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Background: Schizophrenia (SCZ) is one of the most disabling psychiatric disorders. It is thought to be due to a complex interplay between polygenic and various environmental risk factors, although recent reports on genomic copy number variations suggest that a fraction of the cases could result from variably penetrant de novo variants. The gene encoding the synaptic motor protein kinesin 17 (KIF17) involved in glutamatergic synapse is a candidate gene for SCZ., Methods: As part of our Synapse to Disease project, we resequenced KIF17 in a cohort of individuals with sporadic SCZ (188 subjects). Additional populations included autism spectrum disorder (142 subjects), nonsyndromic mental retardation (95 subjects), and control subjects (568 subjects). Functional validation of the human mutation was done in developing zebrafish., Results: Here we report the identification of a de novo nonsense truncating mutation in one patient with SCZ, in kinesin 17, a synaptic motor protein. No de novo or truncating KIF17 mutations were found in the additional samples. We further validated the pathogenic nature of this mutation by knocking down its expression in zebrafish embryos, which resulted in a developmental defect., Conclusions: Together our findings suggest that disruption of KIF17, although rare, could result in a schizophrenia phenotype and emphasize the possible involvement of rare de novo mutations in this disorder., (Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Synapsin III plays a role in neuronal plasticity and maps to chromosome 22q12-13, a region suggested to be linked to schizophrenia. To determine if synapsin III plays a role in this disease, we searched for polymorphisms in this gene in patients with schizophrenia and controls., Methods: The synapsin III gene was initially sequenced from 10 individuals with schizophrenia to identify polymorphisms. Association analysis was then performed using 118 individuals with schizophrenia and 330 population controls. Synapsin III expression was studied by immunoblot analyses, and phosphorylation sites were mapped by sequencing trypsin-digested synapsin III fragments phosphorylated with phosphorus-32., Results: A rare, missense polymorphism, S470N, was identified in the synapsin III gene and appeared more frequently in individuals with schizophrenia than in controls (p =.0048). The site affected by the polymorphism, Ser470, was determined to be a substrate for mitogen-activated protein kinase, a downstream effector of neurotrophin action. Phosphorylation at Ser470 was increased during neonatal development and in response to neurotrophin-3 in cultured hippocampal neurons., Conclusions: Our observations suggest an association of a rare polymorphism in synapsin III with schizophrenia, but further studies will be required to clarify its role in this disease.

Background: Schizophrenia is a complex genetic disorder with no clear pattern of inheritance. Epigenetic modification of genes may thus play a role in its transmission., Methods: In our study, 439 families with at least two ill siblings with schizophrenia (208 with unilineal transmission) were examined for evidence of a parent-of-origin effect (e.g., evidence of parental imprinting on the familial transmission of schizophrenia)., Results: No significant difference in the prevalence of maternal compared with paternal transmission was found. In addition, affected male subjects did not differ from affected female subjects in the proportion of their offspring diagnosed with schizophrenia., Conclusions: Although the transmission of schizophrenia may be influenced by epigenetic events, our study fails to find evidence that one epigenetic mechanism, a parent-of-origin imprinting effect, determines whether an individual expresses the illness.

Background: Previous reports indicate that brain structural abnormalities may be progressive in some patients with schizophrenia. Our study was designed to determine deviations in the shape of midline brain structures at the time of onset of symptoms of schizophrenia and 3-5 years later., Methods: Eleven landmarks were located on the midsagittal magnetic resonance imagery brain scans of 55 patients with schizophrenia and 22 nonpsychiatric control individuals. Geometric morphometric methods were used for the extraction of shape variables from landmark coordinates. Permutation tests were used to test the effects of gender, diagnosis, time elapsed since illness onset, and age on brain shape., Results: The diagnosis-by-time interaction and the effect of gender were significantly different from zero (p<.027 and p <.039, respectively). The effect of time was significant in patients (p <.002), but not in control subjects. Some anatomical abnormalities in mean patient brain morphology seem to be present both at the time of diagnosis and at follow-up. These are similar to anomalies reported by previous geometric morphometrics studies., Conclusions: Some previously identified brain abnormalities are detectable at the time of first hospitalization. The rapid change in midline brain morphology in patients with schizophrenia during the subsequent 3-5 years is consistent with either a neurodegenerative disease process or an effect of treatment with psychiatric drugs. There is a sexual dimorphism in brain morphology that might be reduced by schizophrenia.

Brain morphological abnormalities have been reported in several independent investigations of chronic schizophrenic patients. The present study is a prospective 4-year follow-up of first-episode schizophrenic patients to determine whether some of these abnormalities may be a consequence of regional brain structural change over time after the onset of a first psychotic episode. Whole hemisphere, temporal lobes, superior temporal gyrus, hippocampus, caudate, corpus callosum, and lateral ventricles were measured in a series of MRI scans taken over a 4-year period in 20 patients and five controls. Total volume reduction was noted in both hemispheres to a greater degree in patients than controls. When adjusted for total brain size, left ventricular enlargement occurred in patients, but not controls, over time. These preliminary data suggest that subtle cortical atrophy may be occurring over time after the onset of illness.

Previous studies indicate differences between schizophrenics and normals in thickness and overall size of the corpus callosum, particularly in female subjects. The present study compares the area of the corpus callosum as measured by magnetic resonance imaging (MRI) in men and women experiencing first-episode cases of schizophrenia. The corpus callosum area is also correlated with measures of neuropsychological function. The results of this study suggest that women who are first-episode schizophrenic patients have a smaller total corpus callosum area than female controls, with no difference noted for men. In normal controls, a larger corpus callosum was associated with better cognitive function, whereas in schizophrenics, no such relationship emerged.

