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FXTAS is rare among Portuguese patients with movement disorders: FMR1 premutations may be associated with a wider spectrum of phenotypes

FXTAS is rare among Portuguese patients with movement disorders: FMR1 premutations may be... The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by expansions of 55-200 CGG repeats in the 5’UTR of the FMR1 gene. These FMR1 premutation expansions have relatively high frequency in the general population. To estimate the frequency of FMR1 premutations among Portuguese males with non-familial, late-onset movement disorders of unknown etiology, we assessed CGG repeat size in males with disease onset after the age of 50 and negative or unknown family history for late-onset movement disorders, who were sent for SCA, HD, or PD genetic testing at a reference laboratory. The selected patients had a primary clinical diagnosis based on one of the following cardinal features of FXTAS: ataxia, tremor, or cognitive decline. A total of 86 subjects were genotyped for the CGG repeat in the FMR1 gene. We detected one patient with an expansion in the premutation range. The frequency of FMR1 premutations was 1.9% (1/54) in our group of patients with ataxia as the primary clinical feature, and 1.2% (1/86) in the larger movement disorders group. In the family of the FXTAS case, premutation-transmitting females presented a history of psychiatric symptoms, suggesting that, given the wide phenotypical expression of the premutation in females, neuropsychiatric surveillance is necessary. In conclusion, genetic testing for FXTAS should be made available to patients with adult-onset movement disorders to enable adequate genetic counseling to family members. Findings a higher risk for premature ovarian insufficiency (POI) Expansions of a CGG repeat tract in the 5’UTR region [5]; whereas males may be affected by the fragile X-asso- of the FMR1 gene causes the fragile X syndrome (FXS), ciated tremor/ataxia syndrome (FXTAS) [6,7]. the most common inherited cause of mental retardation. FXTAS is characterized by progressive cerebellar FXS is an X-linked disorder, characterized by moderate ataxia, tremor, and parkinsonism with bradikynesia and to severe mental impairment, facial dysmorphism and rigidity; other symptoms may include cognitive decline behavioral abnormalities in males, and by milder symp- and peripheral neuropathy [8]. Neuroradiological find- toms in some carrier females [1]. Full mutations (more ings show generalized brain atrophy with white matter than 200 CGGs) cause FXS, as they lead to loss of func- lesions in the middle cerebellar peduncle [9,10]. Clinical tion due to gene silencing mediated by abnormal methy- criteria for FXTAS were proposed by Hagerman et al. lation patterns [2,3]. Normal alleles range in length from [11]: presence of a FMR1 premutation, one major clini- 5 to 44 triplets, and repeats of 45-54 CGGs are “grey cal sign (gait ataxia or intention tremor), and one major zone alleles” of unknown biological significance [4]. Pre- finding on neuroimaging (white matter lesions in middle mutations range from 55 to 200 CGGs and have been cerebellar peduncles). Histopathology of FXTAS post- associated with two different phenotypes: females are at mortem brains revealed loss of Purkinje cells in the cer- ebellum, and presence of eosinophilic intranuclear inclusions in neurons and astrocytes of the cortex [12]. * Correspondence: isilveir@ibmc.up.pt The pathogenic mechanism of FXTAS seems to be dif- UnIGENe, IBMC - Instituto de Biologia Molecular e Celular, Universidade do ferent from that of FXS: abnormal methylation does not Porto, Porto, Portugal Full list of author information is available at the end of the article © 2011 Seixas et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Seixas et al. Behavioral and Brain Functions 2011, 7:19 Page 2 of 6 http://www.behavioralandbrainfunctions.com/content/7/1/19 occur with premutation and, therefore, a loss of function absence of SCA, HD, or relevant PD mutations. Only mechanism is unlikely. Instead, it appears to be asso- those presenting with ataxia, parkinsonism, and/or cog- ciated with toxic RNA species containing long CGG nitive decline were included. Genomic DNA was iso- tracts [13]. lated from peripheral blood using standard techniques. Penetrance of FXTAS in males carrying FMR1 premu- All patients gave their informed consent. Assessment of tations increases from 17% in the sixth decade to 75% (CGG) in FMR1 was performed by PCR, improved for after the age of 80. FXTAS in females has been reported amplification of GC-rich sequence regions, as described [14,15], but appears to be rare. Though only 1/4000 previously [18]. PCR products were visualized on agar- men have the full mutation, frequency of premutations ose gel stained with ethidium bromide and compared to is much greater: 1/1000 in Caucasian males [16]. The a control with 30 CGGs; PCR products that appeared high frequency of FMR1 premutations in the general larger were further analyzed by automated fragment population was taken