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.

Keywords: FMR1; FMRP; ataxia; fragile X-associated tremor/ataxia syndrome (FXTAS); neurodegeneration; neuroradiology; premutation; tremor.

Figure 1

Clinical manifestations of the fragile X premutation and fragile X-associated tremor/ataxia syndrome (FXTAS) overtime. * Clinical manifestations which are more prevalent in females with the fragile X premutation than males. (Adapted from Leehey et al. 2007; Greco et al. 2006) [42,75].

Figure 2

Repeat associated non-AUG (RAN) translation in FXTAS. RAN translation leads to the production of RAN products depending on the location where the initiation of translation occurs. Initiation (black triangles) occurring in the +0 reading frame leads to the production of FMRpolyR (green squares), +1 to FMRpolyG (brown squares), and +2, within the CGG-repeat region, to the production of FMRpolyA (yellow squares). (Adapted from Glineburg et al. 2018) [127].

Figure 3

FMR1 RNA induced protein sequestration. The expanded CGG-repeat region in the FMR1 free mRNA can form higher-order structures that can sequester proteins which results in a deficiency within the cell from those proteins. The CGG-repeat region is directly bound by repeat binding proteins such as heterogeneous nuclear ribonucleoproteins A2/B1 (hnRNP A2/B1), DiGeorge syndrome critical region 8 (DGCR8) protein, and Pur-alpha ((Purα) protein. The CGG-repeat region can also indirectly sequester other proteins through the interaction with the directly bound proteins. Proteins that can be indirectly sequestered include Drosha and heterochromatin protein 1 (HP1). (Adapted from Hagerman and Hagerman 2016 and Glineburg et al. 2018) [12,127].

Figure 4

Neuroradiological criteria for the diagnosis of FXTAS. (A) T2-FLAIR: white matter lesions in the splenium of the corpus callosum, (B) T2-TSE: symmetrical white matter lesions in the middle cerebellar peduncles (MCP sign), (C) T2-FLAIR: cerebral white matter lesions and brain atrophy.

Figure 5

New therapeutic approaches and associated molecular pathways. (A) Compounds such as curcumin and piperine have shown to selectively bind the CGG repeat hairpin structure, inhibiting sequestration of RNA and other proteins that are normally involved in cellular mechanisms such as splicing, microRNA processing, and RNA transportation. By inhibiting the sequestration of such proteins, the cell is no longer functionally deficient from them, improving splicing alterations and reducing ribonuclear inclusions formation. (B) Curcumin and piperine can also decrease the synthesis of toxic homopolymeric proteins such as FMRpolyG (brown squares) and FMRpolyA (yellow squares), therefore reducing neuronal toxic effects caused by them [167,168]. (Adapted from Hagerman and Hagerman 2016; Glineburg et al. 2018) [12,127].