The present study is an examination of ventricular and temporal lobe size in 50 DSM-III-R first-episode schizophreniform or schizoaffective patients who were ill for less than 6 months. Two-year clinical follow-up and magnetic resonance imaging (MRI) scan analyses are also reported from data collected on an initial group of 30 first-episode schizophrenic patients and controls. Left ventricular enlargement, which was present in our previously published report of first-episode cases of schizophrenia, is not present to the same extent in this larger group of schizophreniform patients closer to the onset of their illness, and no temporal lobe volume reduction was detected. However, lateral ventricular size at the time of the first-episode was generally correlated with outcome--the larger the ventricles, the poorer the outcome. No mean change in ventricular or temporal lobe size was found at rescanning 2 years later, but the degree of ventricular change was inversely correlated with the number of hospitalizations and the amount of time spent in hospital; it did not correlate with temporal lobe size. When rescanned, some patients showed change greater than 20% in ventricular size and 10% in temporal lobe size. Thus, these findings need further evaluation by serial scans over a longer time period before it can be determined that no progression of brain structural abnormalities is occurring as part of the pathology of schizophrenia, even in a subgroup of patients.

Brain morphology was examined using magnetic resonance imaging in 30 first-episode patients with a schizophreniclike psychosis, 15 chronic schizophrenics, and 20 neurological controls. Statistical analyses of computer-generated measurements of regions of interest were controlled for gender, age, social class, and total brain volume. Lateral ventricular size was increased in both first-episode and chronic schizophrenic patients, with greater significance on the left than on the right side. Only the chronic patients, however, had reduced temporal lobe size, which also was greater on the left side. No major correlations of regional brain morphological measurements with cognitive functioning were found, although some measurements of verbal memory were correlated with parahippocampal size. This is a report of a preliminary study that suggests that some morphological brain changes may be present at the time of first treatment for a psychotic illness, whereas others may occur later in the course of illness. Future prospective studies may determine the clinical significance of these changes and whether they progress with the development of illness chronicity.

As temporal lobe dysfunction has been postulated in the affective disorders, the authors investigated glucose utilization in the temporal lobes of 13 affectively ill patients in comparison with 18 normal volunteer controls and 17 previously reported schizophrenic patients, following injections of fluorine 18-2-deoxy-D-glucose (FDG) during somatosensory stimulation to the right forearm. Using a boundary-finding algorithm to outline each temporal lobe, maximum glucose use relative to maximums elsewhere in the same positron emission tomography (PET) slice were calculated. In a small group of moderately to severely depressed patients, this relative measure was significantly reduced in the right (with a similar trend in the left) temporal lobe compared to normal volunteers and the other comparison groups. The lack of a significant increase in glucose utilization, measured either as a maximum or in relation to other areas in the PET scan slice, suggests that a temporal lobe activation or a seizure-like process is not generally occurring during active depressive phases of the illness.

Computerized tomograms (CT scans) and neuroendocrine challenges (TRH stimulation test and dexamethasone suppression test) were completed in 38 melancholic depressed hospitalized patients. There were no significant differences in ventricular size between delusional and nondelusional depressives. However, 5 of 20 delusional depressives (25%) in contrast to none of 18 nondelusional depressives had ventricular brain ratios greater than 2 standard deviations from the mean of 26 neurological controls. There were no demographic, clinical, or neuroendocrine differences between patients with enlarged ventricles and those with normal CT scans. Two of 5 patients with large ventricles were rehospitalized within the 1st year of ascertainment in contrast to 3 of the other 15 delusional depressed patients. The possible relevance of cerebral ventricular size for depressive disorder is discussed.

Temporal lobe glucose metabolic rate was assessed in 21 off-medication patients with schizophrenia and 19 normal controls by positron emission tomography with 18F-deoxyglucose. Patients with schizophrenia had significantly greater metabolic activity in the left than the right anterior temporal lobe, and the extent of this lateralization was in proportion to the severity of psychopathology.

Magnetic resonance imaging (MRI) brain scans were performed on 24 schizophrenic patients, 22 bipolar affective patients, and 25 normal control subjects without medical or psychiatric illness using a Picker Vista 0.5 tesla scanner. Specific callosal regions and the cerebral area on the midsagittal slice were measured utilizing the technique described by Nasrallah et al. (1986). No significant differences were found among diagnostic groups in anterior, mid, or posterior callosal width, callosal area, cerebral area, callosal to cerebral area ratio, or the genu (first quartile) to splenium (fourth quartile) ratio. However, male subjects had a significantly greater callosal and cerebral area than female subjects. Gender differences were shown in the genu to splenium ratio in the control groups, but not the affective or schizophrenic groups. The implications of these gender differences are discussed in relation to other studies.

Plasma dopamine-beta-hydroxylase (DBH) activity was studied in two different populations of chronic schizophrenic patients and assayed by two independent laboratories. No significant difference between schizophrenic patients and normal controls was found although in both groups chronic undifferentiated schizophrenics with paranoid features had a trend towards lower DBH activity than the other patients and controls. In addition, DBH and monoamine oxidase (MAO) activities were studied in 13 schizophrenic patients and available first degree-relatives. There was no association of low MAO and low DBH activities within the schizophrenic families.

Glucose metabolic rate in the basal ganglia, thalamus, and somatosensory cortex was examined in eight patients with schizophrenia before and after receiving neuroleptic medication. Basal ganglia metabolic rates were increased with medication: more on the right than on the left and more in putamen than caudate. The cortical anteroposterior ratio, an index of relative hypofrontality, was not affected by neuroleptics. The brain areas that were found to be altered by neuroleptics were selected for comparison between off-medication schizophrenics and controls. Metabolic rates in the basal ganglia tended to be low in patients with schizophrenia in comparison to 24 age- and sex-matched controls.