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Update on the Clinical, Radiographic, and Neurobehavioral Manifestations in FXTAS and FMR1 Premutation Carriers

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Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder caused by a repeat expansion in the fragile X mental retardation 1 (FMR1) gene. The disorder is characterized by kinetic tremor and cerebellar ataxia, shows age-dependent penetrance, and occurs more frequently in men. This paper summarizes the key emerging issues in FXTAS as presented at the Second International Conference on the FMR1 Premutation: Basic Mechanisms & Clinical Involvement in 2015. The topics discussed include phenotype-genotype relationships, neurobehavioral function, and updates on FXTAS genetics and imaging.

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References

  1. Murray A, Webb J, MacSwiney F, Shipley E, Morton N, Conway G. Serum concentrations of follicle stimulating hormone may predict premature ovarian failure in FRAXA premutation women. Hum Reprod. 1999;14:1217–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sherman S. Premature ovarian failure in the fragile X syndrome. Am J Med Genet. 2000;97:189–94.

    Article  CAS  PubMed  Google Scholar 

  3. Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J, et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology. 2001;57:127–30.

    Article  CAS  PubMed  Google Scholar 

  4. Fraint A, Vittal P, Szewka A. New observations in the fragile X-associated tremor/ataxia syndrome (FXTAS) phenotype. Front Genet. 2014;5:365.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Leehey M, Berry-Kravis E, Goetz C, Zhang L, Hall D, Li L, et al. FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. Neurology. 2008;70:1397–402.

    Article  CAS  PubMed  Google Scholar 

  6. Litvan I, Agid Y, Calne D. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology. 1996;47:1–9.

    Article  CAS  PubMed  Google Scholar 

  7. O’Keefe JA, Robertson-Dick EE, Hall DA, Berry-Kravis E. Gait and functional mobility deficits in fragile X-associated tremor/ataxia syndrome. Cerebellum. Aug 23. 2015. doi:10.1007/s12311-015-0714-4.

  8. Lord S, Galna B, Verghese J, Coleman S, Burn D, Rochester L. Independent domains of gait in older adults and associated motor and nonmotor attributes: validation of a factor analysis approach. J Gerontol A Biol Sci Med Sci. 2013;68:820–7.

    Article  PubMed  Google Scholar 

  9. Hollman JH, McDade EM, Petersen RC. Normative spatiotemporal gait parameters in older adults. Gait Posture. 2011;34:111–8.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Serrao M, Pierelli F, Ranavolo A, Draicchio F, Conte C, Don R, et al. Gait pattern in inherited cerebellar ataxias. Cerebellum. 2012;11:194–211.

    Article  PubMed  Google Scholar 

  11. Ilg W, Golla H, Thier P, Giese MA. Specific influences of cerebellar dysfunctions on gait. Brain. 2007;130:786–98.

    Article  PubMed  Google Scholar 

  12. Smith. The symbol-digit modalities test: a neuropsychologic test of learning and other cerebral disorders. In: Helmuth J, editor. Learning disorders Seattle: Special Child Publications; 1968. p. 83.

  13. Luria AR. Human brain and psychological processes. New York: Harper and Row; 1966.

    Google Scholar 

  14. Amboni M, Barone P, Hausdorff JM. Cognitive contributions to gait and falls: evidence and implications. Mov Disord. 2013;28:1520–33.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Segev-Jacubovski O, Herman T, Yogev-Seligmann G, Mirelman A, Giladi N, Hausdorff JM. The interplay between gait, falls and cognition: can cognitive therapy reduce fall risk? Expert Rev Neurother. 2011;11:1057–75.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Taylor ME, Delbaere K, Mikolaizak AS, Lord SR, Close JC. Gait parameter risk factors for falls under simple and dual task conditions in cognitively impaired older people. Gait Posture. 2013;37:126–30.

    Article  PubMed  Google Scholar 

  17. Losh M, Klusek J, Martin GE, Sideris J, Parlier M, Piven J. Defining genetically meaningful language and personality traits in relatives of individuals with fragile X syndrome and relatives of individuals with autism. Am J Med Genet B Neuropsychiatr Genet. 2012;159B:660–8.

    Article  PubMed  Google Scholar 

  18. Kraan CM, Hocking DR, Georgiou-Karistianis N, Metcalfe SA, Archibald AD, Fielding J, et al. Impaired response inhibition is associated with self-reported symptoms of depression, anxiety, and ADHD in female FMR1 premutation carriers. Am J Med Genet B Neuropsychiatr Genet. 2014;165B:41–51.

