0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Contribution |

Screen for Excess FMR1 Premutation Alleles Among Males With Parkinsonism FREE

Jeremy Kraff, MD; Hiu-Tung Tang, BA; Roberto Cilia, MD; Margherita Canesi, MD; Gianni Pezzoli, MD; Stefano Goldwurm, MD, PhD; Paul J. Hagerman, MD, PhD; Flora Tassone, PhD
[+] Author Affiliations

Author Affiliations: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis (Drs Kraff, Hagerman, and Tassone); Medical Investigation of Neurodevelopmental Disorders Institute, University of California Davis Medical Center, Sacramento (Mr Tang and Drs Hagerman and Tassone); and Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy (Drs Cilia, Canesi, Pezzoli, and Goldwurm).


Arch Neurol. 2007;64(7):1002-1006. doi:10.1001/archneur.64.7.1002.
Text Size: A A A
Published online

Background  Individuals with fragile X–associated tremor/ataxia syndrome frequently have associated features of parkinsonism, often leading to an initial diagnosis of Parkinson disease or other parkinsonism spectrum disorders. Parkinson disease populations may thus include individuals who harbor premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene.

Objective  To screen DNA samples (male) from an Italian Parkinson disease clinic for an excess of premutation expansions of the FMR1 gene.

Design  DNA samples obtained from 903 unrelated males through consecutive clinic visits were analyzed by an enhanced polymerase chain reaction method for detecting expanded CGG repeats.

Setting  Diagnostic assessments were performed at the Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy. Genotyping was conducted at the University of California Davis School of Medicine.

Participants  A cohort of unrelated males with clinical features of parkinsonism. All but 12 males were of Italian origin, and all reported Caucasian ethnicity.

Main Outcome Measure  CGG repeat number.

Results  Three premutation carriers (61, 69, and 80 CGG repeats) were identified (0.33%), which is not significantly higher than the frequency of premutation alleles in the general population. The outcome of the current study, the largest screen of individuals with parkinsonism to date, supports previous screens of smaller parkinsonism cohorts.

Conclusion  Broad screening for premutation alleles in Parkinson disease populations is unlikely to be productive in the absence of additional clinical or family history data that suggest involvement of the FMR1 gene.

Fragile X–associated tremor/ataxia syndrome (FXTAS) is a late-onset (age, > 50 years), progressive neurological disorder with core features of action tremor and cerebellar gait ataxia. Frequent associated features include parkinsonism, executive dysfunction, and cognitive decline with features of frontal subcortical dementia, dysautonomia, and peripheral neuropathy.15 Characteristic features on magnetic resonance imaging (MRI) include a high signal on T2 fluid-attenuated inversion recovery imaging of the middle cerebellar peduncles (MCP sign), periventricular and subcortical white matter changes, and brain volume loss.6,7 Neuropathology includes the presence of intranuclear inclusions in both astrocytes and neurons of clinically affected individuals.8,9

Fragile X–associated tremor/ataxia syndrome is caused by moderate expansions (55-200 repeats [premutation range]) of a CGG trinucleotide in the fragile X mental retardation 1 (FMR1) gene. The pathogenesis of this disorder involves a direct toxic effect of overexpression of the FMR1 messenger ribonucleic acid.10 Larger expansions (> 200 repeats [full mutation range])—generally accompanied by DNA methylation, transcriptional silencing, and the consequent absence of the fragile X mental retardation 1 protein (FMRP)—give rise to fragile X syndrome, the leading heritable form of cognitive impairment (Online Mendelian Inheritance in Man [OMIM] *309550).

In a recent retrospective study of the initial diagnoses of male FXTAS patients,11 a quarter of the patients surveyed had received an initial diagnosis of some form of parkinsonism, suggesting that some carriers of premutation alleles may be found within cohorts of individuals who are being observed in Parkinson disease (PD) clinics. Initial surveys of several groups of patients with PD or parkinsonism failed to detect an excess of premutation allele.12 However, the screened groups were relatively small, and some would not have detected even relatively high frequencies of premutation alleles within the samples. To further address this issue, we have screened DNA samples from a cohort of 903 males with clinical features of parkinsonism. This cohort is more than twice as large as any previously screened group.

