Male carriers of the FMR1 premutation are at risk of developing the fragile X-associated tremor/ataxia syndrome (FXTAS), a newly recognised and largely under-diagnosed late onset neurodegenerative disorder. Patients affected with FXTAS primarily present with cerebellar ataxia and intention tremor. Cognitive decline has also been associated with the premutation, but the lack of data on its penetrance is a growing concern for clinicians who provide genetic counselling.
The Mattis Dementia Rating Scale (MDRS) was administered in a double blind fashion to 74 men aged 50 years or more recruited from fragile X families (35 premutation carriers and 39 intrafamilial controls) regardless of their clinical manifestation. Based on previous publications, marked cognitive impairment was defined by a score <or=123 on the MDRS.
Both logistic and survival models confirmed that in addition to age and education level, premutation size plays a significant (p<0.01 and p<0.03 for logistic and survival model, respectively) role in cognitive impairment. The estimated penetrance of marked cognitive impairment in our sample (adjusted for the mean age 63.4 years and mean education level 9.7 years) for midsize/large (70-200 CGG) and small (55-69 CGG) premutation alleles was 33.3% (relative risk (RR) 6.5; p = 0.01) and 5.9% (RR 1.15; p = 0.9) respectively. Penetrance in the control group was 5.1%.
Male carriers of midsize to large premutation alleles had a sixfold increased risk of developing cognitive decline and the risk increases with allele size. In addition, it was observed that cognitive impairment may precede motor symptoms. These data provide guidance for genetic counselling although larger samples are required to refine these estimates.
"They were included in the aPM group when the CGG repeat size was equal or >55 but <200 and in the control group when the CGG repeat size was <55. Exclusion criteria included (1) the presence of motor symptoms suggestive of possible or probable FXTAS assessed by a movement disorder specialist using 3 standardized movement disorder scales (Fahn et al., 1993; Stebbins and Goetz, 1998; Trouillas et al., 1997); (2) signs of subcortical dementia using the Mattis Dementia Rating Scale (MDRS) with a cutoff of 123 (Mattis, 1976; Sevin et al., 2009); and (3) WM alterations visible on fluid-attenuated inversion recovery (FLAIR) images examined by an experienced neuroradiologist blind to the genetic status of the participants. Three aPM participants (aged 57, 62, and 66 years) were excluded from the study because of the presence of WM lesions visible on FLAIR images (diffused WM lesions in cerebellum and cerebral hemispheres). "
[Show abstract][Hide abstract] ABSTRACT: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset movement disorder associated with FMR1 premutation alleles. Asymptomatic premutation (aPM) carriers have preserved cognitive functions, but they present subtle executive deficits. Current efforts are focusing on the identification of specific cognitive markers that can detect aPM carriers at higher risk of developing FXTAS. This study aims at evaluating verbal memory and executive functions as early markers of disease progression while exploring associated brain structure changes using diffusion tensor imaging. We assessed 30 aPM men and 38 intrafamilial controls. The groups perform similarly in the executive domain except for decreased performance in motor planning in aPM carriers. In the memory domain, aPM carriers present a significant decrease in verbal encoding and retrieval. Retrieval is associated with microstructural changes of the white matter (WM) of the left hippocampal fimbria. Encoding is associated with changes in the WM under the right dorsolateral prefrontal cortex, a region implicated in relational memory encoding. These associations were found in the aPM group only and did not show age-related decline. This may be interpreted as a neurodevelopmental effect of the premutation, and longitudinal studies are required to better understand these mechanisms.
Neurobiology of aging 02/2014; 35(8). DOI:10.1016/j.neurobiolaging.2014.01.150 · 5.01 Impact Factor
"However, it should be appreciated that a substantial proportion of the variance in age of onset in Huntington disease is due either to variation in genes other than HTT or in the environment (Wexler et al. 2004). Other repeat expansion disorders characterized by reduced penetrance of alleles of intermediate size include fragile X-associated tremor/ataxia syndrome (Jacquemont et al. 2004; Sévin et al. 2009), spinocerebellar ataxia types 10 (Alonso et al. 2006; Rankin et al. 2008) and 17 (Oda et al. 2004; Nolte et al. 2010), inherited prion disease (Kaski et al. 2011) and amyotrophic lateral sclerosis (Boeve et al. 2012; Ogaki et al. 2012). "
[Show abstract][Hide abstract] ABSTRACT: Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known as 'reduced (or incomplete) penetrance'. Reduced penetrance is not uncommon; indeed, there are many known examples of 'disease-causing mutations' that fail to cause disease in at least a proportion of the individuals who carry them. Reduced penetrance may therefore explain not only why genetic diseases are occasionally transmitted through unaffected parents, but also why healthy individuals can harbour quite large numbers of potentially disadvantageous variants in their genomes without suffering any obvious ill effects. Reduced penetrance can be a function of the specific mutation(s) involved or of allele dosage. It may also result from differential allelic expression, copy number variation or the modulating influence of additional genetic variants in cis or in trans. The penetrance of some pathogenic genotypes is known to be age- and/or sex-dependent. Variable penetrance may also reflect the action of unlinked modifier genes, epigenetic changes or environmental factors. At least in some cases, complete penetrance appears to require the presence of one or more genetic variants at other loci. In this review, we summarize the evidence for reduced penetrance being a widespread phenomenon in human genetics and explore some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease.
Human Genetics 07/2013; 132(10). DOI:10.1007/s00439-013-1331-2 · 4.82 Impact Factor
"Specifically, FMR1 dosage increases with CGG repeat length, and males have a higher FMR1 ‘dose’ than females, because the premutation allele is expressed in all of their cells, and they lack a second, unaffected FMR1 allele. In support of a genetically modulated phenotypic spectrum are the findings that individuals with FXS or the premutation (with or without FXTAS) share symptoms of executive function impairments [21-23] that are modulated by CGG repeat length [18,19,24-26], FMR1 mRNA , and FMRP [28-32]. Additionally, CGG repeat length relates to age of onset of FXTAS  and to degree of brain atrophy . "
[Show abstract][Hide abstract] ABSTRACT: Background
A previous study reported enhanced psychomotor speed, and subtle but significant cognitive impairments, modulated by age and by mutations in the fragile X mental retardation 1 (FMR1) gene in adult female fragile X premutation carriers (fXPCs). Because male carriers, unlike females, do not have a second, unaffected FMR1 allele, male fXPCs should exhibit similar, if not worse, impairments. Understanding male fXPCs is of particular significance because of their increased risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS).
Male fXPCs (n = 18) and healthy control (HC) adults (n = 26) aged less than 45 years performed two psychomotor speed tasks (manual and oral) and two visuospatial tasks (magnitude comparison and enumeration). In the magnitude comparison task, participants were asked to compare and judge which of two bars was larger. In the enumeration task, participants were shown between one and eight green bars in the center of the screen, and asked to state the total number displayed. Enumeration typically proceeds in one of two modes: subitizing, a fast and accurate process that works only with a small set of items, and counting, which requires accurate serial-object detection and individuation during visual search. We examined the associations between the performance on all tasks and the age, full-scale intelligent quotient, and CGG repeat length of participants.
We found that in the magnitude comparison and enumeration tasks, male fXPCs exhibited slower reaction times relative to HCs, even after controlling for simple reaction time.
Our results indicate that male fXPCs as a group show impairments (slower reaction times) in numerical visuospatial tasks, which are consistent with previous findings. This adds to a growing body of literature characterizing the phenotype in fXPCs who are asymptomatic for FXTAS. Future longitudinal studies are needed to determine how these impairments relate to risk of developing FXTAS.
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