Diagnosis Of Fragile X-associated Tremor/ataxia Syndrome Research Articles

FXTAS is difficult to differentiate from neuronal intranuclear inclusion disease through skin biopsy: a case report

BackgroundBoth fragile X-associated tremor/ataxia syndrome (FXTAS) and late-onset neuronal intranuclear inclusion disease (NIID) show CGG/GGC trinucleotide repeat expansions. Differentiating these diseases are difficult because of the similarity in their clinical and radiological features. It is unclear that skin biopsy can distinguish NIID from FXTAS. We performed a skin biopsy in an FXTAS case with cognitive dysfunction and peripheral neuropathy without tremor, which was initially suspected to be NIID.Case presentationThe patient underwent neurological assessment and examinations, including laboratory tests, electrophysiologic test, imaging, skin biopsy, and genetic test. A brain MRI showed hyperintensity lesions along the corticomedullary junction on diffusion-weighted imaging (DWI) in addition to middle cerebellar peduncle sign (MCP sign). We suspected NIID from the clinical picture and the radiological findings, and performed a skin biopsy. The skin biopsy specimen showed ubiquitin- and p62-positive intranuclear inclusions, suggesting NIID. However, a genetic analysis for NIID using repeat-primed polymerase chain reaction (RP-PCR) revealed no expansion detected in the Notch 2 N-terminal like C (NOTCH2NLC) gene. We then performed genetic analysis for FXTAS using RP-PCR, which revealed a repeat CGG/GGC expansion in the FMRP translational regulator 1 (FMR1) gene. The number of repeats was 83. We finally diagnosed the patient with FXTAS rather than NIID.ConclusionsFor the differential diagnosis of FXTAS and NIID, a skin biopsy alone is insufficient; instead, genetic analysis, is essential. Further investigations in additional cases based on genetic analysis are needed to elucidate the clinical and pathological differences between FXTAS and NIID.

The Effects of Dual Task Cognitive Interference and Fast-Paced Walking on Gait, Turns, and Falls in Men and Women with FXTAS.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a genetic neurodegenerative disorder characterized by cerebellar ataxia, tremor, and cognitive dysfunction. We examined the impact of dual-task (DT) cognitive-motor interference and fast-paced (FP) gait on gait and turning in FXTAS. Thirty participants with FXTAS and 35 age-matched controls underwent gait analysis using an inertial sensor-based 2-min walk test under three conditions: (1) self-selected pace (ST), (2) FP, and (3) DT with a concurrent verbal fluency task. Linear regression analyses were performed to assess the association between FXTAS diagnosis and gait and turn outcomes. Correlations between gait variables and fall frequency were also calculated. FXTAS participants had reduced stride length and velocity, swing time, and peak turn velocity and greater double limb support time and number of steps to turn compared to controls under all three conditions. There was greater dual task cost of the verbal fluency task on peak turn velocity in men with FXTAS compared to controls. Additionally, stride length variability was increased and cadence was reduced in FXTAS participants in the FP condition. Stride velocity variability under FP gait was significantly associated with the number of self-reported falls in the last year. Greater motor control requirements for turning likely made men with FXTAS more susceptible to the negative effects of DT cognitive interference. FP gait exacerbated gait deficits in the domains of rhythm and variability, and increased gait variability with FP was associated with increased falls. These data may inform the design of rehabilitation strategies in FXTAS.