SUBJECTS

A polymerase chain reaction–based screen for premutation alleles of the FMR1 gene was performed on a cohort of 903 unrelated male patients who had received a diagnosis of either primary degenerative parkinsonism or essential tremor and who had contributed samples to the Human Genetic Bank of Patients Affected by Parkinson Disease and Parkinsonisms, Istituti Clinici di Perfezionamento, Milan, Italy (http://www.parkinson.it/dnabank.html). The cohort was selected on the basis of consecutive clinic visits, regardless of family history of parkinsonism or age at onset of the disease. Written informed consent was obtained from all subjects.

Patients fulfilled criteria for the following: 776 for idiopathic PD, 14 for dementia with Lewy bodies, 3 for frontotemporal dementia, 21 for multiple system atrophy, 21 for progressive supranuclear palsy, 9 for corticobasal degeneration, and 26 for essential tremor. For the remaining 33 cases, the clinical diagnosis was still uncertain; those patients are reported as having undefined primary parkinsonism.

The clinical diagnosis of PD was established according to the UK Parkinson's Disease Society Brain Bank criteria,13,14 which require the presence of bradykinesia, the absence of atypical features or other causes of parkinsonism, and at least 1 of the following: resting tremor, rigidity and postural instability, and a positive response to dopaminergic therapy. In the non-PD cases, diagnoses were assigned according to published diagnostic criteria.15,16 Among the 776 patients with idiopathic PD, the mean age at onset was 54.01 years (range, 14-83 years; SD, 10.81 years), and the mean disease duration was 11.75 years (range, 1-56 years; SD, 6.3 years).

All patients with PD were previously tested for the LRRK2 G2019S mutation and 10 were found to be carriers.17 The parkin gene was tested in all PD patients with an age at onset of 40 years or younger and 8 were homozygous for the mutated gene (J.K., unpublished data, 2007). Such patients were not excluded from this analysis.

All but 12 patients were of Italian origin. The other patients were from Turkey, South Africa, Sri Lanka, the United States, Yugoslavia, Romania, Ireland, Iran, France, Albania, and Argentina. All patients reported Caucasian ethnicity.

CASES IDENTIFIED AS PREMUTATION CARRIERS

Case 1 (C-0230) is a 65-year-old man with an 18-year history of PD. The onset of symptoms occurred when he was aged 48 years, with bradykinesia and rigidity on the right side. He had a good response to treatment with dopaminergic agents. He first experienced wearing-off motor fluctuations 9 years after his initial presentation and peak-dose dyskinesias after 14 years.

He progressively developed severe motor fluctuations and dyskinesia and was considered for subthalamic nucleus deep brain stimulation 14 years after initial symptoms. Neurological examination was assessed both 12 hours after last medication intake (off) and immediately after medication intake (on), with an improvement in Unified Parkinson Disease Rating Scale motor score of 29 to 15 (− 49%). Brain MRI showed mild corticosubcortical atrophy but no white matter signal abnormalities. Brain perfusion single-photon emission computed tomography showed bilateral striatal perfusion reduction. Neuropsychological evaluation revealed no specific cognitive deficit but disclosed psychotic symptoms, such as auditory hallucinations, jealousy, and persecution delusions.

The neuropsychological follow-up assessment (1 year later) revealed mild difficulties with memory and frontal lobe–related abilities but also showed improvement of psychiatric symptoms. Therefore, the patient underwent deep brain stimulation surgery and showed a significant clinical improvement, with reduction of daily time spent in off condition and dyskinesia. Hallucinations were not reported after surgery, but delusions occasionally occurred.

Case 2 (B-0556) is a 50-year-old man with a 16-year history of PD. The onset of symptoms occurred at 34 years of age with resting tremor on the right hand and slowly progressive bradykinesia and rigidity. Dopaminergic treatment was instituted 6 years after the first symptoms appeared. He always showed a good clinical response to medication, experiencing wearing-off fluctuations 11 years from the onset, but no other motor complications.