    Article  PubMed  Google Scholar 

  19. Grigsby J, Cornish K, Hocking D, Kraan C, Olichney JM, Rivera SM, et al. The cognitive neuropsychological phenotype of carriers of the FMR1 premutation. J Neurodev Disord. 2014;6:28,1955-6-28.

  20. Lord C, Rutter M, Le Couteur A. Autism diagnostic interview-revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord. 1994;24:659–85.

    Article  CAS  PubMed  Google Scholar 

  21. Lord C, Rutter M, DiLavore P, Risi S, Gotham K, Bishop S. Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). 2nd ed. Los Angeles: Western Psychological Services; 2012.

    Google Scholar 

  22. Wang J, Yu R, Shete S. X-chromosome genetic association test accounting for X-inactivation, skewed X-inactivation, and escape from X-inactivation. Genet Epidemiol. 2014;38:483–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Berry-Kravis E, Potanos K, Weinberg D, Zhou L, Goetz CG. Fragile X-associated tremor/ataxia syndrome in sisters related to X-inactivation. Ann Neurol. 2005;57:144–7.

    Article  CAS  PubMed  Google Scholar 

  24. Rodriguez-Revenga L, Pagonabarraga J, Gomez-Anson B, Lopez-Mourelo O, Madrigal I, Xuncla M, et al. Motor and mental dysfunction in mother-daughter transmitted FXTAS. Neurology. 2010;75:1370–6.

    Article  CAS  PubMed  Google Scholar 

  25. O’Keefe JA, Robertson-Dick E, Dunn EJ, Li Y, Deng Y, Fiutko AN, et al. Characterization and early detection of balance deficits in fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome (FXTAS). Cerebellum. 2015;14:650–62.

    Article  PubMed  Google Scholar 

  26. Hall DA, Robertson-Dick E, O’Keefe JA, Hadd A, Zhou L, Berry-Kravis E. X-inactivation in the clinical phenotype of fragile X premutation carrier sisters. Neurol Genet. 2016 Feb 3;2(1):e45.

  27. Natus Medical Incorporated. Balance Manager Systems, Clinical Interpretations Guide, Computerized Dynamic Posturography; Natus Medical Incorporated. 2009;D102559-00D:139-145.

  28. Black FO. What can posturography tell us about vestibular function? Ann N Y Acad Sci. 2001;942:446–64.

    Article  CAS  PubMed  Google Scholar 

  29. Salarian A, Horak FB, Zampieri C, Carlson-Kuhta P, Nutt JG, Aminian K. iTUG, a sensitive and reliable measure of mobility. IEEE Trans Neural Syst Rehabil Eng. 2010;18:303–10.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Chen L, Hadd AG, Sah S, Houghton JF, Filipovic-Sadic S, Zhang W, et al. High-resolution methylation polymerase chain reaction for fragile X analysis: evidence for novel FMR1 methylation patterns undetected in Southern blot analyses. Genet Med. 2011;13:528–38.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Valencia K, Wutz A. Recent insights into the regulation of X-chromosome inactivation. Adv Genomics Genet. 2015;5:227–38.

    CAS  Google Scholar 

  32. Alvarez-Mora M, Rodriguez-Revenga L, Feliu A, Badenas C, Madrigal I, Milà M. Skewed X inactivation in women carrying the FMR1 premutation and its relation with fragile-X-associated tremor/ataxia syndrome, Neurodegener Dis. 2015.

  33. Bennett D, Schneider J, Arvanitakis Z, Wilson R. Overview and findings from the religious orders study. Curr Alzheimers Res. 2012;9:628–45.

    Article  CAS  Google Scholar 

  34. Allen EG, Sullivan AK, Marcus M, Small C, Dominguez C, Epstein MP, et al. Examination of reproductive aging milestones among women who carry the FMR1 premutation. Hum Reprod. 2007;22:2142–52.

    Article  CAS  PubMed  Google Scholar 

  35. Rodriguez-Revenga L, Madrigal I, Pagonabarraga J, Xuncla M, Badenas C, Kulisevsky J, et al. Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. Eur J Hum Genet. 2009;17:1359–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wheeler AC, Bailey DB,Jr, Berry-Kravis E, Greenberg J, Losh M, Mailick M, et al. Associated features in females with an FMR1 premutation. J Neurodev Disord. 2014;6:30,1955-6-30.

  37. Bailey Jr DB, Raspa M, Olmsted M, Holiday DB. Co-occurring conditions associated with FMR1 gene variations: findings from a national parent survey. Am J Med Genet A. 2008;146A:2060–9.

