Jim Grigsby

Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates.

We present a series of 26 patients, all >50 years of age, who are carriers of the fragile X premutation and are affected by a multisystem, progressive neurological disorder. The two main clinical features of this new syndrome are cerebellar ataxia and/or intention tremor, which were chosen as clinical inclusion criteria for this series. Other documented symptoms were short-term memory loss, executive function deficits, cognitive decline, parkinsonism, peripheral neuropathy, lower limb proximal muscle weakness, and autonomic dysfunction. Symmetrical regions of increased T2 signal intensity in the middle cerebellar peduncles and adjacent cerebellar white matter are thought to be highly sensitive for this neurologic condition, and their presence is the radiological inclusion criterion for this series. Molecular findings include elevated mRNA and low-normal or mildly decreased levels of fragile X mental retardation 1 protein. The clinical presentation of these patients, coupled with a specific lesion visible on magnetic resonance imaging and with neuropathological findings, affords a more complete delineation of this fragile X premutation-associated tremor/ataxia syndrome and distinguishes it from other movement disorders.

High prevalence of cobalamin deficiency in elderly outpatients.

Objective: To measure the prevalence of cobalamin (vitamin B12) deficiency in geriatric outpatients as documented by both low serum cobalamin levels and elevations of serum methylmalonic acid and homocysteine and to determine the response to cobalamin treatment.

Fragile-X–Associated Tremor/Ataxia Syndrome (FXTAS) in Females with the FMR1 Premutation

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.

Executive Cognitive Abilities and Functional Status Among Community‐Dwelling Older Persons in the San Luis Valley Health and Aging Study

OBJECTIVES: The purpose of this study was to evaluate the contribution of the executive cognitive functions to self‐reported and observed performance of activities of daily living and instrumental activities of daily living.

Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines.

Fragile X‐associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder with core features of action tremor and cerebellar gait ataxia. Frequent associated findings include parkinsonism, executive function deficits and dementia, neuropathy, and dysautonomia. Magnetic Resonance Imaging studies in FXTAS demonstrate increased T2 signal intensity in the middle cerebellar peduncles (MCP sign) in the majority of patients. Similar signal alterations are seen in deep and subependymal cerebral white matter, as is general cortical and subcortical atrophy. The major neuropathological feature of FXTAS is the presence of intranuclear, neuronal, and astrocytic, inclusions in broad distribution throughout the brain and brainstem. FXTAS is caused by moderate expansions (55–200 repeats; premutation range) of a CGG trinucleotide in the fragile X mental retardation 1 (FMR1) gene, the same gene which causes fragile X syndrome when in the full mutation range (200 or greater CGG repeats). The pathogenic mechanism is related to overexpression and toxicity of the FMR1 mRNA per se. Although only recently discovered, and hence currently under‐diagnosed, FXTAS is likely to be one of the most common single‐gene disorders leading to neurodegeneration in males. In this report, we review information available on the clinical, radiological, and pathological features, and prevalence and management of FXTAS. We also provide guidelines for the practitioner to assist with identifying appropriate patients for DNA testing for FXTAS, as well as recommendations for genetic counseling once a diagnosis of FXTAS is made.

Expanded clinical phenotype of women with the FMR1 premutation

Fragile X‐associated tremor/ataxia syndrome (FXTAS) is generally considered to be uncommon in older female carriers of premutation alleles (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene; however, neither prevalence, nor the nature of the clinical phenotype, has been well characterized in female carriers. In this study, we evaluated 146 female carriers (mean, 42.3 years; range, 20–75 years) with and without core features of FXTAS (tremor; gait ataxia), and 69 age‐matched controls (mean, 45.8 years; range, 21–78 years). Compared with controls, carriers with definite or probable FXTAS had greater medical co‐morbidity, with increased prevalence of thyroid disease (P = 0.0096), hypertension (P = 0.0020), seizures (P = 0.0077), peripheral neuropathy (P = 0.0040), and fibromyalgia (P = 0.0097), in addition to the typical symptoms of FXTAS–tremor (P < 0.0001) and ataxia (P < 0.0001). The non‐FXTAS premutation group had more complaints of chronic muscle pain (P = 0.0097), persistent paraesthesias in extremities (P < 0.0001), and history of tremor (P < 0.0123) than controls. The spectrum of clinical involvement in female carriers with FXTAS is quite broad, encompassing a number of medical co‐morbidities as well as the core movement disorder. The remarkable degree of thyroid dysfunction (17% in the non‐FXTAS group and 50% in the FXTAS group) warrants consideration of thyroid function studies in all female premutation carriers, particularly those with core features of FXTAS.