At 48 years of age, neuropsychological assessment revealed mild deficits of frontal lobe functions in the patient. Psychotic features, such as jealousy and persecution delusions, were reported and partially improved with quetiapine treatment. Brain imaging investigation results, such as MRI and perfusion single-photon emission computed tomography results, are not available.

Case 3 (G-0444) is a 63-year-old man who first complained of micrography, bradykinesia, and rigidity on the right side at 43 years of age. The diagnosis of PD was established and dopaminergic treatment was started with good response. He developed motor fluctuations and dyskinesias 7 years following symptom onset. Clinical, radiological, and molecular findings are presented in Table 1.

Table Graphic Jump LocationTable 1. Clinical, Radiological, and Molecular Findings in PD Patient Carriers of the Fragile X Premutation

Neurological examination at 60 years was assessed both in off and on states, with an improvement in Unified Parkinson Disease Rating Scale motor score from 31 to 25 (− 20%). The neuropsychological tests detected mild frontal deficits characterized by reduction in attention and presence of preservative behavior. Impulsiveness, slight apathy, and depressed mood were also observed.

Brain MRI showed moderate subcortical and cerebellar atrophy. Brain perfusion single-photon emission computed tomography revealed bilateral cortical hypoperfusion in the left posterior parietal and occipital areas and asymmetric blood flow reduction in the striatum bilaterally, mainly on the left side.

MRI ASSESSMENT

Following the identification of FMR1 premutation alleles, a neuroradiologist reexamined MRIs of cases 1 and 3 (patients C-0230 and G-0444). Cerebellar atrophy was noted in case 3. However, neither case demonstrated the high-signal lesions (T2-weighted) of the middle cerebellar peduncles (MCP sign) that are characteristic of FXTAS.6

MOLECULAR MEASURES

Genomic DNA was isolated from peripheral blood lymphocytes using standard phenol-chloroform extraction methods. DNA from each patient was amplified using an enhanced polymerase chain reaction technique containing the osmolyte, betaine, and primers c and f, as described by Saluto et al,18 with only minor modifications to optimize betaine concentration (~ 2.2 M). Amplified DNA was then visualized on 2% agarose gels and ethidium bromide stained. Gray zone and premutation alleles were accurately sized on acrylamide gels. Hybridization was performed with a digoxigenin–end-labeled oligonucleotide probe, (CGG)10. Repeat sizes were determined using an Alpha Innotech FluorChem 8800 Image Detection System (Alpha Innotech Corp, San Leandro, California). Details of the method are presented in an article by Tassone et al.19

MAIN OUTCOME MEASURE

The sole outcome measure of this study is the number of CGG repeats, determined from the size of the polymerase chain reaction product. CGG repeats are considered to be premutation expansions if the size of the expansion exceeds 54 CGG repeats but is less than or equal to 200 CGG repeats.

We screened 903 male patients with a diagnosis of primary parkinsonism or essential tremor for the presence of premutation expansions (55-200 CGG repeats) of the FMR1 gene. Three individuals, all with the diagnosis of PD, were identified as carriers of premutation alleles of 61 (case 2), 69 (case 1), and 80 CGG repeats (case 3). The frequency of premutation alleles in this cohort was therefore 0.33% (3 of 903 patients), a value that is not significantly higher than values reported for the general population12,20,21 and is consistent with previous, smaller screens of parkinsonism cohorts (Table 2). In addition, 18 gray-zone alleles (45-54 CGG repeats) were identified. Again, they were not significantly higher than values for the general population. The remaining 882 males harbored a normal allele (< 45 CGG repeats).

Table Graphic Jump LocationTable 2. Screens for Premutation FMR1 Alleles Within Cohorts of Patients With Parkinson Disease or Parkinsonism

The 3 male carriers of the FMR1 premutation did not show any unusual clinical features that would distinguish them from (noncarrier) patients with idiopathic PD. None of the 3 cases revealed features resembling FXTAS. In particular, they did not show cerebellar findings such as action tremor or gait ataxia, dysautonomia, or peripheral neuropathy. Relevant cognitive deficits were not present, though mild frontal lobe–related deficits were reported, which is typical in advanced PD. Magnetic resonance images, available for 2 of 3 premutation carriers, did not demonstrate the FXTAS MCP finding,6,27 though 1 individual did display mild cerebellar cortical atrophy. In addition, the premutation carriers did not have a family history positive for neurological or psychiatric disease, cognitive deficits, or development delays.

