Journal of Investigative Medicine:
EB Symposium Manuscripts
Fragile X-Associated Tremor/Ataxia Syndrome: Clinical Phenotype, Diagnosis, and Treatment
Leehey, Maureen A. MD
From the Department of Neurology, University of Colorado Denver, Aurora, CO.
Received April 18, 2009.
Accepted for publication May 18, 2009.
Reprints: Maureen A. Leehey, MD, Department of Neurology, University of Colorado Denver, Box B185, AO1 Bldg, 12631 E 17th Ave, Aurora, CO 80045. E-mail: Maureen.firstname.lastname@example.org.
This work was supported by the National Institutes of Health Interdisciplinary Research Consortium (Roadmap) grants UL1DE19583 and RL1AG032115 for P.J. Hagerman and R.J. Hagerman, respectively, the NINDS grant NS044299 for J. Grigsby, and the symposium was supported in part by a grant from the National Center for Research Resources (R13 RR023236).
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG repeat expansion in the premutation range (55-200) in the fragile X mental retardation 1 gene. Onset is typically in the early seventh decade, and men are principally affected. The major signs are cerebellar gait ataxia, intention tremor, frontal executive dysfunction, and global brain atrophy. Other frequent findings are parkinsonism (mild), peripheral neuropathy, psychiatric symptoms (depression, anxiety, and agitation), and autonomic dysfunction. The clinical presentation is heterogeneous, with individuals presenting with varied dominating signs, such as tremor, dementia, or neuropathy. Magnetic resonance imaging shows atrophy and patchy white matter lesions in the cerebral hemispheres and middle cerebellar peduncles. The latter has been designated the middle cerebellar peduncle sign, which occurs in about 60% of affected men, and is relatively specific for FXTAS. Affected females generally have less severe disease, less cognitive decline, and some symptoms different from that of men, for example, muscle pain. Management of FXTAS is complex and includes assessment of the patient's neurological and medical deficits, treatment of symptoms, and provision of relevant referrals, especially genetic counseling. Treatment is empirical, based on anecdotal experience and on knowledge of what works for symptoms of other disorders that also exist in FXTAS. Presently, the disorder is underrecognized because the first published report was only in 2001 and because the presentation is variable and mainly consists of a combination of signs common in the elderly. However, accurate diagnosis is critical for the patient and for the family because they need education regarding their genetic and health risks.
Fragile X-associated tremor/ataxia syndrome (FXTAS)1 is an inherited degenerative disorder that affects aging persons, primarily men, and is associated with an array of neurological symptoms and medical conditions. The disorder is caused by a CGG repeat expansion in the premutation range (55-200) in the 5′ noncoding region of the fragile X mental retardation 1 (FMR1) gene. Expansion of the CGG repeat to more than 200 results in the reduction or absence of fragile X mental retardation protein, and consequentially, fragile X syndrome (FXS), the most common known heritable form of mental retardation and autism. Although mutations in FMR1 cause both FXS and FXTAS, the 2 disorders are distinct, as illustrated in Figure 1. In FXTAS, fragile X mental retardation protein is produced in normal or near normal amounts, whereas FMR1 messenger RNA with the expanded repeat is produced in markedly elevated amounts in leukocytes and brain.2,3 The high level of FMR1 messenger RNA is likely toxic and the cause of the cellular injury responsible for the symptoms. Fragile X-associated tremor/ataxia syndrome is a significant cause of morbidity, especially ataxia in aging men,4,5 and the most common known single-gene form of tremor and ataxia, and perhaps also of dementia, in the older adult population.
