Differences in Survival across Monogenic Forms of Parkinson's Disease

Lanore, Aymeric; Casse, Fanny; Tesson, Christelle; Courtin, Thomas; Menon, Poornima Jayadev; Sambin, Sara; Brice, Alexis; Elbaz, Alexis; Corvol, Jean‐Christophe; Agid, Yves; Anheim, Mathieu; Borg, M.; Broussolle, Emmanuel; Damier, Philippe; Defebvre, Luc; Dürr, Alexandra; Durif, Franck; Houeto, Jean Luc; Krack, Paul; Klebe, Stephan; Lesage, Suzanne; Lohmann, Ebba; Martínez, María Teresa González; Mangone, Graziella; Mariani, Louise‐Laure; Pollak, Pierre; Rascol, Olivier; Tison, François; Tranchant, Christine; Vérin, Marc; Viallet, François; Vidailhet, Marie

doi:10.1002/ana.26636

Cited by 9 publications

(7 citation statements)

References 41 publications

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“…Age at onset in our cohort was not limited to less than 50 years and patients had longer disease duration, which might have contributed to the slightly higher rate of progression detected in our study with respect to this previous study. Our data, however, confirms that motor progression in PRKN-PD is significantly slower than previously described for IPD populations, consistent with the previously reported lower mortality rate 33 .…”

Section: Discussionsupporting

confidence: 93%

Genotype–phenotype correlation in PRKN-associated Parkinson’s disease

Menon,

Sambin,

Criniere-Boizet

et al. 2024

npj Parkinsons Dis.

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Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson’s disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p < 0.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of PRKN-PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in PRKN-PD. Our findings on the relationship between the type of variant in PRKN and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials.

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Section: Discussionsupporting

confidence: 93%

Genotype–phenotype correlation in PRKN-associated Parkinson’s disease

Menon,

Sambin,

Criniere-Boizet

et al. 2024

npj Parkinsons Dis.

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“…An increasingly highlighted example of this is the overall more rapid deterioration of motoric and cognitive-behavioral function and poorer survival in patients harboring GBA1 variants [93][94][95]. Some GBA1-PD patients also appear to respond less favorably to treatment with deep brain stimulation (DBS) [94,[96][97][98].…”

Section: Besides Causation/development Of Disease Genetic Factors Can...mentioning

confidence: 99%

Parkinson’s Disease is Predominantly a Genetic Disease

Lim,

Klein

2024

JPD

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The discovery of a pathogenic variant in the alpha-synuclein (SNCA) gene in the Contursi kindred in 1997 indisputably confirmed a genetic cause in a subset of Parkinson’s disease (PD) patients. Currently, pathogenic variants in one of the seven established PD genes or the strongest known risk factor gene, GBA1, are identified in ∼15% of PD patients unselected for age at onset and family history. At first sight, the steep increase in PD prevalence exceeding that of other neurodegenerative diseases may argue against a predominant genetic etiology. Notably, the principal genetic contribution in PD is conferred by pathogenic variants in LRRK2 and GBA1 and, in both cases, characterized by an overall late age of onset and age-related penetrance. In addition, polygenic risk plays a considerable role in PD. However, it is likely that, in the majority of PD patients, a complex interplay of aging, genetic, environmental, and epigenetic factors leads to disease development.5% of PD patients unselected for age at onset and family history. At first sight, the steep increase in PD prevalence exceeding that of other neurodegenerative diseases may argue against a predominant genetic etiology. Notably, the principal genetic contribution in PD is conferred by pathogenic variants in LRRK2 and GBA1 and, in both cases, characterized by an overall late age of onset and age-related penetrance. In addition, polygenic risk plays a considerable role in PD. However, it is likely that, in the majority of PD patients, a complex interplay of aging, genetic, environmental, and epigenetic factors leads to disease development.

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“…Interestingly, while the age of onset of PD in LRRK2 G2019S carriers is comparable to sporadic PD, the disease progression of LRRK2 G2019S PD patients is slower than sporadic PD 74 , 81 , 82 . Thus, it seems that LRRK2-PD has a more favourable clinical phenotype 83 and perhaps even longer survival than iPD patients 84 , 85 . While these group differences remain to be defined unambiguously, it should be emphasized that these clinical phenotypes cannot distinguish, on an individual basis, G2019S from sporadic cases.…”

Section: Introductionmentioning

confidence: 99%

Perspective on the current state of the LRRK2 field

Taymans

Fell

Greenamyre

et al. 2023

npj Parkinsons Dis.

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Almost 2 decades after linking LRRK2 to Parkinson’s disease, a vibrant research field has developed around the study of this gene and its protein product. Recent studies have begun to elucidate molecular structures of LRRK2 and its complexes, and our understanding of LRRK2 has continued to grow, affirming decisions made years ago to therapeutically target this enzyme for PD. Markers of LRRK2 activity, with potential to monitor disease progression or treatment efficacy, are also under development. Interestingly, there is a growing understanding of the role of LRRK2 outside of the central nervous system in peripheral tissues such as gut and immune cells that may also contribute to LRRK2 mediated pathology. In this perspective, our goal is to take stock of LRRK2 research by discussing the current state of knowledge and critical open questions in the field.

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Differences in Survival across Monogenic Forms of Parkinson's Disease

Cited by 9 publications

References 41 publications

Genotype–phenotype correlation in PRKN-associated Parkinson’s disease

Genotype–phenotype correlation in PRKN-associated Parkinson’s disease

Parkinson’s Disease is Predominantly a Genetic Disease

Perspective on the current state of the LRRK2 field

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