FMR1 locus isoforms: potential biomarker candidates in fragile X-associated tremor/ataxia syndrome (FXTAS)

Fragile X associated tremor/ataxia syndrome (FXTAS) is a late adult-onset neurodegenerative disorder that affects movement and cognition in male and female carriers of a premutation allele of 55–200 CGG repeats in the Fragile X mental retardation (FMR1) gene. It is currently unknown if and when an individual carrier of a premutation allele will develop FXTAS, as clinical assessment fails to identify carriers at risk before significant neurological symptoms are evident. The primary objective of this study was to investigate the alternative splicing landscape at the FMR1 locus in conjunction with brain measures in male individuals with a premutation allele enrolled in a very first longitudinal study, compared to age-matched healthy male controls, with the purpose of identifying biomarkers for early diagnosis, disease prediction and, a progression of FXTAS. Our findings indicate that increased expression of FMR1 mRNA isoforms, including Iso4/4b, Iso10/10b, as well as of the ASFMR1 mRNAs Iso131bp, are present in premutation carriers as compared to non-carrier healthy controls. More specifically, we observed a higher expression of Iso4/4b and Iso10/10b, which encode for truncated proteins, only in those premutation carriers who developed symptoms of FXTAS over time as compared to non-carrier healthy controls, suggesting a potential role in the development of the disorder. In addition, we found a significant association of these molecular changes with various measurements of brain morphology, including the middle cerebellar peduncle (MCP), superior cerebellar peduncle (SCP), pons, and midbrain, indicating their potential contribution to the pathogenesis of FXTAS. Interestingly, the high expression levels of Iso4/4b observed both at visit 1 and visit 2 and found to be associated with a decrease in mean MCP width only in those individuals who developed FXTAS over time, suggests their role as potential biomarkers for early diagnosis of FXTAS.

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications.

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55–200 CGG repeats) carriers of FMR1. The premutation has excessive levels of FMR1 mRNA that lead to toxicity and mitochondrial dysfunction. The clinical features usually begin in the 60 s with an action or intention tremor followed by cerebellar ataxia, although 20% have only ataxia. MRI features include brain atrophy and white matter disease, especially in the middle cerebellar peduncles, periventricular areas, and splenium of the corpus callosum. Neurocognitive problems include memory and executive function deficits, although 50% of males can develop dementia. Females can be less affected by FXTAS because of a second X chromosome that does not carry the premutation. Approximately 40% of males and 16% of female carriers develop FXTAS. Since the premutation can occur in less than 1 in 200 women and 1 in 400 men, the FXTAS diagnosis should be considered in patients that present with tremor, ataxia, parkinsonian symptoms, neuropathy, and psychiatric problems. If a family history of a fragile X mutation is known, then FMR1 DNA testing is essential in patients with these symptoms.

Parkinsonism Versus Concomitant Parkinson's Disease in Fragile X-Associated Tremor/Ataxia Syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. FXTAS is characterized by the presence of ubiquitin-positive inclusions in neurons and astrocytes and by cerebellar tremor and ataxia. Parkinsonism has been reported in FXTAS, but most patients lack the characteristic rest tremor and severe rigidity seen in idiopathic Parkinson's disease (PD). To describe the frequency of concomitant PD in FXTAS. We reviewed the medical record of 40 deceased patients diagnosed with FXTAS and performed a pathology analysis to confirm both FXTAS and PD. Clinical histories indicated that 5 FXTAS patients were diagnosed with idiopathic PD and 2 with atypical parkinsonian syndrome. After pathological examination, we found that 7 patients in the PD clinical diagnosis group had dopaminergic neuronal loss; however, only 2 of 7 presented Lewy bodies (LBs) in the substantia nigra. Therefore, a total of 5% of the 40 cohort patients met the pathologic criteria for the concomitant diagnosis of FXTAS and PD. In addition, 2 patients not clinically diagnosed with PD also had nigral neuronal loss with LBs in substantia nigra. In total 10% of these 40 patients had LBs. This report expands our understanding of clinical symptoms and unusual presentations in patients with FXTAS and the concept that the parkinsonism found in FXTAS is sometimes indistinguishable from PD. We propose that FMR1 should be recognized as one of the exceptional genetic causes of parkinsonism with presynaptic dopaminergic loss and LBs.

Age-related functional brain changes in FMR1 premutation carriers.

