Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications

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.

Mutant Huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease

“…The Fmrp, another RBP, can bind to ribosomes and regulate ribosome stalling [16][17][18] . The depletion of Fmr1, as observed in Fragile X syndrome, results in increased protein synthesis that is linked to synaptic and behavioral defects and that can also elicit the neurodegenerative phenotype in Fragile X-associated tremor/ataxia syndrome 19,20 . Deficits in rescuing ribosome stalling may also promote neurodegeneration 2,21 .…”

Human Cerebral Cortex Proteome of Fragile X-Associated Tremor/Ataxia Syndrome

“…Approximately 30-40% of male and 8-16% of female PM carriers will develop FXTAS, with onset of initial symptoms typically beginning in males in their early 60's (Leehey et al, 2007;Hagerman and Hagerman, 2016). Symptoms of FXTAS include intention tremor, gait ataxia, parkinsonism, neuropathy, white matter disease, and cognitive decline (Hall et al, 2014;Hagerman and Hagerman, 2016;Kong et al, 2017;Cabal-herrera et al, 2020). The principal neuropathological feature of FXTAS is the presence of generally solitary intranuclear inclusions in both neurons and astrocytes within the central nervous system (CNS) (Greco et al, 2002(Greco et al, , 2006Garcia-Arocena et al, 2009;Martínez Cerdeño et al, 2018), as well as in diverse non-CNS tissues (Greco et al, 2007;Hunsaker et al, 2011), mitochondrial dysfunction (Ross-Inta et al, 2010;Napoli et al, 2011;Kaplan et al, 2012;Cabal-herrera et al, 2020), microglia activation and senescence (Martínez Cerdeño et al, 2018), iron deposition (Ariza et al, 2018), and dysregulation of neuronal Ca 2+ (Robin et al, 2017;Hagerman et al, 2018).…”

(Dys)function Follows Form: Nucleic Acid Structure, Repeat Expansion, and Disease Pathology in FMR1 Disorders

“…R-loop formation at the FMR1 locus has also been proposed as a source of pathology in PM carriers [49,119] as illustrated in Figure 2B. R-loops are prone to single-stranded breaks and DSBs resulting from clustered single-stranded breaks [120].…”