Genotype-Phenotype correlation in Parkin-Parkinson’s disease (P3-11.012)

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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. Disclosure: The institution of Dr. Jayadev Menon has received research support from Michael J Fox Foundation. Dr. Sambin has nothing to disclose. Mr. CRINIERE-BOIZET has nothing to disclose. Mr. Courtin has nothing to disclose. Mrs. Casse has nothing to disclose. Dr. Tesson has nothing to disclose. Mrs. Ferrien has nothing to disclose. 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. Dr. LEJEUNE has nothing to disclose. Dr. Lanore has nothing to disclose. Graziella Mangone has nothing to disclose. Louise-Laure Mariani has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biophytis. Louise-Laure Mariani has received personal compensation in the range of $0-$499 for serving as a Consultant for Mere. An immediate family member of Louise-Laure Mariani has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biophytis . Louise-Laure 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 Louise-Laure Mariani has received research support from France Parkinson Association. Louise-Laure Mariani has received intellectual property interests from a discovery or technology relating to health care. Jan Aasly has nothing to disclose. 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. Mr. Yu has nothing to disclose. 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. Alexander Zimprich has nothing to disclose. Mr. Alvarez has nothing to disclose. Dr. Pastor has nothing to disclose. Alessio Di Fonzo has nothing to disclose. Dr. Bhatia has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ipsen. Dr. Bhatia has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Mitsubishi. Dr. Bhatia 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 MDS . The institution of Dr. Bhatia has received research support from EU Horizon 2020. Dr. Magrinelli has nothing to disclose. Henry Houlden has nothing to disclose. The institution of Dr. Real has received research support from MJFF/ASAP (Grant number ASAP-000478). The institution of Dr. Narendra has received research support from National Institutes of Health. Dr. Lin has nothing to disclose. Ms. Jovanovic has nothing to disclose. Prof. Koks has stock in Prion OÜ. Prof. Koks has received research support from MSWA. Prof. Koks has received research support from MJFF. Prof. Koks has received research support from Sock It To Sarcoma. Prof. Koks has received intellectual property interests from a discovery or technology relating to health care. Dr. Lynch has nothing to disclose. Dr. Gallagher h

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