Testicular and Pituitary Inclusion Formation in Fragile X Associated Tremor/Ataxia Syndrome

Abstract

Fragile X associated tremor/ataxia syndrome inclusions are formed in tissues outside of the central nervous system. Involvement of the testicles and the pituitary gland may lead to neuroendocrine dysfunction, including testosterone deficiency. These noncentral nervous system components of fragile X associated tremor/ataxia syndrome require further study.

Altered hypothalamus–pituitary–adrenal gland axis regulation in the expanded CGG-repeat mouse model for fragile X-associated tremor/ataxia syndrome

“…Elevated levels of FSH have been found to reflect decreasing ovarian reserve (MacNaughton et al, 1992), which can be correlated to the risk of developing POF seen in female PM carriers. Interestingly, intranuclear inclusions have been reported in the testicles of two men with FXTAS; inclusions were present in the anterior and posterior pituitary gland of one of these for whom the pituitary gland was available (Greco et al, 2007). Finally, a reduced amygdala response has been reported in PM male carriers which may explain the etiology of psychological symptoms involving emotion and social cognition as well ).…”

“…A link has been suggested between pituitary inclusions and dysregulated neuroendocrine function in patients with FXTAS. Increased Follicle Stimulating Hormone (FSH) (Hundscheid et al, 2001;Sullivan et al, 2005;Greco et al, 2007) and decreased inhibin A and B levels in female PM carriers were reported even in those who are cycling normally, suggestive of early ovarian aging and ovarian compromise (Welt et al, 2004). Elevated levels of FSH have been found to reflect decreasing ovarian reserve (MacNaughton et al, 1992), which can be correlated to the risk of developing POF seen in female PM carriers.…”

“…These psychological symptoms could arise from elevated stress hormone levels, thus aberrant regulation of the hypothalamus-pituitary-adrenal gland (HPA) axis. More evidence suggestive of altered regulation of the HPA axis by the PM comes from the observation that ubiquitin-positive intranuclear inclusions are also present in the anterior and posterior lobes of the pituitary gland of patients with FXTAS (Louis et al, 2006;Greco et al, 2007). A link has been suggested between pituitary inclusions and dysregulated neuroendocrine function in patients with FXTAS.…”

“…We explored HPA axis physiology in expanded CGG-repeat mice for two reasons: 1) increased anxiety has been observed in our mouse model (Van Dam et al, 2005) and PM carriers, especially those with elevated FMR1 mrNA experience more psychological distress (Hessl et al, 2005); 2) ubiquitin-positive inclusions have been found in the pituitary gland of male patients with FXTAS (Greco et al, 2007). Here we further characterize the expanded CGG-repeat mouse model for FXTAS and more specifically we demonstrate the presence of inclusions in several endocrine organs of the CGG mice and in the amygdala.…”

Fragile X premutation in women: recognizing the health challenges beyond primary ovarian insufficiency

“…Kenneson et al (2001) [10] found that these patients have an increase in FMR1 RNA transcription proportionally related to the number of CGG repeats and a decrease in FMRP translation inversely related to the number of CGG repeats. The excess of FMR1 mRNA seen in carriers leads to dysregulation of several proteins and its deposition, along with FMR1 mRNA, in the form of cellular inclusions in several parts of the body including the central nervous system, peripheral nervous system (especially autonomic ganglia), Leydig cells, and pituitary among others [11][12][13]. Therefore, any pathology associated with FMR1 premutations would not be caused by a complete absence of FMRP like FXS is, but probably due to partial FMRP deficiency and/or RNA toxicity.…”