Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus.

Aicardi-Goutières syndrome (AGS) presents as a severe neurological brain disease and is a genetic mimic of the sequelae of transplacentally acquired viral infection. Evidence exists for a perturbation of innate immunity as a primary pathogenic event in the disease phenotype. Here, we show that TREX1, encoding the major mammalian 3' --> 5' DNA exonuclease, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. Similar loss of function in the Trex1(-/-) mouse leads to an inflammatory phenotype. Our findings suggest an unanticipated role for TREX1 in processing or clearing anomalous DNA structures, failure of which results in the triggering of an abnormal innate immune response.

The neuropsychology and neurology of sexual deviance: a review and pilot study.

Current neurological hypotheses of paraphilia posit that sexual deviance is associated with frontal and/or temporal lobe damage. This broad conception is based on few investigations, however, and the first goal of this study was to review the existing data derived from neuropsychiatry, neuroimaging and neuropsychology. It is concluded that although fronto-temporal dysfunctions are sporadically reported among sexual offenders, the evidence is scarce and it might not be specific to this type of offending. The second objective of this investigation was to gather preliminary neuropsychological data with more homogeneous subgroups of sexual offenders. A profile of lower-order executive dysfunctions (e.g. sustained attention and inhibition) and verbal deficits with intact or good capacities for higher-order executive functioning (e.g. reasoning and cognitive flexibility) and visuo-spatial processing was preferentially found among sexual offenders, suggesting basal fronto-temporal anomalies. Importantly, pedophiles were more consistently and severely impaired than rapists of adults. However, this basal fronto-temporal profile is not characteristic of sexual deviance, as it is also found in association with delinquency and criminality in general. Future neuropsychological and brain imaging studies should consider subgroups of sexual offenders and recruit non-sexual violent persons and non-violent individuals in order to disentangle the complex relations between brain anomalies and sexual deviance.

Lethal obesity associated with sodium valproate in a brain-injured patient.

A 34-year-old man developed posttraumatic epilepsy and a disinhibited orbitofrontal syndrome following severe head trauma at age 22. After an 11-year prison term marked by repeated impulsive aggression, he was transferred to a state psychiatric hospital. Replacement of phenytoin by valproic acid resulted in a 100-lb weight gain, exacerbation of sleep apnea, and right heart failure. Despite replacement of valproate with topiramate, he died of a cardiorespiratory arrest during a seizure. This case illustrates the potential risks associated with valproate therapy in the obese brain-damaged population.

Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus.

Cree leukoencephalopathy is a rapidly fatal infantile autosomal recessive leukodystrophy of unknown cause observed in the native North American Cree and Chippewayan indigenous population. We found in the brain of affected individuals the typical foamy cells with the oligodendroglial phenotype described in central hypomyelination syndrome/vanishing white matter, a syndrome related to mutations in the genes encoding the five subunits of the eucaryotic translation initiation factor eIF2B. In three patients of two Cree families, we found a homozygous missense mutation resulting in a histidine substitution at arginine 195 of epsilon-eIF2B.