Intranuclear inclusions in a fragile X mosaic male

Dalyir I Pretto,Flora Tassone,Deborah A Hall,Christopher L Cunningham,Paul J Hagerman,Michael R Hunsaker,Claudia M Greco,Randi J Hagerman,Stephen C Noctor

doi:10.1186/2047-9158-2-10

Abstract

Lack of the fragile X mental retardation protein leads to Fragile X syndrome (FXS) while increased levels of FMR1 mRNA, as those observed in premutation carriers can lead to Fragile X- associated tremor ataxia syndrome (FXTAS). Until recently, FXTAS had been observed only in carriers of an FMR1 premutation (55–200 CGG repeats); however the disorder has now been described in individuals carriers of an intermediate allele (45–54 CGG repeats) as well as in a subject with a full mutation with mosaicism.Here, we report on molecular and clinical data of a male FMR1 mosaic individual with full and premutation alleles. Molecular analysis of FMR1 and FMRP expression in this subject is consistent with a FXS phenotype. We observed reduced expression of FMRP in both peripheral blood and brain leading to the FXS diagnosis. In addition, a dramatic 90% depletion of both FMR1 mRNA and FMRP levels was observed in the blood, as normally observed in FXS cases, and an even greater depletion in the brain. A clinical report of this patient, at age 71, described neurodegenerative signs of parkinsonism that were likely, in retrospect, part of a FXTAS scenario as post-mortem examination shows the presence of intranuclear inclusions, the hallmark pathology of FXTAS.The findings presented in this study indicate co-morbidity for both FXS and FXTAS in this individual carrying both full and premutation FMR1 alleles. In addition, based on symptoms and pathological and molecular evidence, this report suggests the need to redefine the diagnostic criteria of FXTAS.

Highlights

Two very different disorders arise from a CGG repeat expansion mutation at the promoter region of the X-linked FMR1 gene: Fragile X syndrome (FXS) and Fragile X -associated tremor ataxia syndrome (FXTAS)
Later in life this individual showed features congruent with the minor diagnostic criteria for FXTAS, but this diagnosis was not given due to lack of appreciable FMR1 mRNA levels and the presence of FXS symptomatology [23]
Upon post mortem analysis we observed the presence of intranuclear inclusions throughout the brain, one of the major diagnostic criteria for FXTAS [27]

Summary

Introduction

Two very different disorders arise from a CGG repeat expansion mutation at the promoter region of the X-linked FMR1 gene: Fragile X syndrome (FXS) and Fragile X -associated tremor ataxia syndrome (FXTAS).Full mutation (FM) individuals with greater than 200 CGG repeats invariably develop FXS, a neurodevelopmental disorder that is present from birth and produces cognitive impairment, behavioral, emotional and sleeping problems [1,2,3]. Two very different disorders arise from a CGG repeat expansion mutation at the promoter region of the X-linked FMR1 gene: Fragile X syndrome (FXS) and Fragile X -associated tremor ataxia syndrome (FXTAS). Approximately 60% of children with FXS can develop autism spectrum disorders (ASD) [4,5]. This expansion mutation usually causes total methylation of the FMR1 gene, which becomes silenced, leading to the absence of the FMR1 protein (FMRP), the underlying cause of FXS. Individuals with shorter ‘premutation’ (PM) expansions in the FMR1 gene, ranging from 55–200 CGG repeats, usually do not have developmental disabilities but are at high risk for developing FXTAS in late adulthood [6]. The presence of eosinophilic intranuclear inclusions throughout the brain [8,9], in testis [10] and in other organs has been reported in both humans [11] and in the CGG KI mouse model of PM [12]

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Conclusion