Abstract Details

Title Novel, Long Sought Splice Site Mutation at Exon 10/Intron 10 Boundary of MAPT Stem Loop Structure in a Family with FTDP-17

Topic Movement Disorders

Presentation(s) P05 - (-)

Poster/Presentation
Number 056

Objective

Background BACKGROUND: The expanding spectrum of FTD (Frontotemporal Dementia) incorporates associations with ALS, Paget disease and parkinsonism (FTDP-17). Pathogenic 5' splice site mutations at exon 10 of MAPT (Microtubule Associated Protein Tau) gene were described in FTDP-17 previously, but a predicted exon 10 splice +15 mutation has not yet been reported in an affected family.

Design/Methods DESIGN/METHODS: Case: A 44 year old man presented with progressive disinhibition (6 years), impulsivity, apathy, amotivation and witzelsucht, preceding a profound amnestic syndrome. Neurological examination normal, apart from primitive reflexes and disinhibition: MOCA 25/30, FAB 17/18. Pedigree revealed autosomal dominant young-onset dementia (previously uncharacterized), identified in 3 generations, including his mother, 3 sisters and first cousin. Brain autopsy had not been performed on deceased cases.

Results RESULTS: Metabolic, infectious, auto-immune screening negative. MRI brain- marked fronto-temporal atrophy bilaterally; PET CT- low anterior temporal metabolic activity. CSF- raised protein: Tau (162 pg/ml), phosphorylated Tau (42.7 pg/ml) and beta-amyloid (501 pg/ml) within normal limits. EEG unremarkable. Molecular genetic testing on DNA: fluorescent sequencing analysis for familial tau variant revealed a sequence variant c.915+15A>C, identified at exon10/intron10 boundary of MAPT gene.Identical variant identified in patient's affected female first cousin: other cases to be tested.

Conclusions CONCLUSIONS: In 1998, Hutton et al described 5' splice site mutations in tau, associated with FTDP-17, affecting a stem-loop structure, resulting in alternate splicing of exon 10 (encodes microtubule binding repeats). Additional exon 10 5'mutations were identified until 2001, but the predicted +15 A>C mutation at intron 10 had not been reported until now. In this unique FTDP-17 family, novel mutation identification may inform genetic counseling and potential future therapeutics. Finding this mutation 14 years after its description highlights the value of pursuing a complete family history to guide appropriate molecular genetic testing.

Authors/Disclosures
Roisin Lonergan, MD (Mater Misericordiae Univeristy Hospital) PRESENTER	No disclosure on file
Kathleen Healey, PhD, NP (University of Nebraska Medical Center)	No disclosure on file
Allan McCarthy, MD (Tallaght Hospital)	Dr. McCarthy has nothing to disclose.
Sean O'Dowd, MD	Dr. O'Dowd has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Axis Consulting.
	No disclosure on file
	No disclosure on file
Timothy Lynch, MD (Dublin Neurological Institute,)	Dr. Lynch has nothing to disclose.

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