Presence of Middle Cerebellar Peduncle Sign in FMR1 Premutation Carriers Without Tremor and Ataxia.

Here we report five cases of male FMR1 premutation carriers who present without clinical symptoms of the fragile X-associated tremor/ataxia syndrome (FXTAS), but who on MRI demonstrate white matter hyperintensities in the middle cerebellar peduncles (MCP sign) and other brain regions, a rare finding. MCP sign is the major radiological feature of FXTAS; it is therefore remarkable to identify five cases in which this MRI finding is present in the absence of tremor and ataxia, the major clinical features of FXTAS. Subjects underwent a detailed neurological evaluation, neuropsychological testing, molecular testing, and MRI evaluation utilizing T2 imaging described here. Additional white matter disease was present in the corpus callosum in four of the five cases. However, all cases were asymptomatic for motor signs of FXTAS.

Enhanced efficiency in helical tomotherapy quality assurance using a custom-designed water-equivalent phantom.

Tomotherapy is an image-guided, intensity-modulated radiation therapy system that delivers highly conformal dose distributions in a helical fashion. This system is also capable of acquiring megavoltage computed-tomography images and registering them to the planning kVCT images for accurate target localization. Quality assurance (QA) of this device is time intensive, but can be expedited by improved QA tools and procedures. A custom-designed phantom was fabricated to improve the efficiency of daily QA of our Tomotherapy machine. The phantom incorporates ionization chamber measurement points, plugs of different densities and slide-out film cartridges. The QA procedure was designed to verify in less than 30 min the vital components of the tomotherapy system: static beam quality and output, image quality, correctness of image registration and energy of the helical dose delivery. Machine output, percent depth dose and off-axis factors are simultaneously evaluated using a static 5 x 40 cm(2) open field. A single phantom scan is used to evaluate image quality and registration accuracy. The phantom can also be used for patient plan-specific QA. The QA results over a period of 6 months are reported in this paper. The QA process was found to be simple, efficient and capable of simultaneously verifying several important parameters.

Better transitions: improving comprehension of discharge instructions.

Discharge out of the hospital is a time of heightened vulnerability for our patients. The combination of shorter lengths of stay and increased clinical acuity results in increased complexity of discharge instructions and higher expectations for patients to perform challenging self-care activities. Yet, the amount of time and resources available for patient and family caregiver preparation prior to discharge has not significantly changed commensurate with these new demands. Inadequate health literacy and unrecognized cognitive impairment are two important contributing factors. In this article we discuss the effects of health literacy and cognitive impairment on patient comprehension of discharge instructions, how this may impact the frequency of adverse events after they leave the hospital, and likelihood of readmission, and offer an evidence-based prototype for how to address the problem.

Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation.

Until recently, individuals with premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene were believed to be psychologically unaffected. However, the recent documentation of abnormal elevation of FMR1 mRNA, discovery of fragile X-associated tremor/ataxia syndrome (FXTAS), and reports of psychiatric disorders in children and adults with the premutation have suggested a pathogenic gene-brain-behavior mechanism. In a large collaborative study, 68 men and 144 women with the FMR1 premutation completed a psychological symptoms checklist and FMR1 genetic testing, including determination of CGG repeat size, percentage of FMR1 protein (FMRP)-positive lymphocytes, and FMR1 mRNA levels. Relative to published norms, men and women with FXTAS symptoms reported higher levels of several types of psychological symptoms. In addition, men and women with the premutation and no overt evidence of FXTAS reported higher levels of obsessive-compulsive symptoms. Elevated FMR1 mRNA, but not CGG repeat size or reduced FMRP (as measured by immunocytochemistry), was significantly associated with increased psychological symptoms, predominantly obsessive-compulsive symptoms and psychoticism, in premutation men with and without FXTAS symptoms. There was no relationship between CGG repeat size, FMR1 mRNA or FMRP and psychological symptoms in premutation women unless the sample was restricted to those with skewed X-activation ratio toward >50% active premutation alleles. The results of this study support the hypothesis that FMR1 function is associated with psychological difficulties in individuals with the premutation, and provide evidence concordant with an RNA toxic gain-of-function model in a neuropsychiatric phenotype.

Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population.

CONTEXT: 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. OBJECTIVE: To study the penetrance of the fragile X-associated tremor/ataxia syndrome (FXTAS) among premutation carriers. DESIGN, SETTING, AND PARTICIPANTS: 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. MAIN OUTCOME MEASURES: Penetrance of intention tremor and ataxia among adult carriers (aged > or =50 years) of premutation expansions of the FMR1 gene. RESULTS: 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. CONCLUSIONS: 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.