title: Widespread non-central nervous system organ pathology in fragile X premutation carriers with fragile X-associated tremor/ataxia syndrome and CGG knock-in mice.
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.
authors.affiliation: Department of Neurological Surgery, University of California, Davis, Davis, CA, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hunsaker
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Greco
authors.forename: Marian A
authors.initials: MA
authors.lastname: Spath
authors.forename: Arie P T
authors.initials: AP
authors.lastname: Smits
authors.forename: Celestine S
authors.initials: CS
authors.lastname: Navarro
authors.forename: Flora
authors.initials: F
authors.lastname: Tassone
authors.forename: Johan M
authors.initials: JM
authors.lastname: Kros
authors.forename: Lies-Anne
authors.initials: LA
authors.lastname: Severijnen
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Berry-Kravis
authors.forename: Robert F
authors.initials: RF
authors.lastname: Berman
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hagerman
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
authors.forename: Randi J
authors.initials: RJ
authors.lastname: Hagerman
authors.forename: Renate K
authors.initials: RK
authors.lastname: Hukema
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001259:Ataxia / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000235:genetics* / Q000473:pathology*; D055879:Gene Knock-In Techniques; D006580:Genetic Carrier Screening; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009928:Organ Specificity / Q000235:genetics; D014202:Tremor / Q000235:genetics / Q000473:pathology*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human; C497684:Fmr1 protein, mouse