Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6-5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3-4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.

We examined the relationship between a functional polymorphism of the serotonin transporter (5-HTTLPR) gene and individual differences in emotional reactivity in two laboratory studies. In study 1, empathic responding and physiological reactivity to viewing films of others in distress were assessed in healthy adults in three age groups. In study 2, emotional responding to watching oneself in an embarrassing situation was assessed in healthy adults and in patients with neurodegenerative diseases. In study 1, participants with two short alleles of 5-HTTLPR reported more personal distress and showed higher levels of physiological responses in response to the films than participants with long alleles. In study 2, participants with two short alleles reported more anger and amusement and displayed more emotional expressive behaviors in response to the embarrassing situation than participants with long alleles. These two findings from diverse samples of participants converge to indicate that individuals who are homozygous for the short allele variant of 5-HTTLPR have greater levels of emotional reactivity in two quite different socially-embedded contexts.

Why do some individuals become dissatisfied with their marriages when levels of negative emotion are high and levels of positive emotions are low, whereas others remain unaffected? Using data from a 13-year longitudinal study of middle-aged and older adults in long-term marriages, we examined whether the 5-HTTLPR polymorphism in the serotonin transporter gene moderates the association between negative and positive emotional behavior (objectively measured during marital conflict) and changes in marital satisfaction over time. For individuals with two short alleles of 5-HTTLPR, higher negative and lower positive emotional behavior at Time 1 predicted declines in marital satisfaction over time (even after controlling for depression and other covariates). For individuals with one or two long alleles, emotional behavior did not predict changes in marital satisfaction. We also found evidence for a crossover interaction (individuals with two short alleles of 5-HTTLPR and low levels of negative or high levels of positive emotion had the highest levels of marital satisfaction). These findings provide the first evidence of a specific genetic polymorphism that moderates the association between emotional behavior and changes in marital satisfaction over time and are consistent with increasing evidence that the short allele of this polymorphism serves as a susceptibility factor that amplifies sensitivity to both negative and positive emotional influences.

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BACKGROUND Sporadic-onset ataxia is common in a tertiary care setting but a significant percentage remains unidentified despite extensive evaluation. Rare genetic ataxias, reported only in specific populations or families, may contribute to a percentage of sporadic ataxia. METHODS Patients with adult-onset sporadic ataxia, who tested negative for common genetic ataxias (SCA1, SCA2, SCA3, SCA6, SCA7, and/or Friedreich ataxia), were evaluated using a stratified screening approach for variants in seven rare ataxia genes. RESULTS We screened patients for published mutations in SYNE1 (n=80) and TGM6 (n=118), copy number variations in LMNB1 (n=40) and SETX (n=11), sequence variants in SACS (n=39) and PDYN (n=119), and the pentanucleotide insertion of spinocerebellar ataxia type 31 (n=101). Overall, we identified one patient with a LMNB1 duplication, one patient with a PDYN variant, and one compound SACS heterozygote, including a novel variant. CONCLUSIONS The rare genetic ataxias examined here do not significantly contribute to sporadic cerebellar ataxia in our tertiary care population.