Analysis of DYT1 and DYT6 in Thai patients with primary dystonia

@# DYT1 and DYT6 dystonias are the two most common genetic primary dystonias. However, they are rare in the Asian population and have never been reported in Thailand. DYT6 dystonia typically presents with craniosegmental dystonia with speech involvement, whereas DYT1 dystonia typically presents with lower limb dystonia, which tends to become generalized over time. Methods: Blood samples were collected from 14 patients with primary dystonia evaluated in five tertiary hospitals in Thailand. Genotyping of the TOR1A and THAP1 gene was performed. Results: Two patients were found to have a missense mutation, p.M143V (c.427A>G), in exon 3 of the THAP1 gene confirming the diagnosis of DYT6 dystonia. One patient was a woman who developed blepharospasm and lower cranial dystonia at the age of 38 years. Her dystonia spread to the neck and arm six months later. The other patient developed focal hand dystonia at the age of 34 years. The TOR1A mutation was not identified in any of these 14 patients.

Rapidly progressive Alzheimer's disease features distinct structures of amyloid-ß.

Genetic and environmental factors that increase the risk of late-onset Alzheimer disease are now well recognized but the cause of variable progression rates and phenotypes of sporadic Alzheimer's disease is largely unknown. We aimed to investigate the relationship between diverse structural assemblies of amyloid-ß and rates of clinical decline in Alzheimer's disease. Using novel biophysical methods, we analysed levels, particle size, and conformational characteristics of amyloid-ß in the posterior cingulate cortex, hippocampus and cerebellum of 48 cases of Alzheimer's disease with distinctly different disease durations, and correlated the data with APOE gene polymorphism. In both hippocampus and posterior cingulate cortex we identified an extensive array of distinct amyloid-ß42 particles that differ in size, display of N-terminal and C-terminal domains, and conformational stability. In contrast, amyloid-ß40 present at low levels did not form a major particle with discernible size, and both N-terminal and C- terminal domains were largely exposed. Rapidly progressive Alzheimer's disease that is associated with a low frequency of APOE e4 allele demonstrates considerably expanded conformational heterogeneity of amyloid-ß42, with higher levels of distinctly structured amyloid-ß42 particles composed of 30-100 monomers, and fewer particles composed of < 30 monomers. The link between rapid clinical decline and levels of amyloid-ß42 with distinct structural characteristics suggests that different conformers may play an important role in the pathogenesis of distinct Alzheimer's disease phenotypes. These findings indicate that Alzheimer's disease exhibits a wide spectrum of amyloid-ß42 structural states and imply the existence of prion-like conformational strains.