Aging in Individuals With the FMR1 Mutation

Abstract

Individuals with fragile X mental retardation 1 (FMR1) premutation (55 to 200 CGG repeats) are typically unaffected by fragile X syndrome. However, a subgroup of older males with the premutation have developed a neurological syndrome, which usually begins between 50 and 70 years and is associated with a progressive intention tremor and/or ataxia manifested by balance problems, frequent falling, and Parkinsonian symptoms, such as masked facies, intermittent resting tremor, and mild rigidity. This finding has been termed the fragile X-associated tremor/ataxia syndrome (FXTAS) and has brought focus to the aging process in individuals with the FMR1 mutation. The premutation is associated with elevated messenger RNA levels leading to the formation of intranuclear inclusions in neurons and astrocytes associated with FXTAS. This review is a summary of our experience with FXTAS in male carriers of the premutation.

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

“…The authors suggested a relationship with the inclusions present in the hippocampus, which is the area with the highest inclusion density in the human FXTAS brain (Jacquemont et al, 2004). Another study described more psychopathology, including phobic anxiety and obsessivecompulsive symptoms in patients with FXTAS compared to published norms (Hessl et al, 2005).…”

“…Recently, observations have accumulated that PM carriers, both with and without FXTAS are more often affected by psychiatric problems than controls (Jacquemont et al, 2004;Hessl et al, 2005;Bacalman et al, 2006;Bourgeois et al, 2007). Although a link between the presence of inclusions in the hippocampus and the frequent occurrence of anxiety and depression in patients with FXTAS has been suggested (Jacquemont et al, 2004), little is known about the origin of the psychopathology.…”

“…Although a link between the presence of inclusions in the hippocampus and the frequent occurrence of anxiety and depression in patients with FXTAS has been suggested (Jacquemont et al, 2004), little is known about the origin of the psychopathology.…”

“…Recent studies have documented that the abnormal elevation of FMR1 mRNA is associated with increased psychological symptoms, such as anxiety, depression, and irritability in adult PM carriers, with or without symptoms of FXTAS, especially males (Jacquemont et al, 2004;Hessl et al, 2005;Bacalman et al, 2006;Bourgeois et al, 2007). These psychological symptoms could arise from elevated stress hormone levels, thus aberrant regulation of the hypothalamus-pituitary-adrenal gland (HPA) axis.…”

Fragile X spectrum disorders

“…This is a neurodegenerative disorder that occurs in approximately 40% of men and 16% of women with the premutation (12,13). FXTAS is hypothesized to be caused by mRNA toxicity from the elevated FMR1 mRNA levels (14) leading to the production of pathognomonic inclusion formation in neurons and astrocytes throughout the CNS, peripheral nervous system and even in some organs such as the adrenals, heart and pancreas (15).…”