neurogenetics

, Volume 12, Issue 2, pp 123–135 | Cite as

New clinical findings in the fragile X-associated tremor ataxia syndrome (FXTAS)

  • Jorge L. Juncos
  • Joash T. Lazarus
  • Emily Graves-Allen
  • Lisa Shubeck
  • Michelle Rusin
  • Gloria Novak
  • Deborah Hamilton
  • Julia Rohr
  • Stephanie L. Sherman
ORIGINAL ARTICLE

Abstract

The objective of this paper was to assess the phenotypic variance in patients with the Fragile X-associated Tremor Ataxia Syndrome (FXTAS) and to further elucidate genotype–phenotype correlations in the illness. A second goal was to generate hypotheses regarding symptom progression based on careful histories in our sample that can now be tested in ongoing longitudinal studies. The variability of clinical signs and symptom progression in FXTAS complicates our understanding of its phenotype and presents a series of problems in clinical trial design. Similarly, pre-motor and non-motor symptoms have not been adequately explored to answer outstanding questions regarding genotype–phenotype associations in FXTAS. This was a cross-sectional study of FMR1 premutation carriers from known fragile X syndrome pedigrees. We report on the first 50 subjects who have completed a full neurologic evaluation and a brain MRI. Subjects were selected on the basis of motor symptoms or abnormal results (>1 SD) on a quantitative instrument designed to detect mild tremor and ataxia (CATSYS 1994). A neuropsychological battery included the WAIS-III, COWA, and WCST. Statistical analysis used ANOVA and Fisher’s exact test with p < 0.05. All FMR1 premutation carriers were men of mean age 65 ± 7 years. According to the diagnostic criteria of Jacquemont et al. (Am J Hum Genet 72(4):869–878, 2003), 21 subjects met criteria for definite FXTAS, 10 for probable, 9 for possible, and 10 were indeterminate. Duration of motor symptoms was significantly longer in the definitive group (8.6 ± 6) compared to the other groups (p < 0.01). The presentations in 40 subjects, excluding the indeterminate group, included: tremor 24, ataxia 5, memory symptoms 3, parkinsonism 2, and torticollis 1. The data suggest at least two dominant phenotypic presentations: (a) a tremor-dominant subtype in which the onset of ataxia is delayed; (b) a second in which ataxia is the dominant presentation from the outset. In both subtypes, once ataxia emerges it tends to track frontal cognitive changes (p < 0.01). The data support the view that FXTAS is a late-life neurodegenerative disorder with involvement of motor, non-motor, and cognitive systems. The results suggest at least two presentations with tremor- and ataxia-predominant phenotypes. In both, global cognitive decline appears to track ataxia. Prospective longitudinal studies are needed to validate this proposed evolution of FXTAS and its relevance to future clinical trials design.

Keywords

Fragile X tremor ataxia syndrome FMR1 premutation Neurodegeneration Ataxia Tremor Parasomnias Sensorineural hearing loss 

Supplementary material

10048_2010_270_MOESM1_ESM.pdf (224 kb)
ESM 1(PDF 223 kb)
10048_2010_270_MOESM2_ESM.pdf (53 kb)
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References

