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Original Contribution |

Fragile X Premutation With Atypical Symptoms at Onset FREE

Elena Cellini, PhD; Paolo Forleo, MD; Andrea Ginestroni, MD; Benedetta Nacmias, PhD; Andrea Tedde, PhD; Silvia Bagnoli, PhD; Mario Mascalchi, MD; Sandro Sorbi, MD; Silvia Piacentini, MD
[+] Author Affiliations

Author Affiliations: Department of Neurological and Psychiatric Sciences (Drs Cellini, Forleo, Ginestroni, Nacmias, Tedde, Bagnoli, Sorbi, and Piacentini) and Radiodiagnostic Section, Department of Clinical Physiopathology (Dr Mascalchi), University of Florence, Florence, Italy.


Arch Neurol. 2006;63(8):1135-1138. doi:10.1001/archneur.63.8.1135.
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Published online

Objective  To evaluate the presence of carriers of the fragile X premutation among male patients with sporadic ataxia without expansion into known spinocerebellar ataxia genes.

Design  Clinical and genetic examinations were performed on patients with sporadic pure ataxia and patients with ataxia associated with extracerebellar features such as pyramidal and extrapyramidal signs, dementia, or peripheral neuropathy.

Setting  University department of neurology.

Patients  One hundred forty-two Italian men with sporadic ataxia with onset at age 30 to 84 years.

Interventions  The CGG repeat size of the FMR1 gene was evaluated with fluorescent polymerase chain reaction. Premutated allele lengths were confirmed with Southern blot analysis.

Results  FMR1 premutation alleles with a repeat number greater than 55 were detected in 3 probands (2.1%) from a total of 142 male subjects initially referred to our university medical center for evaluation of sporadic ataxia. Two patients had typical fragile X syndrome with associated tremor or ataxia, and the third patient had spastic paraparesis without clear symptoms of cerebellar ataxia and without the common signs seen at magnetic resonance imaging.

Conclusions  Genetic analysis of the FMR1 gene could provide a reliable diagnostic tool for the definitive diagnosis of late-onset ataxias. Additional studies are needed to clarify the importance of premutation screening in patients with movement disorders or other associated atypical features at onset, such as paraparesis.

Fragile X syndrome with associated tremor or ataxia (FXTAS) is a late-onset neurologic disorder caused by the presence of a premutation (55-200 CGG repeats) in the 5′ untranslated region of the FMR1 gene1 in affected individuals. Predominant signs in male subjects carrying the premutation include cerebellar ataxia, intention tremor, and cognitive decline, occasionally associated with other symptoms such as peripheral neuropathy, lower limb proximal muscle weakness, and autonomic dysfunction, with age at onset between 50 and 70 years. Magnetic resonance imaging (MRI) in patients with FXTAS reveals diffused brain atrophy with a characteristic peculiar feature consisting of a T2-hyperintense signal of the middle cerebellar peduncles or brainstem that is often associated with cerebral white matter lesions.2,3 A characteristic neuropathologic sign is the presence of ubiquitin-positive intranuclear inclusions in both neurons and astrocytes.4

The wide and variable phenotype of this disorder overlaps the clinical features of some neurologic diseases, making FXTAS diagnosis difficult without molecular analysis. In addition, in female carriers,57 who rarely manifest the disease, the FXTAS phenotype is milder, with later onset than in male subjects. Premutated alleles are not frequently identified in other neurologic disorders or disturbances, including multiple system atrophy,7,8 Parkinson disease,9 and essential tremor10; thus, genetic testing for FMR1 in these patients often is not recommended. In contrast, various screenings for FMR11114 performed in patients with sporadic spinocerebellar ataxia suggest that expanded FMR1 alleles may be considered a possible genetic cause of late-onset ataxia.

We evaluated the presence of carriers of the fragile X premutation among male patients referred to our medical center with a clinical diagnosis of spinocerebellar ataxia and who were negative for expansion in known spinocerebellar ataxia genes (1, 2, 3, 6, 7, 8, 12, 17; dentatorubropallidoluysian atrophy; and Friedreich ataxia).

