Aging in individuals with the FMR1 mutation

Individuals with fragile X mental retardation 1 (FMR1) premutation (55 to 200 CGG repeats) are typically unaffected by fragile X syndrome. However, a subgroup of older males with the premutation have developed a neurological syndrome, which usually begins between 50 and 70 years and is associated with a progressive intention tremor and/or ataxia manifested by balance problems, frequent falling, and Parkinsonian symptoms, such as masked facies, intermittent resting tremor, and mild rigidity. This finding has been termed the fragile X-associated tremor/ataxia syndrome (FXTAS) and has brought focus to the aging process in individuals with the FMR1 mutation. The premutation is associated with elevated messenger RNA levels leading to the formation of intranuclear inclusions in neurons and astrocytes associated with FXTAS. This review is a summary of our experience with FXTAS in male carriers of the premutation.     

Parkinsonism in fragile X-associated tremor/ataxia syndrome (FXTAS): Revisited

BackgroundParkinsonian features have been used as a minor diagnostic criterion for fragile X-associated tremor/ataxia syndrome (FXTAS). However, prior studies have examined parkinsonism (defined as having bradykinesia with at least rest tremor or postural instability) mostly in premutation carriers without a diagnosis of FXTAS. The current study was intended to elaborate this important aspect of the FXTAS spectrum, and to quantify the relationships between parkinsonism, FXTAS clinical staging and genetic/molecular measures.MethodsThirty eight (38) FXTAS patients and 10 age-matched normal controls underwent a detailed neurological examination that included all but one item (i.e. rigidity) of the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS).ResultsThe FXTAS patient group displayed substantially higher prevalence of parkinsonian features including body bradykinesia (57%) and rest tremor (26%), compared to the control group. Furthermore, parkinsonism was identified in 29% of FXTAS patients. Across all patients, body bradykinesia scores significantly correlated with FXTAS clinical stage, FMR1 mRNA level, and ataxic gait of cerebellar origin, while postural instability was associated with intention tremor.InterpretationParkinsonian features in FXTAS appear to be characterized as bradykinesia concurrent with cerebellar gait ataxia, postural instability accompanied by intention tremor, and frequent rest tremor, representing distinctive patterns that highlight the need for further clinical studies including genetic testing for the FMR1 premutation. The association between FMR1 mRNA level and bradykinesia implicates pathophysiological mechanisms which may link FMR1 mRNA toxicity, dopamine deficiency and parkinsonism in FXTAS.     

Atypical neurological symptoms associated with CGG expansions of the FMR1 gene

More than 40 CGG expansions in the 5’ noncoding region of the fragile X mental retardation 1 (FMR1) gene of the X chromosome give rise to several distinct clinical phenotypes, depending on the size of the expansion. First, more than 200 CGG expansions (full mutation) cause an inherited mental retardation called fragile X syndrome. Second, CGG expansions between 55 and 199 (premutation) cause a disorder called fragile X-associated tremor/ataxia syndrome (FXTAS) which typically includes intention tremor, ataxia and specific magnetic resonance imaging (MRI) findings. Indeed, it could develop parkinsonism although it usually shows features of postsynaptic parkinsonism. Finally, CGG expansions between 41 and 54 CGG (gray zone) are not consider normal but rarely develops abnormal neurological conditions. In this sense, the aim of this study is to report two atypical cases associated with CGG expansions of the FMR1 gene. First, a FMR1 premutation alleles carrier with an unusual phenotype, such as a presynaptic parkinsonism indistinguishable from Parkinson disease (PD) and a FMR1 gray zone alleles carrier presented with neurological features, namely hand tremor, parkinsonism and ataxia, usually described in FXTAS, as well as orthostatic tremor. We conclude that, on the one hand, FMR1 premutation alleles might cause two phenotypes of parkinsonism, such as a presynaptic phenotype, indistinguishable from PD, and a postsynaptic phenotype, associated with clinical features of FXTAS. On the other hand, although FMR1 gray zone alleles carriers were believed to have no abnormal neurological conditions, our study supports that they could develop FXTAS and other neurological disorders such as orthostatic tremor which has not been reported before associated with the FMR1 gene.     

