Timothy Syndrome (TS) is caused by very rare exonic mutations of the CACNA1C gene that produce delayed inactivation of Cav1.2voltage-gated calcium channels during cellular action potentials, with greatly increased influx of calcium into the activated cells. The major clinical feature of this syndrome is a long QT interval that results in cardiac arrhythmias. However, TS also includes cognitive impairment, autism, and major developmental delays in many of the patients. We observed the appearance of Bipolar Disorder (BD) in a patient with a previously reported case of TS, who is one of the very few patients to survive childhood. This is most interesting because the common SNP most highly associated with BD is rs1006737, which we show here is a cis-expression quantitative trait locus (eQTL) for CACNA1C in human cerebellum, and the risk allele (A) is associated with decreased expression. To combine the CACNA1C perturbations in the presence of BD in this patient and in patients with the common CACNA1C SNP risk allele, we would propose that either increase or decrease in calcium influx in excitable cells can be associated with BD. In treatment of BD with calcium channel blocking drugs (CCBs), we would predict better response in patients without the risk allele, because they have increased CACNA1C expression.

We report a 42-year-old man who, for 8 months, had intermittent motor abnormalities and mild difficulty falling asleep. A diagnosis of fatal familial insomnia (FFI) became evident over the next 6 months when he developed progressive insomnia, myoclonus, sympathetic hyperactivity, and dementia. The amyloid or prion protein (PrP) genotype showed features typically seen in FFI, with a 178Asn mutation and a 129Met polymorphism. There was also a deletion of one octapeptide repeat, suggesting that the association of 178Asn mutation with the 129Met polymorphism is not due to "founder effect." Western immunoblot showed a trace of protease-resistant PrP in the thalamus--which had the most significant neuronal loss and gliosis--a moderate amount of PrP in the fronto-temporal area, and no detectable protein elsewhere in the brain. Endocrine studies showed that a circadian modulation of hormonal levels could be maintained despite a near-total absence of sleep. Administration of gamma-hydroxybutyrate induced a remarkable increase in slow-wave sleep.

Schizophrenia is a relatively common disorder diagnosed by the presentation of psychotic symptoms in the absence of identifiable neurologic or other organic cause. Frontotemporal dementia (FTD) is a relatively rare progressive neurodegenerative disorder that can present with a multitude of cognitive and behavioral symptoms including psychosis. At times, this phenotypic overlap can mean that schizophrenia and FTD are 2 possibilities in the differential diagnosis of a psychotic presentation. In this article, we systematically review the literature on the relationship between schizophrenia and FTD including case reports that highlight the potential for diagnostic confusion, clinical studies examining the relationship between the disorders, and the molecular evidence of shared pathophysiologic mechanisms. Although a relationship between the disorders is not definitively supported by the current literature, we identify the characteristics of a psychotic presentation that should alert the clinician to the possibility of FTD and describe the areas where further research is needed to clarify the pathophysiologic relationship.

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We treated a patient with Huntington's disease and exhibitionism using leuprolide acetate (Lupron Depot, TAP Pharmaceuticals), a gonadotropin-releasing hormone agonist. The result was elimination of his deviant sexual behavior with few side effects. This regimen may be a safe and effective pharmacological treatment of the paraphilias. The occurrence of paraphilias in basal ganglia disorders is reviewed.