Thus, it is likely that these cases represent coincidental findings. This suggestion is reinforced both by the relatively early ages at onset (34, 43, and 48 years; mean, 41.7 years) for the 3 FMR1 premutation carriers, which are much earlier than the mean age at onset for symptoms of FXTAS (62.6 years [SD, 8.1 years] for tremor; 63.6 years [SD, 7.3 years] for ataxia).28 On the other hand, the early age at onset, which is generally associated with a stronger genetic predisposition, is an interesting finding and suggests that the FMR1 premutation may still have a role in the genetic susceptibility to common idiopathic PD.

In a screen of 903 cases with a prior diagnosis within the category of parkinsonism or essential tremor, there was no increase in the number of premutation FMR1 alleles over that which is expected in the general population, an observation that is not surprising in view of the differences in diagnostic features between patients with idiopathic PD and related disorders and patients with FXTAS. However, our study does underscore that testing for expanded FMR1 alleles within the parkinsonism movement disorder population is not justified in the absence of additional findings, such as cerebellar gait ataxia, MRI findings positive for MCP signs, or a family history of cognitive impairment, developmental delay, autism, or premature ovarian failure,2931 which are all indicators of greater potential for expanded FMR1 alleles.

There is one important caveat with the current findings, as with nearly all of the high-risk screens performed to date, namely, the selection bias intrinsic to the movement disorders population itself. In a retrospective study of known patients with FXTAS, only approximately 4% of patients were initially seen and had their syndrome diagnosed by a movement disorders specialist,11 and so only a small fraction of the FXTAS cases would be expected to be found within cohorts of the type screened here and those presented in Table 2. Of the remaining 96% of cases identified by Hall et al,11 approximately 70% were seen by general neurologists, and another 26% were seen by adult primary care physicians. Thus, there is a need for broader screens of older adult populations, both within and beyond the general neurology clinic.

A screen for expanded CGG-repeat alleles of the FMR1 gene within a cohort of 903 males with clinical presentations, including parkinsonism, detected 3 carriers of premutation alleles (61, 69, and 80 CGG repeats), a frequency (3 of 903 [0.33%]) that is not significantly higher than the frequency of premutation alleles in the general population (0.13%-0.39%).20,21 The outcome of our study, the largest screen to date of individuals with parkinsonism, suggests that broad screening for premutation alleles in PD populations is unlikely to be productive in the absence of additional clinical or family history data suggestive of involvement of the FMR1 gene.

Correspondence: Flora Tassone, PhD, Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, One Shields Avenue, Davis, CA 95616 (ftassone@ucdavis.edu).

Accepted for Publication: January 8, 2007.

Author Contributions:Study concept and design: Kraff, Goldwurm, Hagerman, and Tassone. Acquisition of data: Kraff, Tang, Cilia, Canesi, Pezzoli, Goldwurm, and Tassone. Analysis and interpretation of data: Kraff, Hagerman, and Tassone. Drafting of the manuscript: Kraff, Goldwurm, Hagerman, and Tassone. Critical revision of the manuscript for important intellectual content: Kraff, Tang, Cilia, Canesi, Pezzoli, Goldwurm, Hagerman, and Tassone. Statistical analysis: Tassone. Obtained funding: Pezzoli, Goldwurm, Hagerman, and Tassone. Administrative, technical, and material support: Kraff, Tang, Cilia, Canesi, Goldwurm, Hagerman, and Tassone. Study supervision: Kraff, Goldwurm, Hagerman, and Tassone.

Financial Disclosure: None reported.

Funding/Support: This study was supported by the National Fragile X Foundation. DNA samples were obtained from the Human Genetic Bank of Patients Affected by Parkinson Disease and Parkinsonisms of the Parkinson Institute, Istituti Clinici di Perfezionamento, which is supported by grant GTF04007 from the Italian Telethon Foundation.

