LRRK2 G2019S Parkinson's disease with more benign phenotype than idiopathic

Romdhan, Sawssan Ben; Farhat, Nouha; Nasri, Amina; Lesage, Suzanne; Hdiji, Olfa; Djebara, Mouna Ben; Landoulsi, Zied; Stevanin, Giovanni; Brice, Alexis; Damak, Mariem; Gouider, Riadh; Mhiri, Chokri

doi:10.1111/ane.12996

Cited by 26 publications

(21 citation statements)

References 35 publications

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“…In our study, patients with the G2019S mutation had a mean AAO of ~52 years, a high proportion of patients with late AAO (>50 years), a good response to levodopa, a predominance of tremor as a first symptom of PD, about a quarter had cognitive impairment, about 10% had dysautonomia, but no other atypical signs after a mean disease duration of ~10 years. Although the clinical features of the LRRK2 Gly2019Ser carriers compared with patients with idiopathic PD in literature are conflicting [meta-analysis in ( 25 )], even for the same ethnic PD population [i.e., of North-African origin; ( 26 – 31 )], our data are consistent with those of 724 LRRK2 mutation carriers listed in the MDSGene database. Like LRRK2 mutation carriers, VPS35 Asp620Asn carriers had a phenotype very similar overall to that of idiopathic PD: absence of atypical signs, excellent levodopa response, normal cognition, and absence of neuropsychiatric features.…”

Section: Discussionsupporting

confidence: 82%

Genetic and Phenotypic Basis of Autosomal Dominant Parkinson's Disease in a Large Multi-Center Cohort

Lesage

Houot²,

Mangone

et al. 2020

Front. Neurol.

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LRRK2, SNCA, and VPS35 are unequivocally associated with autosomal dominant Parkinson's disease (PD). We evaluated the prevalence of LRRK2, SNCA, and VPS35 mutations and associated clinical features in a large French multi-center cohort of PD patients. Demographic and clinical data were collected for 1,805 index cases (592 with autosomal dominant inheritance and 1,213 isolated cases) since 1990. All probands were Lesage et al. Characterization of Dominant Parkinson's Disease screened with TaqMan assays for LRRK2 Gly2019Ser. In the absence of this mutation, the coding sequences of the three genes were analyzed by Sanger sequencing and/or next-generation sequencing. The data for the three genes were analyzed according to age at onset, family history, ethnic origin and clinical features. We identified 160 index cases (8.9%) with known pathogenic variants: 138 with pathogenic LRRK2 variants (7.6%), including 136 with the Gly2019Ser mutation, 19 with SNCA point mutations or genomic rearrangements (1.1%), and three with the VPS35 Asp620Asn mutation (0.16%). Mutation frequencies were higher in familial than isolated cases, consistent with autosomal dominant inheritance (12.0 vs. 7.3%; OR 1.7, 95% CI [1.2-2.4], p = 0.001). PD patients with LRRK2 variants were more likely to have higher rates of late-onset PD (>50 years; OR 1.5, 95% CI [1.0-2.1], p = 0.03), whereas those with SNCA mutations tended to have earlier age at onset disease (≤50 years, p = 0.06). The clinical features of LRRK2 carriers and those without any pathogenic variants in known PD-associated genes were similar. The likelihood of detecting disease-causing mutations was higher in cases compatible with autosomal dominant inheritance.

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Section: Discussionsupporting

confidence: 82%

Genetic and Phenotypic Basis of Autosomal Dominant Parkinson's Disease in a Large Multi-Center Cohort

Lesage

Houot²,

Mangone

et al. 2020

Front. Neurol.

