Abstract
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder generally presenting with intention tremor and gait ataxia, but with a growing list of co-morbid medical conditions including hypothyroidism, hypertension, peripheral neuropathy, and cognitive decline. The pathological hallmark of FXTAS is the presence of intranuclear inclusions in both neurons and astroglia. However, it is unknown to what extent such inclusions are present outside the central nervous system (CNS). To address this issue, we surveyed non-CNS organs in ten human cases with FXTAS and in a CGG repeat knock-in (CGG KI) mouse model known to possess neuronal and astroglial inclusions. We find inclusions in multiple tissues from FXTAS cases and CGG KI mice, including pancreas, thyroid, adrenal gland, gastrointestinal, pituitary gland, pineal gland, heart, and mitral valve, as well as throughout the associated autonomic ganglia. Inclusions were observed in the testes, epididymis, and kidney of FXTAS cases, but were not observed in mice. These observations demonstrate extensive involvement of the peripheral nervous system and systemic organs. The finding of intranuclear inclusions in non-CNS somatic organ systems, throughout the PNS, and in the enteric nervous system of both FXTAS cases as well as CGG KI mice suggests that these tissues may serve as potential sites to evaluate early intervention strategies or be used as diagnostic factors.
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References
Adams JS, Adams PE, Nguyen DV et al (2007) Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS). Neurology 69(9):851–859
Adams PE, Adams JS, Nguyen DV et al (2010) Psychological symptoms correlate with reduced hippocampal volume in fragile X premutation carriers. Am J Med Genet B 153B(3):775–785
Akins RS, Boyd A, Coffey S et al (2008) High frequency of migraine in FMR1 premutation carriers. In: 11th international fragile X conference, July 23–27. St. Louis
Allen EG, He W, Yadav-Shah M, Sherman SL (2004) A study of the distributional characteristics of FMR1 transcript levels in 238 individuals. Hum Genet 114(5):439–447
Bailey DB Jr, Raspa M, Olmsted M, Holiday DB (2008) Co-occurring conditions associated with FMR1 gene variations: findings from a national parent survey. Am J Med Genet A 146A(16):2060–2069
Bergink S, Severijnen LA, Wijgers N et al (2006) The DNA repair-ubiquitin-associated HR23 proteins are constituents of neuronal inclusions in specific neurodegenerative disorders without hampering DNA repair. Neurobiol Dis 23(3):708–716
Berman RF, Willemsen R (2009) Mouse models of fragile x-associated tremor ataxia. J Investig Med 57(8):837–841
Berry-Kravis E, Lewin F, Wuu J et al (2003) Tremor and ataxia in fragile X premutation carriers: blinded videotape study. Ann Neurol 53(5):616–623
Berry-Kravis E, Potanos K, Weinberg D, Zhou L, Goetz CG (2005) Fragile X-associated tremor/ataxia syndrome in sisters related to X-inactivation. Ann Neurol 57(1):144–147
Berry-Kravis E, Abrams L, Coffey SM et al (2007) Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines. Mov Disord 22(14):2018–2030
Berry-Kravis E, Goetz CG, Leehey MA et al (2007) Neuropathic features in fragile X premutation carriers. Am J Med Genet A 143(1):19–26
Berry-Kravis E, Hall D, Leehey M, Hagerman RJ (2011) Treatment and Management of FXTAS. In: Tassone F, Berry-Kravis E (eds) The fragile X-associated tremor ataxia syndrome (FXTAS). Springer, New York, pp 137–154
Bourgeois JA, Farzin F, Brunberg JA et al (2006) Dementia with mood symptoms in a fragile X premutation carrier with the fragile X-associated tremor/ataxia syndrome: clinical intervention with donepezil and venlafaxine. J Neuropsychiatry Clin Neurosci 18(2):171–177
Bourgeois JA, Cogswell JB, Hessl D et al (2007) Cognitive, anxiety and mood disorders in the fragile X-associated tremor/ataxia syndrome. Gen Hosp Psychiatry 29(4):349–356
