Fragile X-Associated Tremor Ataxia Syndrome: The Expanding Clinical Picture, Pathophysiology, Epidemiology, and Update on Treatment

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive degenerative movement disorder characterized by kinetic tremor, cerebellar gait ataxia, parkinsonism, and cognitive decline. This disorder occurs in both males and females, frequently in families with children who have fragile X syndrome. The clinical features of this disorder, both classic and newly described, are summarized in this paper. In screening studies, fragile X mental retardation 1 (FMR1) gene premutation (55-200 CGG) expansions are most frequently seen in men with ataxia who have tested negative for spinocerebellar ataxias. Since the original description, the classic FXTAS phenotype has now been reported in females and in carriers of smaller (45-54 CGG) and larger (.200 CGG) expansions in FMR1. Premutation carriers may present with a Parkinson disease phenotype or hypotension, rather than with tremor and/or ataxia. Parkinsonism and gait ataxia may also be seen in individuals with gray zone (41-54 CGG) expansions. Studies regarding medication to treat the symptoms in FXTAS are few in number and suggest that medications targeted to specific symptoms, such as kinetic tremor or gait ataxia, may be most beneficial. Great progress has been made in regards to FXTAS research, likely given the readily available gene test and the screening of multiple family members, including parents and grandparents, of fragile X syndrome children. Expansion of genotypes and phenotypes in the disorder may suggest that a broader disease definition might be necessary in the future.

Late Onset Tremor and Ataxia Syndrome: FXTAS and its Ignored Peripheral Nervous System Findings in Diagnostic Criteria

“…Pathological studies show that FXTAS is an inclusion disorder, likely to be related to an RNA toxicity mechanism precipitated by an increased level of FMR1 mRNA, which includes CGG expansion. The most prominent neuropathological features obtained from autopsy researches of FXTAS are as follows: ubiquitin-positive eosinophilic intranuclear inclusions in neurons and astrocytes throughout the brain and brainstem and spongiform changes in the white matter with mild axonal and myelin loss (3,4,5,6). The increased signal intensity in the middle cerebellar peduncle (MCP) has been incorporated in the diagnostic criteria for "definite" FXTAS (2,3,4).…”

“…Although there are many reports about peripheral neuropathy in FMR1 premutation carriers with FXTAS, this common feature has not been added to the diagnostic criteria (1,2,5,7,8). Postmortem pathological analysis of individuals with FXTAS has shown this widespread central and peripheral nervous system and non-nervous system involvement (3,6,9). FXTAS is a late life neurodegenerative disorder involved in both the central and peripheral nervous systems.…”

A Chinese case of fragile X-associated tremor/ataxia syndrome (FXTAS) with orthostatic tremor:case report and literature review on tremor in FXTAS

“…The premutation is also associated with fragile Xassociated primary ovarian insufficiency (FXPOI) in female and full-mutation carriers with over 200 repeats is associated with the Fragile X Syndrome (FXS), which is characterized by childhood-onset intellectual disability, seizures and autism. In western countries the FMR1 premutation occurs in 1/800 males and 1/250 females, with FXTAS affecting 40-45% of male and 8-16% of female premutation carriers over the age of 50 [42]. It is estimated that there are many FXTAS patients in China because of the huge baseline population.…”

Postural Tremor and Ataxia Progression in Spinocerebellar Ataxias

“…Among hereditary ataxic disorders, patients with SCA10 7 , 8 or fragile X-associated tremor/ataxia syndrome 9 have prominent postural tremor as the disease hallmark. Postural tremor has been reported to be present in other forms of SCA patients in several case reports, 10 – 19 and can also be a prominent feature in CAG-repeat SCAs, 20 – 23 especially in SCA2.…”