as an indication that they could analysis in a 3730xl DNA Analyzer (Applied Biosystems, represent a major cause of non-familial cases of late- Foster City, CA) for assessment of repeat number. Pre- onset ataxia. A review of the literature reported that the mutation status was established for alleles with 55-200 frequency of FMR1 premutations, in all combined ataxia CGGs. Full mutations were detected by double digestion cases, was 1.3% in men and 0.24% in women [17]. As with EcoRI and EagIof10 μg of genomic DNA, followed ataxia in FXTAS is often associated with tremor and/or by electrophoresis in agarose gels and blotting onto cognitive decline, it is plausible that some cases of Hybond N+ membranes (Amersham, UK). Probe Ox1.9 FXTAS could present for testing with a clinical diagno- was labeled by P -dCTP nick translation and hybridized sis other than cerebellar ataxia; therefore, other move- according to standard methodology. Autoradiography ment disorders have also been screened for FMR1 was carried out for 24-48 hours at -70°C, using intensi- premutations. The combination of all studies published fying screens and Kodak X-Omat-RP films. up to 2008, in patients with movement disorders other A total of 86 male patients were identified as candi- than ataxia (including essential tremor, parkinsonism, dates, following application of the defined criteria. and multiple system atrophy), gives a total frequency of Demographics and clinical features are summarized in CGG repeat length in the FXTAS range of 0.37%, higher Table 1; 54/86 patients (63%) had ataxia, and 50/86 than the overall population rate [17]. (58%) had no known family history of late-onset move- Here,wepresent thefirst studyonthefrequencyof ment disorders. We identified one patient with approxi- FMR1 premutations in a sample of Portuguese males mately 95 CGGs. Frequency of premutations in the total sent for genetic testing, with late-onset movement disor- sample was 1.2%. In the subset of patients with ataxia, ders characterized by one or more of the FXTAS cardi- frequency was 1.9%. nal clinical features (ataxia, tremor, or cognitive The patient carrying the FMR1 premutated allele was decline). Additionally, we investigated transmission of a 73-year-old male, who reported onset at age 51, and the FMR1 repeat among FXTAS family relatives. was sent for genetic testing of SCAs (Figure 1). He had Cases were ascertained from a pool of patients an initial clinical diagnosis of essential tremor that did referred to a reference laboratory in Portugal for genetic not improve upon treatment with beta-blockers and testing for neurological diseases. Inclusion criteria were antiepileptic drugs. Further examination at age 66 as follows: males with onset after age 50 years, absent or revealed a mild cerebellar syndrome with gait ataxia and unknown family history of autosomal dominant late- dysarthria, difficulties with memory and executive func- onset movement disorders, clinical diagnosis of late- tion, and neurosensorial deafness. MRI showed diffuse onset movement disorder (spinocerebellar ataxia, SCA; atrophy of the cerebellum and cerebellar peduncles. At Huntington disease, HD; or Parkinson disease, PD), and age 72, the patient presented with aggravated cognitive Table 1 Demographics and clinical features of the patient population Cardinal clinical feature Ataxia Tremor Cognitive deficits Total (n = 54) (n = 4) (n = 28) (N = 86) Age (mean ± SD) 67.7 ± 9.1 59.0 ± 8.6 70.0 ± 9.2 68.0 ± 9.3 Age-of-onset (mean ± SD) 59.0 ± 6.8 54.0 ± 1.4 60.5 ± 6.7 59.2 ± 6.7 With additional cardinal features (n)13 1 4 18 Family history (n) None 33 3 14 50 Unknown 21 1 14 36 Seixas et al. Behavioral and Brain Functions 2011, 7:19 Page 3 of 6 http://www.behavioralandbrainfunctions.com/content/7/1/19 FXS FXTAS I:1 I:2 Mental retardation Psychiatric symptoms Cognitive impairment II:1 II:2 II:3 II:4 * . III:1 III:2 III:3 III:4 N/Premutation (86 CGG) * * ** IV:1 IV:2 IV:3 IV:4 IV:5 IV:6 IV:7 IV:8 Premutation Full mutation N/Full mutation N/N N/N (95 CGG) Figure 1 Family pedigree of the FXTAS patient. There is family history of mental retardation in males, and psychiatric disease in females. Individual IV:3 also presents tremor. Individual IV:4 died in infancy and was never tested for FXS. FMR1 repeat lengths are available for individuals marked with an asterisk. Symbols with the black circle are obligatory carriers of a FMR1 expanded allele. An arrow indicates the proband. (N, normal repeat size). deficits. These clinical features and radiological findings the range reported by multiple studies (0% to 4.1%), and confirmed a probable FXTAS diagnosis. 