A Review of Fragile X Premutation Disorders: Expanding the Psychiatric Perspective

CONTEXT Fragile X premutation conditions are associated with a significant degree of psychopathology and thus are of interest to the psychiatrist. Remarkable advances at the molecular level have enhanced our understanding of fragile X premutation disorders. OBJECTIVE The authors review the genetic, molecular, neuroimaging, and clinical (systemic, neurologic, and psychiatric) manifestations of the premutation carrier state (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. DATA SOURCES The search for the psychiatric clinical manifestations of fragile X-associated conditions was accomplished by PubMed for clinical papers published between 1970 and 2008 with the following search terms: Fragile X syndrome, depression, psychosis, anxiety, and dementia. STUDY SELECTION Articles addressing psychiatric symptoms in premutation carriers based on review of the abstracts were reviewed. As the majority of the literature on this topic is based on case reports and small case series, these were included in the database. RESULTS Reported clinical manifestations of psychiatric illness in premutation carriers include an apparently significant rate of cognitive, mood, anxiety, and other psychiatric disorders. Fragile X premutation-associated conditions are part of the clinical differential diagnosis of several psychiatric syndromes, particularly in pedigrees with known fragile X syndrome cases. CONCLUSIONS Fragile X-associated psychiatric manifestations serve as a useful model for a molecular genesis of neuropsychiatric illness. Because of the multigenerational expression of fragile X-associated neuropsychiatric illness, there is a prominent role for genetic testing and genetic counseling of patients and their relatives. Genetic testing is confirmatory of the FMR1 premutation and is an essential component of the clinical evaluation. Psychopharmacologic and psychotherapeutic treatment of fragile X-associated psychiatric illnesses may improve patient function and assist in adaptation to the burden of a genetic neuropsychiatric illness.