Impairment in the cognitive functioning of men with fragile X-associated tremor/ataxia syndrome (FXTAS)

Disorders associated with fragile X syndrome involve a trinucleotide (CGG) repeat expansion in the FMR1 gene. Recently, a progressive movement disorder (fragile X-associated tremor/ataxia syndrome [FXTAS]) has been identified in premutation carriers, persons with 55 to 200 CGG repeats. In addition to ataxia, action tremor, and Parkinsonism, early case reports suggested that FXTAS involves impaired cognition, but the precise nature of the impairment has not been elucidated. In this first, preliminary study of the subject, circumscribed aspects of cognitive functioning were examined in 25 men with FXTAS. Subjects' performance on the cognitive tests was compared with normative data. Scores on two measures of executive cognitive functioning showed a high prevalence of substantial impairment. Capacity for inhibition was severely affected in one-quarter of this highly educated sample; information processing speed was profoundly impaired in most subjects. Although mean verbal and performance IQ scores were not significantly different from the general population, they were quite low given the sample's educational level. Cognitive and functional impairment was greater for men with more CGG repeats, although number of repeats was not associated with age of onset of either tremor or ataxia. The results provide evidence that FXTAS involves marked impairment of executive cognitive abilities.     

Genetic analysis of SCA 2 and 3 repeat expansions in essential tremor and atypical Parkinsonism.

Anecdotal reports suggest that patients with spinocerebellar ataxia (SCA 2) patients can present with postural tremor with ataxia. We determined the prevalence of SCA2 and SCA3 mutations in a cohort of ET and atypical Parkinsonism patients. A total of 277 subjects comprising of 177 ET and 100 atypical Parkinsonism were examined. We identified one positive case of SCA3 among those who were diagnosed with ET, yielding a prevalence of 0.5%, but a zero prevalence among our atypical Parkinsonism patients. No study subjects carried an abnormal SCA2 repeat expansion. Our study highlights that SCA3 can present initially with ET symptoms, expanding the spectrum of genetic diseases that can be associated with ET-like phenotype. Routine screening for SCA2 and SCA3 in ET and atypical Parkinsonism patients may not be cost effective. However, in the long-term follow-up of patients who present with an ET phenotype, clinicians should be vigilant for other neurological signs, which may be point to an alternate diagnosis.     

Which Approach is Better: Bilateral Versus Unilateral Thalamic Deep Brain Stimulation in Patients with Fragile X–Associated Tremor Ataxia Syndrome

Fragile X–associated tremor ataxia syndrome (FXTAS) is a relatively recently described condition that is frequently misdiagnosed as essential tremor and then occasionally treated as such with deep brain stimulation (DBS) to the nucleus ventralis intermedius of the thalamus (Vim). Reports of ataxia worsening after bilateral Vim DBS in FXTAS patients are conflicting, and only five FXTAS patients treated with Vim DBS for intractable tremor have been reported in the literature, three of whom having undergone a bilateral procedure. We report a patient who underwent a staged Vim DBS procedure, with excellent contralateral hand tremor control and no worsening of ataxia after the first procedure, but immediate worsening of his ataxia after the second one, arguing in favor of a unilateral surgical approach for intractable tremor in FXTAS.     