PATIENTS

We selected and clinically examined 142 Italian men with ataxia with age at onset between 30 and 84 years. Among these patients, 65 (46%) were 50 years or older at onset of the initial symptoms.

All patients provided a complete history and underwent physical and neurologic examinations and laboratory testing to exclude other diseases. The diagnosis of sporadic ataxia was based on a history of sporadically occurring progressive deterioration of the cerebellar function manifested by at least 2 signs, gait or limb ataxia along with ocular dysmetria and dysarthria, in the absence of other causes of ataxia such as medications, cerebellar neoplasia, and multiple sclerosis. Patients with progressive ataxia variably associated with extracerebellar features such as pyramidal signs, extrapyramidal signs, dementia, and peripheral neuropathy were also included.

The ethical committee at our institution approved the project. Written informed consent was obtained from the patients participating in the study.

MOLECULAR ANALYSIS

The CGG repeat size of the FMR1 gene was evaluated with fluorescent polymerase chain reaction15 and standard-sized markers using an automatic DNA sequencer (ALF Express; Pharmacia LKB, Uppsala, Sweden) and fragment analysis software (Fragment Manager; Pharmacia LKB). DNA samples from patients with fragile X syndrome and carriers of the fragile X premutation served as positive controls. Premutated allele lengths were confirmed with Southern blot analysis.

Among the 142 patients, FMR1 premutation alleles with a repeat number greater than 55 were detected in 3 probands (2.1%) with late-onset ataxia (Table). None of the patients had a family history of fragile X syndrome.

Table Graphic Jump LocationTable. Clinical, Neurologic, and Molecular Characteristics in Patients Carrying the FMR1 Premutation

Proband 1 was a 62-year-old man who was initially examined because of mild paraparetoataxic gait who had diabetes mellitus and mild hypertension with no cognitive impairment. The proband is a moderate smoker (half a pack per day). The proband reported that gait symptoms worsened in the last few months, causing difficulties in daily life, with increased muscle tone in the lower limbs (Ashworth scale score, 2 bilaterally), diffuse hyperreflexia, no clonus, and a positive bilateral Babinski sign. The proband underwent brain and spinal MRI, with normal findings; brain spectroscopy, also with normal findings; and stimulation of motor and somatosensory evoked potentials, which indicated pyramidal tract alterations predominantly in the lower limbs and mild sensory impairment. A lumbar puncture was performed, and all chemical and microbiologic test results were normal. The International Cooperative Ataxia Rating scale score was 13/100. The patient now has a peculiar paraparetic-spastic gait and mild kinetic tremor of the right arm.

Proband 2 was a 70-year-old man who was referred for evaluation of left hand resting tremor that began at the age of 56 years. The symptoms had increased with time, with a element postural component progressively involving the contralateral limbs. At age 62 years, the patient experienced several falls caused by gait disequilibrium, lateral and retropulsion; later, bradykinesis developed, and the patient became apathetic and was unable to stand without falling. He has been wheelchair bound since 2004. The International Cooperative Ataxia Rating scale score was 53/100. Brain MRIs showed marked cerebral atrophy, moderate subcortical and brainstem white matter lesions, and definite hyperintensity on T2-weighted images that was localized in the white matter of the middle cerebellar peduncles. Measurement of the repeat length showed that both probands 1 and 2 carried FMR1 alleles of 80 CGG triplets.

Proband 3 was a 69-year-old man. At the age of 55 years, he had isolated right hand intentional tremor. The neurologic examination did not indicate involvement of the extrapyramidal and pyramidal systems. Five years after disease onset, pancerebellar dysfunction developed, including gait ataxia, decreased muscle tone, dysmetria, and dysarthria. The International Cooperative Ataxia Rating scale score was 53/100. An MRI T2-weighted image of the brain obtained 2 years previously showed symmetrically increased signal intensity in the cerebral white matter and in the middle cerebellar peduncles. The proband carried an FMR1 premutation of 103 CGG repeats.