Bourgeois JA, Coffey SM, Rivera SM et al (2009) A review of fragile X premutation disorders: expanding the psychiatric perspective. J Clin Psychiatry 70(6):852–862
Bourgeois JA, Seritan AL, Casillas EM et al (2011) Lifetime prevalence of mood and anxiety disorders in fragile X premutation carriers. J Clin Psychiatry 72(2):175–182
Brouwer JR, Mientjes EJ, Bakker CE et al (2007) Elevated Fmr1 mRNA levels and reduced protein expression in a mouse model with an unmethylated Fragile X full mutation. Exp Cell Res 313(2):244–253
Brouwer JR, Huizer K, Severijnen IA et al (2008) CGG-repeat length and neuropathological and molecular correlates in a mouse model for fragile X-associated tremor/ataxia syndrome. J Neurochem 107(6):1671–1682
Brouwer JR, Severijnen E, de Jong FH et al (2008) Altered hypothalamus-pituitary-adrenal gland axis regulation in the expanded CGG-repeat mouse model for fragile X-associated tremor/ataxia syndrome. Psychoneuroendocrinology 33(6):863–873
Brouwer JR, Willemsen R, Oostra BA (2009) The FMR1 gene and fragile X-associated tremor/ataxia syndrome. Am J Med Genet B 150B(6):782–798
Brunberg JA, Jacquemont S, Hagerman RJ et al (2002) Fragile X premutation carriers: Characteristic MR imaging findings in adult males with progressive cerebellar and cognitive dysfunction. Am J Neuroradiol 23(10):1757–1766
Chen Y, Tassone F, Berman RF et al (2010) Murine hippocampal neurons expressing Fmr1 gene premutations show early developmental deficits and late degeneration. Hum Mol Genet 19(1):196–208
Cilia R, Kraff J, Canesi M et al (2009) Screening for the presence of FMR1 premutation alleles in women with parkinsonism. Arch Neurol 66(2):244–249
Coffey SM, Cook K, Tartaglia N et al (2008) Expanded clinical phenotype of women with the FMR1 premutation. Am J Med Genet A 146A(8):1009–1016
Cohen S, Masyn K, Adams J et al (2006) Molecular and imaging correlates of the fragile X-associated tremor/ataxia syndrome. Neurology 67(8):1426–1431
Entezam A, Biacsi R, Orrison B et al (2007) Regional FMRP deficits and large repeat expansions into the full mutation range in a new Fragile X premutation mouse model. Gene 395(1–2):125–134
Fernandez-Carvajal I, Lopez Posadas B, Pan R, Raske C, Hagerman PJ, Tassone F (2009) Expansion of an FMR1 grey-zone allele to a full mutation in two generations. J Mol Diagn 11(4):306–310
Garcia-Arocena D, Hagerman PJ (2010) Advances in understanding the molecular basis of FXTAS. Hum Mol Genet 19(R1):R83–R89
Garcia-Arocena D, Yang JE, Brouwer JR et al (2010) Fibroblast phenotype in male carriers of FMR1 premutation alleles. Hum Mol Genet 19(2):299–312
Gokden M, Al-Hinti JT, Harik SI (2009) Peripheral nervous system pathology in fragile X tremor/ataxia syndrome (FXTAS). Neuropathology 29(3):280–284
Greco CM, Hagerman RJ, Tassone F et al (2002) Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 125(8):1760–1771
Greco CM, Berman RF, Martin M et al (2006) Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain 129(Pt 1):243–255
Greco CM, Soontarapornchai K, Wirojanan J, Gould JE, Hagerman PJ, Hagerman RJ (2007) Testicular and pituitary inclusion formation in fragile X associated tremor/ataxia syndrome. J Urol 177(4):1434–1437
Greco CM, Tassone F, Garcia-Arocena D et al (2008) Clinical and neuropathologic findings in a woman with the FMR1 premutation and multiple sclerosis. Arch Neurol 65(8):1114–1116
Hagerman RJ, Leehey M, Heinrichs W et al (2001) Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 57(1):127–130
Hagerman RJ, Coffey SM, Maselli R et al (2007) Neuropathy as a presenting feature in fragile X-associated tremor/ataxia syndrome. Am J Med Genet A 143(19):2256–2260
Hagerman RJ, Hall D, Coffey S et al (2008) Treatment of fragile X-associated tremor ataxia syndrome (FXTAS) and related neurological problems. Clin Interv Aging 3(2):251–262