The mean (SD) age of onset of tremor and/or ataxia in males is 61.6 (7.9) years.6 The classic presentation of FXTAS is a man in his early 60s with progressive cerebellar ataxia, action tremor, parkinsonism, and cognitive decline, especially executive dysfunction. Other features, which are present in variable degrees among individually affected persons, are psychiatric disturbances and autonomic and peripheral neuropathies.7,8 The frequency of these various signs is presented in Table 1. However, as shown in Table 2, a number of different clinical features and presentations with varied dominating signs have been reported in persons with FXTAS. Even within families, affected persons have disparate clinical presentations, for example, a presentation that looks like essential tremor in 1 brother and a classic FXTAS presentation in another.9
Approximately 1 in 260 females and 1 in 813 males in the general population are premutation carriers.10,11 Penetrance of FXTAS is age dependent, with approximately 40% of males older than 50 years12 and 8% of female carriers older than 40 years13 developing the disorder. Although large-scale epidemiologic studies of FXTAS have not been conducted, the predicted lifetime cumulated risk among men in the general population has been estimated to be approximately 1 in 8000.14 Thus, FXTAS is much less common than essential tremor and Parkinson disease in older adults but similar in prevalence to that of other neurodegenerative disorders, for example, other inherited ataxias, amyotrophic lateral sclerosis, and progressive supranuclear palsy.15
Although the symptoms of FXTAS vary among individuals, almost all affected persons develop problematic cerebellar gait ataxia as the disorder progresses. Unexplained falls are frequent, and the tandem gait is significantly abnormal in about 50% of male carriers older than 50 years (Leehey et al., 2007, unpublished data). Although cerebellar dysfunction is a nearly constant feature that affects the gait, other impairments such as parkinsonism, sensory neuropathy, and weakness also contribute to poor balance. Hypermetria and dysdiadochokinesis are frequently present in the upper extremities.
Action tremor is a common finding, but the severity is quite variable among individuals. Many affected persons, probably because of poor insight related to executive dysfunction, deny having any tremor despite their spouse noting that a mild, intermittent tremor has been present for months or years. Others have an obvious, severe tremor that impairs daily function. Fifty percent of males have at least mild, and 17% at least moderate intention tremors compared with 25% and 4%, respectively, of age-matched male controls (Leehey et al., 2007, unpublished data). The tremor of FXTAS has not been quantitatively studied, but it looks like essential tremor. Furthermore, affected persons usually have definite tremor reduction with the use of medications commonly prescribed for essential tremor.
Another frequent motor sign is parkinsonism, which is generally mild and mainly manifested by masked facies, generalized rigidity, overall bradykinesia, and slow gait. Occasionally, affected persons have a parkinsonian posture. Resting tremor is uncommon, and when present, may be due to reoccurrence of the postural tremor in the rest position. Carriers with parkinsonism generally have minor and only transient improvement with dopaminergic medication, suggesting that the underlying mechanism causing parkinsonism is not the same as in primary Parkinson disease. Gait ataxia, intention tremor, and parkinsonism worsen with increasing age, and the severity of tremor and ataxia correlate strongly with increasing CGG repeat size through the premutation range.16
Cognitive dysfunction is a very disabling feature in many aging male carriers.17 Male carriers older than 50 years selected without regard to motor signs of FXTAS show normal to mild full-scale IQ deficits and significant memory and frontal executive dysfunctions.18-21 Men with motor signs have prominent executive impairment, and as the disease progresses develop global deficits (dementia), affecting intelligence, working memory, declarative learning and memory, remote recall, information-processing speed, and temporal sequencing, and perhaps visuospatial functioning. These deficits are suggested to be largely because of the prominent executive dysfunction that occurs in FXTAS.22 Of note, verbal comprehension and language are relatively preserved.21 The dementia is of a mixed subcortical-cortical pattern due to the involvement of cerebral and cerebellar white matter, frontal cortex, and hippocampus.23 Dementia occurs in approximately 40% of men23,24 and less often in females,23 and the frequency may be higher in late-stage FXTAS.
Psychiatric and behavioral disorders, the latter mainly due to impaired executive function, are also common and disabling features of FXTAS. Males older than 50 years, selected without regard to motor signs, demonstrate increased rates of anxiety, irritability, agitation, hostility, obsessive-compulsiveness, apathy, and depression.17,25 Affected men are unaware of their change in personality and thus will not report these symptoms, but if untreated, they can lead to significant marital discord. Female carriers have higher rates of depression and obsessive thinking than matched controls.25
The peripheral nervous system is also affected in carriers.1,8,26,27 Males have greater loss of distal lower extremity tendon reflexes and vibration sense than age-matched male controls.28 Distal leg strength is generally preserved. The neuropathy may be the presenting feature of FXTAS, the only significant neurological finding in a carrier,26 or asymptomatic. Electrical studies in males with FXTAS document a predominately axonal sensorimotor polyneuropathy.27 The degree of reflex impairment correlates with severity of ataxia; thus, the neuropathy may contribute to gait difficulties in some affected persons.