Telemedicine: Where It Is and Where It's Going

Telemedicine has proliferated throughout much of the industrialized world, reflecting the convergence of scientific, technological, economic, and social factors. During the past 20 years, high-capacity digital networks and improved switching technologies have been deployed in many regions of North America. Computer hardware and software have become fast, powerful, easy to use, and affordable. Compressible, high-resolution digital images can be enhanced and manipulated. The availability of and access to health-related information has improved substantially. Telemedicine has begun to take hold, almost 40 years after the first experiments in providing medical care at a distance demonstrated its feasibility. Telemedicine Defined Telemedicine uses technology to deliver medical services to the point of need. In its report on the evaluation of clinical applications of telemedicine, a committee of the Institute of Medicine defined telemedicine as the use of electronic information and communications technologies to provide and support health care when distance separates the participants [1]. The committee settled on this expansive definition after considering at least 10 others [2-6]. Probably the most inclusive definition cited in the Institute of Medicine report was that telemedicine encompasses all of the health care, education, information and administrative services that can be transmitted over distances by telecommunications technologies [7]. Broad definitions of telemedicine have complicated the discussion of telemedicine policy. Telemedicine covers a range of technologies, including telephone, radio, facsimile, modem, and video. It may be conducted in real time, as with interactive video, or asynchronously, for the transmission of text or graphic data, auditory verbal information, still images, short video clips, and full-motion video. Robotics and virtual reality interfaces have been introduced into some experimental applications [8]. These technologies may be applied in various ways (management of chronic conditions, routine consultation, preventive medicine, public health, and patient education, for example). Some definitions of telemedicine even encompass meetings of hospital administrators, access to MEDLINE, and continuing medical education. Because the term telemedicine can be defined in so many ways, discussions of such issues as the cost-effectiveness of telemedicine become meaningless. Hence, we have limited the scope of this paper to a somewhat narrower definition of telemedicine: the use of telecommunications and information technology to provide health care services to persons at a distance from the provider. The Range of Transmission Media Telemedicine has used various terrestrial and space-based (satellite) transmission media. The medium that is used is important in part because its bandwidth or bit rate (the amount of information sent per unit of time) limits the type of technology that may be used. Narrow-bandwidth systems, such as ordinary telephone lines, are inexpensive but lack the capacity for full-motion video. They may be adequate, however, for transmitting still images, voice, text, or data. No single technology or bandwidth is best for all telemedicine purposes; rather, each systems capacities and capabilities must be determined by the needs of the users. Broad-bandwidth networks have transmission rates that permit interactive, full-motion video. For example, T1 lines have a relatively high bit rate of 1.544 megabits per second. They are not, however, available in many rural and frontier areas. Interactive video may be used with narrower bandwidths if data compression algorithms are also used, but the images are sometimes too jerky to permit resolution of detail or subtle movement. Broad-bandwidth networks are costly because transmission charges are directly related to bandwidth. This problem was partly addressed by rules that were developed by the U.S. Federal Communications Commission for the implementation of changes in the universal service program under the Telecommunications Act of 1996. These rules provide subsidies for telecommunications services, for which certain rural health care providers are eligible. Clinical Uses of Telemedicine Most of the early telemedicine programs used interactive video to bring patients, referring providers, and consultants together. From 1959 until the 1970s, telemedicine was tested in medical schools, state psychiatric hospitals, municipal airports, jails, nursing homes, Native American reservations, and other settings [9-16]. Most of these early programs proved too costly to be self-sustaining and were terminated when external funding ran out. The clinical applications of telemedicine are even more varied than the technologies, although considerable attention has been focused on the use of interactive video for specialty and subspecialty consultation in rural areas. The generic interactive video telemedicine system typically uses fixed, studio-type video equipment to link a rural facility with an urban tertiary care center. Consultants communicate with patients and, often, with their primary care providers in an interactive situation. The precise configuration of these networks varies, ranging from a single source of referrals (for example, a rural community hospital) and a single source of consultants (such as an academic medical center) to complex hub-and-spoke networks involving many referring and consulting facilities. Almost every clinical specialty has used telemedicine in some way, although some have used it more than others. Radiologists, for example, have embraced the technology on a large scale. Cardiologists, dermatologists, and psychiatrists have been the clinical specialists most actively involved in telemedicine. The reasons for this are unclear, but this distribution may represent a kind of founders effect because physicians practicing these specialties were among the clinicians to first become involved with telemedicine. Nevertheless, the fact that these specialists choose to see patients through telemedicine suggests that the medium is suited to many of their consultative tasks. A 1996 survey of almost 2400 nonfederal rural hospitals [17] found that about 17% were participating in a telemedicine network of some kind (including services as limited as facsimile) and that another 13% had definite plans to begin using telemedicine. The number of clinics and outpatient facilities participating in such networks is unknown. Despite widespread interest in telemedicine, the actual number of patients per telemedicine program who receive telemedicine services remains relatively low [18]. One recent survey of 80 programs (1032 sites on hub-and-spoke networks) estimated that about 21 000 consultations occurred in 1996 (mean, 37.4 consultations per site per year) [19]. Telemedicine has proven its feasibility in several challenging environments, including peacekeeping missions and the space shuttle (Pool SL, Stonesifer JC, Belasco N. Application of telemedicine systems in future manned space flight [Presented paper]. Second Telemedicine Workshop, 1975, Tucson, Arizona; [20-22]), and in the more prosaic settings of the home, clinic, hospital, and long-term care facility. It has been used for many years in Canadas maritime provinces ([23]; House AM, Keough EM. Distance health systems-collaboration brings success: the past, present, and future of telemedicine in Newfoundland [Presented paper]. Conference on Information Technology in Community Health, 1992, Victoria, Canada) and in Norway above the Arctic Circle [24]. The program at Memorial University of Newfoundland in Canada has used many technologies, from facsimile (transmission of electroencephalograms) to interactive video. In addition to gaining improved access to care for patients, referring physicians may benefit from increased contact with their colleagues and greater opportunities for continuing medical education. One observer described telemedicine as a means by which medical schools can provide an extended warranty on medical education. Trends in Telemedicine Technology Although the early 1990s saw the proliferation of telemedicine systems that provided real-time, broad-bandwidth, synchronous consultations, the focus has shifted toward more personal computer-based store-and-forward telemedicine. Desktop systems are a convenient and probably cost-effective means of providing services. Store-and-forward technology can be used to forward medical records, laboratory results, and radiographs and other diagnostic images to a consultant. By using a multimedia e-mail format, consultants can conduct an increasing number of telemedical consultations across a readily available, accessible, and inexpensive Internet platform. The consultant has convenient access to e-mailed consultative requests that accommodate his or her schedule. The data can be reviewed, and a report of diagnostic impressions can be e-mailed to the referring physician. Government Telemedicine Policy Since the 1960s, the federal government has supported the development of telemedicine through grants, contracts, and National Aeronautics and Space Administration and Department of Defense budget line items that total several hundred million dollars. Several agencies currently provide such support, and their representatives have been actively involved in discussions that shape both policy and directions of growth in telemedicine. Although a comprehensive discussion of those policy issues is beyond the scope of this paper, we address one especially important and problematic matter: coverage and payment for telemedical services. With a few exceptions (teleradiology, some telepathology, and some cardiologic data and facsimile transmission applications), Medicare reimbursement of fee-for-service telemedicine is generally not available. The reasons for this are complex, but the most immediate impediment to the coverage of telemedici