1.2% (1/86) in our global sample. A review of all such After identification of this FXTAS patient, we studied studies (Table 2) shows that the FMR1 premutation rate the family and discovered a clinical history of FXS (Fig- among men with cerebellar syndromes averages 1.2%. ure 1) in two first cousins of the proband (IV:5 and Ascertainment of subjects, criteria used and the popula- IV:6). Information provided by the proband’s son and by tion studied may explain some of the frequency variabil- sisters of the FXS patients also suggests a history of psy- ity. As ascertainment via test request for SCA could fail chiatric disease among premutation-transmitting to detect other FXTAS cases, we also included indivi- females; III:2 had an admission to a psychiatric hospital. duals referred for testing for PD and HD. We also In addition, IV:3 was reported to have a tremor and applied stringent criteria, as only males with onset cognitive deficits, but no neurological exam or DNA above age 50 years and no suggestive family history of were available. Consanguinity was present in the family, late-onset movement disorders were included. However, thus increasing the risk for genetic diseases. No addi- we found no FMR1 premutations in 32 patients with a tional information was obtained for this family. Two movement disorder other than ataxia, which is consis- patients carrying ‘grey zone’ alleles of 49 and 52 repeats tent with the literature (Table 2). Only 3 premutation (a frequency of 2.3% in the total sample) were also carriers (a rate of 0.3%) have been found in movement disorder cohorts that exclude ataxia cases - two had an found. In the general population, the frequency of grey zone alleles is 3-4/100 males [16,19]. initial diagnosis of multisystem atrophy (important in This study presents the first FXTAS screening in the the differential diagnosis of ataxia), while the other was Portuguese population of males with adult-onset move- referred for HD testing. ment disorders sent for genetic testing. The frequency Our study provides further evidence that a primary of FMR1 premutations was 1.9% (1/54) in patients with diagnosis of cerebellar ataxia is still the cardinal feature ataxia as the cardinal clinical feature, which is within of the vast majority of FXTAS cases. There has been Seixas et al. Behavioral and Brain Functions 2011, 7:19 Page 4 of 6 http://www.behavioralandbrainfunctions.com/content/7/1/19 Table 2 Frequency of FMR1 premutations among male patients with adult-onset movement disorders Sample origin Ascertainment via Inclusion criteria Premutation Study rate United Kingdom Referral for genetic test of SCA Ataxia 2/59 (Macpherson et al., 2003) [23] USA Clinical diagnosis of ET ET 0/40 (Garcia Arocena et al., 2004) [24] USA Clinical diagnosis of MSA MSA 0/40 (Garland et al., 2004) [25] USA Referral for genetic test of SCA Ataxia; age > 50 1/167 (Milunsky and Maher 2004) [26] Singapore Clinical diagnosis of movement ET; age > 45 0/34 (Tan et al., 2004) [27] disorder Ataxia; isolated 0/30 MSA 0/12 APD 0/15 Japan Clinical diagnosis of MSA MSA 0/36 (Yabe et al., 2004) [28] Germany Referral for genetic test of SCA Ataxia; AOO > 50 0/269 (Zuhlke et al., 2004) [29] Europe (mixed) Clinical diagnosis of MSA or related MSA 0/76 (Biancalana et al., 2005) [30] Ataxia 1/19 Italy Clinical diagnosis of SCA Ataxia 6/275 (Brussino et al., 2005) [31] Europe (mixed) Clinical diagnosis of MSA MSA* 2/253 (Kamm et al., 2005) [32] USA Referral for genetic test of SCA and Cerebellar disease 1/73 (Seixas et al., 2005) [18] HD Basal ganglia disease 0/6 Mixed Clinical diagnosis of PD PD 0/414 (Toft et al., 2005) [33] Belgium Referral for genetic test of SCA Ataxia; age > 50 5/122 (Van Esch et al., 2005) [34] Spain Clinical diagnosis of SCA Ataxia; isolated; age > 45 1/87 (Rodriguez-Revenga et al., 2007) [35] USA Referral for genetic test of SCA Ataxia; age > 50 1/286 (Adams et al., 2008) [17] Poland Clinical diagnosis of SCA Ataxia; age > 50 1/178 (Rajkiewicz et al., 2008) [36] Brazil Clinical diagnosis of movement Ataxia, and/or tremor, and/or 0/66 (Reis et al., 2008) [37] disorder parkinsonism; age > 45 Spain Referral for genetic test of HD HD 1/95 (Rodriguez-Revenga et al., 2008) [38] United Kingdom Clinical diagnosis of SCA Ataxia 0/105 (Wardle et al., 2009) [39] Portugal Referral for genetic test of SCA, HD, Ataxia; isolated; AOO > 50 1/54 This study and PD Tremor or cognitive decline 0/32 Total of ataxia 20/1724 referrals Total of movement disorder referrals (other than ataxia) 3/1119 SCA, spinocerebellar ataxia; ET, essential tremor; MSA, multisystem atrophy; PD, Parkinson disease; APD, atypical Parkinson disease; AOO, age of onset. *Includes proven, possible, and probable MSA FXTAS patients, including memory and balance pro- debate as to whether genetic testing for FXTAS should be included in screening panels for late-onset movement blems, tremor, and psychiatric disturbances [20]. Motor disorders. We conclude that, though the prevalence of and mental dysfunction was recently reported in a FXTAS appears low, genetic testing should be made FXTAS premutation carrier in a mother-daughter trans- available to patients with late-onset movement disorders, mission [21]. Another study identified a high lifetime particularly with a clinical diagnosis of ataxia, and in risk of mood and anxiety disorders among male and agreement with the guidelines suggested by Berry-Kravis female carriers of the FMR1 premutation [22]. These et al. [9]. findings concur with our observation that, in the family FXTAS