Widespread non-central nervous system organ pathology in fragile X premutation carriers with fragile X-associated tremor/ataxia syndrome and CGG knock-in mice

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 M. R. Hunsaker and C. M. Greco contributed equally to this manuscript. M. R. Hunsaker  R. F. Berman Department of Neurological Surgery, University of California, Davis, Davis, CA, USA C. M. Greco  C. S. Navarro Department of Pathology, University of California, Davis, Davis, CA, USA C. M. Greco  R. F. Berman  P. J. Hagerman  R. J. Hagerman (&) M.I.N.D. Institute, University of California at Davis Medical Center, 2825 50th Street, Sacramento, CA 95817, USA e-mail: randi.hagerman@ucdmc.ucdavis.edu M. A. Spath  A. P. T. Smits Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands F. Tassone  P. J. Hagerman Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, CA, USA F. Tassone  R. F. Berman  P. J. Hagerman  R. Willemsen  R. J. Hagerman NeuroTherapeutics Research Institute, University of California, Davis, Davis, CA, USA J. M. Kros Department of Pathology, Erasmus MC, Rotterdam, The Netherlands L.-A. Severijnen  R. Willemsen  R. K. Hukema CBG-Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands E. M. Berry-Kravis Departments of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Chicago, IL, USA R. J. Hagerman Department of Pediatrics, University of California at Davis Medical Center, Sacramento, CA, USA 123 Acta Neuropathol DOI 10.1007/s00401-011-0860-9 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.