Women with Fragile X–associated Tremor/Ataxia Syndrome

Abstract

Background Background: Fragile X-associated tremor and ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder linked to the FMR1 premutation. Objectives Objectives: FXTAS in women is far less common than in men, and this study represents the largest sample reported to date. Methods Methods: A total of 53 female premutation carriers with FXTAS (mean age , 66.83 years; FXTAS stages 2-5) and 55 age-matched and demographic background-matched control participants (mean age , 61.94 years) underwent a comprehensive molecular, physiological, neuropsychological, and psychiatric assessment. Results Results: The large sample of female premutation carriers showed a wide range of variability of clinical signs and symptom progression. The imaging results showed a middle cerebellar peduncles sign in only 6 patients; another symptom included high-signal intensity in the splenium of the corpus callosum, and diffuse cerebral deep white matter changes (e.g., in the pons) are more common. The rate of psychiatric disorders, especially depression, is higher than in the general population. There is a clear impairment in executive functioning and fine motor skills in connection with a higher FXTAS stage. Conclusions Conclusions: The manifestation of FXTAS symptoms in female carriers can be diverse with a milder phenotype and a lower penetrance than those observed in male premutation carriers. The middle cerebellar peduncles sign is present in only a small percentage of the sample, and we propose that the imaging criteria for FXTAS in women need to be expanded.

Dystonia in a Female Fragile X Premutation Carrier

“…Radiological abnormalities in thalamus, basal ganglia and the splenium of the corpus callosum have also been reported 9 . However, radiologic findings are milder in female premutation carriers as compared with males and white matter hyperintensities in the splenium and genu of corpus callosum are more frequent than the MCP sign 5 …”

“…Therefore, our report contributes to the previous literature emphasizing that dystonia should be included in the spectrum of clinical manifestations in FMR1 premutation carriers. That is of interest as dystonia is not included in the diagnostic criteria of FXTAS and could potentially be another etiology of the tremor seen in FXTAS 5 …”

“…That is of interest as dystonia is not included in the diagnostic criteria of FXTAS and could potentially be another etiology of the tremor seen in FXTAS. 5 Premutation carriers have slightly reduced FMR1 protein levels with significant elevation of FMR1 messenger RNA (mRNA) and a potential toxic effect in brain white matter and motor fiber tracts has been proposed. 6,7 Pathophysiologic findings in patients with FXTAS include marked dropout of Purkinje cells and white matter disease throughout the cerebellum, including the MCP.…”

“…9 However, radiologic findings are milder in female premutation carriers as compared with males and white matter hyperintensities in the splenium and genu of corpus callosum are more frequent than the MCP sign. 5 Recent studies have suggested that alterations in activity, connectivity and structure of the cerebellum may play a role in the development of dystonia. There is evidence supporting that cerebellar atrophy, cerebellar degenerative disease, cerebellar lesions and histopathological alterations such as Purkinje cell loss or dentate nucleus cell loss may be associated with dystonia.…”

Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

“…The worldwide prevalence of the PM is approximately 1:300 in females and 1:850 in males [5]. The risk to develop FXTAS (OMIM #300623) is higher in men than in women: from 17% to 75% of the PM male carriers as age increases, and only from 8 to 16% in PM carrier women [6,7] who exhibit a diverse phenotype much milder than those observed in men, possibly due to the female inactivation of chromosome X [8]. FXTAS is a late onset neurodegenerative disorder characterized by intention tremor usually accompanied by slow movement and parkinsonism, which develop into cerebellar gait ataxia and dystonia as the disease progresses, and by cognitive deficits (e.g., short-term memory loss, executive functions impairment, language capacity affectation), mood disorders and neuropsychiatric alterations, peripheral neuropathy, sleep disturbance and other signs [6,9,10].…”