Clinical traits of LRRK2-associated Parkinson's disease in Ireland: A link between familial and idiopathic PD

doi:10.1016/j.parkreldis.2005.05.004

Parkinsonism & Related Disorders

Volume 11, Issue 6, September 2005, Pages 349-352

https://doi.org/10.1016/j.parkreldis.2005.05.004 Get rights and content

Abstract

The role of genetics in parkinsonism has been confirmed over the last decade with the identification of genetic variation in seven genes, which are causative in familial forms of the disorder. A number of pathogenic mutations have been identified in the latest gene LRRK2, with a Gly2019Ser amino acid substitution identified in two siblings and one patient with idiopathic Parkinson's disease from Ireland. The clinical features resemble the idiopathic variant with a tremor predominant clinical picture shared by the siblings, slow progression of symptoms, and no observation of cognitive disturbance in all. The family and the sporadic individual were apparently not related and originated from different regions of Ireland, although haplotype analysis does suggest they share a common founder. The influence of the G2019S substitution on protein function and disease phenotype has yet to be fully resolved, but its elucidation will undoubtedly further our understanding of the mechanisms underlying Parkinson's disease.

Introduction

The etiology and pathogenesis of Parkinson's disease (PD) remain unknown, however, it has been suggested that PD may be a multifactorial disorder caused by a combination of age, environmental and genetic factors. During the last decade, the identification of pathogenic mutations in seven genes (α-synuclein, parkin, UCH-L1, MAPT, DJ-1, PINK1 and LRRK2) has confirmed the role of genetics in parkinsonism and stimulated a great deal of research interest. The latest is the novel gene, leucine-rich repeat kinase 2 (LRRK2), in which six disease-segregating mutations, in six independent families with PARK8-linked autosomal-dominant parkinsonism (PARK8 [OMIM*609007]) have been described [1], [2].

Since 2000, we have been constructing a clinical-genetic database of PD patients, both familial and sporadic from all regions of Ireland. Patients were either recruited from outpatients, referred from another consultant neurologist, a physician with a specialised interest in PD, or were recruited from the community. For each case, the diagnosis of PD was made by a consultant neurologist or the principal research physician (DG). The Gelb criteria for a diagnosis of PD were used [3]. Patients exhibited at least two of the classical triad of symptoms, a progressive history, a good initial response to levodopa, and the absence of clinical signs pertaining to atypical parkinsonism. Cognitive function was assessed using the modified mini-mental status examination (MMSE).

Ethics Committee approval was obtained and informed written consent given by all subjects.

Section snippets

Methods and results

A LRRK2 6055G→A mutation resulting in a glycine-2019-serine (G2019S) amino acid substitution was identified in one affected member of Family 3211 from Ireland (Fig. 1). The other family members were then genotyped with one more affected found to harbor the mutation, 3211b [4]. Parkinsonism in this kindred appeared to have an autosomal dominant mode of inheritance and previously was reported to have suggestive evidence for linkage to the chromosomal region PARK8 [5]. Screening of a further 271

Discussion

The identification of a Lrrk2 G2019S substitution in one Irish family with PARK8-linked autosomal dominant mode of inheritance and one apparently sporadic PD patient is one of the few links between the rare familial and more common sporadic forms of this disorder in the same population.

The G2019S variant is relatively frequent in PD series and is estimated to account for ∼5% familial and ∼1% of apparently sporadic disease [4], [6], [7], [8]. The identification of only one (0.5%) sporadic

Acknowledgements

We are grateful to the following organizations for their support of this work: Mayo Clinic Jacksonville is a M.K. Udall Parkinson's Disease Research Centre of Excellence (NINDS P01 NS40256). The R&D Office of the Health and Personal Social Services (Northern Ireland). The Republic of Ireland research consortium was supported by The Irish Institute of Neurology and Neurosurgery Galen fellowship (DG&TL), a Conway Neuroscience PRTLI award (TL), and a Mater Hospital Research Scholarship. We thank

