Congenital Cytomegalovirus and Zika Infections.

Congenital infections affecting newborn infants can have potentially devastating clinical outcomes. They are usually caused by viruses that infect mothers during pregnancy and are transmitted to the fetus or newborn during the prenatal, perinatal or postnatal periods. Congenital cytomegalovirus (cCMV) is the most common congenital infection affecting up to 2.5% of all live births. Even though most infected infants are asymptomatic at birth, cCMV is an important cause of neurodevelopmental impairment and represents the main cause of non-hereditary sensorineural hearing loss. Also, congenital Zika infection has emerged in recent years as a cause of microcephaly and neurodevelopmental delays. Currently, universal screening is not recommended for either infection in pregnant women or newborn infants. Therefore, screening for both conditions is based on multiple factors such as maternal immune status, exposure, and clinical manifestations of the infant. Use of antiviral medications on symptomatic cCMV has shown improvement in outcomes, in contrast with congenital Zika for which there are no therapeutic options available. Even though both viruses can be present in breast milk, there are no recommendations against breastfeeding in full-term infants. Close follow-up for affected infants is necessary to monitor for developmental delays and sensory impairments to implement interventional therapies at the earliest time possible.

Acute cerebellar knockdown of Sgce reproduces salient features of myoclonus-dystonia (DYT11) in mice.

Myoclonus dystonia (DYT11) is a movement disorder caused by loss-of-function mutations in SGCE and characterized by involuntary jerking and dystonia that frequently improve after drinking alcohol. Existing transgenic mouse models of DYT11 exhibit only mild motor symptoms, possibly due to rodent-specific developmental compensation mechanisms, which have limited the study of neural mechanisms underlying DYT11. To circumvent potential compensation, we used short hairpin RNA (shRNA) to acutely knock down Sgce in the adult mouse and found that this approach produced dystonia and repetitive, myoclonic-like, jerking movements in mice that improved after administration of ethanol. Acute knockdown of Sgce in the cerebellum, but not the basal ganglia, produced motor symptoms, likely due to aberrant cerebellar activity. The acute knockdown model described here reproduces the salient features of DYT11 and provides a platform to study the mechanisms underlying symptoms of the disorder, and to explore potential therapeutic options.

A role for cerebellum in the hereditary dystonia DYT1.

DYT1 is a debilitating movement disorder caused by loss-of-function mutations in torsinA. How these mutations cause dystonia remains unknown. Mouse models which have embryonically targeted torsinA have failed to recapitulate the dystonia seen in patients, possibly due to differential developmental compensation between rodents and humans. To address this issue, torsinA was acutely knocked down in select brain regions of adult mice using shRNAs. TorsinA knockdown in the cerebellum, but not in the basal ganglia, was sufficient to induce dystonia. In agreement with a potential developmental compensation for loss of torsinA in rodents, torsinA knockdown in the immature cerebellum failed to produce dystonia. Abnormal motor symptoms in knockdown animals were associated with irregular cerebellar output caused by changes in the intrinsic activity of both Purkinje cells and neurons of the deep cerebellar nuclei. These data identify the cerebellum as the main site of dysfunction in DYT1, and offer new therapeutic targets.