Men with FMR1 premutation alleles of less than 71 CGG repeats have low risk of being affected with fragile X-associated tremor/ataxia syndrome (FXTAS)

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset condition characterised by cerebellar ataxia and intention tremor, usually found in individuals with FMR1 premutation alleles (PM—CGG expansion of 55–199 repeats). Population studies estimate that between 1 in 250 and 1 in 1600 men have a PM, with up to 45% of these men suggested to develop FXTAS by age 80. We used a Bayesian approach to compare the probability of finding a specific PM genotype in an ataxia population to a population control group and found an estimated penetrance of <1% (0.031%; CI 0.007% to 0.141%) for men with ≤70 CGGs. These findings suggest that men with a PM of ≤70 CGGs, who comprise the vast majority of those with a PM, have a much lower risk of being affected with FXTAS than previously suggested. This is an issue of growing importance for accurate genetic counselling, as those with a PM of ≤70 CGGs are increasingly detected through community carrier screening or neurodevelopmental assessment programmes.

Relationships Between Mitochondrial Function, AMPK and TORC1 Signalling in Lymphoblasts with Premutation Alleles of the FMR1 Gene

“…Individuals in the 'FXTAS' group exhibited CGG expansion sizes with an apparent peak in the 80-99 repeat size range (Figure 2). Only 3 individuals (all males) in the 'FXTAS' group had CGG repeat numbers < 70, consistent with the relative rarity of FXTAS at the low end of the PM expansion size range [5,10]. The cohort of premutation participants thus exhibited the typically expected range of clinical phenotypes.…”

“…Because FMR1 resides on the X chromosome, neurological symptoms are typically milder in females, though nearly 30% of female premutation carriers present with early menopause (Fragile Xassociated primary ovarian insufficiency). A minority of PM carriers remain asymptomatic independent of their age and males with <70 repeats have been reported to be at extremely low risk of developing the condition [10]. As with many other neurodegenerative diseases, mitochondrial dysfunction has been implicated in the cytopathology of FXTAS.…”

The polyG diseases: a new disease entity

“…Women who carry the expansion will experience lower than 20% risk in having FXTAS due to random inactivation in one of two X chromosomes [ 34 ]. Males with CGG repeat numbers less than 71 have low penetrance of FXTAS [ 71 ]. In the general population, the prevalence of premutation in CGG repeat expansions is approximately 1 in 300 females and 1 in 850 males [ 21 ].…”