    Article  CAS  PubMed  Google Scholar 

  38. Lachiewicz A, Dawson D, Spiridigliozzi G, Cuccaro M, Lachiewicz M, McConkie-Rosell A. Indicators of anxiety and depression in women with the fragile X premutation: assessment of a clinical sample. J Intellect Disabil Res. 2010;54:597–610.

    Article  PubMed  Google Scholar 

  39. Roberts JE, Bailey Jr DB, Mankowski J, Ford A, Sideris J, Weisenfeld LA, et al. Mood and anxiety disorders in females with the FMR1 premutation. Am J Med Genet B Neuropsychiatr Genet. 2009;150B:130–9.

    Article  PubMed  Google Scholar 

  40. Lewis SJ, Lawlor DA, Davey Smith G, Araya R, Timpson N, Day IN, et al. The thermolabile variant of MTHFR is associated with depression in the British Women’s Heart and Health study and a meta-analysis. Mol Psychiatry. 2006;11:352–60.

    Article  CAS  PubMed  Google Scholar 

  41. Peerbooms OL, van Os J, Drukker M, Kenis G, Hoogveld L, MTHFR in Psychiatry Group, et al. Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: evidence for a common genetic vulnerability? Brain Behav Immun. 2011;25:1530–43.

    Article  CAS  PubMed  Google Scholar 

  42. Ginsberg LD, Oubre AY, Daoud YA. L-methylfolate Plus SSRI or SNRI from treatment initiation compared to SSRI or SNRI monotherapy in a major depressive episode. Innov Clin Neurosci. 2011;8:19–28.

    PubMed  PubMed Central  Google Scholar 

  43. Jacquemont S, Hagerman R, Leehey M, Grigsby J, Zhang L, Brunberg J. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates.Am J Hum Genet. 2003;72.

  44. Apartis E, Blancher A, Meissner W. FXTAS: new insights and the need for revised diagnostic criteria. Neurology. 2012;79:1898–907.

    Article  PubMed  Google Scholar 

  45. Scheltens P, Barkhof F, Leys D, Pruvo J, Naura J, Vermersch P, et al. A semiquantitative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging. J Neurol Sci. 1993;114:7–12.

    Article  CAS  PubMed  Google Scholar 

  46. Tha KK, Terae S, Tsukahara A, Soma H, Morita R, Yabe I, et al. Hyperintense putaminal rim at 1.5 T: prevalence in normal subjects and distinguishing features from multiple system atrophy. BMC Neurol. 2012;12:39.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Fujii S, Matsusue E, Kinoshita T, Sugihara S, Ohama E, Ogawa T. Hyperintense putaminal rim at 3T reflects fewer ferritin deposits in the lateral marginal area of the putamen. AJNR Am J Neuroradiol. 2007;28:777–81.

    CAS  PubMed  Google Scholar 

  48. Borkowski J, Benton A, Spreen O. Word fluency and brain damage. Neuropsychologia. 1967;5:135–40.

    Article  Google Scholar 

  49. Wiens A, Fuller K, Crossen J. Paced auditory serial addition test: adult norms and moderator variables. J Clin Exp Neuropsychol. 1997;19:473–83.

    Article  CAS  PubMed  Google Scholar 

  50. Brown SS, Stanfield AC. Fragile X premutation carriers: a systematic review of neuroimaging findings. J Neurol Sci. 2015;352(1-2):19–28.

    Article  PubMed  Google Scholar 

  51. Napoli E, Ross-Inta C, Wong S, Omanska-Klusek A, Barrow C, Iwahashi C, et al. Altered zinc transport disrupts mitochondrial protein processing/import in fragile X-associated tremor/ataxia syndrome. Hum Mol Genet. 2011;20:3079–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ariza J, Steward C, Rueckert F, Widdison M, Coffman R, Afjei A, et al. Dysregulated iron metabolism in the choroid plexus in fragile X-associated tremor/ataxia syndrome. Brain Res. 2015;1598:88–96.

    Article  CAS  PubMed  Google Scholar 

  53. Seritan AL, Nguyen DV, Mu Y, Tassone F, Bourgeois JA, Schneider A, et al. Memantine for fragile X-associated tremor/ataxia syndrome: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2014;75:264–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Brinton RD. Neurosteroids as regenerative agents in the brain: therapeutic implications. Nat Rev Endocrinol. 2013;9:241–50.

    Article  CAS  PubMed  Google Scholar 

  55. Irwin RW, Brinton RD. Allopregnanolone as regenerative therapeutic for Alzheimer’s disease: translational development and clinical promise. Prog Neurobiol. 2014;113:40–55.

