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.

Fig. 1

a Intranuclear inclusions in cardiomyocytes in Case 7 (x400; Immunoperoxidase (IP) stain). Insert Extremely large, oval-shaped inclusion in a cardiomyocyte from Case 6 (x1,000). b Intranuclear inclusions in pinealocytes and astrocytes in pineal gland of Case 1 (x1,000; H&E stain). c Autonomic ganglion of the myenteric/Auerbach’s plexus is seen between longitudinal and circular muscular layers of the rectosigmoid colon (x40; IP stain) in Case 4. Insert Higher magnification identifies intranuclear inclusions in ganglion cells (x400). d Intranuclear inclusions in cells of the distal tubule of the kidney in Case 6 (x1,000; IP stain). e Intranuclear inclusions in thyroid of Case 6 (x1,000; IP stain). f Intranuclear inclusion in pancreas of Case 6 (x1,000; IP stain). All immunoperoxidase stains counterstained with hematoxylin. All scale bars represent 100 μm

Fig. 2

a Intranuclear inclusions in cardiomyocytes of CGG KI mice (x1,000; IP stain). b Intranuclear inclusions in pinealocytes of CGG KI mouse pineal gland (x1,000; IP stain). c Intranuclear inclusions in ganglion cells of the myenteric plexus of the colon in CGG KI mice (x1,000; IP stain). d Intranuclear inclusions in adrenal gland of CGG KI mice (x1,000; IP stain). e Intranuclear inclusions in thyroid of CGG KI mice (1,000x; IP stain). f Intranuclear inclusions in pancreas of CGG KI mice (x1,000; IP stain). g Immunofluorescence of intranuclear inclusions (red) and somatostatin (green) in pancreas of CGG KI Mice (nuclei counterstained with DAPI (blue)) (x1,000; IP stain). h Immunofluorescence of intranuclear inclusions (red) and glucagon (green; IP stain) in pancreas of CGG KI mice (nuclei counterstained with DAPI (blue)) (x1,000). All scale bars represent 50 μm