Widespread non-central nervous system organ pathology in fragile X premutation carriers with fragile X-associated tremor/ ataxia syndrome and CGG knock-in mice Michael R. HunsakerClaudia M. GrecoMarian A. SpathArie P. T. SmitsCelestine S. Navarro • Flora TassoneJohan M. KrosLies-Anne SeverijnenElizabeth M. Berry-KravisRobert F. Berman • Paul J. HagermanRob WillemsenRandi J. HagermanRenate K. Hukema

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 neu- ropathy, 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 inclu- sions in multiple tissues from FXTAS cases and CGG KI mice, including pancreas, thyroid, adrenal gland, gastro- intestinal, 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 involve- ment of the peripheral nervous system and systemic organs. The finding of intranuclear inclusions in non-CNS somatic