Additional Contributions: We thank the patients and their relatives for their participation in this research.

Jacquemont  SHagerman  RJLeehey  MA  et al.  Penetrance of the fragile X–associated tremor/ataxia syndrome in a premutation carrier population. JAMA 2004;291 (4) 460- 469
PubMed Link to Article
Jacquemont  SFarzin  FHall  D  et al.  Aging in individuals with the FMR1 mutation. Am J Ment Retard 2004;109 (2) 154- 164
PubMed Link to Article
Hagerman  PJHagerman  RJ Fragile X-associated tremor/ataxia syndrome (FXTAS). Ment Retard Dev Disabil Res Rev 2004;10 (1) 25- 30
PubMed Link to Article
Bacalman  SFarzin  FBourgeois  JA  et al.  Psychiatric phenotype of the fragile X-associated tremor/ataxia syndrome (FXTAS) in males: newly described fronto-subcortical dementia. J Clin Psychiatry 2006;67 (1) 87- 94
PubMed Link to Article
Grigsby  JBrega  AGJacquemont  S  et al.  Impairment in the cognitive functioning of men with fragile X-associated tremor/ataxia syndrome (FXTAS). J Neurol Sci 2006;248 (1-2) 227- 233
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;23 (10) 1757- 1766
PubMed
Cohen  SMasyn  KAdams  J  et al.  Molecular and imaging correlates of the fragile X-associated tremor/ataxia syndrome. Neurology 2006;67 (8) 1426- 1431
PubMed Link to Article
Greco  CMHagerman  RJTassone  F  et al.  Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 2002;125 (pt 8) 1760- 1771
PubMed Link to Article
Greco  CMBerman  RFMartin  RM  et al.  Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain 2006;129 (pt 1) 243- 255
PubMed Link to Article
Hagerman  PJHagerman  RJ The fragile-X premutation: a maturing perspective. Am J Hum Genet 2004;74 (5) 805- 816
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). Neurology 2005;65 (2) 299- 301
PubMed Link to Article
Jacquemont  SLeehey  MAHagerman  RJBeckett  LAHagerman  PJ Size bias of fragile X premutation alleles in late-onset movement disorders. J Med Genet 2006;43 (10) 804- 809
PubMed Link to Article
Hughes  AJDaniel  SEKilford  LLees  AJ Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55 (3) 181- 184
PubMed Link to Article
Hughes  AJDaniel  SELees  AJ Improved accuracy of clinical diagnosis of Lewy body Parkinson's disease. Neurology 2001;57 (8) 1497- 1499
PubMed Link to Article
Litvan  IBhatia  KPBurn  DJ  et al.  Movement Disorders Society Scientific Issues Committee report: SIC Task Force appraisal of clinical diagnostic criteria for Parkinsonian disorders. Mov Disord 2003;18 (5) 467- 486
PubMed Link to Article
Elble  RJ Diagnostic criteria for essential tremor and differential diagnosis. Neurology 2000;54 (11) (suppl 4)S2- S6
PubMed Link to Article
Goldwurm  SZini  MDi Fonzo  A  et al.  LRRK2 G2019S mutation and Parkinson's disease: a clinical, neuropsychological and neuropsychiatric study in a large Italian sample. Parkinsonism Relat Disord 2006;12 (7) 410- 419
