Prenatal maternal infection and risk for autism in offspring: A meta-analysis.

While prenatal maternal infection has received attention as a preventable and treatable risk factor for autism, findings have been inconsistent. This paper presents the results of a meta-analysis to determine whether the weight of the evidence supports such an association. Studies with a categorical diagnosis of autism as the outcome and an assessment of its association with prenatal maternal infection or fever (or the data necessary to compute this association) were included. A total of 36 studies met these criteria. Two independent reviewers extracted data on study design, methods of assessment, type of infectious agent, site of infection, trimester of exposure, definition of autism, and effect size. Analyses demonstrated a statistically significant association of maternal infection/fever with autism in offspring (OR = 1.32; 95% CI = 1.20-1.46). Adjustment for evident publication bias slightly weakened this association. There was little variation in effect sizes across agent or site of infection. Small differences across trimester of exposure were not statistically significant. There was some evidence that recall bias associated with status on the outcome variable leads to differential misclassification of exposure status. Nonetheless, the overall association is only modestly reduced when studies potentially contaminated by such bias are removed. Although causality has not been firmly established, these findings suggest maternal infection during pregnancy confers an increase in risk for autism in offspring. Given the prevalence of this risk factor, it is possible that the incidence of autism would be reduced by 12%-17% if maternal infections could be prevented or safely treated in a timely manner. LAY SUMMARY: This study is a meta-analysis of the association of maternal infection during pregnancy and subsequent autism in offspring. In combining the results from 36 studies of this association we find that a significant relationship is present. The association does not vary much across the types of infections or when they occur during pregnancy. We conclude that the incidence of autism could be substantially reduced if maternal infections could be prevented or safely treated in a timely manner.

Misuse of atypical antipsychotics in conjunction with alcohol and other drugs of abuse.

Non-medical use of atypical antipsychotics by substance abusers has been reported in the literature, although no detailed studies exist. Among 429 addiction treatment inpatients screened, 73 (17.0%) reported misuse of antipsychotics with alcohol, opioids, cocaine, methamphetamine and/or cannabis; 39 (9.1%) within the past year. Of past year misusers, 25 (64.1%) were interviewed. Most were male (76.0%), non-Caucasian (56.0%), and polysubstance abusers (84.0%). Quetiapine, the most abused drug (96.0%), was obtained primarily from doctors (52.0%) and family/friends (48.0%). Reasons for use included to "recover" from other substances (66.7%), "enhance" the effects of other substances (25.0%), and "experiment" (20.8%). The most frequently reported positive effect was "feeling mellow" (75.0%); negative effects were consistent with antipsychotic use (e.g., feeling thirsty, trouble concentrating). Compared to a normative sample of inpatient substance abusers, ASI composite scores were higher. Findings suggest that physicians should assess for use/misuse of atypical antipsychotics among patients with addiction.

Rare NRXN1 promoter variants in patients with schizophrenia.

Copy number variants (CNVs) affecting the neurexin 1 (NRXN1) gene have been found in a subgroup of patients with schizophrenia (SZ). NRXN1 expression is complex, with multiple alternative splice forms generated from two major transcripts; NRXN1alpha and NRXN1beta. The majority of CNVs in SZ are deletions affecting the proximal NRXN1alpha exons and promoter region. Rare chromosomal events are useful in understanding the genetic basis of complex psychiatric disorders since affected genes become feasible targets to analyze for more subtle genetic alterations. As a first step towards this goal, we resequenced the NRXN1alpha promoter region in 170 patients with SZ and a similar number of controls. Two rare mutations were identified in the patient population. One previously unknown single nucleotide polymorphism (SNP) was found in controls. Bioinformatics analysis suggests that binding to several transcription factors may be affected by the minor alleles. The findings suggest that in addition to chromosomal alterations disrupting the NRXN1alpha promoter, rare point mutations in the region may also be involved in SZ pathogenesis.

Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase gamma.

POLG is the human gene that encodes the catalytic subunit of DNA polymerase gamma (Pol gamma), the replicase for human mitochondrial DNA (mtDNA). A POLG Y955C point mutation causes human chronic progressive external ophthalmoplegia (CPEO), a mitochondrial disease with eye muscle weakness and mtDNA defects. Y955C POLG was targeted transgenically (TG) to the murine heart. Survival was determined in four TG (+/-) lines and wild-type (WT) littermates (-/-). Left ventricle (LV) performance (echocardiography and MRI), heart rate (electrocardiography), mtDNA abundance (real time PCR), oxidation of mtDNA (8-OHdG), histopathology and electron microscopy defined the phenotype. Cardiac targeted Y955C POLG yielded a molecular signature of CPEO in the heart with cardiomyopathy (CM), mitochondrial oxidative stress, and premature death. Increased LV cavity size and LV mass, bradycardia, decreased mtDNA, increased 8-OHdG, and cardiac histopathological and mitochondrial EM defects supported and defined the phenotype. This study underscores the pathogenetic role of human mutant POLG and its gene product in mtDNA depletion, mitochondrial oxidative stress, and CM as it relates to the genetic defect in CPEO. The transgenic model pathophysiologically links human mutant Pol gamma, mtDNA depletion, and mitochondrial oxidative stress to the mtDNA replication apparatus and to CM.

Targeted transgenic overexpression of mitochondrial thymidine kinase (TK2) alters mitochondrial DNA (mtDNA) and mitochondrial polypeptide abundance: transgenic TK2, mtDNA, and antiretrovirals.

Mitochondrial toxicity limits nucleoside reverse transcriptase inhibitors (NRTIs) for acquired immune deficiency syndrome. NRTI triphosphates, the active moieties, inhibit human immunodeficiency virus reverse transcriptase and eukaryotic mitochondrial DNA polymerase pol-gamma. NRTI phosphorylation seems to correlate with mitochondrial toxicity, but experimental evidence is lacking. Transgenic mice (TGs) with cardiac overexpression of thymidine kinase isoforms (mitochondrial TK2 and cytoplasmic TK1) were used to study NRTI mitochondrial toxicity. Echocardiography and nuclear magnetic resonance imaging defined cardiac performance and structure. TK gene copy and enzyme activity, mitochondrial (mt) DNA and polypeptide abundance, succinate dehydrogenase and cytochrome oxidase histochemistry, and electron microscopy correlated with transgenesis, mitochondrial structure, and biogenesis. Antiretroviral combinations simulated therapy. Untreated hTK1 or TK2 TGs exhibited normal left ventricle mass. In TK2 TGs, cardiac TK2 gene copy doubled, activity increased 300-fold, and mtDNA abundance doubled. Abundance of the 17-kd subunit of complex I, succinate dehydrogenase histochemical activity, and cristae density increased. NRTIs increased left ventricle mass 20% in TK2 TGs. TK activity increased 3 logs in hTK1 TGs, but no cardiac phenotype resulted. NRTIs abrogated functional effects of transgenically increased TK2 activity but had no effect on TK2 mtDNA abundance. Thus, NRTI mitochondrial phosphorylation by TK2 is integral to clinical NRTI mitochondrial toxicity.