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LRRK2 is a multiple domain-containing protein that functions both as a GTPase and a kinase (Anand and Braithwaite, 2009; Bae and Lee, 2015). Because mutations in LRRK2 constitute the greatest known genetic component of familial Parkinson’s disease (PD) (Goldwurm et al., 2005; Gosal et al., 2005; Khan et al., 2005), much of what is known about LRRK2 comes from studies of central nervous system (CNS) cells, where it functions in a number of cellular pathways (Cookson, 2012; Wallings et al., 2015). In non-CNS cells, LRRK2 has been linked to intracellular membrane trafficking through RAB phosphorylation (Steger et al., 2016), endolysosomal dynamics (Härtlova et al., 2018; Herbst et al., 2020), and mitochondrial homeostasis (Eberhardt et al., 2020; Hsieh et al., 2016; Ludtmann et al., 2019).
Although mutations in mitochondrial-associated genes are linked to inflammation and susceptibility to infection, their mechanistic contributions to immune outcomes remain ill-defined. We discovered that the disease-associated gain-of-function allele Lrrk2^G2019S (leucine-rich repeat kinase 2) perturbs mitochondrial homeostasis and reprograms cell death pathways in macrophages. When the inflammasome is activated in Lrrk2^G2019S macrophages, elevated mitochondrial ROS (mtROS) directs association of the pore-forming protein gasdermin D (GSDMD) to mitochondrial membranes. Mitochondrial GSDMD pore formation then releases mtROS, promoting a switch to RIPK1/RIPK3/MLKL-dependent necroptosis. Consistent with enhanced necroptosis, infection of Lrrk2^G2019S mice with Mycobacterium tuberculosis elicits hyperinflammation and severe immunopathology. Our findings suggest a pivotal role for GSDMD as an executer of multiple cell death pathways and demonstrate that mitochondrial dysfunction can direct immune outcomes via cell death modality switching. This work provides insights into how LRRK2 mutations manifest or exacerbate human diseases and identifies GSDMD-dependent necroptosis as a potential target to limit Lrrk2^G2019S-mediated immunopathology.
Prevalence of ten LRRK2 variants in Parkinson's disease: A comprehensive review
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In total, 581 estimates of variant prevalence across 52 countries were included. Eight [19–26] of the 161 included studies drew cases primarily from community-based settings, whereas the majority of the remaining studies drew cases primarily (and usually exclusively) from tertiary referral centers, often university hospitals.. Country-specific crude prevalence estimates for the four most common pathogenic variants—G2019S, R1441C, R1441G, and R1441H—are shown in Table 1.
Variants in the leucine-rich repeat kinase 2 gene (LRRK2) are risk factors for Parkinson's disease (PD), but their prevalence varies geographically, reflecting the locations of founder events and dispersion of founders' descendants.
A comprehensive literature review was conducted to identify studies providing prevalence estimates for any of ten variants in LRRK2 (G2019S, R1441C, R1441G, R1441H, I2020T, N1437H, Y1699C, S1761R, G2385R, R1628P) among individuals with PD globally. We calculated crude country-specific variant prevalence estimates and, when possible, adjusted estimates for ethno-racial composition. For clinic-based studies, probands were used over other familial cases, whereas for population-based studies, all PD cases were used.
The analysis included 161 articles from 52 countries yielding 581 prevalence estimates across the ten variants. G2019S was the most common variant, exceeding 1.0% in 26 of 51 countries with estimates. The other variants were far less common. G2385R and R1628P were observed almost exclusively in East Asian countries, where they were found in ∼5–10% of cases. All prevalence estimates adjusted for ethno-racial composition were lower than their unadjusted counterparts, although data permitting this adjustment was only available for six countries.
Except for G2019S, the LRRK2 variants covered in this review were uncommon in most countries studied. However, there were countries with higher prevalence for some variants, reflecting the uneven geographic distribution of LRRK2 variants. The fact that ethno-racial group‒adjusted estimates were lower than crude estimates suggests that estimates derived largely from clinic-based studies may overstate the true prevalence of some LRRK2 variants in PD.
LRRK2 and mitochondria: Recent advances and current views
2019, Brain Research
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Recently, it is shown that LRRK2 contributes to the risk of sporadic PD (Nalls et al., 2014). Importantly, in most LRRK2 mutation carriers, the clinical and pathological features are indistinguishable from those of sporadic PD, demonstrating an unprecedentedly significant role of LRRK2 in PD pathogenesis (Gosal et al., 2005). LRRK2 is a multifunctional complex protein, 2527-amino-acids long with multiple domains, including a leucine-rich repeat (LRR), a ROC-COR GTPase, a mitogen-activated protein kinase, and WD40 domains.
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene account for most common causes of familial and sporadic Parkinson’s disease (PD) and are one of the strongest genetic risk factors in sporadic PD. Pathways implicated in LRRK2-dependent neurodegeneration include cytoskeletal dynamics, vesicular trafficking, autophagy, mitochondria, and calcium homeostasis. However, the exact molecular mechanisms still need to be elucidated. Both genetic and environmental causes of PD have highlighted the importance of mitochondrial dysfunction in the pathogenesis of PD. Mitochondrial impairment has been observed in fibroblasts and iPSC-derived neural cells from PD patients with LRRK2 mutations, and LRRK2 has been shown to localize to mitochondria and to regulate its function. In this review we discuss recent discoveries relating to LRRK2 mutations and mitochondrial dysfunction.