Identification of FXTAS presenting with SCA 12 like phenotype in India

BackgroundFragile X-associated Tremor/Ataxia syndrome (FXTAS) is a clinically heterogeneous disorder characterized predominantly by tremor, followed by late onset gait ataxia, autonomic dysfunction and/or cognitive impairment. We aimed to screen FMR1-CGG repeats in our cohort of progressive late-onset cerebellar ataxia/tremor cohort to characterize the occurrence of FXTAS in India.MethodsWe have screened FMR1-CGG repeats in 109 patients and 173 healthy control subjects. Our cohort comprised: a)group of patients with predominant cerebellar ataxia and/or tremor. b.)suspected cases of MSA and c.)patients who presented SCA12-like neurological manifestations (late onset predominant tremor and/or ataxia). All the cases were ruled out for known triplet-repeat-expansion (TRE) SCA mutations.ResultsWe have found three FMR1-premutation carriers among the cases. Two of them (with CGG-96 and CGG-102) were under evaluation for their SCA12-like manifestations and another (CGG-78) had progressive gait ataxia. Overall the frequency of FXTAS in our cohort was found to be 3.3% among cases of late onset cerebellar-ataxia/tremor; however, incidences were higher among cases with SCA12-like syndrome (9%, 2/23).ConclusionFinding FXTAS in patients with SCA12-like manifestation suggests that TRE in the 5′UTR of the gene is the common cue connecting two disorders with common phenotype of tremor/ataxia. This knowledge might shed light upon their sharing of molecular neuropathology.     

Tremor/ataxia syndrome and fragile X premutation: diagnostic caveats.

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a newly discovered late-onset neurodegenerative disorder caused by a premutation in the FMR1 X-linked gene. We present examples of a discrepancy between obvious brain changes observed on MRI, and minimal clinical neurological manifestations in three older carriers of this premutation. This discrepancy occurred in three of nine carriers ascertained in an unbiased manner. If the systematic follow-up studies of adult carriers confirm this trend, this will have an impact on early diagnosis of neurological involvement and possible prevention. If MRI changes precede clinical manifestation of FXTAS this may explain the low detection rate of fragile X carriers among patients with neurological syndromes associated with tremor/ataxia.     

Fragile X-associated tremor/ataxia syndrome

Carriers of premutation within the FMR1 gene are typically normal intellectually, although a limited number of them have been reported to have either learning disabilities or mild dysmorphic features. A neurological condition involving intention tremor, ataxia and cognitive decline has recently been identified among older males carrying premutation alleles of the FMR1 gene, including grandfathers of children affected with fragile X syndrome. Characteristic findings from magnetic resonance imaging include cerebral and cerebellar volume loss and altered signal intensities of the middle cerebellar peduncles. This syndrome may represent one of the more common causes of tremor, ataxia and dementia among older males. The diagnosis of FXTAS is straightforward if a family at high genetic risk could be identified. Thus genetic counseling should be offered to such family.     

Screening for intermediate CGG alleles of FMR1 gene in male Iranian patients with Parkinsonism

Male carriers of an expansion of CGG alleles (with 55–200 CGG repeats) in the FMR1 gene are affected with Fragile X-associated tremor/ataxia syndrome (FXTAS). On the other hand, individuals with Parkinson’s disease (PD) or Parkinsonism spectrum disorders may have some clinical features that overlap with FXTAS. To investigate the possible association between PD and FMR1 expanded alleles, we screened a total of 154 male PD patients and 190 gender- and age-matched healthy control subjects from Iran. Eleven intermediate allele carriers (7.14 %) were detected among PD patients, compared with three carriers (1.57 %) among the controls (P = 0.01). No pre-mutation carriers were identified. Our results indicate that there is a potential association between FMR1 intermediate expanded alleles and PD.     

Progression of tremor and ataxia in male carriers of the FMR1 premutation.

Premutation alleles of the fragile X mental retardation 1 (FMR1) gene give rise to a late-onset movement disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), characterized by progressive intention tremor and gait ataxia, with associated dementia and global brain atrophy. The natural history of FXTAS is largely unknown. To address this issue, a family-based, retrospective, longitudinal study was conducted with a cohort of 55 male premutation carriers. Analysis of the progression of the major motor signs of FXTAS, tremor and ataxia, shows that tremor usually occurs first, with median onset at approximately 60 years of age. From the onset of the initial motor sign, median delay of onset of ataxia was 2 years; onset of falls, 6 years; dependence on a walking aid, 15 years; and death, 21 years. Preliminary data on life expectancy are variable, with a range from 5 to 25 years.     