appears to be quite rare among women carry- of the Portuguese FXTAS patient, there is an increased ing premutations, but a recent study describes a higher risk for motor and/or mental dysfunction in relatives rate of neuropsychiatric symptoms among daughters of carrying the premutation. Seixas et al. Behavioral and Brain Functions 2011, 7:19 Page 5 of 6 http://www.behavioralandbrainfunctions.com/content/7/1/19 8. Hagerman RJ, Hall DA, Coffey S, Leehey M, Bourgeois J, Gould J, Zhang L, In light of this, and given the complex phenotypic Seritan A, Berry-Kravis E, Olichney J, Miller JW, Fong AL, Carpenter R, expression of the FMR1 expansions, psychological and Bodine C, Gane LW, Rainin E, Hagerman H, Hagerman PJ: Treatment of neurologic surveillance (in addition to screening for POI fragile X-associated tremor ataxia syndrome (FXTAS) and related neurological problems. Clin Interv Aging 2008, 3:251-262. in females) may be necessary for relatives of FXS and 9. Berry-Kravis E, Abrams L, Coffey SM, Hall DA, Greco C, Gane LW, Grigsby J, FXTAS patients, and perhaps for carriers in general. Bourgeois JA, Finucane B, Jacquemont S, Brunberg JA, Zhang L, Lin J, The complex inheritance and wide spectrum of pheno- Tassone F, Hagerman PJ, Hagerman RJ, Leehey MA: Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing types associated with the FMR1 (CGG) reinforces the guidelines. Mov Disord 2007, 22:2018-2030. importance of genetic counseling in these families. 10. Jacquemont S, Hagerman RJ, Leehey M, Grigsby J, Zhang L, Brunberg JA, Greco C, Des Portes V, Jardini T, Levine R, Berry-Kravis E, Brown WT, Schaeffer S, Kissel J, Tassone F, Hagerman PJ: Fragile X premutation Acknowledgements tremor/ataxia syndrome: molecular, clinical, and neuroimaging We would like to thank the patients and their families for participating in correlates. Am J Hum Genet 2003, 72:869-878. the study, and E. Cruz, A.M. Lopes, V. Mendes, and J. Cerqueira for technical 11. Hagerman PJ, Hagerman RJ: The fragile-X premutation: a maturing assistance. This work was supported by research grant PIC/IC/82897/2007, perspective. Am J Hum Genet 2004, 74:805-816. FCT (Fundação para a Ciência e Tecnologia) and co-funded by FEDER. A.I.S. 12. Greco CM, Hagerman RJ, Tassone F, Chudley AE, Del Bigio MR, was the recipient of a scholarship from FCT (SFRH/BD/30702/2006). The Jacquemont S, Leehey M, Hagerman PJ: Neuronal intranuclear inclusions experiments performed complied with the currently accepted ethical norms in a new cerebellar tremor/ataxia syndrome among fragile X carriers. and national laws. Brain 2002, 125:1760-1771. 13. Tassone F, Iwahashi C, Hagerman PJ: FMR1 RNA within the intranuclear Author details inclusions of fragile X-associated tremor/ataxia syndrome (FXTAS). RNA UnIGENe, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Biol 2004, 1:103-105. Porto, Porto, Portugal. Department of Neurology, Hospital de Egas Moniz, 14. Hagerman RJ, Leavitt BR, Farzin F, Jacquemont S, Greco CM, Brunberg JA, Lisboa, Portugal. Centro de Genética Médica Dr. Jacinto Magalhães, INSA, Tassone F, Hessl D, Harris SW, Zhang L, Jardini T, Gane LW, Ferranti J, Ruiz L, Porto, Portugal. Department of Neurology, Hospital de São Sebastião, Feira, Leehey MA, Grigsby J, Hagerman PJ: Fragile-X-associated tremor/ataxia Portugal. Division of Neurobiology, Department of Psychiatry, Johns syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Hopkins University School of Medicine, Baltimore, USA. ICBAS, Universidade Genet 2004, 74:1051-1056. do Porto, Portugal. 15. Jacquemont S, Hagerman RJ, Leehey MA, Hall DA, Levine RA, Brunberg JA, Zhang L, Jardini T, Gane LW, Harris SW, Herman K, Grigsby J, Greco CM, Authors’ contributions Berry-Kravis E, Tassone F, Hagerman PJ: Penetrance of the fragile X- Study concept and design: AIS and IS. Acquisition of data: AIS, JV, IM, RS, IA, associated tremor/ataxia syndrome in a premutation carrier population. AMF, JPB and PC. Critical revision of the manuscript for important Jama 2004, 291:460-469. intellectual content: AIS, RLM, JS and IS. Study supervision: IS. All authors 16. Crawford DC, Meadows KL, Newman JL, Taft LF, Pettay DL, Gold LB, read and approved the final manuscript. Hersey SJ, Hinkle EF, Stanfield ML, Holmgreen P, Yeargin-Allsopp M, Boyle C, Sherman SL: Prevalence and phenotype consequence of FRAXA and Competing interests FRAXE alleles in a large, ethnically diverse, special education-needs The author declares that they have no competing interests. population. Am J Hum Genet 1999, 64:495-507. 17. Adams SA, Steenblock KJ, Thibodeau SN, Lindor NM: Premutations in the Received: 3 March 2011 Accepted: 3 June 2011 Published: 3 June 2011 FMR1 gene are uncommon in men undergoing genetic testing for spinocerebellar ataxia. J Neurogenet 2008, 22:77-92. 18. 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FXTAS is rare among Portuguese patients with movement disorders: FMR1 premutations may be associated with a wider spectrum of phenotypes

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Copyright © 2011 by Seixas et al; licensee BioMed Central Ltd.