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“…A recent study conducted in South Africa found that 8 out of 647 patients screened were G2019S-carriers but all are of Ashkenazi Jewish origin except one (whose grandfather was German) (49). In a study on African Arabic patients in Tunisia, G2019S-carriers had similar PD symptoms to non-G2019S idiopathic PD cases but had a younger age at onset (AAO), a more benign phenotype and less cognitive impairment (59). In the South African study, the average AAO of the eight G2019S carriers was 56.6 years (SD 10.9), they had typical PD symptoms, and the homozygous mutation carrier did not exhibit a more severe disease to the others, although two patients had severe lower limb dystonia (49).…”

Section: Genetics Of Pd In African Populationsmentioning

confidence: 99%

Parkinson's Disease Research on the African Continent: Obstacles and Opportunities

et al. 2020

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The burden of Parkinson's disease (PD) is becoming increasingly important in the context of an aging African population. Although PD has been extensively investigated with respect to its environmental and genetic etiology in various populations across the globe, studies on the African continent remain limited. In this Perspective article, we review some of the obstacles that are limiting research and creating barriers for future studies. We summarize what research is being done in four sub-Saharan countries and what the key elements are that are needed to take research to the next level. We note that there is large variation in neurological and genetic research capacity across the continent, and many opportunities for unexplored areas in African PD research. Only a handful of countries possess appropriate infrastructure and personnel, whereas the majority have yet to develop such capacity. Resource-constrained environments strongly determines the possibilities of performing research locally, and unidirectional export of biological samples and genetic data remains a concern. Local-regional partnerships, in collaboration with global PD consortia, should form an ethically appropriate solution, which will lead to a reduction in inequality and promote capacity building on the African continent.

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“…Interestingly, the G2019S mutation is more frequently associated with LB pathology compared to other LRRK2 mutations [ 88 ]. In terms of the severity of disease, there was no gene dosage effect observed, and G2019S carriers showed a more benign disease course [ 89 ]. In terms of biological readouts, some limited information is available from the analysis of biosamples from G2019S carriers.…”

Section: Understanding Lrrk2 In Pd Through the Study Of Disease-linked Or Associated Variants Of Lrrk2mentioning

confidence: 99%

Mind the Gap: LRRK2 Phenotypes in the Clinic vs. in Patient Cells

Goveas

Mutez

Chartier-Harlin

et al. 2021

Cells

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Mutations in the Parkinson’s disease (PD) protein Leucine Rich Repeat Kinase 2 (LRRK2) have been under study for more than 15 years and our understanding of the cellular phenotypes for the pathogenic mutant forms of LRRK2 has significantly advanced. In parallel to research on LRRK2 mutations in experimental systems, clinical characterization of patients carrying LRRK2 mutations has advanced, as has the analysis of cells that are derived from these patients, including fibroblasts, blood-derived cells, or cells rendered pluripotent. Under the hypothesis that patient clinical phenotypes are a consequence of a cascade of underlying molecular mechanisms gone astray, we currently have a unique opportunity to compare findings from patients and patient-derived cells to ask the question of whether the clinical phenotype of LRRK2 Parkinson’s disease and cellular phenotypes of LRRK2 patient-derived cells may be mutually informative. In this review, we aim to summarize the available information on phenotypes of LRRK2 mutations in the clinic, in patient-derived cells, and in experimental models in order to better understand the relationship between the three at the molecular and cellular levels and identify trends and gaps in correlating the data.

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LRRK2 G2019S Parkinson's disease with more benign phenotype than idiopathic

Abstract: In this study, G2019S carriers had a more benign phenotype than non-carriers. Cognitive impairment and depression were less common in G2019S male carriers compared with females. In addition, we found that LRRK2 gene dosage does not influence the severity of PD.

Cited by 26 publications

References 35 publications

Genetic and Phenotypic Basis of Autosomal Dominant Parkinson's Disease in a Large Multi-Center Cohort

Genetic and Phenotypic Basis of Autosomal Dominant Parkinson's Disease in a Large Multi-Center Cohort

Parkinson's Disease Research on the African Continent: Obstacles and Opportunities

Mind the Gap: LRRK2 Phenotypes in the Clinic vs. in Patient Cells

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