Autonomic dysfunction has been described in FXTAS, but controlled studies are needed. In a study of 20 men with FXTAS, 55% reported urinary incontinence and 30% bowel incontinence.8 Urinary and fecal incontinence mainly occur in late-stage FXTAS.29,30 Some individuals have symptomatic orthostasis and syncope.30-33 Pugliese et al.31 reported a 73-year-old man that presented with postprandial hypotension and was then found to have had hand tremor and 73 CGG repeats in FMR1. There was no family history suggestive of FMR1-related disorders, and the patient did not have ataxia. This case report suggests that autonomic impairment can be a presenting and dominant feature of FXTAS. Of note, autonomic nervous system involvement has been documented in neuropathologic studies of paraspinal sympathetic ganglia,34 myenteric ganglia of the stomach, and subepicardial autonomic ganglia.30
Some medical conditions have been reported to be associated with the FMR1 premutation. Hypertension was more common in male (P = 0.06)12 and female (P = 0.002)13 carriers than controls. Anecdotal evidence suggests that cardiac dysfunction, for example, arrhythmia, ischemia, and congestive heart failure, may occur more frequently in men with FXTAS. Other disorders also seem to be more common in persons with FXTAS than expected. For example, many men with advancing FXTAS have diet-controlled hyperglycemia that leads to diabetes requiring oral therapy. In addition, many affected men have episodes of dizziness. In some cases these episodes seem to be due to lightheadedness related to orthostatic hypotension, and in other instances, seem to be due to vestibular dysfunction. Studies of hyperglycemia and vestibular dysfunction in FXTAS are needed to determine if and how these are related to the FMR1 premutation.
Fragile X-associated tremor/ataxia syndrome is a progressive disease, but prospective studies on its natural history are lacking. A retrospective study29 on the progression of tremor and ataxia in 55 men with FXTAS found that after the initial motor sign, usually tremor, median delay of onset of ataxia was 2 years; onset of falls, 6 years; dependence on a walking aid, 15 years; inability to do most daily activities, 16 years; and death, 21 years. Life expectancy ranged from 5 to 25 years, and other reports cite death occurred in 5 to 7 years after presentation for evaluation.30,32-34 Death was due to congestive heart failure, pneumonia, cardiac arrest, or progression of neurologic disease. At end stage, affected persons are bedridden, dysphagic, dysarthric, parkinsonian, and without bladder or bowel control.29,33
FEMALE PREMUTATION CARRIERS
Even before the finding that a neurodegenerative disorder, FXTAS, occurs in carriers, female carriers were known to be at an increased risk for primary ovarian insufficiency (POI).35 Approximately 20% develop POI,36,37 and it does not seem to be related to the risk of FXTAS.13 In addition, female carriers have been found to have higher rates of depression and anxiety than controls.25,38-40 Although this could be related to the stress of raising a difficult child with FXS, recent studies suggest that depression41 and anxiety42 are secondary, at least in part, to the premutation.
Fragile X-associated tremor/ataxia syndrome affects male carriers more12 partially because of a protective effect of the second X chromosome in females.43,44 Most research on FXTAS to date has been in males. The data available on females suggest that the premutation may confer different neurological and medical risks with aging13,45 than those that occur in males, perhaps because of hormonal and other, as yet unknown, factors.
Generally, female carriers do not develop as much tremor and ataxia as males.16,46 A quantitative study16 showed that the risk for cerebellar ataxia for females older than 50 years correlated with increasing CGG repeat size only when the activation ratio, the percent of normal FMR1 alleles that are on the active X chromosome, was factored in. Female carriers without FXTAS report more sensory loss (45%), chronic muscle pain (26%), and tremor (12%) than controls.13 Interestingly, preliminary data suggest that female carriers, regardless of the presence of motor signs, have higher rates of psychogenic signs, including movement disorders and seizures, than expected. (Leehey M, Seritan A, 2009, unpublished data).
Some female carriers do develop classic features of FXTAS,43,45,47,48 but they also have some distinct differences from affected males. Females with FXTAS probably have less cognitive dysfunction than males,23,45 although individual case reports document that dementia does occur.49,50 Also, chronic muscle pain and a diagnosis of fibromyalgia are frequently reported by affected females. Furthermore, approximately 50% of affected females have thyroid dysfunction, usually hypothyroidism.13
Imaging in FXTAS is useful because it typically shows atrophy, white matter changes, and a distinctive abnormality of the middle cerebellar peduncles (MCPs). These finding are usually more severe in affected males than females.51 Magnetic resonance imaging (MRI) reveals atrophy of the cerebrum, cerebellar cortex, corpus callosum, and pons. The cerebral and cerebellar white matter have increased T2 and decreased T1 signal intensity. These white matter image changes resemble that typically seen in microvascular ischemia, except that it is often subcortical and patchy.52 The MCPs have increased T2 signal in about 60% of affected men and 13% of affected women.51,52 This is called the MCP sign and is relatively specific for FXTAS. It has also been reported in multiple system atrophy,53,54 acquired hepatocerebral degeneration,55 and recessive ataxia.54 To date, however, there have been only 2 patients, 1 with recessive ataxia and 1 with multiple system atrophy,54 reported with the MCP sign that were tested and not found to have the FMR1 premutation.