  1. 1.
    Sherman S, Pletcher BA, Driscoll DA (2005) Fragile X syndrome: diagnostic and carrier testing. Genet Med 7(8):584–587PubMedCrossRefGoogle Scholar
  2. 2.
    Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J, Grigsby J, Gage B, Hagerman PJ (2001) Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 57(1):127–130PubMedGoogle Scholar
  3. 3.
    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 (2003) Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 72(4):869–878PubMedCrossRefGoogle Scholar
  4. 4.
    Grigsby J, Brega AG, Jacquemont S, Loesch DZ, Leehey MA, Goodrich GK, Hagerman RJ, Epstein J, Wilson R, Cogswell JB, Jardini T, Tassone F, Hagerman PJ (2006) Impairment in the cognitive functioning of men with fragile X-associated tremor/ataxia syndrome (FXTAS). J Neurol Sci 248(1–2):227–233.PubMedCrossRefGoogle Scholar
  5. 5.
    Brega AG, Goodrich G, Bennett RE, Hessl D, Engle K, Leehey MA, Bounds LS, Paulich MJ, Hagerman RJ, Hagerman PJ, Cogswell JB, Tassone F, Reynolds A, Kooken R, Kenny M, Grigsby J (2008) The primary cognitive deficit among males with fragile X-associated tremor/ataxia syndrome (FXTAS) is a dysexecutive syndrome. J Clin Exp Neuropsychol:30(8):853-869Google Scholar
  6. 6.
    Bacalman S, Farzin F, Bourgeois JA, Cogswell J, Goodlin-Jones BL, Gane LW, Grigsby J, Leehey MA, Tassone F, Hagerman RJ (2006) Psychiatric phenotype of the fragile X-associated tremor/ataxia syndrome (FXTAS) in males: newly described fronto-subcortical dementia. J Clin Psychiatry 67(1):87–94PubMedCrossRefGoogle Scholar
  7. 7.
    Brunberg JA, Jacquemont S, Hagerman RJ, Berry-Kravis EM, Grigsby J, Leehey MA, Tassone F, Brown WT, Greco CM, Hagerman PJ (2004) Fragile X premutation carriers: characteristic MR imaging findings of adult male patients with progressive cerebellar and cognitive dysfunction. Am J Neuroradiol 23(10):1757-1766Google Scholar
  8. 8.
    Hagerman PJ, Hagerman RJ (2007) Fragile X-associated tremor/ataxia syndrome—an older face of the fragile X gene. Nat Clin Pract Neurol 3(2):107–112PubMedCrossRefGoogle Scholar
  9. 9.
    Greco CM, Berman RF, Martin RM, Tassone F, Schwartz PH, Chang A, Trapp BD, Iwahashi C, Brunberg J, Grigsby J, Hessl D, Becker EJ, Papazian J, Leehey MA, Hagerman RJ, Hagerman PJ (2006) Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain 129(Pt 1):243–255PubMedGoogle Scholar
  10. 10.
    Greco CM, Hagerman RJ, Tassone F, Chudley AE, Del Bigio MR, Jacquemont S, Leehey M, Hagerman PJ (2002) Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 125(Pt 8):1760–1771PubMedCrossRefGoogle Scholar
  11. 11.
    De Cock VC, Vidailhet M, Arnulf I (2008) Sleep disturbances in patients with parkinsonism. Nat Clin Pract Neurol 4(5):254–266PubMedCrossRefGoogle Scholar
  12. 12.
    Bhatt MH, Podder N, Chokroverty S (2005) Sleep and neurodegenerative diseases. Semin Neurol 25(1):39–51PubMedCrossRefGoogle Scholar
  13. 13.
    Clemens S, Rye D, Hochman S (2006) Restless legs syndrome: revisiting the dopamine hypothesis from the spinal cord perspective. Neurology 67(1):125–130PubMedCrossRefGoogle Scholar
  14. 14.
    Berry-Kravis E, Goetz CG, Leehey MA, Hagerman RJ, Zhang L, Li L, Nguyen D, Hall DA, Tartaglia N, Cogswell J, Tassone F, Hagerman PJ (2007) Neuropathic features in fragile X premutation carriers. Am J Med Genet A 143(1):19–26PubMedGoogle Scholar
  15. 15.
    Hagerman RJ, Coffey SM, Maselli R, Soontarapornchai K, Brunberg JA, Leehey MA, Zhang L, Gane LW, Fenton-Farrell G, Tassone F, Hagerman PJ (2007) Neuropathy as a presenting feature in fragile X-associated tremor/ataxia syndrome. Am J Med Genet A 143A(19):2256–2260PubMedCrossRefGoogle Scholar
  16. 16.
    Allen EG, Juncos J, Letz R, Rusin M, Hamilton D, Novak G, Shubeck L, Tinker SW, Sherman SL (2008) Detection of early FXTAS motor symptoms using the CATSYS computerised neuromotor test battery. J Med Genet 45(5):290–297PubMedCrossRefGoogle Scholar
  17. 17.
    Van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, vG J (1988) Interobserver agreement for the assessment of handicap in stroke patients. Stroke 19(5):604–607PubMedGoogle Scholar
  18. 18.
    Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H (2005) The montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 53(4):695–699PubMedCrossRefGoogle Scholar
  19. 19.
    Stefansson H, Rye DB, Hicks A, Petursson H, Ingason A, Thorgeirsson TE, Palsson S, Sigmundsson T, Sigurdsson AP, Eiriksdottir I, Soebech E, Bliwise D, Beck JM, Rosen A, Waddy S, Trotti LM, Iranzo A, Thambisetty M, Hardarson GA, Kristjansson K, Gudmundsson LJ, Thorsteinsdottir U, Kong A, Gulcher JR, Gudbjartsson D, Stefansson K (2007) A genetic risk factor for periodic limb movements in sleep. N Engl J Med 357(7):639–647PubMedCrossRefGoogle Scholar
  20. 20.
    Redline S, Strohl KP (1998) Recognition and consequences of obstructive sleep apnea hypopnea syndrome. Clin Chest Med 19(1):1–19PubMedCrossRefGoogle Scholar
  21. 21.
    Redline S, Strohl KP (1999) Recognition and consequences of obstructive sleep apnea hypopnea syndrome. Otolaryngol Clin North Am 32(2):303–331PubMedCrossRefGoogle Scholar
  22. 22.
    Visser M, Marinus J, Stiggelbout AM, Van Hilten JJ (2004) Assessment of autonomic dysfunction in Parkinson’s disease: the SCOPA-AUT. Mov Disord 19(11):1306–1312PubMedCrossRefGoogle Scholar
  23. 23.
    Allen EG, Sullivan AK, Marcus M, Small C, Dominguez C, Epstein MP, Charen K, He W, Taylor KC, Sherman SL (2007) Examination of reproductive aging milestones among women who carry the FMR1 premutation. Hum Reprod 22(8):2142–2152PubMedCrossRefGoogle Scholar
  24. 24.
    Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55(3):181–184PubMedCrossRefGoogle Scholar
  25. 25.
    Bacon CG, Mittleman MA, Kawachi I, Giovannucci E, Glasser DB, Rimm EB (2003) Sexual function in men older than 50 years of age: results from the health professionals follow-up study. Ann Intern Med 139(3):161–168PubMedGoogle Scholar
  26. 26.
    Mold JW, Vesely SK, Keyl BA, Schenk JB, Roberts M (2004) The prevalence, predictors, and consequences of peripheral sensory neuropathy in older patients. J Am Board Fam Pract 17 (5):309–18Google Scholar
  27. 27.
    Cruickshanks KJ, Tweed TS, Wiley TL, Klein BE, Klein R, Chappell R, Nondahl DM, Dalton DS (2003) The 5-year incidence and progression of hearing loss: the epidemiology of hearing loss study. Arch Otolaryngol Head Neck Surg 129(10):1041–1046PubMedCrossRefGoogle Scholar
  28. 28.
    Ohayon MM, Caulet M, Priest RG (1997) Violent behavior during sleep. J Clin Psychiatry 58(8):369–376, quiz 377PubMedCrossRefGoogle Scholar
  29. 29.
    Kara CO, Zencir M, Topuz B, Ardic N, Kocagozoglu B (2005) The prevalence of snoring in adult population. Kulak Burun Bogaz Ihtis Derg 14(1–2):18–24PubMedGoogle Scholar
  30. 30.
    Leehey MA, Berry-Kravis E, Min SJ, Hall DA, Rice CD, Zhang L, Grigsby J, Greco CM, Reynolds A, Lara R, Cogswell J, Jacquemont S, Hessl DR, Tassone F, Hagerman R, Hagerman PJ (2007) Progression of tremor and ataxia in male carriers of the FMR1 premutation. Mov Disord 22(2):203–206PubMedCrossRefGoogle Scholar
  31. 31.
    Hall DA, Jacquemont S (2010) Epidemiology of FXTAS. In: Tassone F, Berry-Kravis E (eds) The Fragile X associated tremor/ataxia syndrome, 1st edn. Springer, New York, pp 17–30CrossRefGoogle Scholar
  32. 32.
    Temple R (2002) Policy developments and regulatory approval. Stat Med 21(19):2939–2948PubMedCrossRefGoogle Scholar
  33. 33.
    Shahed J, Jankovic J (2007) Exploring the relationship between essential tremor and Parkinson’s disease. Parkinsonism Relat Disord 13(2):67–76PubMedCrossRefGoogle Scholar
  34. 34.
    Singer C, Sanchez-Ramos J, Weiner WJ (1994) Gait abnormality in essential tremor. Mov Disord 9(2):193–196PubMedCrossRefGoogle Scholar
  35. 35.
    Stolze H, Petersen G, Raethjen J, Wenzelburger R, Deuschl G (2001) The gait disorder of advanced essential tremor. Brain 124(Pt 11):2278–2286PubMedCrossRefGoogle Scholar
  36. 36.
    Williams-Gray CH, Foltynie T, Brayne CE, Robbins TW, Barker RA (2007) Evolution of cognitive dysfunction in an incident Parkinson’s disease cohort. Brain 130(Pt 7):1787–1798PubMedCrossRefGoogle Scholar
  37. 37.
    Dolan RJ (1998) A cognitive affective role for the cerebellum. Brain 121(Pt 4):545–546PubMedCrossRefGoogle Scholar