Cognitive Profile of Fragile X Premutation Carriers With and Without Fragile X-Associated Tremor/Ataxia Syndrome

Fragile X-associated tremor/ataxia syndrome (FXTAS) develops in a subset of fragile X premutation carriers and involves gait ataxia, action tremor, Parkinsonism, peripheral neuropathy, autonomic disorders, and cognitive impairment. The study was designed to define the nature of cognitive deficits affecting male premutation carriers with and without FXTAS. A sample of 109 men underwent motor, cognitive, genetic, and neurologic testing, as well as brain magnetic resonance imaging. Subjects were classified into 3 groups: (a) asymptomatic premutation carriers, (b) premutation carriers with FXTAS, and (c) normal controls. Men with FXTAS performed worse than controls on mental status, intelligence, executive cognitive functioning (ECF), working memory, remote recall of information, declarative learning and memory, information processing speed, and temporal sequencing, as well as 1 measure of visuospatial functioning. Language and verbal comprehension were spared. Asymptomatic carriers performed worse than controls on ECF and declarative learning and memory. This comprehensive examination of cognitive impairment in male premutation carriers suggests that FXTAS involves substantial executive impairment and diffuse deficits in other cognitive functions. Longitudinal research currently underway will provide insight into the progression of the disorder.

Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS)

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder occurring in male and rare female carriers of a premutation expansion (55 to 200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Methods: Volumetric MRI studies, clinical staging, cognitive testing, and molecular analysis were conducted in 15 female premutation carriers affected by FXTAS (age 59.5 ± 10.3 years), 20 unaffected female carriers (43.3 ± 11.2 years), 11 genetically normal female controls (51.0 ± 10.3 years), 36 affected male carriers (65.0 ± 5.6 years), 25 unaffected male carriers (53.5 ± 12.5 years), and 39 male controls (58.0 ± 15.0 years). Female and male carriers with FXTAS were matched on duration of disease. Results: We found less pronounced reductions of cerebellar volume and a lower incidence of involvement (symmetric high T2 signal) of the middle cerebellar peduncles (MCP sign) in females affected by FXTAS (13%) compared with affected males (58%). We found reduced brain volumes and increased white matter disease associated with the presence of FXTAS in females compared with female controls. We also observed significant associations between reduced cerebellar volume and both increased severity of FXTAS symptoms and increased length of the CGG repeat expansion in male premutation carriers, but not in females. Conclusions: Females affected by fragile X-associated tremor/ataxia syndrome (FXTAS) demonstrated milder brain changes than affected males, although they showed a similar pattern of radiologic findings consistent with brain atrophy and white matter disease. FXTAS should be considered (by ordering fragile X DNA testing) in females who present with late-onset ataxia, action tremor, or neuropathy, particularly in those with a family history of mental retardation, autism, or premature ovarian failure.