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Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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Abstract

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by expansions of 55-200 CGG repeats in the 5’UTR of the FMR1 gene. These FMR1 premutation expansions have relatively high frequency in the general population. To estimate the frequency of FMR1 premutations among Portuguese males with non-familial, late-onset movement disorders of unknown etiology, we assessed CGG repeat size in males with disease onset after the age of 50 and negative or unknown family history for late-onset movement disorders, who were sent for SCA, HD, or PD genetic testing at a reference laboratory. The selected patients had a primary clinical diagnosis based on one of the following cardinal features of FXTAS: ataxia, tremor, or cognitive decline. A total of 86 subjects were genotyped for the CGG repeat in the FMR1 gene. We detected one patient with an expansion in the premutation range. The frequency of FMR1 premutations was 1.9% (1/54) in our group of patients with ataxia as the primary clinical feature, and 1.2% (1/86) in the larger movement disorders group. In the family of the FXTAS case, premutation-transmitting females presented a history of psychiatric symptoms, suggesting that, given the wide phenotypical expression of the premutation in females, neuropsychiatric surveillance is necessary. In conclusion, genetic testing for FXTAS should be made available to patients with adult-onset movement disorders to enable adequate genetic counseling to family members. Findings a higher risk for premature ovarian insufficiency (POI) Expansions of a CGG repeat tract in the 5’UTR region [5]; whereas males may be affected by the fragile X-asso- of the FMR1 gene causes the fragile X syndrome (FXS), ciated tremor/ataxia syndrome (FXTAS) [6,7]. the most common inherited cause of mental retardation. FXTAS is characterized by progressive cerebellar FXS is an X-linked disorder, characterized by moderate ataxia, tremor, and parkinsonism with bradikynesia and to severe mental impairment, facial dysmorphism and rigidity; other symptoms may include cognitive decline behavioral abnormalities in males, and by milder symp- and peripheral neuropathy [8]. Neuroradiological find- toms in some carrier females [1]. Full mutations (more ings show generalized brain atrophy with white matter than 200 CGGs) cause FXS, as they lead to loss of func- lesions in the middle cerebellar peduncle [9,10]. Clinical tion due to gene silencing mediated by abnormal methy- criteria for FXTAS were proposed by Hagerman et al. lation patterns [2,3]. Normal alleles range in length from [11]: presence of a FMR1 premutation, one major clini- 5 to 44 triplets, and repeats of 45-54 CGGs are “grey cal sign (gait ataxia or intention tremor), and one major zone alleles” of unknown biological significance [4]. Pre- finding on neuroimaging (white matter lesions in middle mutations range from 55 to 200 CGGs and have been cerebellar peduncles). Histopathology of FXTAS post- associated with two different phenotypes: females are at mortem brains revealed loss of Purkinje cells in the cer- ebellum, and presence of eosinophilic intranuclear inclusions in neurons and astrocytes of the cortex [12]. * Correspondence: isilveir@ibmc.up.pt The pathogenic mechanism of FXTAS seems to be dif- UnIGENe, IBMC - Instituto de Biologia Molecular e Celular, Universidade do ferent from that of FXS: abnormal methylation does not Porto, Porto, Portugal Full list of author information is available at the end of the article © 2011 Seixas et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Seixas et al. Behavioral and Brain Functions 2011, 7:19 Page 2 of 6 http://www.behavioralandbrainfunctions.com/content/7/1/19 occur with premutation and, therefore, a loss of function absence of SCA, HD, or relevant PD mutations. Only mechanism is unlikely. Instead, it appears to be asso- those presenting with ataxia, parkinsonism, and/or cog- ciated with toxic RNA species containing long CGG nitive decline were included. Genomic DNA was iso- tracts [13]. lated from peripheral blood using standard techniques. Penetrance of FXTAS in males carrying FMR1 premu- All patients gave their informed consent. Assessment of tations increases from 17% in the sixth decade to 75% (CGG) in FMR1 was performed by PCR, improved for after the age of 80. FXTAS in females has been reported amplification of GC-rich sequence regions, as described [14,15], but appears to be rare. Though only 1/4000 previously [18]. PCR products were visualized on agar- men have the full mutation, frequency of premutations ose gel stained with ethidium bromide and compared to is much greater: 1/1000 in Caucasian males [16]. The a control with 30 CGGs; PCR products that appeared high frequency of FMR1 premutations in the general larger were further analyzed by automated fragment population was taken as an indication that they