Phenotypes of hypofrontality in older female fragile X premutation carriers

Abstract

Objective To investigate the nature of cognitive impairments and underlying brain mechanisms in older female fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome (FXTAS). Methods Extensive neuropsychological testing and cognitive event-related brain potentials (ERPs, particularly, the auditory P300) were examined in 84 female participants: 33 fragile X premutation carriers with FXTAS (mean age = 62.8), 25 premutation carriers without FXTAS (mean age = 55.4) and 26 normal healthy controls (mean age = 59.3). Results Both premutation groups exhibited executive dysfunction on the Behavioral Dyscontrol Scale (BDS), with subtle impairments in inhibition and performance monitoring in female carriers without FXTAS, and more substantial deficits in FXTAS women. However, the female carrier group without FXTAS showed more pronounced deficiencies in working memory. Abnormal ERPs were recorded over the frontal lobes, where FXTAS patients showed both P300 amplitude reduction and latency prolongation, while only decreased frontal P300 amplitudes were found in carriers without FXTAS. These frontal P3 measures correlated with executive function and information processing speed. Interpretation The neuropsychological testing and ERP results of the present study provide support for the hypothesis that executive dysfunction is the primary cognitive impairment among older female premutation carriers both with and without FXTAS, although these deficits are relatively mild compared to those in FXTAS males. These findings are consistent with a synergistic effect of the premutation and aging on cognitive impairment among older female fragile X premutation carriers, even in those without FXTAS symptoms.

Complex Neurological Phenotype in Female Carriers of <b><i>NHE6</i></b> Mutations

“…Visuospatial and executive function deficits have been found in individuals with other X-linked disorders such as Fragile X [21] and Turner [22] syndromes, as well as in female carriers of Fragile X mutations [23, 24]. Such deficits may be linked to the frontoparietal white and gray matter abnormalities [22, 25], consistent with the known localization of visuospatial and executive functions to the parietal and frontal regions, respectively.…”

“…Alternatively, as the lateral and posterior cerebellar regions are involved in visuospatial and executive functions [26] and given the cerebellar atrophy observed in some CS probands [2], cerebellar involvement could be the underlying mechanism of impaired visuospatial and executive functioning in female carriers. Furthermore, visuospatial and executive dysfunction with associated frontoparietal abnormalities is also known to occur in relevant neurodegenerative conditions such as Fragile X-associated tremor/ataxia syndrome [23, 24, 27] and CBD [28, 29]. Similar to other X-linked disorders, visuospatial and executive dysfunction may represent a neurocognitive phenotype in the female carriers of NHE6 mutations.…”

Bryostatin-1 Restores Hippocampal Synapses and Spatial Learning and Memory in Adult Fragile X Mice

“…The FXS includes general deficits in cognition ( Van der Molen et al, 2010;Yang et al, 2013), abnormal in memory (Koekkoek et al, 2005), and anxiety and autistic-like behavior (Sabaratnam et al, 2003;Garber et al, 2008).…”

Genetics of primary ovarian insufficiency: a review

“…In any case, these deficits are relatively mild if compared to those in FXTAS males [31]. In 2013, a case of a 31-year-old patient with FMR1 premutation and a low ovarian reserve was published, in whom, as a result of the very low response of these patients to stimulation with exogenous gonadotropins, a decision was made to carry out a serial in vitro oocyte maturation (IVM) protocol.…”