FMR1 premutations were not present in the group of patients with onset of symptoms before age 50 years. With the exception of the 3 patients with premutated alleles, the FMR1 triplet repeat distribution in the group with late onset of symptoms was fewer than 42 triplets.

Genetic analysis of FMR1 expansion in our cohort of patients reveals the presence of the premutation in 3 of 142 male subjects initially referred to our medical center for evaluation of sporadic ataxia without pathogenic expansions in the known spinocerebellar ataxia genes. Two patients had typical FXTAS, including common disease features such as ataxia and tremor and alterations seen on MRIs. One patient exhibited symptoms attributable to spastic paraparesis with mild ataxia.

Recently, Jacquemont et al16 described 3 carriers of the FMR1 premutation (2 female, 1 male) with a severe form of FXTAS characterized by, in addition to the other typical symptoms, early onset of spastic paraparesis, which represents a new clinical feature not previously associated with the common manifestations of the disease. Our proband 1 had an atypical form, differing from the previously described cases16 in that it was characterized by spastic paraparesis with late onset of initial symptoms. The absence of a clear cerebellar ataxia syndrome, along with normal spinal and brain MRIs, creates doubt that this patient truly has an unusual form of FXTAS. However, we cannot exclude the possibility that the more common symptoms of this disease will develop later.16 Inasmuch as carriers of the FMR1 premutation have been reported among patients initially seen because of other common neurologic diseases,17 such as spastic paraparesis16 and Alzheimer disease,18 we can assume that FXTAS may occasionally be misdiagnosed. These results, therefore, suggest that patients with atypical features at onset should also be examined for FXTAS until a definitive diagnosis is ascertained. We could speculate that paraparesis may be one of the various but less frequently expressed features in the wide clinical spectrum of FXTAS, occasionally an early clinical sign of the FMR1 premutation.

Our results confirm that FXTAS could be a recurrent cause of sporadic ataxia in patients with adult onset of the disease. In addition, in men with older age at onset, we found that approximately 4.6% (3/65) of FXTAS cases with sporadic ataxia may be attributable to the effects of premutated alleles, confirming previous data in the Italian population.13

Findings in probands 1 and 2 in our study confirm the basic clinical and radiologic features of the disease and the similar premutated allele size in patients with sporadic ataxia and those in families with fragile X with an FXTAS phenotype. This suggests that the toxic effects of premutated FMR1 RNA on the nervous system could lead to a clinical manifestation that is indistinguishable from spinocerebellar ataxia, possibly sharing common pathogenic mechanisms. That the preexpanded alleles of some genes could manifest as a not fully penetrant but clinically evident neurologic disease raises an important issue for other genetic risk factors possibly involved in spinocerebellar ataxias or other triplet expansion disorders.

Genetic analysis of the FMR1 gene could prove to be a reliable diagnostic tool for the definitive diagnosis of late-onset ataxias in male patients even if more precise details of the FXTAS prevalence in the general population are needed before making definitive conclusions about the contribution of this premutation to movement disorders. We hypothesize that the molecular analysis of patients with movement disorders or other associated atypical features at onset, coexisting with later onset of ataxia, may yield expanded FMR1 alleles. However, we confirm the notion that a careful neuroradiologic examination should be performed in all patients with spinocerebellar disorders because the hyperintense signal on T2-weighted images of the middle cerebellar peduncles is specific to FXTAS and can be considered an important indication for precise and cost-effective premutation screening.

Correspondence: Elena Cellini, PhD, Department of Neurological and Psychiatric Sciences, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy (elena.cellini@unifi.it).

Accepted for Publication: February 10, 2006.