The FMR1 premutation confers a 40–60% risk for males of developing a neurodegenerative disease called the Fragile X-associated Tremor Ataxia Syndrome (FXTAS). FXTAS is a late-onset disease that primarily involves progressive symptoms of tremor and ataxia, as well as cognitive decline that can develop into dementia in some patients. At present, it is not clear whether changes to brain function are detectable in motor regions prior to the onset of frank symptomatology. The present study therefore aimed to utilize an fMRI motor task for the first time in an asymptomatic premutation population.Premutation carriers without a diagnosis of FXTAS (n = 17) and a group of healthy male controls (n = 17), with an age range of 24–68 years old, were recruited for this cross-sectional study. This study utilized neuroimaging, molecular and clinical measurements, employing an fMRI finger-tapping task with a block design consisting of sequential finger-tapping, random finger-tapping and rest conditions. The imaging analysis contrasted the sequential and random conditions to investigate activation changes in response to a change in task demand. Additionally, measurements were obtained of participant tremor, co-ordination and balance using the CATSYS-2000 system and measures of FMR1 mRNA were quantified from peripheral blood samples using quantitative real-time PCR methodology.Premutation carriers demonstrated significantly less cerebellar activation than controls during sequential versus random finger tapping (FWEcorr < 0.001). In addition, there was a significant age by group interaction in the hippocampus, inferior parietal cortex and temporal cortex originating from a more negative relationship between brain activation and age in the carrier group compared to the controls (FWEcorr < 0.001).Here, we present for the first time functional imaging-based evidence for early movement-related neurodegeneration in Fragile X premutation carriers. These changes pre-exist the diagnosis of FXTAS and are greatest in older carriers suggesting that they may be indicative of FXTAS vulnerability.

Fragile X-associated tremor/ataxia syndrome: An under-recognised cause of tremor and ataxia

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive degenerative movement disorder resulting from a fragile X “premutation”, defined as 55–200 CGG repeats in the 5′-untranslated region of the FMR1 gene. The FMR1 premutation occurs in 1/800 males and 1/250 females, with FXTAS affecting 40–45% of male and 8–16% of female premutation carriers over the age of 50. FXTAS typically presents with kinetic tremor and cerebellar ataxia. FXTAS has a classical imaging profile which, in concert with clinical manifestations and genetic testing, participates vitally in its diagnosis. The revised FXTAS diagnostic criteria include two major radiological features. The “MCP sign”, referring to T2 hyperintensity in the middle cerebellar peduncle, has long been considered the radiological hallmark of FXTAS. Recently included as a major radiological criterion in the diagnosis of FXTAS is T2 hyperintensity in the splenium of the corpus callosum. Other imaging features of FXTAS include T2 hyperintensities in the pons, insula and periventricular white matter as well as generalised brain and cerebellar atrophy. FXTAS is an under-recognised and misdiagnosed entity. In patients with unexplained tremor, ataxia and cognitive decline, the presence of middle cerebellar peduncle and/or corpus callosum splenium hyperintensity should raise suspicion of FXTAS. Diagnosis of FXTAS has important implications not only for the patient but also, through genetic counselling and testing, for future generations.

Relevance of corpus callosum splenium versus middle cerebellar peduncle hyperintensity for FXTAS diagnosis in clinical practice.

