A More Homogeneous Phenotype in Parkinson's Disease Related to R1441G Mutation in the LRRK2 Gene

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.

A Review on Response to Device-Aided Therapies Used in Monogenic Parkinsonism and GBA Variants Carriers: A Need for Guidelines and Comparative Studies

“…Remarkably, LRRK2 p.G2019S carriers with a PIGD phenotype have a lower risk of dementia than observed in non-carriers with this phenotype [51]. Overall, LRRK2-PD have a lower risk of dementia [48,[52][53][54], manifests less olfactory impairment [49,55], and RBD [56,57] than noncarriers with PD.…”

Precision Medicine in Parkinson’s Disease: From Genetic Risk Signals to Personalized Therapy

“…In specific populations the prevalence significantly increases, reaching 29% and 37% of familial PD cases in Ashkenazi Jewish and North Africans, respectively [ 144 ]. Some pathogenic mutations are further specific to selected populations, such as p.R1441G (OMIM*609007.0003) which is responsible for nearly 46% of familial Basque ascent PD cases, due to a founder effect [ 144 , 145 ]. LRRK2 mutations display variable penetrance, depending on age, ancestral genetic background, and environment [ 144 ].…”

“…Clinically, LRRK2-related PD strongly resembles idiopathic PD [ 144 ], despite some reports suggesting a slower motor progression in p.G2019S mutation carriers [ 143 , 145 , 150 ] and an overall, less severe burden of non-motor symptoms compared to PD noncarriers [ 144 , 151 ].…”

“…Cross: blocked pathwas; full arrow: promoting activities; dashed arrow: final effect of the strategies. From [ 145 ].…”

Homozygous mutation of the LRRK2 ROC domain as a novel genetic model of parkinsonism

“…R1441G is most prevalent in the Basque region of Spain (16.4–46% of familial PD cases and 1.7–4% of sporadic PD cases) [ 17 , 21 , 50 ]. Although most PD patients with LRRK2 mutations are heterozygous missense mutations with an autosomal dominant inheritance pattern, there is a large population of patients carrying homozygous (HOM) mutations in LRRK2 R1441G and G2019S worldwide [ 2 , 25 , 26 , 58 ]. Patients with mutations in the LRRK2 gene show the phenotypic features of sporadic PD, including not only motor symptoms but also nonmotor symptoms such as depression, and cognitive impairment.…”