Case Study

Continuing Medical EducationNature Clinical Practice Neurology (2007) 3, 107-112
doi:10.1038/ncpneuro0373  
Received 14 July 2006 | Accepted 15 September 2006

Fragile X-associated tremor/ataxia syndrome—an older face of the fragile X gene

Paul J Hagerman* and Randi J Hagerman  About the authors

Correspondence *Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, One Shields Avenue, Davis, CA 95616, USA

Email
 pjhagerman@ucdavis.edu

Summary

Background A 76-year-old man presented with an 8-year history of balance problems and a 2-year history of short-term memory loss. He had also been experiencing long-term problems with impotence and episodes of urinary incontinence, and had been managed for hypertension for 25 years. His medical history was otherwise unremarkable. Three of his grandchildren had been diagnosed with fragile X syndrome.

Investigations Neurological examination, cognitive and neuropsychological testing, nerve conduction studies, MRI, and genetic testing.

Diagnosis Fragile X-associated tremor/ataxia syndrome (FXTAS) resulting from a premutation (CGG repeat) expansion of the FMR1 gene.

Management Explanation of the genetic ramifications of premutation carrier status for the FMR1 gene, and symptomatic treatment for the clinical difficulties experienced by the patient.

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The case

A 76-year-old man presented to a movement disorders clinic with a history of gait ataxia that had commenced at the age of 68 years. His wife had noted at that time that his gait would drift to one side, and he began to fall on a regular basis while jogging. He had used a walking stick intermittently since the age of 72 years, from which age he had also noticed a marked reduction in his stamina levels, although he could still walk a mile when necessary. After reaching the age of 74 years, he experienced several falling episodes—two resulting in fractured ribs. When he was aged 75 years, he first noted tremor in his left hand during walking; the tremor did not occur at other times.

Memory problems became increasingly apparent to the patient from the age of 74 years, and he experienced occasional episodes of confusion—for example not knowing whether to move forward at a red traffic light. At the age of 75 years his primary health-care provider commenced him on donepezil 5 mg daily, which the patient felt helped his memory and decreased his episodes of confusion.

In the months before his visit to the clinic, the patient experienced sleep disturbance that was found to improve with the prescription of trazodone 50 mg daily. He also experienced restless leg syndrome, for which his primary care physician prescribed gabapentin 100 mg daily, which appeared to improve his symptoms. The patient had experienced problems with impotence for many years, and during the year before his visit to the clinic he had occasional episodes of urinary frequency and mild urinary incontinence. He also experienced episodes of light-headedness when standing up rapidly; he had had hypertension for 25 years, which was managed with hydrochlorothiazide and atenolol. When questioned, the patient denied any numbness or tingling in his extremities, thyroid disease, diabetes, migraine, weakness, swallowing problems, or bowel incontinence. His past medical history was unremarkable apart from an ongoing high serum cholesterol level that was treated with a statin, and partial loss of hearing.

His family history revealed that two of his three daughters had children; five in total. All three of his granddaughters had full-mutation alleles (>200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene (Online Mendelian Inheritance in Man® [OMIM] 309550; Johns Hopkins University, Baltimore, MD), with mental impairment ranging from learning disabilities to mild mental retardation. Of his two grandsons, one was a carrier of the premutation allele (55–200 CGG repeats) with learning disabilities, and the other was without a fragile X mutation. One of his daughters, the mother of two of the full-mutation children, suffered from premature ovarian failure (POF)—the cessation of menses prior to the age of 40 years. Genetic testing of the patient was subsequently carried out using the standard FMR1 DNA test, which confirmed his status as a premutation carrier (78 CGG repeats).

Neurological examination demonstrated a significant bilateral ataxia on heel-to-shin movements, and a broad-based gait. The patient could not tandem walk, and the pull test was positive. Although the patient had no rest tremor, a mild tremor was present in his left hand while walking, and his walking arm swing was decreased bilaterally, with greater decrease on the left. He displayed no other features of parkinsonism, such as increased tone. Tremor was absent with finger-to-nose testing, but the patient had a slight postural tremor in the left hand. His palmomental reflex and snout reflex were positive. Deep tendon reflexes were symmetrical—2+ in the upper extremities, 3+ at the knees, but barely detectable in the ankles. Vibration sense was absent in the toes and ankles and present in the right knee, but was decreased by 50% in the left knee as well as in the right and left forefingers. Pinprick sensation and temperature and position sense were normal in the upper and lower extremities.

