Fragile-X–Associated Tremor/Ataxia Syndrome (FXTAS) in Females with the FMR1 Premutation

Abstract

We describe five female carriers of the FMR1 premutation who presented with symptoms of tremor and ataxia and who received a diagnosis of definite or probable fragile-X-associated tremor/ataxia syndrome (FXTAS). Unlike their male counterparts with FXTAS, none of the women had dementia. Females had not been reported in previous studies of FXTAS, suggesting that they may be relatively protected from this disorder. Brain tissue was available from one of the five subjects, a women who died at age 85 years; microscopic examination revealed intranuclear neuronal and astrocytic inclusions, in accord with the findings previously reported in males with FXTAS. The work-up of families with the FMR1 mutation should include questions regarding neurological symptoms in both older male and female carriers, with the expectation that females may also manifest the symptoms of FXTAS, although more subtly and less often than their male counterparts.

Cognitive, anxiety and mood disorders in the fragile X-associated tremor/ataxia syndrome

“…Six cases (cases 1,7,9,11,12,14) were diagnosed with mood disorders, while 4 cases (cases 4, 7, 9, 11) were diagnosed with anxiety disorders. Table 2 details demographic data, number of CGG repeats, years of FXTAS, age of FXTAS onset, FXTAS stage, psychiatric diagnoses, degree of MCP sign, and other MRI findings, as well as a description of FXTAS stages.…”

Molecular genetic testing for fragile X syndrome: laboratory performance on the College of American Pathologists proficiency surveys (2001–2009)

“…2 The unstable, premutation range of 55-200 repeats is coupled with an increased risk of POI in females and the late-onset, progressive neurodegenerative condition FXTAS in males and, less often, females. 3 In female premutation carriers, the risk of expansion to a full mutation in the next generation increases with the size of the premutation, with essentially 100% risk with greater than 100 repeats. 4 Therefore, accurate diagnostic sizing in this range is essential for genetic counseling for risk of affected offspring.…”

Molecular testing for Fragile X Syndrome: Lessons learned from 119,232 tests performed in a clinical laboratory

“…11,12 Recently some premutation carrier females have been found to have some features of FXTAS. 13 In contrast, premutation alleles when inherited through the male do not expand, but his daughters are at risk of having affecting children. Although "gray zone" alleles (45-55 CGG repeats) are considered above the normal range, there have been no reported instances of an allele below 56 repeats expanding to a full allele in a single meiosis.…”