AUTHOR=Vinagre-Aragón Ana , Campo-Caballero David , Mondragón-Rezola Elisabet , Pardina-Vilella Lara , Hernandez Eguiazu Haizea , Gorostidi Ana , Croitoru Ioana , Bergareche Alberto , Ruiz-Martinez Javier TITLE=A More Homogeneous Phenotype in Parkinson's Disease Related to R1441G Mutation in the LRRK2 Gene JOURNAL=Frontiers in Neurology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2021.635396 DOI=10.3389/fneur.2021.635396 ISSN=1664-2295 ABSTRACT=

Parkinson's disease (PD) is characterized by a great clinical heterogeneity. Nevertheless, the biological drivers of this heterogeneity have not been completely elucidated and are likely to be complex, arising from interactions between genetic, epigenetic, and environmental factors. Despite this heterogeneity, the clinical patterns of monogenic forms of PD have usually maintained a good clinical correlation with each mutation once a sufficient number of patients have been studied. Mutations in LRRK2 are the most commonly known genetic cause of autosomal dominant PD known to date. Furthermore, recent genome-wide association studies have revealed variations in LRRK2 as significant risk factors also for the development of sporadic PD. The LRRK2-R1441G mutation is especially frequent in the population of Basque ascent based on a possible founder effect, being responsible for almost 50% of cases of familial PD in our region, with a high penetrance. Curiously, Lewy bodies, considered the neuropathological hallmark of PD, are absent in a significant subset of LRRK2-PD cases. Indeed, these cases appear to be associated with a less aggressive primarily pure motor phenotype. The aim of our research is to examine the clinical phenotype of R1441G-PD patients, more homogeneous when we compare it with sporadic PD patients or with patients carrying other LRRK2 mutations, and reflect on the value of the observed correlation in the genetic forms of PD. The clinical heterogeneity of PD leads us to think that there may be as many different diseases as the number of people affected. Undoubtedly, genetics constitutes a relevant key player, as it may significantly influence the phenotype, with differences according to the mutation within the same gene, and not only in familial PD but also in sporadic forms. Thus, extending our knowledge regarding genetic forms of PD implies an expansion of knowledge regarding sporadic forms, and this may be relevant due to the future therapeutic implications of all forms of PD.