could analysis in a 3730xl DNA Analyzer (Applied Biosystems, represent a major cause of non-familial cases of late- Foster City, CA) for assessment of repeat number. Pre- onset ataxia. A review of the literature reported that the mutation status was established for alleles with 55-200 frequency of FMR1 premutations, in all combined ataxia CGGs. Full mutations were detected by double digestion cases, was 1.3% in men and 0.24% in women [17]. As with EcoRI and EagIof10 μg of genomic DNA, followed ataxia in FXTAS is often associated with tremor and/or by electrophoresis in agarose gels and blotting onto cognitive decline, it is plausible that some cases of Hybond N+ membranes (Amersham, UK). Probe Ox1.9 FXTAS could present for testing with a clinical diagno- was labeled by P -dCTP nick translation and hybridized sis other than cerebellar ataxia; therefore, other move- according to standard methodology. Autoradiography ment disorders have also been screened for FMR1 was carried out for 24-48 hours at -70°C, using intensi- premutations. The combination of all studies published fying screens and Kodak X-Omat-RP films. up to 2008, in patients with movement disorders other A total of 86 male patients were identified as candi- than ataxia (including essential tremor, parkinsonism, dates, following application of the defined criteria. and multiple system atrophy), gives a total frequency of Demographics and clinical features are summarized in CGG repeat length in the FXTAS range of 0.37%, higher Table 1; 54/86 patients (63%) had ataxia, and 50/86 than the overall population rate [17]. (58%) had no known family history of late-onset move- Here,wepresent thefirst studyonthefrequencyof ment disorders. We identified one patient with approxi- FMR1 premutations in a sample of Portuguese males mately 95 CGGs. Frequency of premutations in the total sent for genetic testing, with late-onset movement disor- sample was 1.2%. In the subset of patients with ataxia, ders characterized by one or more of the FXTAS cardi- frequency was 1.9%. nal clinical features (ataxia, tremor, or cognitive The patient carrying the FMR1 premutated allele was decline). Additionally, we investigated transmission of a 73-year-old male, who reported onset at age 51, and the FMR1 repeat among FXTAS family relatives. was sent for genetic testing of SCAs (Figure 1). He had Cases were ascertained from a pool of patients an initial clinical diagnosis of essential tremor that did referred to a reference laboratory in Portugal for genetic not improve upon treatment with beta-blockers and testing for neurological diseases. Inclusion criteria were antiepileptic drugs. Further examination at age 66 as follows: males with onset after age 50 years, absent or revealed a mild cerebellar syndrome with gait ataxia and unknown family history of autosomal dominant late- dysarthria, difficulties with memory and executive func- onset movement disorders, clinical diagnosis of late- tion, and neurosensorial deafness. MRI showed diffuse onset movement disorder (spinocerebellar ataxia, SCA; atrophy of the cerebellum and cerebellar peduncles. At Huntington disease, HD; or Parkinson disease, PD), and age 72, the patient presented with aggravated cognitive Table 1 Demographics and clinical features of the patient population Cardinal clinical feature Ataxia Tremor Cognitive deficits Total (n = 54) (n = 4) (n = 28) (N = 86) Age (mean ± SD) 67.7 ± 9.1 59.0 ± 8.6 70.0 ± 9.2 68.0 ± 9.3 Age-of-onset (mean ± SD) 59.0 ± 6.8 54.0 ± 1.4 60.5 ± 6.7 59.2 ± 6.7 With additional cardinal features (n)13 1 4 18 Family history (n) None 33 3 14 50 Unknown 21 1 14 36 Seixas et al. Behavioral and Brain Functions 2011, 7:19 Page 3 of 6 http://www.behavioralandbrainfunctions.com/content/7/1/19 FXS FXTAS I:1 I:2 Mental retardation Psychiatric symptoms Cognitive impairment II:1 II:2 II:3 II:4 * . III:1 III:2 III:3 III:4 N/Premutation (86 CGG) * * ** IV:1 IV:2 IV:3 IV:4 IV:5 IV:6 IV:7 IV:8 Premutation Full mutation N/Full mutation N/N N/N (95 CGG) Figure 1 Family pedigree of the FXTAS patient. There is family history of mental retardation in males, and psychiatric disease in females. Individual IV:3 also presents tremor. Individual IV:4 died in infancy and was never tested for FXS. FMR1 repeat lengths are available for individuals marked with an asterisk. Symbols with the black circle are obligatory carriers of a FMR1 expanded allele. An arrow indicates the proband. (N, normal repeat size). deficits. These clinical features and radiological findings the range reported by multiple studies (0% to 4.1%), and confirmed a probable FXTAS diagnosis. 