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;7 (5) 605- 612
PubMed Link to Article
Tassone  FHagerman  RJGarcia-Arocena  DKhandjian  EWGreco  CMHagerman  PJ Intranuclear inclusions in neural cells with premutation alleles in fragile X associated tremor/ataxia syndrome. J Med Genet 2004;41 (4) e43
PubMed Link to Article
Dawson  AJChodirker  BNChudley  AE Frequency of FMR1 premutations in a consecutive newborn population by PCR screening of Guthrie blood spots. Biochem Mol Med 1995;56 (1) 63- 69
PubMed Link to Article
Dombrowski  CLevesque  SMorel  MLRouillard  PMorgan  KRousseau  F Premutation and intermediate-size FMR1 alleles in 10572 males from the general population: loss of an AGG interruption is a late event in the generation of fragile X syndrome alleles. Hum Mol Genet 2002;11 (4) 371- 378
PubMed Link to Article
Annesi  GNicoletti  GTarantino  P  et al.  FRAXE intermediate alleles are associated with Parkinson's disease. Neurosci Lett 2004;368 (1) 21- 24
PubMed Link to Article
Toft  MAasly  JBisceglio  G  et al.  Parkinsonism, FXTAS, and FMR1 premutations. Mov Disord 2005;20 (2) 230- 233
PubMed Link to Article
Deng  HLe  WJankovic  J Premutation alleles associated with Parkinson disease and essential tremor. JAMA 2004;292 (14) 1685- 1686
PubMed
Tan  EKZhao  YPuong  KY  et al.  Expanded FMR1 alleles are rare in idiopathic Parkinson's disease. Neurogenetics 2005;6 (1) 51- 52
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;20 (8) 1060- 1062
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;72 (4) 869- 878
PubMed Link to Article
Tassone  FAdams  JBerry-Kravis  EM  et al.  CGG correlates with age of onset of motor signs of the fragile X-associated tremor/ataxia syndrome (FXTAS) [published online ahead of print April 10, 2007]. Am J Med Genet B Neuropsychiatr Genet 2007;144 (4) 566- 569
PubMed Link to Article
Allingham-Hawkins  DJBabul-Hirji  RChitayat  D  et al.  Fragile X premutation is a significant risk factor for premature ovarian failure: the International Collaborative POF in Fragile X study, preliminary data. Am J Med Genet 1999;83 (4) 322- 325
PubMed Link to Article
Marozzi  AVegetti  WManfredini  E  et al.  Association between idiopathic premature ovarian failure and fragile X premutation. Hum Reprod 2000;15 (1) 197- 202
PubMed Link to Article
Sullivan  AKMarcus  MEpstein  MP  et al.  Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod 2005;20 (2) 402- 412
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Clinical, Radiological, and Molecular Findings in PD Patient Carriers of the Fragile X Premutation
Table Graphic Jump LocationTable 2. Screens for Premutation FMR1 Alleles Within Cohorts of Patients With Parkinson Disease or Parkinsonism