  38. 38.
    Schmahmann JD, Sherman JC (1997) Cerebellar cognitive affective syndrome. Int Rev Neurobiol 41:433–440PubMedCrossRefGoogle Scholar
  39. 39.
    Allen EG, Hunter JE, Rusin M, Juncos J, Novak G, Hamilton D, Shubeck L, Charen K, Sherman SL (2011) Neuropsychological findings from older premutation carrier males and their non-carrier siblings from families with fragile X syndrome. NeuropsychologyGoogle Scholar
  40. 40.
    Siddiqui MF, Rast S, Lynn MJ, Auchus AP, Pfeiffer RF (2002) Autonomic dysfunction in Parkinson’s disease: a comprehensive symptom survey. Parkinsonism Relat Disord 8(4):277–284PubMedCrossRefGoogle Scholar
  41. 41.
    Schneider A, Ballinger E, Chavez A, Tassone F, Hagerman RJ, Hessl D (2010) Prepulse inhibition in patients with fragile X-associated tremor ataxia syndrome. Neurobiol AgingGoogle Scholar
  42. 42.
    Hsu CH, Kwon H, Perng CL, Bai RK, Dai P, Wong LJ (2005) Hearing loss in mitochondrial disorders. Ann NY Acad Sci 1042:36–47PubMedCrossRefGoogle Scholar
  43. 43.
    Hutchin TP, Cortopassi GA (2000) Mitochondrial defects and hearing loss. Cell Mol Life Sci 57(13–14):1927–1937PubMedCrossRefGoogle Scholar
  44. 44.
    Ghorayeb I, Bioulac B, Tison F (2005) Sleep disorders in multiple system atrophy. J Neural Transm 112(12):1669–1675PubMedCrossRefGoogle Scholar
  45. 45.
    Ngai S, Tang YM, Du L, Stuckey S (2006) Hyperintensity of the middle cerebellar peduncles on fluid-attenuated inversion recovery imaging: variation with age and implications for the diagnosis of multiple system atrophy. AJNR Am J Neuroradiol 27(10):2146–2148PubMedGoogle Scholar
  46. 46.
    Allen EG, Leehey MA, Tassone F, Sherman SL (2010) Genotype/phenotype relationships in FXTAS. In: Tassone F, Berry-Kravis E (eds) The fragile X-associated tremor/ataxia syndrome. Springer, New York, pp 95–122CrossRefGoogle Scholar
  47. 47.
    Leehey MA, Berry-Kravis E, Goetz CG, Zhang L, Hall DA, Li L, Rice CD, Lara R, Cogswell J, Reynolds A, Gane L, Jacquemont S, Tassone F, Grigsby J, Hagerman RJ, Hagerman PJ (2008) FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. Neurology 70(16 Pt 2):1397–1402PubMedCrossRefGoogle Scholar
  48. 48.
    Berry-Kravis E, Abrams L, Coffey SM, Hall DA, Greco C, Gane LW, Grigsby J, Bourgeois JA, Finucane B, Jacquemont S, Brunberg JA, Zhang L, Lin J, Tassone F, Hagerman PJ, Hagerman RJ, Leehey MA (2007) Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines. Mov Disord 22(14):2018–2030, quiz 2140PubMedCrossRefGoogle Scholar
  49. 49.
    Tassone F, Adams J, Berry-Kravis EM, Cohen SS, Brusco A, Leehey MA, Li L, Hagerman RJ, Hagerman PJ (2007) CGG repeat length correlates with age of onset of motor signs of the fragile X-associated tremor/ataxia syndrome (FXTAS). Am J Med Genet B Neuropsychiatr Genet 144B(4):566–569PubMedCrossRefGoogle Scholar
  50. 50.
    Sullivan AK, Marcus M, Epstein MP, Allen EG, Anido AE, Paquin JJ, Yadav-Shah M, Sherman SL (2005) Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod 20(2):402–412PubMedCrossRefGoogle Scholar
  51. 51.
    Kamm C, Healy DG, Quinn NP, Wullner U, Moller JC, Schols L, Geser F, Burk K, Borglum AD, Pellecchia MT, Tolosa E, del Sorbo F, Nilsson C, Bandmann O, Sharma M, Mayer P, Gasteiger M, Haworth A, Ozawa T, Lees AJ, Short J, Giunti P, Holinski-Feder E, Illig T, Wichmann HE, Wenning GK, Wood NW, Gasser T (2005) The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA Study Group. Brain 128(Pt 8):1855–1860PubMedCrossRefGoogle Scholar
  52. 52.
    Toft M, Aasly J, Bisceglio G, Adler CH, Uitti RJ, Krygowska-Wajs A, Lynch T, Wszolek ZK, Farrer MJ (2005) Parkinsonism, FXTAS, and FMR1 premutations. Mov Disord 20(2):230–233PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Jorge L. Juncos
    • 1
  • Joash T. Lazarus
    • 2
  • Emily Graves-Allen
    • 2
  • Lisa Shubeck
    • 2
  • Michelle Rusin
    • 2
  • Gloria Novak
    • 2
  • Deborah Hamilton
    • 2
  • Julia Rohr
    • 2
  • Stephanie L. Sherman
    • 2
  1. 1.Department of NeurologyEmory UniversityAtlantaUSA
  2. 2.Department of Human GeneticsEmory UniversityAtlantaUSA

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