Poornima Jayadev Menon1, Sara Sambin1, Baptiste Criniere-Boizet1, Thomas Courtin1, Fanny Casse1, Christelle Tesson1, Melanie Ferrien1, Emmanuel Flamand-Roze1, Francois-Xavier Lejeune1, Aymeric Lanore1, Graziella Mangone1, Louise-Laure Mariani1, Jan Aasly2, Ziv Gan Or3, Eric Yu3, Yves Dauvilliers4, Alexander Zimprich5, Ignacio Alvarez Fernandez6, Pau Pastor6, Alessio Di Fonzo7, Khailash Bhatia8, Francesca Magrinelli8, Henry Houlden8, Raquel Real 8, Derek Narendra9, Hsin-Pin Lin9, Carna Jovanovic10, Sulev Koks 11, Timothy Lynch12, Amy Gallagher12, Wim Vandenberghe13, Thomas Gasser14, Huw Morris8, Christine Klein15, Kathrin Brockmann14, Olga Corti1, Alexis Brice1, Suzanne Lesage1, Jean-Christophe Corvol1
1ICM/ Paris Brain Institute, 2NTNU, 3McGill University, 4Montpellier, 5Medizinische Universität Wien, 6University Mutua de Terrassa, 7University of Milan, 8UCL, 9NIH, 10University of Belgrade, 11University of Perron, 12Dublin Neurological Institute, 13University of Leuven, 14University of Tuebingen, 15University of Luebeck
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.