Author Contributions:Study concept and design: Cellini, Nacmias, and Sorbi. Acquisition of data: Ginestroni, Tedde, and Piacentini. Analysis and interpretation of data: Forleo, Nacmias, Bagnoli, Mascalchi, and Sorbi. Drafting of the manuscript: Ginestroni, Tedde, Bagnoli, Mascalchi, and Sorbi. Critical revision of the manuscript for important intellectual content: Cellini, Forleo, Nacmias, Sorbi, Piacentini. Statistical analysis: Tedde. Obtained funding: Piacentini. Administrative, technical, and material support: Cellini, Ginestroni, Bagnoli, and Mascalchi. Study supervision: Forleo, Nacmias, and Sorbi.

Funding/Support: This study was supported by the University of Florence (Clinical and genetic characterization of sporadic and familial patients with spinocerebellar ataxia A.20100.549.R001.Piacaten 2004-2005).

Hagerman  RJLeehey  MHeinrichs  W  et al.  Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 2001;57127- 130
PubMed Link to Article
Jacquemont  SHagerman  RJLeehey  M  et al.  Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 2003;72869- 878
PubMed Link to Article
Brunberg  JAJacquemont  SHagerman  RJ  et al.  Fragile X premutation carriers: characteristic MR imaging findings of adult male patients with progressive cerebellar and cognitive dysfunction. AJNR Am J Neuroradiol 2002;231757- 1766
PubMed
Greco  CMHagerman  RJTassone  F  et al.  Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 2002;1251760- 1771
PubMed Link to Article
Hagerman  RJLeavitt  BRFarzin  F  et al.  Fragile-X–associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Genet 2004;741051- 1056
PubMed Link to Article
Zuhlke  CBudnik  AGehlken  U  et al.  FMR1 premutation as a rare cause of late onset ataxia–evidence for FXTAS in female carriers. J Neurol 2004;2511418- 1419
PubMed Link to Article
Biancalana  VToft  MLe Ber  I  et al.  FMR1 premutations associated with fragile X-associated tremor/ataxia syndrome in multiple system atrophy. Arch Neurol 2005;62962- 966
PubMed
Kamm  CHealy  DGQuinn  NP  et al. European Multiple System Atrophy Study Group, The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA Study Group. Brain 2005;1281855- 1860
PubMed Link to Article
Hedrich  KPramstaller  PPStubke  K  et al.  Premutations in the FMR1 gene as a modifying factor in Parkin-associated Parkinson's disease? Mov Disord 2005;201060- 1062
PubMed Link to Article
Leehey  MAMunhoz  RPLang  AE  et al.  The fragile X premutation presenting as essential tremor. Arch Neurol 2003;60117- 121
PubMed Link to Article
Macpherson  JWaghorn  AHammans  SJacobs  P Observation of an excess of fragile-X premutations in a population of males referred with spinocerebellar ataxia. Hum Genet 2003;112619- 620
PubMed
Milunsky  JMMaher  TA Fragile X carrier screening and spinocerebellar ataxia in older males [letter]. Am J Med Genet A 2004;125320
Link to Article
Brussino  AGellera  CSaluto  A  et al.  FMR1 gene premutation is a frequent genetic cause of late-onset sporadic cerebellar ataxia. Neurology 2005;64145- 147
PubMed Link to Article
Van Esch  HDom  RBex  D  et al.  Screening for FMR-1 premutations in 122 older Flemish males presenting with ataxia. Eur J Hum Genet 2005;13121- 123
PubMed Link to Article
Saluto  ABrussino  ATassone  F  et al.  An enhanced polymerase chain reaction assay to detect pre- and full mutation alleles of the fragile X mental retardation 1 gene. J Mol Diagn 2005;7605- 612
PubMed Link to Article
Jacquemont  SOrrico  AGalli  L  et al.  Spastic paraparesis, cerebellar ataxia, and intention tremor: a severe variant of FXTAS? J Med Genet 2005;42e14
PubMed Link to Article
Hall  DABerry-Kravis  EJacquemont  S  et al Initial diagnoses given to persons with the fragile X associated tremor/ataxia syndrome (FXTAS). Neurology200565299301 [published correction appears in Neurology. 2005;65:784]
PubMed
Mothersead  PKConrad  KHagerman  RJGreco  CMHessl  DTassone  F Grand rounds: an atypical progressive dementia in a male carrier of the fragile X premutation—an example of fragile X-associated tremor/ataxia syndrome. Appl Neuropsychol 2005;12169- 178
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable. Clinical, Neurologic, and Molecular Characteristics in Patients Carrying the FMR1 Premutation