1.2% (1/86) in our global sample. A review of all such After identification of this FXTAS patient, we studied studies (Table 2) shows that the FMR1 premutation rate the family and discovered a clinical history of FXS (Fig- among men with cerebellar syndromes averages 1.2%. ure 1) in two first cousins of the proband (IV:5 and Ascertainment of subjects, criteria used and the popula- IV:6). Information provided by the proband’s son and by tion studied may explain some of the frequency variabil- sisters of the FXS patients also suggests a history of psy- ity. As ascertainment via test request for SCA could fail chiatric disease among premutation-transmitting to detect other FXTAS cases, we also included indivi- females; III:2 had an admission to a psychiatric hospital. duals referred for testing for PD and HD. We also In addition, IV:3 was reported to have a tremor and applied stringent criteria, as only males with onset cognitive deficits, but no neurological exam or DNA above age 50 years and no suggestive family history of were available. Consanguinity was present in the family, late-onset movement disorders were included. However, thus increasing the risk for genetic diseases. No addi- we found no FMR1 premutations in 32 patients with a tional information was obtained for this family. Two movement disorder other than ataxia, which is consis- patients carrying ‘grey zone’ alleles of 49 and 52 repeats tent with the literature (Table 2). Only 3 premutation (a frequency of 2.3% in the total sample) were also carriers (a rate of 0.3%) have been found in movement disorder cohorts that exclude ataxia cases - two had an found. In the general population, the frequency of grey zone alleles is 3-4/100 males [16,19]. initial diagnosis of multisystem atrophy (important in This study presents the first FXTAS screening in the the differential diagnosis of ataxia), while the other was Portuguese population of males with adult-onset move- referred for HD testing. ment disorders sent for genetic testing. The frequency Our study provides further evidence that a primary of FMR1 premutations was 1.9% (1/54) in patients with diagnosis of cerebellar ataxia is still the cardinal feature ataxia as the cardinal clinical feature, which is within of the vast majority of FXTAS cases. There has been Seixas et al. Behavioral and Brain Functions 2011, 7:19 Page 4 of 6 http://www.behavioralandbrainfunctions.com/content/7/1/19 Table 2 Frequency of FMR1 premutations among male patients with adult-onset movement disorders Sample origin Ascertainment via Inclusion criteria Premutation Study rate United Kingdom Referral for genetic test of SCA Ataxia 2/59 (Macpherson et al., 2003) [23] USA Clinical diagnosis of ET ET 0/40 (Garcia Arocena et al., 2004) [24] USA Clinical diagnosis of MSA MSA 0/40 (Garland et al., 2004) [25] USA Referral for genetic test of SCA Ataxia; age > 50 1/167 (Milunsky and Maher 2004) [26] Singapore Clinical diagnosis of movement ET; age > 45 0/34 (Tan et al., 2004) [27] disorder Ataxia; isolated 0/30 MSA 0/12 APD 0/15 Japan Clinical diagnosis of MSA MSA 0/36 (Yabe et al., 2004) [28] Germany Referral for genetic test of SCA Ataxia; AOO > 50 0/269 (Zuhlke et al., 2004) [29] Europe (mixed) Clinical diagnosis of MSA or related MSA 0/76 (Biancalana et al., 2005) [30] Ataxia 1/19 Italy Clinical diagnosis of SCA Ataxia 6/275 (Brussino et al., 2005) [31] Europe (mixed) Clinical diagnosis of MSA MSA* 2/253 (Kamm et al., 2005) [32] USA Referral for genetic test of SCA and Cerebellar disease 1/73 (Seixas et al., 2005) [18] HD Basal ganglia disease 0/6 Mixed Clinical diagnosis of PD PD 0/414 (Toft et al., 2005) [33] Belgium Referral for genetic test of SCA Ataxia; age > 50 5/122 (Van Esch et al., 2005) [34] Spain Clinical diagnosis of SCA Ataxia; isolated; age > 45 1/87 (Rodriguez-Revenga et al., 2007) [35] USA Referral for genetic test of SCA Ataxia; age > 50 1/286 (Adams et al., 2008) [17] Poland Clinical diagnosis of SCA Ataxia; age > 50 1/178 (Rajkiewicz et al., 2008) [36] Brazil Clinical diagnosis of movement Ataxia, and/or tremor, and/or 0/66 (Reis et al., 2008) [37] disorder parkinsonism; age > 45 Spain Referral for genetic test of HD HD 1/95 (Rodriguez-Revenga et al., 2008) [38] United Kingdom Clinical diagnosis of SCA Ataxia 0/105 (Wardle et al., 2009) [39] Portugal Referral for genetic test of SCA, HD, Ataxia; isolated; AOO > 50 1/54 This study and PD Tremor or cognitive decline 0/32 Total of ataxia 20/1724 referrals Total of movement disorder referrals (other than ataxia) 3/1119 SCA, spinocerebellar ataxia; ET, essential tremor; MSA, multisystem atrophy; PD, Parkinson disease; APD, atypical Parkinson disease; AOO, age of onset. *Includes proven, possible, and probable MSA FXTAS patients, including memory and balance pro- debate as to whether genetic testing for FXTAS should be included in screening panels for late-onset movement blems, tremor, and psychiatric disturbances [20]. Motor disorders. We conclude that, though the prevalence of and mental dysfunction was recently reported in a FXTAS appears low, genetic testing should be made FXTAS premutation carrier in a mother-daughter trans- available to patients with late-onset movement disorders, mission [21]. Another study identified a high lifetime particularly with a clinical diagnosis of ataxia, and in risk of mood and anxiety disorders among male and agreement with the