Nonmotor Signs in Genetic Forms of Parkinson's Disease
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Although only a minority (i.e., ~5%) of Parkinson's disease (PD) cases is due to well-defined genetic causes, important clues about the common, “idiopathic” PD (iPD) can be garnered from monogenic model diseases. Nonmotor signs (NMS) are also present in monogenic PD and reviewed in this chapter for the confirmed PD genes SNCA, LRRK2, VPS35, Parkin, PINK1, DJ-1, and the risk factor gene GBA. Within the context of the MDSGene database (www.mdsgene.org), we performed a systematic literature search and extracted information on cognitive decline, depression, psychotic signs and symptoms, autonomic signs and symptoms, anxiety, sleep disorder, and olfactory impairment. Notably, relatively few studies specifically addressed NMS in genetic PD and missing data ranged from 42% to 100%. Diagnostic criteria and examination methods were variable and cases differed widely for age at onset, disease duration, ethnicity, treatment, and comorbidity. Although in comparison to IPD, SNCA duplication carriers have the most similar course of disease, even for duplication carriers the frequencies of dementia, hallucinations, and depression seem higher than in IPD. Supporting the notion that LRRK2-linked PD has a similar course to iPD but is slightly more benign, the frequency of dementia is below that of iPD. For Parkin, the frequency of cognitive decline falls within the range of the general population above the age of 65 years. GBA mutations are associated with a distinct profile of cognitive impairment and a greater prevalence of depression. Despite the current data gaps, NMS should be considered as an important and often treatable concomitant feature of genetic parkinsonism.
A comparative study of Parkinson's disease and leucine-rich repeat kinase 2 p.G2019S parkinsonism
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LRRK2 p.G2019S clinical features compared with iPD in literature are contradictory. Overall, the clinical presentation of iPD and LRRK2 parkinsonism are similar (Aasly et al., 2005; Gosal et al., 2005; Healy et al., 2008; Hulihan et al., 2008; Ishihara et al., 2006; Lesage et al., 2005; Saunders-Pullman et al., 2011). Pilot studies suggest some disparities in terms of motor and non-motor dysfunction.
Parkinson disease is a progressive neurodegenerative disease for which leucine-rich repeat kinase 2 (LRRK2 carriers) p.G2019S confers substantial genotypic and population attributable risk. With informed consent, we have recruited clinical data from 778 patients from Tunisia (of which 266 have LRRK2 parkinsonism) and 580 unaffected subjects. Motor, autonomic, and cognitive assessments in idiopathic Parkinson disease and LRRK2 patients were compared with regression models. The age-associated cumulative incidence of LRRK2 parkinsonism was also estimated using case-control and family-based designs. LRRK2 parkinsonism patients had slightly less gastrointestinal dysfunction and rapid eye movement sleep disorder. Overall, disease penetrance in LRRK2 carriers was 80% by 70 years but women become affected a median 5 years younger than men. Idiopathic Parkinson disease patients with younger age at diagnosis have slower disease progression. However, age at diagnoses does not predict progression in LRRK2 parkinsonism. LRRK2 p.G2019S mutation is a useful aid to diagnosis and modifiers of disease in LRRK2 parkinsonism may aid in developing therapeutic targets.
Worldwide frequency of G2019S LRRK2 mutation in Parkinson's disease: A systematic review
2010, Parkinsonism and Related Disorders
The LRRK2 G2019S mutation is the most frequent known cause of familial and sporadic Parkinson's disease. Knowledge of its worldwide frequency distribution is essential for clinical and molecular research as well as genetic counseling.
To conduct a systematic review of the reported frequency of G2019S in different populations and to assess critically the quality of the clinical studies.
We conducted a systematic review of all published papers on G2019S frequency in homogeneous ethnic groups or sub-groups of patients. Selected papers were analyzed for methodological quality.
68 studies from 32 countries were included in the analysis. A heterogeneous distribution was observed with high frequencies in North African Arab countries, the Middle East, southern Europe, North American Ashkenazi Jewish populations and in South American countries with known European ethnic influence. Frequencies ranged from the no cases to 35.7% in sporadic and 42% in familial North-African Arab patients. Only one paper from one sub-Saharan country was found. Methodological pitfalls were identified.
Estimated frequencies were found to be variable, which may reflect ethnic differences and methodological discrepancies. We make recommendations on the methods of selection of participants and on the definition of familial Parkinson's disease to improve the quality of frequency studies on LRRK2 mutations.

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Clinical traits of LRRK2-associated Parkinson's disease in Ireland: A link between familial and idiopathic PD

Abstract

Introduction

Section snippets

Methods and results

Discussion

Acknowledgements

Neuron

Neuron

Am J Hum Genet

Lancet

Lancet

Lancet