Fragile X-associated tremor ataxia syndrome (FXTAS) is caused by FMR1 premutation. The features include ataxia, action tremor and middle cerebellar peduncle (MCP) hyperintensity, the latter being the only major radiological criterion in the diagnosis of definite FXTAS until very recently. The importance of corpus callosum splenium (CCS) hyperintensity was recently reported and this sign is now considered as an additional major radiological diagnostic criterion in the diagnosis of FXTAS. However, little is known about its relevance for the diagnosis of FXTAS in clinical practice. We report a practical justification of the relevance of CCS hyperintensity in parallel with MCP hyperintensity for the diagnosis of FXTAS. Clinical and radiological study of 22 FMR1 premutation carriers with neurological signs that may be encountered in FXTAS compared to series of patients with essential tremor, multiple system atrophy of cerebellar type, Parkinson's disease, Alzheimer's disease and stroke. Among the 22 patients with FMR1 premutation [17 men, 5 women; mean age, 63 ± 7.5 (46-84)], 14 were diagnosed with definite FXTAS with the initial criteria. Considering CCS hyperintensity as a new major radiological criterion permitted the diagnosis of definite FXTAS in 3 additional patients. Overall CCS proved as frequent as MCP hyperintensity (64 versus 64 %), while 23 % of patients had CCS but not MCP hyperintensity, 14 % of patients had CCS hyperintensity but neither MCP, nor brainstem hyperintensity. In contrast with CCS hyperintensity, MCP hyperintensity proved less frequent in women than in men. CCS and MCP hyperintensity were more frequent in FXTAS than in the other neurodegenerative disorders. The combination of CCS and MCP hyperintensity was specific of FXTAS. We confirmed the relevance of CCS hyperintensity in FXTAS and we clarified its interest compared to MCP hyperintensity. Our results support the inclusion of CCS hyperintensity in the diagnostic criteria as a new major radiological criterion.

35.: Case report: Concurrent occurrence of Fragile X syndrome and Fragile X associated tremor ataxia syndrome due to CGG repeat and methylation mosaicism

Fragile X syndrome (FXS) is a genetic disorder resulting from CGG trinucleotide repeat lengths greater than 200 and subsequent methylation of the FMR1 gene on the X chromosome. Fragile X associated tremor/ataxia syndrome (FXTAS) is a recently described syndrome of tremor and ataxia in a relative of a FXS patient with clinical signs not seen in typical FXS patients. This syndrome is typically seen in patients over the age of 50 and is thought to be a result of neuronal toxicity from excess mRNA production due to CGG repeat lengths of 55 to 200. We present a 34-year-old gentleman with a previous diagnosis of FXS presenting with phenotypic features of FXTAS including cerebellar ataxia. Genetic testing with methylation assay revealed that he is a FXS and FXTAS mosaic with methylated CGG repeat lengths of 110 and 540 contributing to FXS and unmethylated CGG repeat lengths of 90 and 600 contributing to cerebellar ataxia and diagnosis of FXTAS. Despite the close genotypic relationship between FXS an FXTAS there are distinct phenotypic differences attributable to different methylation state. To our knowledge this is the first case to be reported of FXS/FXTAS mosaicism and adds to the increasing understanding of the role played by methylation in determining phenotypic expression of genetic disorders, in particular the importance of methylation mosaicism. We suggest that in a FXS patient presenting with cerebellar ataxia or tremor without an apparent cause, further genetic testing with methylation analysis should be considered in the diagnostic process.

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.