Hall D, Pickler L, Riley K, Tassone F, Hagerman RJ (2010) Parkinsonism and cognitive decline in a fragile X mosaic male. Mov Disord 25(10):1523–1524
Hessl D, Tassone F, Loesch DZ et al (2005) Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation. Am J Med Genet B 139B(1):115–121
Hunsaker MR, Wenzel HJ, Willemsen R, Berman RF (2009) Progressive spatial processing deficits in a mouse model of the fragile X premutation. Behav Neurosci 123(6):1315–1324
Hunsaker MR, Goodrich-Hunsaker NJ, Willemsen R, Berman RF (2010) Temporal ordering deficits in female CGG KI mice heterozygous for the fragile X premutation. Behav Brain Res 213(2):263–268
Hunsaker MR, von Leden RE, Ta BT et al (2011) Motor deficits on a ladder rung task in male and female adolescent and adult CGG knock-in mice. Behav Brain Res 222(1):117–121
Iwahashi CK, Yasui DH, An HJ et al (2006) Protein composition of the intranuclear inclusions of FXTAS. Brain 129(Pt 1):256–271
Jacquemont S, Hagerman RJ, Leehey M et al (2003) Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 72(4):869–878
Jacquemont S, Hagerman RJ, Leehey MA et al (2004) Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA 291(4):460–469
Jacquemont S, Hagerman RJ, Hagerman PJ, Leehey MA (2007) Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1. Lancet Neurol 6(1):45–55
Kaufmann H, Biaggioni I (2003) Autonomic failure in neurodegenerative disorders. Semin Neurol 23(4):351–363
Kovari E, Horvath J, Bouras C (2009) Neuropathology of Lewy body disorders. Brain Res Bull 80(4–5):203–210
Kulikova-Schupak R, Knupp KG, Pascual JM, Chin SS, Kairam R, Patterson MC (2004) Rectal biopsy in the diagnosis of neuronal intranuclear hyaline inclusion disease. J Child Neurol 19(1):59–62
Leehey M, Berry-Kravis E, Goetz CG, Hagerman R (2011) Clinical neurological phenotype of FXTAS. In: Tassone F, Berry-Kravis E (eds) The fragile X-associated tremor ataxia syndrome (FXTAS). Springer, New York, pp 1–16
Leehey M, Legg W, Tassone F, Hagerman R (2011) Fibromyalgia in fragile X mental retardation 1 gene premutation carriers. Rheumatology, Oxford (in press)
Leehey MA, Berry-Kravis E, Min SJ et al (2007) Progression of tremor and ataxia in male carriers of the FMR1 premutation. Mov Disord 22(2):203–206
Loesch DZ, Litewka L, Brotchie P, Huggins RM, Tassone F, Cook M (2005) Magnetic resonance imaging study in older fragile X premutation male carriers. Ann Neurol 58(2):326–330
Louis E, Moskowitz C, Friez M, Amaya M, Vonsattel JP (2006) Parkinsonism, dysautonomia, and intranuclear inclusions in a fragile X carrier: a clinical-pathological study. Mov Disord 21(3):420–425
Munoz DG (2002) Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 58(6):987 (author reply 987–988)
Nishie M, Mori F, Fujiwara H et al (2004) Accumulation of phosphorylated alpha-synuclein in the brain and peripheral ganglia of patients with multiple system atrophy. Acta Neuropathol 107(4):292–298
Peprah E, He W, Allen E, Oliver T, Boyne A, Sherman SL (2010) Examination of FMR1 transcript and protein levels among 74 premutation carriers. J Hum Genet 55(1):66–68
Peprah EK, Allen EG, Williams SM, Woodard LM, Sherman SL (2010) Genetic diversity of the fragile X syndrome gene (FMR1) in a large Sub-Saharan West African population. Ann Hum Genet 74(4):316–325
Qin M, Entezam A, Usdin K et al (2011) A mouse model of the fragile X premutation: Effects on behavior, dendrite morphology, and regional rates of cerebral protein synthesis. Neurobiol Dis 42(1):85–98
Raske C, Hagerman PJ (2009) Molecular pathogenesis of fragile X-associated tremor/ataxia syndrome. J Investig Med 57(8):825–829
Reis AH, Ferreira AC, Gomes KC et al (2008) Frequency of FMR1 premutation in individuals with ataxia and/or tremor and/or parkinsonism. Genet Mol Res 7(1):74–84
