Abstract Details

Title Genotype-Phenotype correlation in Parkin-Parkinson’s disease

Topic Movement Disorders

Presentation(s) P3 - Poster Session 3 (5:30 PM-6:30 PM)

Poster/Presentation
Number 5-012

Objective To investigate whether the location and/or the type of mutation in PRKN can predict the age at onset and motor severity in Parkinson disease (PD) patients with bi-allelic mutations.

Background Mutations in PRKN is the most common cause of early-onset autosomal recessive inherited PD, with over 170 different mutations spanning the entire gene described as being pathogenic.

Design/Methods PD patients with bi-allelic pathogenic mutations in PRKN and with no pathogenic mutations in other genes known to result in monogenic PD were included. Phenotypic characteristics of this population including age at onset, motor severity, cognition, and levodopa equivalent daily dose (LEDD) were assessed longitudinally. The type of mutation in PRKN was analysed for an association with the age at onset and motor severity, considering disease duration as a covariant.

Results

517 patients were included for analysis [age at onset (32 ± 11.1 years), disease duration (18 ± 11.6 years)].

Mean UPDRS part III (on) score at the time of disease onset was 13.3 ± 1.6 and increased by 3.9 ± 0.7 points every 10 years (n=274, p=9.4e-07). There was no deterioration in cognition with an increase in disease duration. The average initial LEDD was 330 ± 53mg, and this increased by 105 ± 2.6 mg every 10 years (n=129, p=0.0001).

The most common mutation was structural variants (366 cases, 71%), with exon 3 deletion being the most frequent overall (103 cases, 20%). The Ubiquitin-like domain was the most frequently affected protein domain (183 cases, 35%).

Patients with 2 missense variants had a later age of onset (37± 12.1 years), compared to those with 2 structural variants (31±10.8 years) (p=0.004).

Conclusions We confirm the slow motor progression, preserved cognition and demonstrate the limited increase in dopaminergic medications with time in PRKN-PD. Missense variants were associated with a more benign progression of the disease.

Authors/Disclosures
Poornima Jayadev Menon, MbBchBAO, MRCPI PRESENTER	The institution of Dr. Jayadev Menon has received research support from Michael J Fox Foundation.
	No disclosure on file
	No disclosure on file
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Emmanuel Roze, MD, PhD	Dr. Roze has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for merz. Dr. Roze has received personal compensation in the range of $500-$4,999 for serving as a Consultant for orkyn. Dr. Roze has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for elivie. Dr. Roze has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for allergan. Dr. Roze has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Orkyn. Dr. Roze has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for elivie. Dr. Roze has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Aguettant. The institution of Dr. Roze has received research support from merz. The institution of Dr. Roze has received research support from Orkyn. Dr. Roze has received research support from elivie. The institution of Dr. Roze has received research support from allergan. The institution of Dr. Roze has received research support from fondation desmarest. The institution of Dr. Roze has received research support from everpharma. Dr. Roze has received research support from AMADYS. The institution of Dr. Roze has received research support from ADCY5.org. The institution of Dr. Roze has received research support from agence nationale de la recherche. The institution of Dr. Roze has received research support from société française de médecine esthétique. The institution of Dr. Roze has received research support from dystonia medical research foundation.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Louise-Laure Mariani, MD, PhD (Federation Des Maladies Du Systeme Nerveux)	Dr. Mariani has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Oculis. Dr. Mariani has received personal compensation in the range of $0-$499 for serving as a Consultant for Merz. Dr. Mariani has received personal compensation in the range of $0-$499 for serving as a Consultant for Emeis. Dr. Mariani has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Paris Brain Institute. Dr. Mariani has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Owkin. Dr. Mariani has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Elivie. Dr. Mariani has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Dr. Mariani has received personal compensation in the range of $500-$4,999 for serving as a Consultant for DIGITAL MEDICAL HUB. Dr. Mariani has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for John Libbey. The institution of Dr. Mariani has received research support from France Parkinson Association. The institution of Dr. Mariani has received research support from Fondation de France. The institution of Dr. Mariani has received research support from Paris Brain Institute. The institution of Dr. Mariani has received research support from French Ministry of Health. Dr. Mariani has received intellectual property interests from a discovery or technology relating to health care.
Jan O. Aasly, MD, PhD	No disclosure on file
Ziv Gan-Or, MD, PhD (McGill University)	Dr. Gan-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neuron23. Dr. Gan-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Idorsia. Dr. Gan-Or has received personal compensation in the range of $0-$499 for serving as a Consultant for Lighthouse. Dr. Gan-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ono Therapeutics. Dr. Gan-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. Dr. Gan-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Handl Therapeutics. Dr. Gan-Or has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bial Biotech.
	No disclosure on file
Yves Dauvilliers, MD, PhD (Hopital Gui De Chaulliac)	Yves Dauvilliers, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for idorsia. Yves Dauvilliers, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for JAZZ. Yves Dauvilliers, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Takeda. Yves Dauvilliers, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Avadel. Yves Dauvilliers, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alkermes. Yves Dauvilliers, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Centessa. Yves Dauvilliers, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bioprojet. Yves Dauvilliers, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Harmony Bioscience.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Kailash P. Bhatia, MD, FAAN (UCL)	Dr. Bhatia has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ipsen. Dr. Bhatia has received publishing royalties from a publication relating to health care.
	No disclosure on file
Henry Houlden	No disclosure on file
	No disclosure on file
Derek Narendra, MD (NINDS, NIH)	The institution of Dr. Narendra has received research support from National Institutes of Health.
Hsin-Pin Lin, MD, PhD	Dr. Lin has nothing to disclose.
	No disclosure on file
	No disclosure on file
Timothy Lynch, MD (Dublin Neurological Institute,)	Dr. Lynch has nothing to disclose.
	No disclosure on file
Wim Vandenberghe (Dept. Neurology, University Hospital Leuven)	Dr. Vandenberghe has nothing to disclose.
	No disclosure on file
Huw R. Morris, MD, PhD	Dr. Morris has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Morris has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Aprinoia. Dr. Morris has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Morris has received personal compensation in the range of $50,000-$99,999 for serving as an Expert Witness for Personal injury / Negligence cases. The institution of Dr. Morris has received research support from Parkinson's UK. The institution of Dr. Morris has received research support from Michael J Fox Foundartion. The institution of Dr. Morris has received research support from Cure Parkinson's Trust. The institution of Dr. Morris has received research support from PSP Association. The institution of Dr. Morris has received research support from CBD Solutions. The institution of Dr. Morris has received research support from Drake Foundation. The institution of Dr. Morris has received research support from Medical Research Council. Dr. Morris has received intellectual property interests from a discovery or technology relating to health care. Dr. Morris has a non-compensated relationship as a Scientific Advisory Board with Cure PSP that is relevant to AAN interests or activities. Dr. Morris has a non-compensated relationship as a Scientific Advisory Board with Parkinson's UK that is relevant to AAN interests or activities.
Christine Klein, MD (University of Luebeck)	Dr. Klein has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Centogene and Retromer Therapeutics. Dr. Klein 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 Mov Disord, Ann Neurol, Science Adv. The institution of Dr. Klein has received research support from Centogene. Dr. Klein has received publishing royalties from a publication relating to health care.
	No disclosure on file
	No disclosure on file
Alexis Brice, MD	Dr. Brice has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for ICM.
Suzanne Lesage, PhD (INSERM U1127, ICM, Hopital Pitie-Salpetriere)	Dr. Lesage has nothing to disclose.
Jean Christophe Corvol, MD (GH Pitie Salpetriere)	No disclosure on file

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