Differential Progression of Motor Dysfunction Between Male and Female Fragile X Premutation Carriers Reveals Novel Aspects of Sex-Specific Neural Involvement

Abstract

Expansions of the CGG repeat in the non-coding segment of the FMR1 X-linked gene are associated with a variety of phenotypic changes. Large expansions (>200 repeats), which cause a severe neurodevelopmental disorder, the fragile x syndrome (FXS), are transmitted from the mothers carrying smaller, unstable expansions ranging from 55 to 200 repeats, termed the fragile X premutation. Female carriers of this premutation may themselves experience a wide range of clinical problems throughout their lifespan, the most severe being the late onset neurodegenerative condition called “Fragile X-Associated Tremor Ataxia Syndrome” (FXTAS), occurring between 8 and 16% of these carriers. Male premutation carriers, although they do not transmit expanded alleles to their daughters, have a much higher risk (40–50%) of developing FXTAS. Although this disorder is more prevalent and severe in male than female carriers, specific sex differences in clinical manifestations and progress of the FXTAS spectrum have been poorly documented. Here we compare the pattern and rate of progression (per year) in three motor scales including tremor/ataxia (ICARS), tremor (Clinical Tremor Rating scale, CRST), and parkinsonism (UPDRS), and in several cognitive and psychiatric tests scores, between 13 female and 9 male carriers initially having at least one of the motor scores ≥10. Moreover, we document the differences in each of the clinical and cognitive measures between the cross-sectional samples of 21 female and 24 male premutation carriers of comparable ages with FXTAS spectrum disorder (FSD), that is, who manifest one or more features of FXTAS. The results of progression assessment showed that it was more than twice the rate in male than in female carriers for the ICARS-both gait ataxia and kinetic tremor domains and twice as high in males on the CRST scale. In contrast, sex difference was negligible for the rate of progress in UPDRS, and all the cognitive measures. The overall psychiatric pathology score (SCL-90), as well as Anxiety and Obsessive/Compulsive domain scores, showed a significant increase only in the female sample. The pattern of sex differences for progression in motor scores was consistent with the results of comparison between larger, cross-sectional samples of male and female carriers affected with the FSD. These results were in concert with sex-specific distribution of MRI T2 white matter hyperintensities: all males, but no females, showed the middle cerebellar peduncle white matter hyperintensities (MCP sign), although the distribution and severity of these hyperintensities in the other brain regions were not dissimilar between the two sexes. In conclusion, the magnitude and specific pattern of sex differences in manifestations and progression of clinically recorded changes in motor performance and MRI lesion distribution support, on clinical grounds, the possibility of certain sex-limited factor(s) which, beyond the predictable effect of the second, normal FMR1 alleles in female premutation carriers, may have neuroprotective effects, specifically concerning the cerebellar circuitry.

Cellular Bioenergetics and AMPK and TORC1 Signalling in Blood Lymphoblasts Are Biomarkers of Clinical Status in FMR1 Premutation Carriers

“…Notably, the Basal Respiration Rate, ATP synthesis and Non-mitochondrial bioenergetics components are also highly correlated with the SCL90 GSI total, and /or Anxiety and Depression domains. This finding is not unexpected considering that neuropsychiatric features have been a major issue in both FXTAS and non-FXTAS carriers, especially females (6,29,(80)(81)(82)(83). Consistent with the extent of these problems across carrier categories, in this study we found significant correlations of these neuropsychiatric features with bioenergetic changes in the FXTAS subgroup, as well as in the combined (FXTAS and non-FXTAS) sample of PM carriers.…”

“…Consistent with the extent of these problems across carrier categories, in this study we found significant correlations of these neuropsychiatric features with bioenergetic changes in the FXTAS subgroup, as well as in the combined (FXTAS and non-FXTAS) sample of PM carriers. This result calls for more attention to these well-documented and prevalent neuropsychiatric problems; since they occur both in obviously affected and non-affected PM carriers, the need for early intervention is emphasised, following our earlier recommendations for the female carriers (6). Moreover, both measures of executive functioning (Matrix Reasoning and Digit Span Backward), which are known to be affected early in the non-FXTAS carriers, are significantly correlated with the elevated bioenergetics and cellular stress response components in this subgroup.…”

“…The other source of the female cohort (10 individuals) was an earlier 2008–2010 project supported by a research grant from the National Health and Medical Research of Australia (NHMRC) to ES and DL. These females, who had originally been ascertained either through their Fragile X Syndrome (FXS) children diagnosed at the Genetic Counselling clinics in the states of Victoria and South Australia, or were identified through cascade testing, were incorporated in an earlier study of progression of motor dysfunction based on a larger sample of female PM carriers ( 6 ). All PM participants were originally classified as belonging to the “FXTAS” spectrum (“FXTAS”), asymptomatic (“Unaffected”), and “Other” categories [as in: ( 40 )]; the latter category comprising individuals with isolated features occurring in FXTAS, such as fibromyalgia, dementia, isolated kinetic tremor, mild ataxia, anxiety/depression, autism.…”

“…The most severe premutation-associated disorder affecting carriers of the FMR1 premutation allele is the late onset progressive neurodegenerative condition termed Fragile X Associated Tremor/Ataxia Syndrome (FXTAS), affecting 40−50% of male carriers after the age of 55, and 8-16.5% female carriers in the same age group (2)(3)(4). The much lower risk of FXTAS in females than in males may be, at least partly, attributed to the protective role of the normal FMR1 allele on the second X chromosome (5), but the existence of other sex-limited protective factors has recently been postulated (6). The standard diagnostic (core) features of FXTAS require one or more of the following pathological changes: intention tremor; cerebellar ataxia; and white matter disease in the middle cerebellar peduncles (MCP sign) seen on magnetic resonance imaging (MRI) (7,8); white matter disease in the splenium of the corpus callosum (9) has more recently been considered another core FXTAS feature.…”

‘Essential Tremor’ Phenotype in FMR1 Premutation/Gray Zone Sibling Series: Exploring Possible Genetic Modifiers

“…Especially considering that the postulated modifying effect of this parkinsonian genome, this is more likely to only apply to subpopulations of individuals in respective diagnostic categories who also manifest parkinsonian features in addition to their specific FXTAS or ET phenotypes. This assumption is substantiated by the common (in~30%) occurrence of parkinsonian features in FXTAS, combined with the lack of ameliorating effect of the normal FMR1-X chromosome on the parkinsonian (UPDRS) score in a cohort of the female PM carriers (Loesch et al, 2021). On the other hand, the reported excess of carriers of GZ alleles in several independent PD cohorts (Hall et al, 2011;Loesch et al, 2009;Loesch et al, 2013;Loesch et al, 2018) indicates a possible combined effect of these alleles and the assumed PD risk genotype.…”