Cognitive testing at the age of 72 years using the Wechsler Adult Intelligence Scale®—Third Edition (WAIS-III; The Psychological Corporation, San Antonio, TX) had demonstrated a full-scale IQ of 111 (verbal 108; performance 113). At the time of the patient's presentation at the age of 76 years, his full-scale IQ was found to have diminished to 103 (verbal, 112; performance, 92). Additional neuropsychological testing at this time revealed memory problems on the Rey Auditory–Verbal Learning Test (RAVLT), with scores ranging from the 6th to the 18th percentiles for age. The patient also demonstrated executive function deficits on the Stroop color–word test with deficits in inhibition (T score of 31), and on the Behavior Dyscontrol Scale 2 (BDS2; score 11 = severely impaired). These results indicated significant deficits in his executive function and short-term memory.

An MRI scan at the age of 72 years had displayed mild brain atrophy, which was found to have progressed to moderate atrophy by the time of the patient's presentation at the age of 76 years. There was an increased T2 signal intensity in the subcortical and periventricular white matter, which was accompanied by characteristic involvement of the deep cerebellar white matter and middle cerebellar peduncles (MCPs) at both age 72 years (Figure 1) and age 76 years.

Figure 1 MRI of the patient at the age of 72 years.
Figure 1 : MRI of the patient at the age of 72 years. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

(A) Axial T2-weighted image demonstrating symmetric, increased signal within the middle cerebellar peduncles. (B) Axial fluid-attenuated inversion recovery (FLAIR) image revealing increased signal within the periventricular cerebral white matter. (C) Sagittal T1 image demonstrating mild atrophy of the caudal pons, mild cerebral volume loss and thinning of the corpus callosum. Images courtesy of J Brunberg.

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Nerve conduction velocity studies showed a slowing of motor conduction velocity across the elbow (40 m/s; normal >48 m/s) and a reduction of sensory nerve action potential amplitude in the right ulnar nerve (2 mV; normal >7 mV) that was consistent with entrapment neuropathy. In the lower extremities, there was evidence of a mild motor and sensory neuropathy as demonstrated by absence of the right sural nerve action potential, temporal dispersion of the compound muscle action potential in the left tibial nerve on proximal nerve stimulation, and bilateral absence of tibial H-reflexes.

The genetic ramifications of premutation carrier status for the FMR1 gene were explained to the patient, and he was continued on his current medications although the dose of his donepezil was increased to 10 mg per day. He was also subsequently offered a trial of amantadine 100 mg twice daily for ataxia. Both the patient and his wife felt that the donepezil was helpful; follow-up has been scheduled to assess improvement in his symptoms with medication.

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Discussion of diagnosis

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder found among carriers of premutation alleles of the FMR1 gene; larger repeat expansions (>200 CGG repeats) give rise to a neurodevelopmental disorder called fragile X syndrome (FXS), which is caused by silencing of the FMR1 gene. FXTAS is thought to arise through an entirely distinct pathogenic mechanism to that involved in FXS, and involves an RNA toxic gain of function that is caused by overexpression rather than lack of expression of the FMR1 gene (twofold to eightfold elevated FMR1 mRNA levels1; Figure 2).2 The core clinical features of FXTAS are gait ataxia and intention tremor, which commonly—but not invariably—co-occur.3, 4, 5 Associated features often include cognitive decline and memory loss,6 psychiatric involvement including dysinhibition and mood disturbance,7 peripheral neuropathy, parkinsonism, dysautonomia involving impotence, and urinary and bowel incontinence.3, 4 The present case displayed most of the associated features, in addition to ataxia and the MCP sign on MRI. The prevalence of FXTAS increases with age among male premutation carriers. In a study of carriers within known FXS families, symptoms of FXTAS were found in 17% of male carriers in their 50s, 38% in their 60s, 47% in their 70s, and 75% in their 80s.4 Far fewer female carriers will develop the disorder, in part because of the protective effects of the second, normal X chromosome.8