    Article  CAS  PubMed  Google Scholar 

  56. Irwin RW, Solinsky CM, Brinton RD. Frontiers in therapeutic development of allopregnanolone for Alzheimer’s disease and other neurological disorders. Front Cell Neurosci. 2014;8:203.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Conde V, Palomar FJ, Lama MJ, Martinez R, Carrillo F, Pintado E, et al. Abnormal GABA-mediated and cerebellar inhibition in women with the fragile X premutation. J Neurophysiol. 2013;109:1315–22.

    Article  CAS  PubMed  Google Scholar 

  58. Cao Z, Hulsizer S, Tassone F, Tang HT, Hagerman RJ, Rogawski MA, et al. Clustered burst firing in FMR1 premutation hippocampal neurons: amelioration with allopregnanolone. Hum Mol Genet. 2012;21:2923–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We sincerely thank our premutation carrier and control participants. This work was supported by the following: R01NS082416 (DH); R01MH091131 and R01DC010191 (ML); R01HD032071 (RH); FIS PI 0770 (BGA); NIH (GM082773), Friedman Brain Institute, and Seaver Faculty Scholar (RL); MH094681 (VMC); Strategic Initiative Review Committee of the University of Colorado School of Medicine (JG); Australian Postgraduate Award (ALS); National Fragile X Foundation Fellowship award (ER); and Rush Translational Sciences Consortium Award (JO).

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Authors and Affiliations

  1. Department of Neurological Sciences, Rush University, Chicago, IL, USA

    Deborah A. Hall, Elizabeth Berry-Kravis & Joan A. O’Keefe

  2. Department of Anatomy and Cell Biology, Rush University, 507 Academic Facility, 600 South Paulina Street, Chicago, IL, 60612, USA

    Erin Robertson & Joan A. O’Keefe

  3. School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, Australia

    Annie L. Shelton

  4. Roxelyn and Richard Pepper Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL, USA

    Molly C. Losh

  5. Servei de Bioquímica i Genètica Molecular. Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain

    Montserrat Mila

  6. Neuroradiology Unit, Hospital Santa Creu i Sant Pau, Barcelona, Spain

    Esther Granell Moreno & Beatriz Gomez-Anson

  7. Neuroimaging Research Group, Hospital Sant Pau, IIB-Sant Pau, UAB, Barcelona, Spain

    Esther Granell Moreno & Beatriz Gomez-Anson

  8. Universitat Autonoma Barcelona, Barcelona, Spain

    Beatriz Gomez-Anson

  9. Department of Pathology and Laboratory Medicine, University of California at Davis Medical Center, Sacramento, CA, USA

    Verónica Martínez-Cerdeño

  10. Departments of Medicine and Psychology at the University of Colorado Denver, Aurora, CO, USA

    Jim Grigsby

  11. Seaver Autism Center for Research and Treatment, Departments of Genetics and Genomic Sciences, Psychiatry, and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Reymundo Lozano

  12. Department of Pediatrics & MIND Institute, University of California at Davis Medical Center, Sacramento, CA, USA

    Randi Hagerman

  13. Cytogenetics and Molecular Laboratory, Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile

    Lorena Santa Maria

  14. Departments of Pediatrics and Biochemistry, Rush University, Chicago, IL, USA

    Elizabeth Berry-Kravis

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  1. Deborah A. Hall
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  2. Erin Robertson
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Correspondence to Joan A. O’Keefe.

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Conflict of Interests

Randi Hagerman has received funding from Novartis, Roche, Neuren, and Alcobra for treatment trials in fragile X syndrome (FXS). She has also consulted with Roche/Genentech, Alcobra and Novartis regarding treatment trials in FXS. Elizabeth Berry-Kravis has received funding from Neuren and Alcobra to carry out treatment studies in patients with FXS. She has also received funding from Vtesse to carry out a clinical trial in Niemann-Pick type C. She has also consulted with Neuren, Alcobra, and Neurotrope regarding treatment studies in patients with FXS. Deborah Hall has received research funds from NINDS, Shapiro Foundation, National Parkinson Disease Foundation, Pfizer, and Neurocrine. Dr. Lozano has consulted for Ambry genetics, Courtagen and ClearView Healthcare Partners. The authors declare that they have no conflict of interest.

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Hall, D.A., Robertson, E., Shelton, A.L. et al. Update on the Clinical, Radiographic, and Neurobehavioral Manifestations in FXTAS and FMR1 Premutation Carriers. Cerebellum 15, 578–586 (2016). https://doi.org/10.1007/s12311-016-0799-4

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