TY - JOUR
T1 - Intranuclear inclusions in a fragile X mosaic male
AU - Pretto, Dalyir I.
AU - Hunsaker, Michael R.
AU - Cunningham, Christopher L.
AU - Greco, Claudia M.
AU - Hagerman, Randi J.
AU - Noctor, Stephen C.
AU - Hall, Deborah A.
AU - Hagerman, Paul J.
AU - Tassone, Flora
N1 - Funding Information:
Dr. Randi Hagerman has received funding from Roche, Novartis, Seaside Therapeutics, Forest, Curemark and the National Fragile X Foundation for clinical trials in fragile X syndrome and/or autism. She has also consulted with Novartis regarding treatment in fragile X syndrome. All other authors declare that they have no conflict of interests. This work is dedicated to the memory of Matteo.
Funding Information:
This work was supported by NICH through individual research awards HD02274 and HD36071. Brain tissue for this study was obtained from the UC Davis brain repository (NIH HD040661). Control tissues were obtained from the Brain Endowment Bank, Dept. Neurology University of Miami Miller School of Medicine.
PY - 2013/5/21
Y1 - 2013/5/21
N2 - 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.
AB - 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.
KW - FXS
KW - FXTAS
KW - Intranuclear inclusions
KW - Premutation
UR - http://www.scopus.com/inward/record.url?scp=84883602770&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84883602770&partnerID=8YFLogxK
U2 - 10.1186/2047-9158-2-10
DO - 10.1186/2047-9158-2-10
M3 - Article
C2 - 23692864
AN - SCOPUS:84883602770
SN - 2047-9158
VL - 2
JO - Translational Neurodegeneration
JF - Translational Neurodegeneration
IS - 1
M1 - 10
ER -