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The fragile X mental retardation 1 gene (FMR1): historical perspective, phenotypes, mechanism, pathology, and epidemiology.

ABSTRACT: To provide an historical perspective and overview of the phenotypes, mechanism, pathology, and epidemiology of the fragile X-associated tremor/ataxia syndrome (FXTAS) for neuropsychologists.Selective review of the literature on FXTAS.FXTAS is an X-linked neurodegenerative disorder of late onset. One of several phenotypes associated with different mutations of the fragile X mental retardation 1 gene (FMR1), FXTAS involves progressive action tremor, gait ataxia, and impaired executive functioning, among other features. It affects carriers of the FMR1 premutation, which may expand when passed from a mother to her children, in which case it is likely to cause fragile X syndrome (FXS), the most common inherited developmental disability.This review briefly summarizes current knowledge of the mechanisms, epidemiology, and mode of transmission of FXTAS and FXS, as well as the neuropsychological, neurologic, neuropsychiatric, neuropathologic, and neuroradiologic phenotypes of FXTAS. Because it was only recently identified, FXTAS is not well known to most practitioners, and it remains largely misdiagnosed, despite the fact that its prevalence may be relatively high.

SUBMITTER: Grigsby J

PROVIDER: S-EPMC5011753 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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The fragile X mental retardation 1 gene (FMR1): historical perspective, phenotypes, mechanism, pathology, and epidemiology.

Grigsby Jim J

The Clinical neuropsychologist 20160629 6

<h4>Objectives</h4>To provide an historical perspective and overview of the phenotypes, mechanism, pathology, and epidemiology of the fragile X-associated tremor/ataxia syndrome (FXTAS) for neuropsychologists.<h4>Methods</h4>Selective review of the literature on FXTAS.<h4>Results</h4>FXTAS is an X-linked neurodegenerative disorder of late onset. One of several phenotypes associated with different mutations of the fragile X mental retardation 1 gene (FMR1), FXTAS involves progressive action tremo ...[more]

PMID: 27356167

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Project description:BackgroundIndividuals with premutation alleles of the fragile X mental retardation 1 (FMR1) gene are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS) during aging. Characterization of motor issues associated with aging in FMR1 premutation carriers is needed to determine neurodegenerative processes and establish new biobehavioral indicators to help identify individuals at greatest risk of developing FXTAS.MethodsWe examined postural stability in 18 premutation carriers ages 46-77 years and 14 age-matched healthy controls. Participants completed a test of static stance and two tests of dynamic postural sway on a force platform to quantify postural variability and complexity. CGG repeat length was measured for each premutation carrier, and MRI and neurological evaluations were conducted to identify carriers who currently met criteria for FXTAS. Of the 18 premutation carriers, seven met criteria for definite/probable FXTAS (FXTAS+), seven showed no MRI or neurological signs of FXTAS (FXTAS-), and four were inconclusive due to insufficient data.ResultsCompared to controls, premutation carriers showed increased center of pressure (COP) variability in the mediolateral (COPML) direction during static stance and reduced COP variability in the anterior-posterior (COPAP) direction during dynamic AP sway. They also showed reductions in COPML complexity during each postural condition. FXTAS+ individuals showed reduced COPAP variability compared to FXTAS- carriers and healthy controls during dynamic AP sway. Across all carriers, increased sway variability during static stance and decreased sway variability in target directions during dynamic sways were associated with greater CGG repeat length and more severe neurologically rated posture and gait abnormalities.ConclusionOur findings indicate that aging FMR1 premutation carriers show static and dynamic postural control deficits relative to healthy controls implicating degenerative processes of spinocerebellar and cerebellar-brainstem circuits that may be independent of or precede the onset of FXTAS. Our finding that FXTAS+ and FXTAS- premutation carriers differed on their level of intentional AP sway suggests that neural mechanisms of dynamic postural control may be differentially impacted in patients with FXTAS, and its measurement may be useful for rapidly and precisely identifying disease presence and onset.

Project description:Fragile X premutation alleles have 55-200 CGG repeats in the 5' UTR of the FMR1 gene. Altered zinc (Zn) homeostasis has been reported in fibroblasts from >60 years old premutation carriers, in which Zn supplementation significantly restored Zn-dependent mitochondrial protein import/processing and function. Given that mitochondria play a critical role in synaptic transmission, brain function, and cognition, we tested FMRP protein expression, brain bioenergetics, and expression of the Zn-dependent synaptic scaffolding protein SH3 and multiple ankyrin repeat domains 3 (Shank3) in a knock-in (KI) premutation mouse model with 180 CGG repeats. Mitochondrial outcomes correlated with FMRP protein expression (but not FMR1 gene expression) in KI mice and human fibroblasts from carriers of the pre- and full-mutation. Significant deficits in brain bioenergetics, Zn levels, and Shank3 protein expression were observed in the Zn-rich regions KI hippocampus and cerebellum at PND21, with some of these effects lasting into adulthood (PND210). A strong genotype × age interaction was observed for most of the outcomes tested in hippocampus and cerebellum, whereas in cortex, age played a major role. Given that the most significant effects were observed at the end of the lactation period, we hypothesized that KI milk might have a role at compounding the deleterious effects on the FMR1 genetic background. A higher gene expression of ZnT4 and ZnT6, Zn transporters abundant in brain and lactating mammary glands, was observed in the latter tissue of KI dams. A cross-fostering experiment allowed improving cortex bioenergetics in KI pups nursing on WT milk. Conversely, WT pups nursing on KI milk showed deficits in hippocampus and cerebellum bioenergetics. A highly significant milk type × genotype interaction was observed for all three-brain regions, being cortex the most influenced. Finally, lower milk-Zn levels were recorded in milk from lactating women carrying the premutation as well as other Zn-related outcomes (Zn-dependent alkaline phosphatase activity and lactose biosynthesis-whose limiting step is the Zn-dependent ?-1,4-galactosyltransferase). In premutation carriers, altered Zn homeostasis, brain bioenergetics and Shank3 levels could be compounded by Zn-deficient milk, increasing the risk of developing emotional and neurological/cognitive problems and/or FXTAS later in life.

Dataset Information

The fragile X mental retardation 1 gene (FMR1): historical perspective, phenotypes, mechanism, pathology, and epidemiology.

Publications

The fragile X mental retardation 1 gene (FMR1): historical perspective, phenotypes, mechanism, pathology, and epidemiology.

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