References

Hagerman  RJLeehey  MHeinrichs  W  et al.  Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 2001;57127- 130
PubMed Link to Article
Jacquemont  SHagerman  RJLeehey  M  et al.  Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 2003;72869- 878
PubMed Link to Article
Brunberg  JAJacquemont  SHagerman  RJ  et al.  Fragile X premutation carriers: characteristic MR imaging findings of adult male patients with progressive cerebellar and cognitive dysfunction. AJNR Am J Neuroradiol 2002;231757- 1766
PubMed
Greco  CMHagerman  RJTassone  F  et al.  Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 2002;1251760- 1771
PubMed Link to Article
Hagerman  RJLeavitt  BRFarzin  F  et al.  Fragile-X–associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Genet 2004;741051- 1056
PubMed Link to Article
Zuhlke  CBudnik  AGehlken  U  et al.  FMR1 premutation as a rare cause of late onset ataxia–evidence for FXTAS in female carriers. J Neurol 2004;2511418- 1419
PubMed Link to Article
Biancalana  VToft  MLe Ber  I  et al.  FMR1 premutations associated with fragile X-associated tremor/ataxia syndrome in multiple system atrophy. Arch Neurol 2005;62962- 966
PubMed
Kamm  CHealy  DGQuinn  NP  et al. European Multiple System Atrophy Study Group, The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA Study Group. Brain 2005;1281855- 1860
PubMed Link to Article
Hedrich  KPramstaller  PPStubke  K  et al.  Premutations in the FMR1 gene as a modifying factor in Parkin-associated Parkinson's disease? Mov Disord 2005;201060- 1062
PubMed Link to Article
Leehey  MAMunhoz  RPLang  AE  et al.  The fragile X premutation presenting as essential tremor. Arch Neurol 2003;60117- 121
PubMed Link to Article
Macpherson  JWaghorn  AHammans  SJacobs  P Observation of an excess of fragile-X premutations in a population of males referred with spinocerebellar ataxia. Hum Genet 2003;112619- 620
PubMed
Milunsky  JMMaher  TA Fragile X carrier screening and spinocerebellar ataxia in older males [letter]. Am J Med Genet A 2004;125320
Link to Article
Brussino  AGellera  CSaluto  A  et al.  FMR1 gene premutation is a frequent genetic cause of late-onset sporadic cerebellar ataxia. Neurology 2005;64145- 147
PubMed Link to Article
Van Esch  HDom  RBex  D  et al.  Screening for FMR-1 premutations in 122 older Flemish males presenting with ataxia. Eur J Hum Genet 2005;13121- 123
PubMed Link to Article
Saluto  ABrussino  ATassone  F  et al.  An enhanced polymerase chain reaction assay to detect pre- and full mutation alleles of the fragile X mental retardation 1 gene. J Mol Diagn 2005;7605- 612
PubMed Link to Article
Jacquemont  SOrrico  AGalli  L  et al.  Spastic paraparesis, cerebellar ataxia, and intention tremor: a severe variant of FXTAS? J Med Genet 2005;42e14
PubMed Link to Article
Hall  DABerry-Kravis  EJacquemont  S  et al Initial diagnoses given to persons with the fragile X associated tremor/ataxia syndrome (FXTAS). Neurology200565299301 [published correction appears in Neurology. 2005;65:784]
PubMed
Mothersead  PKConrad  KHagerman  RJGreco  CMHessl  DTassone  F Grand rounds: an atypical progressive dementia in a male carrier of the fragile X premutation—an example of fragile X-associated tremor/ataxia syndrome. Appl Neuropsychol 2005;12169- 178
PubMed Link to Article

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