Abstract Details

Title Phenotype and Neuropathology of FMR1 Gray Zone Carriers in Community-Dwelling Older Subjects

Topic Movement Disorders

Presentation(s) S53 - Movement Disorders: Genetics and Clinical Features (4:58 PM-5:09 PM)

Poster/Presentation
Number 009

Background ‘Premutation’ size expansions of 55-199 CGG repeats in FMR1 cause fragile X-associated tremor/ataxia syndrome (FXTAS), which is manifested by movement disorders and intra-nuclear mRNA inclusions in neurons and glia. Gray zone FMR1 expansions (41-54 CGG) have also been associated with neurological signs, but neuropathological findings in these cases have never been reported.

Objective The associations between FMR1 gray zone expansions, neuropathological changes, and parkinsonism, motor, and cognitive function in community based individuals were examined in this study.

Design/Methods

Automated FMR1 PCR was performed on samples from two longitudinal studies of aging and dementia: the Rush Memory and Aging Project and the Religious Orders Study. Subjects consented to brain donation and underwent a detailed clinical evaluation including 17 cognitive tests, a modified Unified Parkinson Disease Rating Scale, and a composite score of global motor function. A detailed neuropathological examination of the brain was performed to detect degenerative and vascular diseases and ubiquitin immunohistochemistry was performed to detect intranuclear neuronal and glial inclusions in the hippocampus, pons, and mid-frontal gyrus.

Results The average age of the population (n=2362) was 85.6±7.3 years and average age at death was 88.4±6.4 years, with 72% women. Gray zone carrier women were younger at the age of death than non-carriers (p<0.001). Gray zone carrier men were more likely to have parkinsonism than non-carriers (p<0.01), but there was no difference in the global motor (p=0.76) or global cognition scores (p=0.38). Carrier women had higher (better) global motor scores compared to controls (p=.04). No differences were seen in brain pathology in carriers compared to non-carriers and no intranuclear inclusions were identified in neurons and glia.

Conclusions

Phenotypic differences were seen in both men and women with FMR1 gray zone expansions, compared to non-carriers. However, the characteristic neuropathological changes seen in larger expansion carriers or FXTAS were not identified.

Authors/Disclosures
Deborah Hall, MD, PhD, FAAN (Rush University) PRESENTER	Dr. Hall has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for ��ɫ��. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier - Parkinsonism and Related Disorders. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Annals of Neurology. The institution of Dr. Hall has received research support from Parkinson's Foundation. The institution of Dr. Hall has received research support from CHDI. The institution of Dr. Hall has received research support from Uniqure. The institution of Dr. Hall has received research support from NIH.
	No disclosure on file
Elizabeth M. Berry-Kravis, MD, PhD (Rush University Medical Center)	The institution of Dr. Berry-Kravis has received research support from NIH. The institution of Dr. Berry-Kravis has received research support from Ionis. The institution of Dr. Berry-Kravis has received research support from Zynerba. The institution of Dr. Berry-Kravis has received research support from Roche. The institution of Dr. Berry-Kravis has received research support from CDC. The institution of Dr. Berry-Kravis has received research support from FRAXA Research Foundation. The institution of Dr. Berry-Kravis has received research support from GeneTx. The institution of Dr. Berry-Kravis has received research support from Angelman Syndrome Foundation. The institution of Dr. Berry-Kravis has received research support from Acadia. The institution of Dr. Berry-Kravis has received research support from Ultragenyx. The institution of Dr. Berry-Kravis has received research support from Mallinckrodt. The institution of Dr. Berry-Kravis has received research support from Together Strong Foundation. The institution of Dr. Berry-Kravis has received research support from Zevra. The institution of Dr. Berry-Kravis has received research support from Taysha. The institution of Dr. Berry-Kravis has received research support from Tetra. The institution of Dr. Berry-Kravis has received research support from Neuren.
Aisha M. Ali, MD	Dr. Ali has nothing to disclose.
Bichum Ouyang	Bichum Ouyang has nothing to disclose.
	No disclosure on file
Aron S. Buchman, MD (Rush Alzheimer's Disease Center)	No disclosure on file
	No disclosure on file
David A. Bennett, MD (Rush University Medical Center)	Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Origent. Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AbbVie. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as a Study section, DMC, NACA Council with NIH. Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving as a invited lectures with AMCs. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as a invited paper with National Academy of Sciences. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as a lecture with National Academy of Neuropsychology.

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