What is FXTAS and the FMR1 gene?
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder first described in 2001 by Hagerman et al. observed in premutation carriers of the FMR1 gene [1]. FMR1 stands for Fragile X Messenger Ribonucleoprotein 1, which replaced the former name, Fragile X Mental Retardation 1 gene, in 2022 [2]. The FMR1 gene contains a CGG repeat in the promotor region that is up to 45 CGGs long in the normal population. Carriers of the premutation allele have between 55 and 200 CGG repeats and are at risk of developing FXTAS. The repeat can expand or contract from one generation to the next. An expansion to more than 200 repeats occurs only during maternal transmission and is associated with the silencing of the FMR1 gene leading to the lack of production of Fragile X messenger ribonucleoprotein (FMRP). This is the cause of fragile X syndrome (FXS), which is the most common inherited single-gene disorder that causes autism and intellectual disability. Due to the expansion effect of the CGG repeat length over generations, it is common to find FXTAS in one generation and FXS in the grandchildren within the same family [3].
How frequent is it?
Approximately 1 in 200 women and 1 in 400 men in the general population are carriers of the FMR1 premutation. FXTAS penetrance and severity increases with age, CGG repeat length increase, and in men compared to women due to the protective effect of a second usually normal FMR1 allele in women. Around 60% of male carriers and 16% of female carriers will develop FXTAS by age 70 [3] [1].
What are the symptoms of FXTAS?
The classic clinical presentation of FXTAS is kinetic tremor and cerebellar gait ataxia in male or female FMR1 premutation carriers over the age of 60. To a lesser extent, they may present peripheral neuropathy, endocrinological alterations, executive function deficits, memory deficits and autonomic dysfunction (including hypertension, hypotension, erectile dysfunction and incontinence). Eventually, approximately 50% of men with FXTAS will develop dementia. Table 1 shows the 6 FXTAS stages which have been ascribed according to the severity of motor symptoms [3] [1]. (Figure 1)
What is the pathophysiology of FXTAS?
The pathophysiology of FXTAS is proposed to involve RNA toxicity due to elevated levels of FMR1 mRNA containing the expanded CGG repeat tract in the premutation range, which can sequester a variety of proteins important for neuronal functioning [1].
Intranuclear inclusions within neurons and astrocytes have been observed in the brains of patients with FXTAS and constitute the main anatomopathological hallmark of the disorder [3] [1].
How is FXTAS diagnosed?
FXTAS is diagnosed by fulfilling criteria, which include being an FMR1 premutation carrier and the appearance of neurological, MRI and pathological findings, as shown in Table 2 [3]. (Figure 2)
Is there any treatment for FXTAS?
Currently, no evidence-based curative treatment for FXTAS is available, although symptomatic treatments of associated cognitive, psychiatric and movement disorders have proven to be useful [1].