References

Jacquemont  SHagerman  RJLeehey  MA  et al.  Penetrance of the fragile X–associated tremor/ataxia syndrome in a premutation carrier population. JAMA 2004;291 (4) 460- 469
PubMed Link to Article
Jacquemont  SFarzin  FHall  D  et al.  Aging in individuals with the FMR1 mutation. Am J Ment Retard 2004;109 (2) 154- 164
PubMed Link to Article
Hagerman  PJHagerman  RJ Fragile X-associated tremor/ataxia syndrome (FXTAS). Ment Retard Dev Disabil Res Rev 2004;10 (1) 25- 30
PubMed Link to Article
Bacalman  SFarzin  FBourgeois  JA  et al.  Psychiatric phenotype of the fragile X-associated tremor/ataxia syndrome (FXTAS) in males: newly described fronto-subcortical dementia. J Clin Psychiatry 2006;67 (1) 87- 94
PubMed Link to Article
Grigsby  JBrega  AGJacquemont  S  et al.  Impairment in the cognitive functioning of men with fragile X-associated tremor/ataxia syndrome (FXTAS). J Neurol Sci 2006;248 (1-2) 227- 233
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;23 (10) 1757- 1766
PubMed
Cohen  SMasyn  KAdams  J  et al.  Molecular and imaging correlates of the fragile X-associated tremor/ataxia syndrome. Neurology 2006;67 (8) 1426- 1431
PubMed Link to Article
Greco  CMHagerman  RJTassone  F  et al.  Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 2002;125 (pt 8) 1760- 1771
PubMed Link to Article
Greco  CMBerman  RFMartin  RM  et al.  Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain 2006;129 (pt 1) 243- 255
PubMed Link to Article
Hagerman  PJHagerman  RJ The fragile-X premutation: a maturing perspective. Am J Hum Genet 2004;74 (5) 805- 816
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). Neurology 2005;65 (2) 299- 301
PubMed Link to Article
Jacquemont  SLeehey  MAHagerman  RJBeckett  LAHagerman  PJ Size bias of fragile X premutation alleles in late-onset movement disorders. J Med Genet 2006;43 (10) 804- 809
PubMed Link to Article
Hughes  AJDaniel  SEKilford  LLees  AJ Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55 (3) 181- 184
PubMed Link to Article
Hughes  AJDaniel  SELees  AJ Improved accuracy of clinical diagnosis of Lewy body Parkinson's disease. Neurology 2001;57 (8) 1497- 1499
PubMed Link to Article
Litvan  IBhatia  KPBurn  DJ  et al.  Movement Disorders Society Scientific Issues Committee report: SIC Task Force appraisal of clinical diagnostic criteria for Parkinsonian disorders. Mov Disord 2003;18 (5) 467- 486
PubMed Link to Article
Elble  RJ Diagnostic criteria for essential tremor and differential diagnosis. Neurology 2000;54 (11) (suppl 4)S2- S6
PubMed Link to Article
Goldwurm  SZini  MDi Fonzo  A  et al.  LRRK2 G2019S mutation and Parkinson's disease: a clinical, neuropsychological and neuropsychiatric study in a large Italian sample. Parkinsonism Relat Disord 2006;12 (7) 410- 419
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;7 (5) 605- 612
PubMed Link to Article
Tassone  FHagerman  RJGarcia-Arocena  DKhandjian  EWGreco  CMHagerman  PJ Intranuclear inclusions in neural cells with premutation alleles in fragile X associated tremor/ataxia syndrome. J Med Genet 2004;41 (4) e43
PubMed Link to Article
Dawson  AJChodirker  BNChudley  AE Frequency of FMR1 premutations in a consecutive newborn population by PCR screening of Guthrie blood spots. Biochem Mol Med 1995;56 (1) 63- 69
PubMed Link to Article
Dombrowski  CLevesque  SMorel  MLRouillard  PMorgan  KRousseau  F Premutation and intermediate-size FMR1 alleles in 10572 males from the general population: loss of an AGG interruption is a late event in the generation of fragile X syndrome alleles. Hum Mol Genet 2002;11 (4) 371- 378
PubMed Link to Article
Annesi  GNicoletti  GTarantino  P  et al.  FRAXE intermediate alleles are associated with Parkinson's disease. Neurosci Lett 2004;368 (1) 21- 24
PubMed Link to Article
Toft  MAasly  JBisceglio  G  et al.  Parkinsonism, FXTAS, and FMR1 premutations. Mov Disord 2005;20 (2) 230- 233
PubMed Link to Article
Deng  HLe  WJankovic  J Premutation alleles associated with Parkinson disease and essential tremor. JAMA 2004;292 (14) 1685- 1686
PubMed
Tan  EKZhao  YPuong  KY  et al.  Expanded FMR1 alleles are rare in idiopathic Parkinson's disease. Neurogenetics 2005;6 (1) 51- 52
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;20 (8) 1060- 1062
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;72 (4) 869- 878
PubMed Link to Article
Tassone  FAdams  JBerry-Kravis  EM  et al.  CGG correlates with age of onset of motor signs of the fragile X-associated tremor/ataxia syndrome (FXTAS) [published online ahead of print April 10, 2007]. Am J Med Genet B Neuropsychiatr Genet 2007;144 (4) 566- 569
PubMed Link to Article
Allingham-Hawkins  DJBabul-Hirji  RChitayat  D  et al.  Fragile X premutation is a significant risk factor for premature ovarian failure: the International Collaborative POF in Fragile X study, preliminary data. Am J Med Genet 1999;83 (4) 322- 325
PubMed Link to Article
Marozzi  AVegetti  WManfredini  E  et al.  Association between idiopathic premature ovarian failure and fragile X premutation. Hum Reprod 2000;15 (1) 197- 202
PubMed Link to Article
Sullivan  AKMarcus  MEpstein  MP  et al.  Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod 2005;20 (2) 402- 412
PubMed Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

718 Views
18 Citations
×

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Jobs