Figure 2 Clinical and pathogenic consequences of expanded CGG repeats in the FMR1 gene.
Figure 2 : Clinical and pathogenic consequences of expanded CGG repeats in the FMR1 gene. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

In the left portion of the figure, the various expansion ranges are indicated. The CGG repeat (yellow) is located within the 5' untranslated portion of the gene (purple; i.e. the expanded CGG repeat is not incorporated into protein). For full-mutation alleles (>200 CGG repeats), the promoter and CGG repeat regions are usually methylated (red spots), which leads in turn to gene silencing. Absence of the mRNA and fragile X mental retardation 1 protein (FMRP) gives rise to fragile X syndrome. By contrast, premutation alleles (55–200 CGG repeats) are associated with substantial increases in fragile X mental retardation 1 gene (FMR1) mRNA; the excess RNA itself results in inclusion formation through excess binding of a number of nuclear proteins (red spheres), dysregulation of the nuclear lamin A/C architecture, and the clinical manifestations of fragile X-associated tremor/ataxia syndrome. With premutation alleles, FMRP levels are almost normal or only slightly reduced, and are not thought to contribute to fragile X-associated tremor/ataxia syndrome. Abbreviation: FXTAS, fragile X-associated tremor/ataxia syndrome.

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On the basis of the diagnostic criteria in Table 1, including the required presence of a premutation allele and major clinical and MRI features, this patient received a diagnosis of definite FXTAS.3, 5 For some premutation carriers, particularly those with pacemakers or other implanted metal, MRI analysis is not possible. In the presence of major clinical findings, such individuals are normally designated as probable FXTAS cases (Table 1). For those individuals who have died with clinical findings of FXTAS, however, the presence of eosinophilic intranuclear inclusions in neurons and astrocytes confirms the diagnosis post mortem (Figure 3). In addition to the presence of inclusions, neuropathologic examination generally reveals cerebral and cerebellar atrophy with white matter disease, axonal loss, significant activation of subcortical astrocytes, and Purkinje cell dropout.9 Significant cerebellar involvement is consistent with both radiological and clinical findings of FXTAS.

Figure 3 Ubiquitin-positive intranuclear inclusions (black arrowhead) within a centrally located neuronal cell body and two adjacent astroglial nuclei from a patient who died with fragile X-associated tremor/ataxia syndrome.
Figure 3 : Ubiquitin-positive intranuclear inclusions (black arrowhead) within a centrally located neuronal cell body and two adjacent astroglial nuclei from a patient who died with fragile X-associated tremor/ataxia syndrome. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

Note that the nucleolus (white arrowhead) is visible as a separate structure within the neuronal nucleus. (Original image times400 magnification.) Image courtesy of C Greco.

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Table 1 Diagnostic criteria for fragile X-associated tremor/ataxia syndrome.a
Table 1 - Diagnostic criteria for fragile X-associated tremor/ataxia syndrome.a
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Differential diagnosis

With the exception of the required premutation allele, none of the clinical features is absolutely specific for FXTAS. Although around 80% of cases have gait ataxia and intention tremor,3 some individuals do not manifest both core features. In the present case, the tremor was somewhat atypical in that it was present during walking and with posture (i.e. positioning of the hands with the index fingers separated by 1 cm), but not during action. Involvement of the MCPs on MRI is an important diagnostic feature, but it is present in only about 60% of cases and is not completely specific to FXTAS.3, 10 In particular, a significant proportion of patients with the cerebellar subtype of multiple system atrophy (MSA-C) also display increased T2-weighted signal in the MCPs.11 Indeed, there is substantial clinical overlap between FXTAS and MSA-C, with both conditions displaying features of cerebellar dysfunction, parkinsonism, and dysautonomia. In a recent meta-analysis of screening studies of movement disorders populations,12 approximately 2% of an MSA-C cohort were found to have premutation alleles of the FMR1 gene. Another area of FXTAS diagnostic overlap arises with the late-onset cerebellar ataxias. Nearly 50% of FXTAS cases have an initial presentation of ataxia only,13 and in the review of screening studies referred to above approximately 2% of cerebellar ataxia cases were found to be carriers of FMR1 premutation alleles.12 Thus, FMR1 testing should be considered for cases of MSA-C and cerebellar ataxia. Finally, in a recent survey of known FXTAS cases,14 approximately a quarter of all cases received an initial diagnosis of some form of parkinsonism; however, genetic screens of cohorts with parkinsonism failed to yield a significant increase in the number of patients with premutation alleles. One possible explanation for this disparity is that most of the FXTAS cases were not initially seen by movement disorders specialists,14 and particularly those cases in whom the initial presentation consisted of dementia, neuropathy, or other non-movement-disorder clinical features.