Pure psychiatric presentation of Fragile X‐associated tremor/ataxia syndrome

Fragile X syndrome is a leading cause of intellectual disability in childhood related to the presence of more than 200 repeats of CGG triplets in the FMR1 gene [1]. By contrast, premutation carriers (number of CGG triplets between 55 and 200) have normal development but are at high risk of developing in their late adulthood the so-called Fragile Xassociated tremor/ataxia syndrome (FXTAS) [2]. This syndrome is characterized by late-onset cerebellar ataxia and intention tremor often associated with executive dysfunction. Other frequent clinical manifestations are parkinsonism, psychiatric symptoms, peripheral neuropathy and lower limb weakness [2–4]. The case of a patient affected by FXTAS whose presentation was psychiatric, without tremor and without ataxia, is reported. A 66-year-old right-handed man was referred for behavioural disturbances. He had been in good health until 10 years ago when he presented a first major depressive episode that lasted several months under antidepressant drugs. Three years before admission, his wife began complaining of short lasting episodes of sudden irritability and aggressive behaviour. He was treated by tianeptin and bromazepam for ‘atypical’ depression, but the symptoms kept worsening. His wife became frightened to stay alone with him. Antipsychotic drugs were prescribed with partial efficacy. A few weeks before admission, the patient saw an ear, nose and throat specialist for brief episodes of vertigo. A benign paroxysmal positional vertigo was diagnosed and a brain MRI was systematically prescribed, which revealed symmetrical abnormalities in the cerebellum. The patient was referred to our neurological department. He was kind and alert. His speech was adapted and coherent. He had no particular complaint but admitted having difficulties controlling himself on some occasions. On examination, motor and sensory testing was unremarkable. He had no rest, postural or intention tremor in either hand. He had no truncal or segmental ataxia but a slightly wide-based gait. Tandem walking was possible. Muscle tone and oculomotor movements were normal. There was no dysarthria, sphincter disturbances or orthostatic hypotension. Mini-mental state examination score was 28/30. He performed the clock drawing test well but otherwise showed mild dysexecutive symptoms and reduction of speed processing. Evaluation by a psychiatrist revealed no personality disorder but some elements of delusional jealousy, without depressed mood. The aspect of brain MRI was that of global brain atrophy with large ventricles and typical hyperintense signal in both middle cerebellar peduncles (Fig. 1). The diagnosis of FXTAS was considered. Data about the patient’s family were scarce as they were living in Algeria. He was an only child, but his mother had two daughters and two sons from another marriage. One of his half-brothers had three daughters, one of whom had two sons with severe behavioural disturbances in childhood. The other one had two daughters, one of whom had a son with severe intellectual disability. Genetic testing with both PCR and southern blot methods confirmed a premutation in the FMR1 gene with 95 repeats of the CGG triplet. The potential links between FMR1 premutation and psychiatric comorbidities are under debate [5]. Here, the appearance after the age of 50 of atypical psychiatric symptoms strongly suggests a causal link with the presence of the premutation. More generally, physicians must pay attention to familial history of both psychiatric and neurological symptoms when facing late-onset atypical psychiatric symptoms. Because the prevalence of the Fragile X premutation is high in the general population (estimated around one in 813 in males and one in 259 in females [2]), general neurologists should be aware of this diagnosis. Genetic counselling does not only involve the patient but also his whole family, as his daughters are obligate carriers. This was particularly true in the present case, as two of his daughters were actively considering pregnancy.

FXTAS

Fragile X-associated tremor ataxia syndrome (FXTAS) is defined by FMR1 premutation, cerebellar ataxia, intentional tremor, and middle cerebellar peduncle (MCP) hyperintensities. We delineate the clinical, neurophysiologic, and morphologic characteristics of FXTAS. Clinical, morphologic (brain MRI, (123)I-ioflupane SPECT), and neurophysiologic (tremor recording, nerve conduction studies) study in 22 patients with FXTAS, including 4 women. A total of 43% of patients had no family history of fragile X syndrome (FXS), which contrasts with previous FXTAS series. A total of 86% of patients had tremor and 81% peripheral neuropathy. We identified 3 electroclinical tremor patterns: essential-like (35%), cerebellar (29%), and parkinsonian (12%). Two electrophysiologic patterns evocative of non-length-dependent (56%) and length-dependent sensory neuropathy (25%) were identified. Corpus callosum splenium (CCS) hyperintensity was as frequent (68%) as MCP hyperintensities (64%). Sixty percent of patients had parkinsonism and 47% abnormal (123)I-ioflupane SPECT. Unified Parkinson's Disease Rating Scale motor score was correlated to abnormal (123)I-ioflupane SPECT (p = 0.02) and to CGG repeat number (p = 0.0004). Scale for the assessment and rating of ataxia correlated with dentate nuclei hyperintensities (p = 0.03) and CCS hyperintensity was a marker of severe disease progression (p = 0.04). We recommend to include in the FXTAS testing guidelines both CCS hyperintensity and peripheral neuropathy and to consider them as new major radiologic and minor clinical criterion, respectively, for the diagnosis of FXTAS. FXTAS should also be considered in women or when tremor, MCP hyperintensities, or family history of FXS are lacking. Our study broadens the spectrum of tremor, peripheral neuropathy, and MRI abnormalities in FXTAS, hence revealing the need for revised criteria.

