Fragile X‐associated tremor/ataxia syndrome (FXTAS) is an adult‐onset neurodegenerative disorder associated with premutation alleles of the fragile X mental retardation 1 (FMR1) gene. Approximately ...40% of older male premutation carriers, and a smaller proportion of females, are affected by FXTAS; due to the lower penetrance the characterization of the disorder in females is much less detailed. Core clinical features of FXTAS include intention tremor, cerebellar gait ataxia and frequently parkinsonism, autonomic dysfunction and cognitive deficits progressing to dementia in up to 50% of males.
In this study, we report the clinical, molecular and neuropathological findings of eight female premutation carriers. Significantly, four of these women had dementia; of the four, three had FXTAS plus dementia. Post‐mortem examination showed the presence of intranuclear inclusions in all eight cases, which included one asymptomatic premutation carrier who died from cancer. Among the four subjects with dementia, three had sufficient number of cortical amyloid plaques and neurofibrillary tangles to make Alzheimer's disease a highly likely cause of dementia and a fourth case had dementia with cortical Lewy bodies. Dementia appears to be more common than originally reported in females with FXTAS. Although further studies are required, our observation suggests that in a portion of FXTAS cases there is Alzheimer pathology and perhaps a synergistic effect on the progression of the disease may occur.
Glecaprevir and pibrentasvir are direct-acting antiviral agents with pangenotypic activity and a high barrier to resistance. We evaluated the efficacy and safety of 8-week and 12-week courses of ...treatment with 300 mg of glecaprevir plus 120 mg of pibrentasvir in patients without cirrhosis who had hepatitis C virus (HCV) genotype 1 or 3 infection.
We conducted two phase 3, randomized, open-label, multicenter trials. Patients with genotype 1 infection were randomly assigned in a 1:1 ratio to receive once-daily glecaprevir-pibrentasvir for either 8 or 12 weeks. Patients with genotype 3 infection were randomly assigned in a 2:1 ratio to receive 12 weeks of treatment with either glecaprevir-pibrentasvir or sofosbuvir-daclatasvir. Additional patients with genotype 3 infection were subsequently enrolled and nonrandomly assigned to receive 8 weeks of treatment with glecaprevir-pibrentasvir. The primary end point was the rate of sustained virologic response 12 weeks after the end of treatment.
In total, 1208 patients were treated. The rate of sustained virologic response at 12 weeks among genotype 1-infected patients was 99.1% (95% confidence interval CI, 98 to 100) in the 8-week group and 99.7% (95% CI, 99 to 100) in the 12-week group. Genotype 3-infected patients who were treated for 12 weeks had a rate of sustained virologic response at 12 weeks of 95% (95% CI, 93 to 98; 222 of 233 patients) with glecaprevir-pibrentasvir and 97% (95% CI, 93 to 99.9; 111 of 115) with sofosbuvir-daclatasvir; 8 weeks of treatment with glecaprevir-pibrentasvir yielded a rate of 95% (95% CI, 91 to 98; 149 of 157 patients). Adverse events led to discontinuation of treatment in no more than 1% of patients in any treatment group.
Once-daily treatment with glecaprevir-pibrentasvir for either 8 weeks or 12 weeks achieved high rates of sustained virologic response among patients with HCV genotype 1 or 3 infection who did not have cirrhosis. (Funded by AbbVie; ENDURANCE-1 and ENDURANCE-3 ClinicalTrials.gov numbers, NCT02604017 and NCT02640157 .).
We describe five female carriers of the
FMR1 premutation who presented with symptoms of tremor and ataxia and who received a diagnosis of definite or probable fragile-X–associated tremor/ataxia ...syndrome (FXTAS). Unlike their male counterparts with FXTAS, none of the women had dementia. Females had not been reported in previous studies of FXTAS, suggesting that they may be relatively protected from this disorder. Brain tissue was available from one of the five subjects, a women who died at age 85 years; microscopic examination revealed intranuclear neuronal and astrocytic inclusions, in accord with the findings previously reported in males with FXTAS. The work-up of families with the
FMR1 mutation should include questions regarding neurological symptoms in both older male and female carriers, with the expectation that females may also manifest the symptoms of FXTAS, although more subtly and less often than their male counterparts.