guidelines suggested by Berry-Kravis female carriers of the FMR1 premutation [22]. These et al. [9]. findings concur with our observation that, in the family FXTAS appears to be quite rare among women carry- of the Portuguese FXTAS patient, there is an increased ing premutations, but a recent study describes a higher risk for motor and/or mental dysfunction in relatives rate of neuropsychiatric symptoms among daughters of carrying the premutation. Seixas et al. Behavioral and Brain Functions 2011, 7:19 Page 5 of 6 http://www.behavioralandbrainfunctions.com/content/7/1/19 8. Hagerman RJ, Hall DA, Coffey S, Leehey M, Bourgeois J, Gould J, Zhang L, In light of this, and given the complex phenotypic Seritan A, Berry-Kravis E, Olichney J, Miller JW, Fong AL, Carpenter R, expression of the FMR1 expansions, psychological and Bodine C, Gane LW, Rainin E, Hagerman H, Hagerman PJ: Treatment of neurologic surveillance (in addition to screening for POI fragile X-associated tremor ataxia syndrome (FXTAS) and related neurological problems. Clin Interv Aging 2008, 3:251-262. in females) may be necessary for relatives of FXS and 9. Berry-Kravis E, Abrams L, Coffey SM, Hall DA, Greco C, Gane LW, Grigsby J, FXTAS patients, and perhaps for carriers in general. Bourgeois JA, Finucane B, Jacquemont S, Brunberg JA, Zhang L, Lin J, The complex inheritance and wide spectrum of pheno- Tassone F, Hagerman PJ, Hagerman RJ, Leehey MA: Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing types associated with the FMR1 (CGG) reinforces the guidelines. Mov Disord 2007, 22:2018-2030. importance of genetic counseling in these families. 10. Jacquemont S, Hagerman RJ, Leehey M, Grigsby J, Zhang L, Brunberg JA, Greco C, Des Portes V, Jardini T, Levine R, Berry-Kravis E, Brown WT, Schaeffer S, Kissel J, Tassone F, Hagerman PJ: Fragile X premutation Acknowledgements tremor/ataxia syndrome: molecular, clinical, and neuroimaging We would like to thank the patients and their families for participating in correlates. Am J Hum Genet 2003, 72:869-878. the study, and E. Cruz, A.M. Lopes, V. Mendes, and J. Cerqueira for technical 11. Hagerman PJ, Hagerman RJ: The fragile-X premutation: a maturing assistance. This work was supported by research grant PIC/IC/82897/2007, perspective. Am J Hum Genet 2004, 74:805-816. FCT (Fundação para a Ciência e Tecnologia) and co-funded by FEDER. A.I.S. 12. Greco CM, Hagerman RJ, Tassone F, Chudley AE, Del Bigio MR, was the recipient of a scholarship from FCT (SFRH/BD/30702/2006). The Jacquemont S, Leehey M, Hagerman PJ: Neuronal intranuclear inclusions experiments performed complied with the currently accepted ethical norms in a new cerebellar tremor/ataxia syndrome among fragile X carriers. and national laws. Brain 2002, 125:1760-1771. 13. Tassone F, Iwahashi C, Hagerman PJ: FMR1 RNA within the intranuclear Author details inclusions of fragile X-associated tremor/ataxia syndrome (FXTAS). RNA UnIGENe, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Biol 2004, 1:103-105. Porto, Porto, Portugal. Department of Neurology, Hospital de Egas Moniz, 14. Hagerman RJ, Leavitt BR, Farzin F, Jacquemont S, Greco CM, Brunberg JA, Lisboa, Portugal. Centro de Genética Médica Dr. Jacinto Magalhães, INSA, Tassone F, Hessl D, Harris SW, Zhang L, Jardini T, Gane LW, Ferranti J, Ruiz L, Porto, Portugal. Department of Neurology, Hospital de São Sebastião, Feira, Leehey MA, Grigsby J, Hagerman PJ: Fragile-X-associated tremor/ataxia Portugal. Division of Neurobiology, Department of Psychiatry, Johns syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Hopkins University School of Medicine, Baltimore, USA. ICBAS, Universidade Genet 2004, 74:1051-1056. do Porto, Portugal. 15. Jacquemont S, Hagerman RJ, Leehey MA, Hall DA, Levine RA, Brunberg JA, Zhang L, Jardini T, Gane LW, Harris SW, Herman K, Grigsby J, Greco CM, Authors’ contributions Berry-Kravis E, Tassone F, Hagerman PJ: Penetrance of the fragile X- Study concept and design: AIS and IS. Acquisition of data: AIS, JV, IM, RS, IA, associated tremor/ataxia syndrome in a premutation carrier population. AMF, JPB and PC. Critical revision of the manuscript for important Jama 2004, 291:460-469. intellectual content: AIS, RLM, JS and IS. Study supervision: IS. All authors 16. Crawford DC, Meadows KL, Newman JL, Taft LF, Pettay DL, Gold LB, read and approved the final manuscript. Hersey SJ, Hinkle EF, Stanfield ML, Holmgreen P, Yeargin-Allsopp M, Boyle C, Sherman SL: Prevalence and phenotype consequence of FRAXA and Competing interests FRAXE alleles in a large, ethnically diverse, special education-needs The author declares that they have no competing interests. population. Am J Hum Genet 1999, 64:495-507. 17. Adams SA, Steenblock KJ, Thibodeau SN, Lindor NM: Premutations in the Received: 3 March 2011 Accepted: 3 June 2011 Published: 3 June 2011 FMR1 gene are uncommon in men undergoing genetic testing for spinocerebellar ataxia. J Neurogenet 2008, 22:77-92. 18. 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