Purpose: Fragile X-associated tremor/ataxia syndrome (FXTAS) was originally defined as tremor, ataxia, cognitive decline, and parkinsonism in individuals who carry between 55 and 200 CGG repeats in the promoter region of the fragile X mental retardation 1 (FMR1) gene. This paper describes a series of patients who meet the definition of FXTAS who presented for care between 2009 and 2014.Methods/Results: Retrospective chart review of patients seen in the FXTAS clinic at Rush University in Chicago.Conclusions: Patients with FXTAS may present with a progressive supranuclear palsy-like phenotype and other eye movement abnormalities are common in these patients as well. Rapid worsening of gait abnormalities in FXTAS may be due to a secondary spinal issue and should be aggressively treated to regain function. Finally, the FXTAS Rating Scale score does not reliably inform the certainty of diagnosis or CGG repeat size in these patients.

Hepatitis C virus (HCV) infection is usually treated with the combination of interferon and ribavirin, but only a small fraction of patients develop a sustained remission. There is need for the development of specific molecular approaches for the treatment of chronic HCV infection. We propose that RNA interference is highly effective antiviral strategy that offers great potential for the treatment of HCV infection. Three plasmid constructs expressing small interfering RNAs (siRNAs) targeted to sequences encoding the structural gene (E2) and non-structural genes (NS3, NS5B) of HCV1a genome were prepared. Antiviral properties of siRNAs against the HCV1a strain were studied in a transient replication model that involved the use of a transcription plasmid containing the full-length HCV genome and an adenovirus expressing T7 RNA polymerase. We found that siRNAs targeted to the E2, NS3 and NS5B regions of the HCV genome efficiently inhibited expression of the HCV core and NS5A protein measured by Western blot analysis and immunocytochemical staining. Intracytoplasmic immunization of siRNAs in HCV-transfected cells efficiently degraded genomic positive strand HCV RNA, as shown by ribonuclease protection assay (RPA). All three siRNAs efficiently inhibited synthesis of replicative negative strand HCV RNA in the transfected cells. A control siRNA plasmid against a Epstein--Barr virus latency gene did not inhibit protein expression and negative strand HCV RNA. These results suggest that RNAi is an effective and alternative approach that can be used to inhibit HCV expression and replication.

ObjectiveTo explore the association of a splice variant of the antisense fragile X mental retardation 1 (ASFMR1) gene, loss of fragile X mental retardation 1 (FMR1) AGG interspersions and FMR1 CGG repeat size with manifestation, and severity of clinical symptoms of fragile X-associated tremor/ataxia syndrome (FXTAS).MethodsPremutation carriers (PMCs) with FXTAS, without FXTAS, and normal controls (NCs) had a neurologic evaluation and collection of skin and blood samples. Expression of ASFMR1 transcript/splice variant 2 (ASFMR1-TV2), nonspliced ASFMR1, total ASFMR1, and FMR1 messenger RNA were quantified and compared using analysis of variance. Least absolute shrinkage and selection operator (LASSO) logistic regression and receiver operating characteristic analyses were performed.ResultsPremutation men and women both with and without FXTAS had higher ASFMR1-TV2 levels compared with NC men and women (n = 135,135, p < 0.0001), and ASFMR1-TV2 had good discriminating power for FXTAS compared with NCs but not for FXTAS from PMC. After adjusting for age, loss of AGG, larger CGG repeat size (in men), and elevated ASFMR1-TV2 level (in women) were strongly associated with FXTAS compared with NC and PMC (combined).ConclusionsThis study found elevated levels of ASFMR1-TV2 and loss of AGG interruptions in both men and women with FXTAS. Future studies will be needed to determine whether these variables can provide useful diagnostic or predictive information.