 10q26, 11q23, 12q24, 17p11-p12, 22q11, and 22q13. The cross-isolate homogeneity in linkage patterns may be ascribed to an identical-by-descent "metahaplotype" block with pathogenic loci derived from the Daghestan ethnic groups' common ancestral metapopulation, while the cross-isolate differences may reflect differences in gene drift and recombination events in the history of local isolates. The results obtained support the notion that mapping genes of any complex disease (e.g., schizophrenia) in demographically older genetic isolates may be more time and cost effective in comparison with demographically younger isolates, especially in genetically heterogeneous outbred populations, due to higher clinical and genetic homogeneity of the primary isolates. A study at higher genotyping density across the regions of interest and fluorescence in situ hybridization analyses are currently underway.

No association between the sigma receptor type 1 gene and schizophrenia: results of analysis and meta-analysis of case-control studies.

BACKGROUND: Several lines of evidence have supported possible roles of the sigma receptors in the etiology of schizophrenia and mechanisms of antipsychotic efficacy. An association study provided genetic evidence that the sigma receptor type 1 gene (SIGMAR1) was a possible susceptibility factor for schizophrenia, however, it was not replicated by a subsequent study. It is necessary to evaluate further the possibility that the SIGMAR1 gene is associated with susceptibility to schizophrenia. METHODS: A case-control association study between two polymorphisms of the SIGMAR1 gene, G-241T/C-240T and Gln2Pro, and schizophrenia in Japanese population, and meta-analysis including present and previous studies. RESULTS: There was no significant association of any allele or genotype of the polymorphisms with schizophrenia. Neither significant association was observed with hebephrenic or paranoid subtype of schizophrenia. Furthermore, a meta-analysis including the present and previous studies comprising 779 controls and 636 schizophrenics also revealed no significant association between the SIGMAR1 gene and schizophrenia. CONCLUSION: In view of this evidence, it is likely that the SIGMAR1 gene does not confer susceptibility to schizophrenia.

CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia.

To examine the cannabinoid hypothesis for pathogenesis of schizophrenia, we examined two kinds of polymorphisms of the CNR1 gene, which encodes human CB1 receptor, a subclass of central cannabinoid receptors, in schizophrenics and age-matched controls in the Japanese population. Allelic and genotypic distributions of polymorphism 1359G/A at codon 453 in the coding region and AAT triplet repeats in the 3' flanking region in the Japanese population were quite different from those in Caucasians. Although the polymorphism 1359G/A was not associated with schizophrenia, the triplet repeat polymorphism of the CNR1 gene was significantly associated with schizophrenia, especially the hebephrenic subtype (P = 0.0028). Hebephrenic schizophrenia showed significantly increased rate of the 9 repeat allele (P = 0.032, OR = 2.30, 95% CI (1.91-2.69)), and decreased rate of the 17 repeat allele (P = 0.011, OR = 0.208, 95% CI (0.098-0.439)). The present findings indicated that certain alleles or genotypes of the CNR1 gene may confer a susceptibility of schizophrenia, especially of the hebephrenic type.

Does the Schizotypal Personality Questionnaire reflect the biological-genetic vulnerability to schizophrenia?

We investigated whether the Schizotypal Personality Questionnaire (SPQ) [Schizophr. Bull. 17 (1991) 555.] could be an indicator of the biological-genetic vulnerability to schizophrenia. We hypothesized that the mean scores on three dimensions of the SPQ of different groups of relatives of patients with schizophrenia would parallel their risk for developing schizophrenia. The SPQ was administered to 51 first-episode schizophrenia patients, 63 parents of schizophrenia patients, 42 siblings of schizophrenia patients and 12 children of schizophrenia patients. Patients differed from the relatives on all three dimensions. Siblings and children scored significantly higher than parents on Positive Schizotypy, and the insignificant difference between the siblings and children was in the expected direction. The results could not be explained by the differences in age, sex, IQ or substance abuse. No differences were found for Disorganization Schizotypy between the relatives. Children scored higher than parents on Negative Schizotypy. The current study offers support to the hypothesis that the positive dimension of SPQ reflects the genetic vulnerability to schizophrenia.

Synapsin III gene polymorphisms and schizophrenia.

Synapsins are synaptic vesicle-associated phosphoproteins and are thought to play crucial roles in synaptogenesis and neurotransmitter release. Synaptic abnormalities have been reported in the pathophysiology of schizophrenia. In addition, the synapsin III gene, a member of the synapsin gene family, has been located at 22q12-13, which has been suggested as a potential susceptibility locus for schizophrenia. We investigated a genetic association between schizophrenia and the synapsin III gene polymorphisms (-631C/G and -196G/A) in 160 schizophrenic patients and 153 controls. No significant positive association between either polymorphism and schizophrenia was observed. Furthermore, no significant association was observed between either polymorphism and the diagnostic subtypes. Our results suggested that the synapsin III gene polymorphisms do not confer increased susceptibility to schizophrenia.

Adult-type metachromatic leukodystrophy with a compound heterozygote mutation showing character change and dementia.

A 26-year-old Japanese woman slowly developed a change of character such as hypospontaneity and blunted affect, followed by obvious mental deterioration. She was diagnosed as having a disorganized type of schizophrenia at the first examination. Brain magnetic resonance imaging demonstrated diffuse high intensity in the cerebral white matter, particularly in the frontal lobes. The single photon emission computed tomography images using 123I-IMP disclosed diffuse cerebral hypofusion, especially in the frontal lobes. Electroencephalogram showed a moderate amount of 5-6Hz theta waves on the background of alpha activity. Nerve conduction velocities in the extremities were delayed. The level of leucocyte arylsulphatase was low. In the arylsulphatase A gene analysis, a compound heterozygote having the 99Gly-->Asp and 409Thr-->Ile mutations was confirmed. The patient was diagnosed as having metachromatic leukodystrophy. She gradually showed obvious dementing symptoms such as memory disturbance and disorientation. The characteristics of the psychiatric symptoms in the leukodystrophy are discussed.