A Japanese Case of Fragile-X-Associated Tremor/ataxia Syndrome (FXTAS)

A 71-year-old man developed postural tremor and was treated as an essential tremor patient. Nine years after the tremor onset, he developed symptoms resembling Fragile-X-associated tremor/ataxia syndrome (FXTAS), including exacerbated (increased coarseness and amplitude) tremor in the right arm, ataxic gait, and brain MRI showed lesions in the bilateral middle cerebellar peduncles (MCP). Evidence of premutation in the form of 83 CGG repeats of the Fragile-X-mental retardation 1 (FMR1) gene confirmed the diagnosis of FXTAS. FXTAS causes various neurological symptoms including in some cases tremor resembling essential tremor in the early stages. FMR1 gene premutation should be checked when the patient develops intention tremor, cerebral dysfunction and/or a brain MRI shows MCP lesions.

Fragiles X-assoziiertes Tremor-/Ataxie-Syndrom

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently characterized adult onset neurodegenerative disorder affecting both male and female (male>female) carriers of premutation CGG repeat expansions of the FMR1 gene. Onset typically occurs after the age of 50 years with a lifetime risk of FXTAS in males of about 1 in 3,000-6,000. Core features include progressive gait ataxia and cerebellar tremor with associated features of cognitive deficits, peripheral neuropathy and dysautonomia. The diagnosis of FXTAS is established based on clinical presentation, cerebral imaging and genetic testing. Due to the still low level of awareness of FXTAS and its variable clinical picture FXTAS is substantially underdiagnosed. However, confirming the diagnosis is essential for genetic counseling of the patients as the offspring are at risk for fragile X syndrome, premature ovarian insufficiency (POI) or FXTAS. Furthermore, many features of FXTAS can be treated symptomatically.

Ataxie cérébelleuse tardive due à la prémutation de l’X fragile

Introduction The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that affects carriers, principally males after 50 years of age, of premutation alleles of the fragile X mental retardation 1 (FMR1) gene. Clinical features of FXTAS are an intention tremor and/or a cerebellar ataxia, with or without parkinsonism, cognitive disorders, neuropathy and autonomic dysfunction. MRI shows symmetrical signal abnormalities in the middle cerebellar peduncles and deep cerebellar white matter, typically sparing the dentate nucleus, associated with generalized atrophy. We report a case of FXTAS with isolated cerebellar ataxia. Case report We report the case of a 60-year-old right-handed man with an uneventful personal and familial history. Since 2002, he progressively developed gait ataxia associated with paresthesia in the lower limbs. The physical examination revealed static and kinetic cerebellar ataxia with dysarthria. Exhaustive screening tests (inflammatory, immunological, metabolic, infectious and neoplasic) and the cerebrospinal fluid analysis were normal. The brain MRI T2-weighted sequences showed diffuse increased signal in both cerebellar white matter and middle peduncles suggestive of FXTAS. Functional explorations (evoked somesthesic and visual potentials, electromyogram, and cerebral scintigraphy) confirmed the isolated cerebellar involvement. The FXTAS was suggested and the genotype was explored. Southern Blot revealed an expansion of trinucleotide CGG with 107 repetitions, confirming the diagnosis of FXTAS. Discussion In patients with a fragile X premutation, FMR1 protein levels are gradually reduced with increased repeat number, despite elevated FMR1 transcripts levels. Neuropathologic examination reveals eosinophilic intranuclear inclusions in neurons and astrocytes throughout the cortex, subcortical regions, and brain stem. The pathogenic hypothesis would be related to a gain of function with toxic effects of FMR1 messenger RNA on cellular metabolism. Cerebellar ataxia, which may be isolated or not, is the most frequent neurologic manifestation, like many studies showed. Conclusion FXTAS should be suspected in patients with unexplained late-onset cerebellar ataxia. Typical presentation includes a male in his fifties with progressive ataxia and tremor. Brain MRI with symmetrical cerebellar abnormalities is very suggestive of this diagnosis. Genetic screening and advice for the patient and his family must be proposed in order to detect the fragile X syndrome.