Roberts J, Mazzocco MM, Murphy MM, Hoehn-Saric R (2008) Arousal modulation in females with fragile X or Turner syndrome. J Autism Dev Disord 38(1):20–27
Roberts JE, Bailey DB Jr, Mankowski J et al (2009) Mood and anxiety disorders in females with the FMR1 premutation. Am J Med Genet B 150B(1):130–139
Rodriguez-Revenga L, Madrigal I, Pagonabarraga J et al (2009) Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. Eur J Hum Genet 17(10):1359–1362
Ross-Inta C, Omanska-Klusek A, Wong S et al (2010) Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome. Biochem J 429(3):545–552
Sellier C, Rau F, Liu Y et al (2010) Sam68 sequestration and partial loss of function are associated with splicing alterations in FXTAS patients. EMBO J 29(7):1248–1261
Soontarapornchai K, Maselli R, Fenton-Farrell G et al (2008) Abnormal nerve conduction features in fragile X premutation carriers. Arch Neurol 65(4):495–498
Sullivan AK, Marcus M, Epstein MP et al (2005) Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod 20(2):402–412
Takahashi-Fujigasaki J (2003) Neuronal intranuclear hyaline inclusion disease. Neuropathology 23(4):351–359
Tassone F, Hagerman RJ, Taylor AK, Gane LW, Godfrey TW, Hagerman PJ (2000) Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in the fragile-X syndrome. Am J Hum Genet 66(1):6–15
Tassone F, Hagerman RJ, Garcia-Arocena D, Khandjian EW, Greco CM, Hagerman PJ (2004) Intranuclear inclusions in neural cells with premutation alleles in fragile X associated tremor/ataxia syndrome. J Med Genet 41(4):e43
Tassone F, Iwahashi C, Hagerman PJ (2004) FMR1 RNA within the intranuclear inclusions of fragile X-associated tremor/ataxia syndrome (FXTAS). RNA Biol 1(2):103–105
Van Dam D, Errijgers V, Kooy RF et al (2005) Cognitive decline, neuromotor and behavioural disturbances in a mouse model for fragile-X-associated tremor/ataxia syndrome (FXTAS). Behav Brain Res 162(2):233–239
Wakabayashi K, Mori F, Tanji K, Orimo S, Takahashi H (2010) Involvement of the peripheral nervous system in synucleinopathies, tauopathies and other neurodegenerative proteinopathies of the brain. Acta Neuropathol 120(1):1–12
Wenzel HJ, Hunsaker MR, Greco CM, Willemsen R, Berman RF (2010) Ubiquitin-positive intranuclear inclusions in neuronal and glial cells in a mouse model of the fragile X premutation. Brain Res 1318:155–166
Willemsen R, Hoogeveen-Westerveld M, Reis S et al (2003) The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome. Hum Mol Genet 12(9):949–959
Yachnis AT, Roth HL, Heilman KM (2010) Fragile X dementia Parkinsonism syndrome (FXDPS). Cogn Behav Neurol 23(1):39–43
Yamada M, Hayashi S, Tsuji S, Takahashi H (2001) Involvement of the cerebral cortex and autonomic ganglia in Machado-Joseph disease. Acta Neuropathol 101(2):140–144
Acknowledgments
This work was supported by National Institute of Health (NIH) grants HD036071, HD056031, NS044299, AG024488, HD02274, MH77554, MH078041, RL1 AG032115, RL1NS062411, and RL1 AG032119; the National Fragile X Foundation; the Circle of Service Foundation; and the M.I.N.D. Institute. This work was also made possible by a grant (UL1 DE019583) from the National Institute of Dental and Craniofacial Research (NIDCR) in support of the NeuroTherapeutics Research Institute (NTRI) consortium; and by a grant (UL1 RR024146) from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research.
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M. R. Hunsaker and C. M. Greco contributed equally to this manuscript.
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Hunsaker, M.R., Greco, C.M., Spath, M.A. et al. Widespread non-central nervous system organ pathology in fragile X premutation carriers with fragile X-associated tremor/ataxia syndrome and CGG knock-in mice. Acta Neuropathol 122, 467–479 (2011). https://doi.org/10.1007/s00401-011-0860-9
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DOI: https://doi.org/10.1007/s00401-011-0860-9