[Diagnostic problems in juvenile Huntington chorea]. / Diagnostische Probleme bei einer juvenilen Chorea Huntington.

Huntington's disease (HD) may cause considerable diagnostic problems because of the highly variable clinical features, especially at the beginning of the illness. We report the case of a 21-year-old woman with definite HD whose main symptoms were psychopathological changes that were misinterpreted as schizophrenia for 7 years. One reason for this misdiagnosis was the unusual, very early onset and the remarkable earlier age of onset of HD compared with that of other affected relatives. The phenomenon of earlier onset within one affected family is well documented in the literature in cases with the paternally transmitted mutated gene. Diagnostic landmarks were consideration of the initially mild disturbances of movement and the once again repeated detailed examination of the family history.

[Hebephrenic symptoms as an expression of an XYY chromosome abnormality? Case report of a patient with suspected sexual abuse of his own 2 minor children]. / Hebephrene Symptomatik als Ausdruck einer XYY-Chromosomenanomalie? Kasuistik über einen Patienten mit Verdacht auf sexuellen Missbrauch zweier leiblicher, minderjähriger Kinder.

A 48 year old patient was hospitalised because of parasuicidal behaviour and suicidal ideation. He was under suspicion of having sexually abused his 4-year old daughter and his 4-year old son. At the age of 17, he was hospitalised in a psychiatric ward under the diagnosis of hebephrenic schizophrenia. He successfully received an insulin coma therapy. Because of his increased height (1.89 m), mental retardation and other psychical disorders in his youth, we now suspected him of having an extra Y chromosome which was confirmed by chromosome analysis. The non-uniform symptomatology of XYY-individuals includes a hebephrenic aspect. Concerning the different therapeutical and juridical consequences, we considered a critical investigation of the former diagnosis "Hebephrenic Schizophrenia".

Clozapine treatment of polydipsia.

A patient with refractory chronic schizophrenia having severe polydipsia and hyponatremia was treated with clozapine. There followed a dramatic improvement in the polydipsia and correction of the hyponatremia. This improvement has been sustained throughout a 6-month follow-up.

Clinical subtypes and age at onset in schizophrenic siblings.

This study examines the concordance of clinical subtypes and age at onset of schizophrenia in 42 sibships of multiply affected schizophrenic patients. Subtypes were defined by four major diagnostic systems (DSM-III, DSM-III-R, ICD-10, and Tsuang-Winokur criteria) and rated both for the first hospitalization and long-term diagnosis. When a sibship method was used, no concordance for subtypes was found in siblings. Age at onset, analyzed as a continuous variable with the intraclass correlation method, was found to be correlated in siblings. This finding suggest that the search for continuous traits distributed in families of schizophrenic patients might constitute an alternative to discrete category-based family studies.

Subtyping familial schizophrenia: reliability, concordance, and stability.

This report examines the reliability, concordance, and long-term stability of the subtypes of schizophrenia defined by four major diagnostic systems (DSM-III, DSM-III-R, ICD-10, and Tsuang-Winokur criteria) and rated both for the first hospitalization and for a best estimate diagnosis reflecting lifetime evolution of symptomatology. Schizophrenics studied belonged to two samples of multiply affected families, namely a sample selected in France and a sample of non-metropolitan French identified in the island of La Réunion. ICD-10 and DSM-III-R show opposite stringency regarding subtyping of schizophrenia, with DSM-III-R having a narrow and ICD-10 a broader definition of specific subtypes. Long-term stability of each subtype was fairly good, stability being the highest for hebephrenics and only intermediate for paranoid and undifferentiated subtypes. Comparison of two different cultural and geographical regions reveals an overall similarity of subtype frequencies in familial schizophrenia. The implications of the results for the choice of diagnostic procedures in family studies of schizophrenia are discussed.

Multiple exostosis, brain ventricular enlargement and schizophrenia.

Case histories of two family members with multiple exostosis and schizophrenia are presented. There are no previous reports of such an association. The computerized axial tomography scan revealed signs of hydrocephalus in one patient and substantial enlargement of lateral brain ventricles in the other. The mutual occurrence of all three clinical findings (multiple exostosis, ventricular brain enlargement and psychosis) in two family members may suggest a subgroup of patients who manifest schizophrenic symptomatology.

HLA antigens and neuroleptic response in clinical subtypes of schizophrenia.

The frequency of HLA antigens of A and B loci was examined in a carefully selected sample of 91 schizophrenic patients from central Italy. This population showed no increase in antigens compared with the control group. However, in agreement with previous studies, a slight increase in A1 was observed in the hebephrenic subgroup and, in a lesser extent, an increase of A2 was found in the paranoid subgroup. Although these increases are more prominent when the subgroups are compared and tend to support the case for genetic heterogeneity, they fail to reach statistical significance. Response to neuroleptic treatment was studied in an attempt to further subdivide the clinical subgroups. A1-negative and A2-positive paranoid patients demonstrated a statistical better response to neuroleptics. The findings suggest that schizophrenia should be considered a heterogenous disease and that response to neuroleptics can be employed as an instrument of biological subclassification.