Rare intranuclear inclusions in the brains of 3 older adult males with fragile X syndrome: Implications for the spectrum of fragile X-associated disorders

Abstract

The FMR1 gene is polymorphic for the length of CGG trinucleotide repeat expansions in the 5′ untranslated region. Premutation (55-200 CGG repeats) and full-mutation (>200 CGG repeats) alleles give rise to their respective disorders by different pathogenic mechanisms: RNA gain-of-function toxicity leads to fragile X-associated tremor/ataxia syndrome in the premutation range, and transcriptional silencing and absence of fragile X mental retardation protein (FMRP) lead to fragile X syndrome in the full-mutation range. However, for the latter, incomplete silencing and/or size-mosaicism might result insome contribution to the disease process from residual messenger RNA production. To address this possibility, we examined the brains of 3 cases of fragile X syndrome for the presence of intranuclear inclusions in the hippocampal dentate gyrus. We identified low levels (0.1%-1.3%) of intranuclear inclusions in all 3 cases. Quantitative reverse transcription-polymerase chain reaction for FMR1 messenger RNA and immunofluorescence for FMRP revealed low but detectable levels of both RNA and protein in the 3 cases, consistent with the presence of small numbers of inclusions. The intranuclear inclusions were only present in FMRP-immunoreactive cells. The small numbers of inclusions and very low levels of both FMR1 RNA and protein suggest that the clinical course in these 3 subjects would not have been influenced by contributions from RNA toxicity. Copyright © 2011 by the American Association of Neuropathologists, Inc.