Genetic Screening for the LRRK2 R1441C and G2019S Mutations in Parkinsonian Patients from Campania

Rosa, Anna De; Michele, Giuseppe De; Guacci, Anna; Carbone, Rosa; Lieto, Maria; Peluso, Silvio; Picillo, Marina; Barone, Paolo; Salemi, Fabrizio; Laiso, Antonio; Saccà, Francesco; Tessitore, Alessandro; Pellecchia, Maria Teresa; Bonifati, Vincenzo; Criscuolo, Chiara

doi:10.3233/jpd-130312

Cited by 12 publications

(13 citation statements)

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“…The MDSGene systematic review also suggested that LRRK2 carriers have a good response to l -DOPA, late age at onset and absence of atypical signs (Trinh et al , 2018). However, other studies have not confirmed these findings (Lesage et al , 2005; Haugarvoll et al , 2008; Healy et al , 2008; Alcalay et al , 2010 b ; Belarbi et al , 2010; Ben Sassi et al , 2012; Puschmann, 2013; De Rosa et al , 2014; Estanga et al , 2014).…”

Section: Discussionmentioning

confidence: 80%

Genetic analysis of Mendelian mutations in a large UK population-based Parkinson’s disease study

Tan

Malek

Lawton

et al. 2019

Brain

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Our objective was to define the prevalence and clinical features of genetic Parkinson’s disease in a large UK population-based cohort, the largest multicentre prospective clinico-genetic incident study in the world. We collected demographic data, Movement Disorder Society Unified Parkinson’s Disease Rating Scale scores, and Montreal Cognitive Assessment scores. We analysed mutations in PRKN (parkin), PINK1, LRRK2 and SNCA in relation to age at symptom onset, family history and clinical features. Of the 2262 participants recruited to the Tracking Parkinson’s study, 424 had young-onset Parkinson’s disease (age at onset ≤ 50) and 1799 had late onset Parkinson’s disease. A range of methods were used to genotype 2005 patients: 302 young-onset patients were fully genotyped with multiplex ligation-dependent probe amplification and either Sanger and/or exome sequencing; and 1701 late-onset patients were genotyped with the LRRK2 ‘Kompetitive’ allele-specific polymerase chain reaction assay and/or exome sequencing (two patients had missing age at onset). We identified 29 (1.4%) patients carrying pathogenic mutations. Eighteen patients carried the G2019S or R1441C mutations in LRRK2, and one patient carried a heterozygous duplication in SNCA. In PRKN, we identified patients carrying deletions of exons 1, 4 and 5, and P113Xfs, R275W, G430D and R33X. In PINK1, two patients carried deletions in exon 1 and 5, and the W90Xfs point mutation. Eighteen per cent of patients with age at onset ≤30 and 7.4% of patients from large dominant families carried pathogenic Mendelian gene mutations. Of all young-onset patients, 10 (3.3%) carried biallelic mutations in PRKN or PINK1. Across the whole cohort, 18 patients (0.9%) carried pathogenic LRRK2 mutations and one (0.05%) carried an SNCA duplication. There is a significant burden of LRRK2 G2019S in patients with both apparently sporadic and familial disease. In young-onset patients, dominant and recessive mutations were equally common. There were no differences in clinical features between LRRK2 carriers and non-carriers. However, we did find that PRKN and PINK1 mutation carriers have distinctive clinical features compared to young-onset non-carriers, with more postural symptoms at diagnosis and less cognitive impairment, after adjusting for age and disease duration. This supports the idea that there is a distinct clinical profile of PRKN and PINK1-related Parkinson’s disease. We estimate that there are approaching 1000 patients with a known genetic aetiology in the UK Parkinson’s disease population. A small but significant number of patients carry causal variants in LRRK2, SNCA, PRKN and PINK1 that could potentially be targeted by new therapies, such as LRRK2 inhibitors.

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Section: Discussionmentioning

confidence: 80%

Genetic analysis of Mendelian mutations in a large UK population-based Parkinson’s disease study

Tan

Malek

Lawton

et al. 2019

Brain

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“…Conversely, p.G2019S is extremely rare in East Asia ( 17 ). The other known pathogenic LRRK2 variants are very rare, with the exception of p.R1441G and p.R1441C, which are founder mutations in Basque and south Italian ethnicities, respectively ( 19 , 20 ). The penetrance of the p.G2019S variant is incomplete and age-dependent, peaking at 42.5–74% at the age of ~80 years ( 17 , 21 ), but varies among different ethnicities ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

Genotype-Phenotype Correlations in Monogenic Parkinson Disease: A Review on Clinical and Molecular Findings

et al. 2021

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Parkinson disease (PD) is a complex neurodegenerative disorder, usually with multifactorial etiology. It is characterized by prominent movement disorders and non-motor symptoms. Movement disorders commonly include bradykinesia, rigidity, and resting tremor. Non-motor symptoms can include behavior disorders, sleep disturbances, hyposmia, cognitive impairment, and depression. A fraction of PD cases instead is due to Parkinsonian conditions with Mendelian inheritance. The study of the genetic causes of these phenotypes has shed light onto common pathogenetic mechanisms underlying Parkinsonian conditions. Monogenic Parkinsonisms can present autosomal dominant, autosomal recessive, or even X-linked inheritance patterns. Clinical presentations vary from forms indistinguishable from idiopathic PD to severe childhood-onset conditions with other neurological signs. We provided a comprehensive description of each condition, discussing current knowledge on genotype-phenotype correlations. Despite the broad clinical spectrum and the many genes involved, the phenotype appears to be related to the disrupted cell function and inheritance pattern, and several assumptions about genotype-phenotype correlations can be made. The interest in these assumptions is not merely speculative, in the light of novel promising targeted therapies currently under development.

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“…In these 2 domains, the G2019S (kinase subunit) and the R1441C (Roc domain) are the most frequent disease‐segregating mutations. Importantly, in southern Italy, the R1441C mutation is more frequent than the G2019S mutation . Recent evidence pointed out that LRRK2 acts directly at the secretory and endocytic molecular machinery.…”

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confidence: 99%

Does motor cortex plasticity depend on the type of mutation in the leucine-rich repeat kinase 2 gene?

et al. 2017

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Genetic Screening for the LRRK2 R1441C and G2019S Mutations in Parkinsonian Patients from Campania

Cited by 12 publications

References 0 publications

Genetic analysis of Mendelian mutations in a large UK population-based Parkinson’s disease study

Genetic analysis of Mendelian mutations in a large UK population-based Parkinson’s disease study

Genotype-Phenotype Correlations in Monogenic Parkinson Disease: A Review on Clinical and Molecular Findings

Does motor cortex plasticity depend on the type of mutation in the leucine-rich repeat kinase 2 gene?

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