Screen for expanded FMR1 alleles in patients with essential tremor.

Fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder, was described recently among male carriers of expanded alleles (55-200 CGG repeats; premutation range) of the fragile X mental retardation 1 (FMR1) gene. Major features of the syndrome include intention tremor, gait ataxia, and parkinsonism in men over 50 years of age. This disorder is believed to be relatively common, possibly affecting 1 in 3,000 men over the age of 50 years in the general population. This raises the possibility that some patients presenting with essential tremor (ET) may harbor expanded FMR1 alleles. We screened 81 ET patients (40 males, 41 females) for expanded FMR1 alleles to determine whether ET is associated with such alleles. None of the ET cases had the premutation genotype. CGG repeat sizes ranged from 5 to 47 repeats within this study population, suggesting that expanded FMR1 alleles are uncommon among patients with ET. Screening of movement disorder patients with other clinical features of FXTAS (e.g., ataxia and parkinsonism) may be more likely to yield expanded FMR1 alleles.     

The fragile x-associated tremor and ataxia syndrome (FXTAS)

FXTAS (Fragile X-associated tremor and ataxia syndrome) is a late- onset neurodegenerative disorder affecting mainly men, over 50 years of age, who are carriers of the FMR1 gene premutation. The full mutation of this gene causes the fragile X syndrome (FXS), the most common cause of inherited mental retardation. Individuals affected by FXTAS generally present intention tremor and gait ataxia that might be associated to specific radiological and/or neuropathological signs. Other features commonly observed are parkinsonism, cognitive decline, peripheral neuropathy and autonomic dysfunction. Nearly a decade after its clinical characterization, FXTAS is poorly recognized in Brazil. Here we present a review of the current knowledge on the clinical, genetic and diagnostic aspects of the disease.     

Initial diagnoses given to persons with the fragile X associated tremor/ataxia syndrome (FXTAS)

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a newly described disorder that occurs in premutation carriers of the fragile X mental retardation 1 (FMR1) gene. Fifty-six patients with FXTAS were given 98 prior diagnoses: most were in the categories of parkinsonism, tremor, ataxia, dementia, or stroke. Data from this study and others were used to develop guidelines for FMR1 diagnostic testing for FXTAS.     

Intrafamilial variability in fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive adult-onset tremor/ataxia syndrome caused by premutations in the FMR1 gene. In cranial MRI, the most characteristic findings are bilateral T2 hyperintense lesions within the middle cerebellar peduncles. Here we present a sibpair of two affected brothers presenting with very different symptoms (typical FXTAS versus essential tremor-like), disease progression, and MRI findings, illustrating broad intrafamilial variability of FXTAS. Also, their family history suggests further evidence of possible manifestation of FXTAS in women.     

Peripheral beta-adrenergic blockade treatment of parkinsonian tremor

The effect of nadolol, a peripherally acting beta-adrenergic blocker, on resting, postural, and intention tremor was examined in 8 patients with idiopathic Parkinson's disease whose motor symptoms, other than tremor, were well controlled with conventional medications. In a double-blind, placebo-controlled, crossover design, patients received 80 to 320 mg of nadolol for six weeks while continuing their previous therapeutic regimen. Accelerometer readings showed a 34% reduction (p less than 0.025) in tremor distance, but no change in tremor frequency, during nadolol therapy. Maximum benefit was achieved with a dose of 240 mg, when resting tremor improved 54%, postural tremor 32%, and intention tremor 54%. Physician ratings and patient reports supported the accelerometer results. Nadolol appears to be a safe, effective adjunct to current dopaminergic and anticholinergic therapy for severe tremor in Parkinson's disease.