Some asymptomatic carriers have atrophy also. Brain stem volume was significantly smaller in unaffected male carriers compared with controls.56 Aging male carriers selected without regard to motor signs had reduced total brain, cerebrum, cerebellum, cerebral cortex, amygdalo-hippocampal complex, and thalamus size.57,58
DIAGNOSIS OF FRAGILE X-ASSOCIATED TREMOR/ATAXIA SYNDROME
The diagnosis of FXTAS is often missed, for 2 reasons. First, because it has only recently been described,1 many physicians are not yet familiar with it. Second, the presentation can be quite variable, resulting in misdiagnosis. Correct diagnosis is not only vital for the patient but also for their family; ensuing generations are at high risk for FXS. Guidelines to aid the physician in deciding who to test for FXTAS are shown in Table 3; and generally accepted diagnostic criteria are presented in Table 4.8 Diagnosis of a premutation carrier requires provision of genetic counseling for the patient and their family.
MANAGEMENT AND THERAPY
Although the patient with FXTAS may have presented with a specific complaint, often a motor symptom, the management of FXTAS is complex and involves other considerations. Appropriate management consists of assessment of the patient's neurological and medical deficits, prescription of appropriate medications and rehabilitative services, genetic counseling for the patient and family, and provision of relevant referrals. Evaluation for other causes of dementia, particularly reversible contributing causes, such as hypothyroidism, vitamin B12 deficiency, folate deficiency, and depression is essential. Furthermore, patients need counseling regarding conditions and medications that may worsen FXTAS, for example, some chemotherapeutic agents (carboplantin)59 and major surgery. Referrals are often indicated to urology, rehabilitative medicine, genetic counseling, and social work. The most disabling symptoms are falls, intention tremor, psychiatric problems such as depression, anxiety, agitation, and disinhibition, and cognitive dysfunction, ranging from memory loss to dementia. In addition, many women complain bitterly of fibromyalgia symptoms, and some affected persons have severe neuropathic leg pain.60
To date, there have not been any controlled trials reported that evaluate disease modifying or symptomatic therapies. Thus, intervention is limited to symptomatic therapy. Current recommendations are based on anecdotal reports and on knowledge of what works for symptoms of other disorders that also exist in FXTAS. For example, the action tremor and the parkinsonism in FXTAS may respond to medications used effectively for essential tremor and Parkinson disease, respectively.
Falls are mainly due to cerebellar dysfunction, which generally does not respond to medical therapy.61 A few persons with FXTAS and other disorders with cerebellar ataxia have shown at least transient improvement with amantadine at standard doses62,63 and with varenicline at a dosage of 0.5 to 1 mg/d.64,65 However, anecdotal reports suggest that varenicline may worsen tremor and exacerbate psychiatric symptoms in FXTAS. Gait difficulties may also be caused by parkinsonism, peripheral neuropathy, extensive central nervous system white matter lesions, and weakness, especially of the proximal lower extremities. Dopaminergic medications improved ataxia in some persons with parkinsonism.66 Physical therapy aimed at improving strength and flexibility may reduce falls and improve function.