On the basis of studies both within families with a known fragile X mutation and within various movement disorders populations, it is estimated that FXTAS will affect between 1 in 3,000 and 1 in 6,000 males—and a smaller number of females—over 50 years of age in the general population,4, 12 making FXTAS one of the more common single-gene forms of late-onset ataxia and tremor. It is not yet known what percentage of patients with FXTAS will eventually develop dementia, and longitudinal studies of cognition in such patients are needed. Preliminary longitudinal data from Leehey and colleagues13 demonstrate that tremor typically occurs before ataxia, with a median onset at age 60 years for tremor and approximately 62 years for ataxia. The onset of falls is typically 6 years after symptom onset, with dependence on a walking aid developing at 15 years after symptom onset, and death at about 21 years after symptom onset.

In addition to undertaking genetic screening for expanded FMR1 alleles in cases for which there is considerable clinical overlap with FXTAS, for example cases of MSA-C or cerebellar ataxia, it is important to consider a patient's family history. Individuals with clinical features suggestive of FXTAS—including intention tremor and parkinsonism—who also have a positive family history (grandchildren/nieces/nephews with learning disabilities, autism spectrum disorders, mental retardation, or identified FXS) should be tested for premutation alleles. Moreover, as approximately 4–14% of cases of POF are caused by premutation expansions,15 a positive family history of POF is another indication that FMR1 testing should be carried out. For cases of suspected FXTAS, the definitive diagnostic test is the fragile X DNA test.

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Treatment and management

There is no targeted treatment for FXTAS, although there are several therapeutic approaches to the condition that are based on existing interventions for the various symptoms of the disorder. Medications such as primidone, beta-blockers, carbidopa and levodopa that have proven useful for the treatment of other movement disorders have been reported anecdotally to be of some benefit for patients with FXTAS.16 There have, however, been no controlled trials of these medications specifically for the treatment of FXTAS. A slowing of cognitive decline has been reported for some patients with FXTAS who receive acetylcholinesterase inhibitors (donepezil, rivastigmine, or galantamine) or memantine.17 In the present case, donepezil was found to be helpful for the patient's cognitive deficits, and similar effects have also been reported by others.16, 17 Improvements in anxiety or mood lability have been reported for patients receiving venlafaxine or selective serotonin reuptake inhibitors.17 Finally, patients with neuropathic pain appear to respond to gabapentin.3, 16

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Conclusion

FXTAS is a neurodegenerative disorder that represents one of the more common single-gene forms of late-onset tremor, ataxia, and perhaps even dementia. Although generally cast in terms of its core clinical features of intention tremor and gait ataxia, FXTAS can present with non-movement-disorder features such as dementia, mood lability or anxiety, dysinhibition, peripheral neuropathy, or various manifestations of dysautonomia. Although allelic with FXS, FXTAS affects a different group of individuals—premutation carriers—and arises through an entirely distinct pathogenic mechanism involving RNA toxicity. The grandparents of children diagnosed with FXS should be asked about possible neurological symptoms that are associated with FXTAS. At present, treatment is largely directed towards symptomatic relief; however, proper diagnosis of FXTAS in terms of the identification of expanded FMR1 alleles is critical so that appropriate genetic counseling of the extended family can be carried out.18

Acknowledgments

The authors wish to thank Dr J Brunberg and Dr C Greco for their contributions of MRI and inclusion images, respectively, and Dr R Maselli and G Fenton-Farrell for their input into the nerve conduction studies. This work was supported by the NINDS (NS43532; PJH), the NIA (AG024488; PJH), the NICHD (HD36071 and HD02274; RJH), and the CDC (U1O/CCU 92513; RJH).

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Competing interests

The authors declared no competing interests.

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