As there is currently a lack of consensus on the most appropriate dose and duration of peginterferon alfa‐2a (PEG‐IFNα‐2a) therapy in hepatitis B e antigen (HBeAg)‐positive patients, the efficacy and ...safety of either 24 or 48 weeks' duration and 90 μg/week or 180 μg/week doses were compared. HBeAg‐positive patients (n = 544; 34% genotype B, 51% genotype C) were randomized to receive PEG‐IFNα‐2a (2 × 2 factorial design) for 24 or 48 weeks and at 90 μg/week or 180 μg/week and included in the per‐protocol population. The primary efficacy endpoint of the noninferiority study was HBeAg seroconversion 6 months posttreatment. The prespecified odds ratio (OR) noninferiority margin was 1.88 with a one‐sided significance level of 0.025. The highest rates of HBeAg seroconversion 6 months posttreatment were in the 180/48 arm (36.2% versus 14.1%‐25.8% in the other arms). When the dose and duration arms were pooled, the OR for noninferiority of 24 weeks versus 48 weeks was 2.17 (95% confidence interval CI 1.43, 3.31; P = 0.749) and for 90 μg versus 180 μg was 1.79 (95% CI 1.18, 2.72; P = 0.410). As the upper limit of the 95% CI of the ORs were >1.88, 24 weeks were inferior to 48 weeks and 90 μg/week was inferior to 180 μg/week. The highest rates of response in the 180/48 arm were achieved by patients with HBsAg <1,500 IU/mL at Week 12 (58%) or Week 24 (57%), whereas patients with HBsAg >20,000 IU/mL did not respond. Adverse events were typical of those associated with PEG‐IFNα‐2a. Conclusion: Compared with lower doses and shorter durations, the licensed PEG‐IFNα‐2a treatment regimen (180μg/48 weeks) was the most efficacious and beneficial for HBeAg‐positive patients predominantly infected with hepatitis B virus genotypes B or C. (HEPATOLOGY 2011;)
Fragile-X syndrome is a trinucleotide-repeat–expansion disorder in which the clinical phenotype is believed to result from transcriptional silencing of the fragile-X mental retardation 1 (
FMR1) gene ...as the number of CGG repeats exceeds ∼200. For premutation alleles (∼55–200 repeats), no abnormalities in
FMR1-gene expression have been described, despite growing evidence of clinical involvement in premutation carriers. To address this (apparent) paradox, we have determined, for 16 carrier males (55–192 repeats), the relative levels of leukocyte
FMR1 mRNA, by use of automated fluorescence-detection reverse transcriptase–PCR, and the percent of lymphocytes that are immunoreactive for
FMR1 protein (FMRP). For some alleles with >100 repeats, there was a reduction in the number of FMRP-positive cells. Unexpectedly,
FMR1 mRNA levels were elevated at least fivefold within this same range. No significant increase in
FMR1 mRNA stability was observed in a lymphoblastoid cell line (160 repeats) derived from one of the carrier males, suggesting that the increased message levels are due to an increased rate of transcription. Current results support a mechanism of involvement in premutation carriers, in which reduced translational efficiency is at least partially compensated through increased transcriptional activity. Thus, diminished translational efficiency may be important throughout much of the premutation range, with a mechanistic switch occurring in the full-mutation range as the
FMR1 gene is silenced.
Summary
Background
In the large randomised NEPTUNE study, peginterferon alfa‐2a 180 μg/wk for 48 weeks produced higher hepatitis B e antigen (HBeAg) seroconversion rates 24 weeks post‐treatment (36%) ...than a lower dose (90 μg/wk) and/or shorter duration (24 weeks) (range 14%‐26%).
Aim
To determine seroconversion rates 5 years after completion of treatment in NEPTUNE.
Methods
HBeAg‐positive patients who completed 24 weeks’ follow‐up in NEPTUNE (with peginterferon alfa‐2a 90 μg/wk × 24 weeks group 1; 180 μg/wk × 24 weeks 2; 90 μg/wk × 48 weeks 3 or 180 μg/wk × 48 weeks 4) were followed up.
Results
Three hundred and eighty three of the 544 patients in the original study were enrolled in the long‐term follow‐up study. Many patients (196 overall; more in groups 1‐3 than 4) received nucleos(t)ide analogues or immunomodulators during follow‐up, and more patients had missing data at year 5 in groups 2 and 4 (48 weeks, 50/112) than in groups 1 and 3 (24 weeks, 23/103), which confounds the planned per‐protocol analysis. HBeAg seroconversion rates in groups 1, 2, 3 and 4 at year 5 were 47.5%, 50.7%, 52.2% and 67.1%, respectively, (odds ratio for group 4 versus 1‐3: 2.02; 95% CI 1.21, 3.38), using multiple imputation methods for missing measurements.
Conclusion
Seroconversion rates are durable for up to 5 years after completion of peginterferon alfa‐2a therapy and, consistent with NEPTUNE, the results suggest that the licensed regimen (180 μg × 48 weeks) is more efficacious for HBeAg‐positive patients than a lower dose and/or shorter treatment duration.
Linked ContentThis article is linked to Wei and Nguyen paper. To view this article visit https://doi.org/10.1111/apt.14657.
Premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are frequent in the general population, with estimated prevalences of 1 per 259 females and 1 per 813 ...males. Several articles have recently described the presence of late-onset neurological symptoms in male carriers of premutation (FMR1) alleles. The main clinical features described in this newly identified syndrome are cerebellar ataxia and intention tremor. Additional documented symptoms include short-term memory loss, executive functional deficits, cognitive decline, parkinsonism, peripheral neuropathy, lower-limb proximal muscle weakness, and autonomic dysfunction.
To study the penetrance of the fragile X-associated tremor/ataxia syndrome (FXTAS) among premutation carriers.
Family-based study of 192 individuals (premutation carriers and controls) whose families belong to the Northern or Southern California Fragile X Associations. Data were collected (March 2002-April 2003) through a survey and a standardized neurological examination, which was videotaped and subsequently scored in a blinded fashion.
Penetrance of intention tremor and ataxia among adult carriers (aged > or =50 years) of premutation expansions of the FMR1 gene.
Data from the survey of 192 individuals demonstrated an age-related penetrance of the combination of reported intention tremor and gait ataxia in male carriers (17%, 38%, 47%, and 75% lower-bound estimates for participants aged 50-59, 60-69, 70-79, and > or =80 years, respectively). The male carrier group had an age-adjusted 13-fold increased risk (95% confidence interval, 3.9-25.4; P =.003) of combined intention tremor and gait ataxia when compared with male controls. The clinical examination data from 93 individuals demonstrated that male carriers experienced more difficulties on each of 3 standardized neurological rating scales compared with controls (P<.05). Female carrier scores were also higher than those of female controls (P<.05) on 2 of the 3 neurological rating scales, but no participant was identified with probable or definite FXTAS.
The study demonstrates that older male carriers of premutation alleles of the FMR1 gene are at high risk of developing FXTAS. Since male premutation carriers are relatively common in the general population, older men with ataxia and intention tremor should be screened for the FMR1 mutation, especially if these signs are accompanied by parkinsonism, autonomic dysfunction, or cognitive decline, regardless of family history.
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