Action tremor may respond to β-blockers, primidone, and topiramate at the doses used to treat essential tremor.66,67 Benzodiazepines such as alprazolam may also be effective in some patients,68 because tremor is aggravated by anxiety and stress. Other options with less published support are gabapentin, levetiracetam, clonazepam, clozapine, nadolol, nimodipine, and botulinum toxin.69 Regarding the latter, injection of just the flexor muscles and not the extensors reduces the occurrence of excessive weakness (J. Jankovic, 2006, personal communication). Occupational therapy may offer techniques to improve function, such as wrist weights or use of the assistive mouse adapter (IBM Watson Research Center, Yorktown Heights, NY), which is designed to assist persons with tremor use a keyboard.70 Thalamic deep brain stimulation is an option for severe, medically intractable tremor9,71 and perhaps should be limited to unilateral treatment because bilateral surgery is more likely to worsen cognition72 and gait.71
Although minimal use of psychoactive medication is indicated in elderly persons with relatively advanced stage FXTAS, judicious treatment of psychiatric symptoms and cognitive decline is generally rewarding. Regarding depression, selective serotonin reuptake inhibitors with minimal drug-drug interaction (eg, citalopram, sertraline, and escitalopram) are preferred for use in the elderly, rather than paroxetine, fluvoxamine, are fluoxetine. Anecdotal experience suggests that the selective serotonin norepinephrine reuptake inhibitors (venlafaxine and duloxetine) are especially effective,60 not only for depression but also for anxiety, agitation, hostility, and irritability.60
Cognitive decline has been reported to slow in a few persons with FXTAS with use of acetylcholinesterase inhibitors.66 This may be because pathological studies in FXTAS show marked pathology in the hippocampus,73 although the clinical profile of cognitive deficits in Alzheimer disease and FXTAS is distinct.23 Addition of memantine is indicated in Alzheimer disease to treat the memory deficit, and is suspected to reduce glutamate-associated excitotoxicity in neurodegenerative disorders. Anecdotal reports suggest memantine may be helpful in FXTAS at the same dose used in Alzheimer disease.60
Pain from peripheral neuropathy may be reduced with anticonvulsants (especially gabapentin and pregabilin), antidepressants (especially cymbalta), and topical analgesics (such as lidocaine cream). Pain from fibromyalgia in women with FXTAS may respond to pregabalin74 and standard therapy.75 Standard therapy includes exercise, psychotherapy, and antidepressants.
Although parkinsonism is usually mild in FXTAS, some patients improve with dopaminergic medications and anticholinergics, at standard doses used in Parkinson disease. In the later stages of FXTAS, when patients are more fragile, l-dopa is expected to be better tolerated than dopamine agonists, and anticholinergics need monitoring for exacerbation of memory and urinary problems. Physical therapy, especially step and gait training, has been shown to improve function in Parkinson disease,76,77 so may be beneficial in carriers with parkinsonism.
Autonomic dysfunction in FXTAS may include impotence, orthostatic hypotension, urinary frequency or incontinence, and bowel incontinence (in the later stages). Urological referral will dictate which types of medication may be helpful for the urinary symptoms. Hyperactive detrusor activity responds to small doses of tricyclic antidepressants, to muscarinic receptor antagonists, and to botulinum toxin injections. Initial treatment of orthostatic hypotension consists of increased salt and fluid intake, eating frequent small meals, use of Jobst stockings, and elevation of the head of the bed at night. Useful medications include mineralocorticoids (fludrocortisones) and midodrine, an α1-adrenergic agonist, which increases blood pressure. Regarding midodrin, patients need to be warned not to lie flat for 4 hours after a dose because a dangerously high blood pressure can occur.78 Some patients benefit from use of both midodrine and fludrocortisones. Orthostasis also responds to pyridostigmine.60,79
A few other points regarding the management of FXTAS are worth noting. Caretakers are often in need of support, emotional and practical, as the patient's disease progresses. Depression and/or anxiety are common in spouses, and treatment with a selective serotonin reuptake inhibitor can be quite helpful. Appropriate referrals are needed to assist the caretaker in obtaining help in the household, legal guardianship, and eventually, placement of the patient in a specialized long-term care facility. Another important point is that the condition of persons with FXTAS will sometimes be misdiagnosed as normal pressure hydrocephalus. However, surgery for this condition in persons with FXTAS has resulted in deterioration.12,60
Mutation of the FMR1 gene is associated with FXS, POI, and FXTAS. The premutation, which causes POI and FXTAS, is relatively common in the general population, and thus an important source of morbidity. To date most persons with FXTAS have been identified only after a grandchild is diagnosed with FXS. Fragile X-associated tremor/ataxia syndrome is underrecognized and misdiagnosed because it has only recently been described and because its presentation is variable and mainly consists of a combination of signs that are common in the elderly. However, accurate diagnosis is important not only for the patient but also for the family members so that they can be educated about serious genetic and health risks.
Many important questions about FMR1 premutation-related disease remain. For example, prospective studies of disease progression and modifying factors would provide valuable information needed for life planning. Most importantly, the basic mechanisms by which the FMR1 premutation cause symptoms need further study so that effective treatment can be developed to slow and prevent the disease.
The author thanks Ms Leah Gaspari for her administrative assistance in the preparation of this manuscript.
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