Clinical characterization of patients with leucine-rich repeat kinase 2 genetic variants in Japan

Li, Yuanzhe; Ikeda, Aya; Yoshino, Hideaki; Oyama, Genko; Kitani, Mitsuhiro; Daida, Kensuke; Hayashida, Arisa; Ogaki, Kotaro; Yoshida, Kiyota; Kimura, Takashi; Nakayama, Yoshiaki; Ito, Hidefumi; Sugeno, Naoto; Akiyama, Masashi; Miyajima, Hiroaki; Kimura, Kensuke; Ueda, Naohisa; Watanabe, Masayuki; Urabe, Takao; Takanashi, Masashi; Funayama, Manabu; Nishioka, Kenya

doi:10.1038/s10038-020-0772-4

Cited by 19 publications

(21 citation statements)

References 48 publications

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“…1f ). We also confirmed a heterozygous mutation of LRRK2 R1441H 29 or I2020T 30 in two patients for comparison in this study (Supplementary Table 1 ). There were no pathogenic variants and risk variants related to familial PD except LRRK2 variants in the G2385R patient and the other two cases (see Clinical and genetic analysis in Methods).…”

Section: Resultssupporting

confidence: 79%

Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson’s disease

Tezuka

Taniguchi

Sano

et al. 2022

npj Parkinsons Dis.

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Missense variants in leucine-rich repeat kinase 2 (LRRK2) lead to familial and sporadic Parkinson’s disease (PD). The pathological features of PD patients with LRRK2 variants differ. Here, we report an autopsy case harboring the LRRK2 G2385R, a risk variant for PD occurring mainly in Asian populations. The patient exhibited levodopa-responsive parkinsonism at the early stage and visual hallucinations at the advanced stage. The pathological study revealed diffuse Lewy bodies with neurofibrillary tangles, amyloid plaques, and mild signs of neuroinflammation. Biochemically, detergent-insoluble phospho-α-synuclein was accumulated in the frontal, temporal, entorhinal cortexes, and putamen, consistent with the pathological observations. Elevated phosphorylation of Rab10, a substrate of LRRK2, was also prominent in various brain regions. In conclusion, G2385R appears to increase LRRK2 kinase activity in the human brain, inducing a deleterious brain environment that causes Lewy body pathology.

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Section: Resultssupporting

confidence: 79%

Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson’s disease

Tezuka

Taniguchi

Sano

et al. 2022

npj Parkinsons Dis.

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“…It has been posited that a "north-south" gradient may exist, since R1441G-PD is significantly less common as we descend in the peninsula, with just isolated cases in Andalucía, which also share the same haplotype. In contrast, this mutation is very uncommon in other European populations, including other regions of Spain, North and South America, and Japan (14,(19)(20)(21)(22). Lifetime penetrance of R1441G mutations increases with age, with figures of 12.8% at 65 years, from 50.2% at 70 years, reaching 83.4% at 80 years of age (23).…”

Section: Y1699c I2012t G2019s and I2020t) (7)mentioning

confidence: 98%

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

et al. 2021

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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.

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“…Neuroimaging of patients with LRRK2 variants shows heterogeneous results. Three of the six patients with p.G2019S show a reduced heart-to-mediastinum ratio of MIBG myocardial scintigraphy ( 97 ), whereas patients with p.R1441G/H show no reduction of heart-to-mediastinum ratio ( 90 , 92 ). The brain MRI commonly show no atrophic changes even over 10 years from disease onset ( 90 , 92 ).…”

Section: Genetic Evidence Clinical and Pathological Features And Mole...mentioning

confidence: 99%

“…The pathogenic variants in the LRRK2 gene are the most common genetic cause of familial PD ( 90 ). The prevalence of LRRK2 p.G2019S is over 30% in the Ashkenazi Jews or Arab Berber.…”

Section: Genetic Evidence Clinical and Pathological Features And Mole...mentioning

confidence: 99%

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Clinical Manifestations and Molecular Backgrounds of Parkinson's Disease Regarding Genes Identified From Familial and Population Studies

et al. 2022

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Over the past 20 years, numerous robust analyses have identified over 20 genes related to familial Parkinson's disease (PD), thereby uncovering its molecular underpinnings and giving rise to more sophisticated approaches to investigate its pathogenesis. α-Synuclein is a major component of Lewy bodies (LBs) and behaves in a prion-like manner. The discovery of α-Synuclein enables an in-depth understanding of the pathology behind the generation of LBs and dopaminergic neuronal loss. Understanding the pathophysiological roles of genes identified from PD families is uncovering the molecular mechanisms, such as defects in dopamine biosynthesis and metabolism, excessive oxidative stress, dysfunction of mitochondrial maintenance, and abnormalities in the autophagy–lysosome pathway, involved in PD pathogenesis. This review summarizes the current knowledge on familial PD genes detected by both single-gene analyses obeying the Mendelian inheritance and meta-analyses of genome-wide association studies (GWAS) from genome libraries of PD. Studying the functional role of these genes might potentially elucidate the pathological mechanisms underlying familial PD and sporadic PD and stimulate future investigations to decipher the common pathways between the diseases.

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Clinical characterization of patients with leucine-rich repeat kinase 2 genetic variants in Japan

Cited by 19 publications

References 48 publications

Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson’s disease

Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson’s disease

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

Clinical Manifestations and Molecular Backgrounds of Parkinson's Disease Regarding Genes Identified From Familial and Population Studies

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