Abstract
The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55–200 CGG repeats) carriers of FMR1. The premutation has excessive levels of FMR1 mRNA that lead to toxicity and mitochondrial dysfunction. The clinical features usually begin in the 60 s with an action or intention tremor followed by cerebellar ataxia, although 20% have only ataxia. MRI features include brain atrophy and white matter disease, especially in the middle cerebellar peduncles, periventricular areas, and splenium of the corpus callosum. Neurocognitive problems include memory and executive function deficits, although 50% of males can develop dementia. Females can be less affected by FXTAS because of a second X chromosome that does not carry the premutation. Approximately 40% of males and 16% of female carriers develop FXTAS. Since the premutation can occur in less than 1 in 200 women and 1 in 400 men, the FXTAS diagnosis should be considered in patients that present with tremor, ataxia, parkinsonian symptoms, neuropathy, and psychiatric problems. If a family history of a fragile X mutation is known, then FMR1 DNA testing is essential in patients with these symptoms.
Highlights
Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and autism spectrum disorder (ASD)
The fragile X mental retardation 1 (FMR1) gene normally codes for the fragile X mental retardation protein (FMRP) and silencing of the gene leads to loss of expression of the protein
Three different molecular mechanisms have been studied with the aim of understanding the molecular abnormalities resulting in the neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS): (1) the production of toxic FMRpolyG by repeat associated non-AUG (RAN) translation, (2) RNAs and protein sequestration into intranuclear inclusions and (3) DNA damage caused by R-loop formation
Summary
Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and autism spectrum disorder (ASD). There have been reports of individuals with the full mutation (FM) who present with a clinical picture consistent with FXTAS These individuals with the FM present with size mosaicism and/or lack of methylation of the FMR1 gene and have elevated mRNA levels and some production of FMRP [15,16,17]. These cases have made experts consider modifications of clinical criteria for diagnosing FXTAS to involve premutation carriers and those with a gray zone or FM repeat number [18]. It is noteworthy that the prevalence varies greatly globally with some countries reporting regions with prevalence as high as 1 in 28 females and 1 in 71 males [20] and with Japan being the country with the lowest reported prevalence of the PM allele [21]
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