Age-dependent cognitive changes in carriers of the fragile X syndrome

Fragile X syndrome is a neurodevelopmental disorder that is caused by the silencing of a single gene on the X chromosome, the fragile X mental retardation 1 ( FMR1) gene. Affected individuals display a unique neurocognitive phenotype that includes significant impairment in inhibitory control, selective attention, working memory, and visual–spatial cognition. In contrast, little is known about the trajectory and specificity of any cognitive impairment associated with the fragile X premutation (i.e., “carrier status”) or its relationship with the recently identified neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). In the present study, we evaluated a broad sample of 40 premutation males (PM) aged 18–69 years matched on age and IQ to 67 unaffected comparison males (NC). Performance was compared across a range of cognitive domains known to be impaired in fragile X syndrome (i.e., “full mutation”). Tremor was also assessed using a self-report neurological questionnaire. PM displayed statistically significant deficits in their ability to inhibit prepotent responses, differentiating them from NC from age 30 onwards. With increasing age, the two groups follow different trajectories, with PM developing progressively more severe problems in inhibitory control. This deficit also has a strong co-occurrence in males displaying FXTAS-related symptomatology ( p < .001). Selective attention was also impaired in PM but did not show any disproportionate aging effect. No other cognitive deficits were observed. We conclude that an inhibitory deficit and its impact across the lifespan are specifically associated with the fragile X premutation status, and may be a precursor for development of a more severe form of cognitive impairment or dementia, which has been reported in patients with the diagnosis of FXTAS.

FXTAS in Spanish Patients with Ataxia: Support for Female FMR1 Premutation Screening

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a newly described disorder characterized by progressive action tremor and ataxia that occurs in premutation carriers of the FMR1 gene. The incidence of FMR1 premutated carriers in the general population is relatively high, and therefore FXTAS might explain a considerable number of sporadic, late-onset ataxias. To better establish the prevalence of FXTAS among undiagnosed Spanish patients with ataxia, we have performed a FMR1 premutation screening. Our results evidenced three individuals carrying premutated alleles, giving an estimated FXTAS prevalence of 1.95% among patients with late-onset ataxia (1.15% for males and 3% for females). Molecular characterization of premutation carriers evidences lower fragile X mental retardation 1 protein levels and increased FMR1 mRNA levels. Clinical and neuroimaging findings support FXTAS diagnosis in these patients. Because of the high prevalence of FMR1 premutation in the general population, the description and characterization of the FXTAS syndrome is of great interest as it may represent one of the more common monogenic causes of ataxia, tremor, and dementia. The results obtained in this study demonstrate that FXTAS should be incorporated to spinocerebellar ataxia genetic screening protocols. Early diagnosis of these patients benefits not only them but also the rest of the family that should be advised for the fragile X syndrome.

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.

Fragile X‐associated tremor/ataxia syndrome: Intrafamilial variability and the size of the FMR1 premutation CGG repeat

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurological progressive disorder associated with the FMR1 gene premutation. We report on variable presentation of findings associated with FXTAS in 3 brothers aged 68, 74, and 73 years, carrying premutation alleles of (CGG)(123,) (CGG)(109), and (CGG)(91) triplets, respectively. Based on previously proposed diagnostic criteria for the syndrome, clinical and radiological data allowed establishing a "definite" diagnosis of FXTAS in the two carriers of the longest (CGG)(n). The carrier of the (CGG)(91) allele, although presenting a major radiological sign of the syndrome (symmetrical white-matter lesions in the middle cerebellar peduncles), did not have any significant neurological manifestation at 73 years of age.