Publicação
LRRK2 mutations in parkinson’s disease
| Resumo: | Parkinson’s disease (PD) is the most frequent neurodegenerative movement disorder, affecting 1-2% of the world population above 65 years of age. Although identified in a minority of patients, mutations in the LRRK2 gene, in particular the G2019S mutation, are the most frequent known cause of PD identified so far. Research on LRRK2 related PD epidemiology and associated phenotypes is of the utmost importance for clinical practice and counseling and for uncovering new molecular pathways and pharmacological targets. The present investigation aims to identify the frequency of LRRK2 G2019S mutation in different populations, to characterize LRRK2 mutations in Portuguese PD patients, to study associated clinical phenotypes, and to contribute to the evaluation of a possible imaging biomarker. Methods To study the frequency of the LRRK2 G2019S mutation in different PD populations we conducted a systematic review of all published papers regarding G2019S frequency in which a PD population with a common ethnic background could be independently analyzed. The quality of published methodology and related susceptibility to bias were assessed through a checklist approach. To clarify the frequency of LRRK2 mutations in Portuguese PD patients, a comprehensive screening of LRRK2 mutations in a consecutively recruited cohort of familial PD probands was performed. Findings were evaluated in a larger PD cohort and in controls, ascertained at the Movements Disorders Outpatient Clinic of the Hospital de Santa Maria in Lisbon. A case-control cross-sectional study was designed to compare the motor and non-motor clinical phenotype between PD patients carrying a LRRK2 gene mutation and PD patients with no mutations identified, matched for age of onset, disease duration and gender. The primary outcome was the Movement Disorders Society- Unified Parkinson’s disease Rating Scale (MDS-UPDRS) part III (motor part) and secondary outcomes concerned other questionnaires and scales for the study of motor and nonmotor symptoms in PD. Retrospective data on motor and nonmotor symptoms was additionally collected and analyzed. A logistic regression model was used to identify PD patients carrying LRRK2 mutations. For the evaluation of the use of neuromelanin-Magnetic Resonance imaging (Neuromelanin-MRI) as biomarker in LRRK2-related PD, we performed a comparative imaging study between PD patients carrying an LRRK2 mutation vs. controls with no known neurodegenerative disorder and PD patients with no mutations identified. Results Sixty-eight studies from 32 countries were included in the systematic review on reported G2019S frequency in different PD populations. Heterogeneity in frequency in different PD populations was observed, ranging from 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. Sixty-one familial PD probands were included in the analysis of the entire LRRK2 coding region and respective exon-intron boundaries. The G2019S mutation was found in 16.4% of the probands, the R1441H mutation in 3.3% and five novel coding LRRK2 variants were identified, each in one patient. Identified mutations were tested in additional familial and sporadic patients, and together with previous results, we found a frequency of G2019S carriers of 14% for familial cases (12/86) and 3.5% for sporadic cases (8/226). The five novel coding variants were absent from 191 sporadic PD patients. No mutations or novel variants were identified in 138 control individuals. For studying the LRRK2 associated clinical phenotype, 342 PD patients were additionally screened for LRRK2 mutations. 24 PD patients carrying a LRRK2 mutation (20 G2019S, 4 R1441H) and 48 PD controls with no mutations identified were included in the case-control cross-sectional study. With a mean disease duration of 16.0±8.7 years, PD patients with a LRRK2 mutation presented no significant difference in MDS-UPDRS III and significantly less frequent nocturia when compared with PD patients with no mutations identified. REM sleep behavior disorder (RBD) related symptoms were significantly less reported in PD patients carrying a LRRK2 mutation. The Odds Ratio of a PD patient not carrying a LRRK2 mutation was 7.96 if RBD related symptoms were ever reported. Neuromelanin-MRI was performed in 13 PD patients with a LRRK2 mutation (10 G2019S, 3 R1441H), in 13 PD patients with no LRRK2 mutations identified and in 10 controls with no known neurodegenerative disorder. The SN neuromelanin signal area was significantly decreased in both LRRK2-related PD and PD patients with no LRRK2 mutations when compared to controls. There was no significant difference in neuromelanin signal areas between PD groups with and without LRRK2 mutations. The neuromelanin-MRI area measurement had a 92.3% sensitivity and 100% specificity in discriminating LRRK2-related PD patients from controls. Conclusions Worldwide frequencies of G2019S LRRK2 PD mutation carriers are heterogeneous and highly variable, reflecting differences in populations and possible methodological discrepancies. In order to improve accuracy in reporting, recommendations on the methods of selection of participants and on the definition of familial PD are made. Concerning Portugal, our comprehensive genetic screening study confirms G2019S as the most important genetic cause of PD known so far in Portuguese PD patients and supports R1441H as pathogenic. Together with our first study, our results show that Portugal has one of the highest frequencies of G2019S PD carriers in Europe. Concerning LRRK2-related PD clinical expression, our results confirm that also for patients with long disease duration, the LRRK2-associated motor phenotype largely overlaps with idiopathic Parkinson’s disease. Nocturia and RBD were significantly less frequent in LRRK2-PD patients and emerged as main differences to be further investigated. Neuromelanin-MR images of the SN can accurately differentiate LRRK2-related PD from control individuals. Our results may have important implications for clinical practice, counseling, molecular and clinical research, in preclinical, prodromal and post diagnostic phases of the disease. |
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| Autores principais: | Miranda, Maria Leonor Brito de Arriaga Correia Guedes Möller, 1973- |
| Assunto: | Doença de Parkinson LRRK2 Frequência Fenótipo Imagem Teses de doutoramento - 2017 |
| Ano: | 2017 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso restrito |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Parkinson’s disease (PD) is the most frequent neurodegenerative movement disorder, affecting 1-2% of the world population above 65 years of age. Although identified in a minority of patients, mutations in the LRRK2 gene, in particular the G2019S mutation, are the most frequent known cause of PD identified so far. Research on LRRK2 related PD epidemiology and associated phenotypes is of the utmost importance for clinical practice and counseling and for uncovering new molecular pathways and pharmacological targets. The present investigation aims to identify the frequency of LRRK2 G2019S mutation in different populations, to characterize LRRK2 mutations in Portuguese PD patients, to study associated clinical phenotypes, and to contribute to the evaluation of a possible imaging biomarker. Methods To study the frequency of the LRRK2 G2019S mutation in different PD populations we conducted a systematic review of all published papers regarding G2019S frequency in which a PD population with a common ethnic background could be independently analyzed. The quality of published methodology and related susceptibility to bias were assessed through a checklist approach. To clarify the frequency of LRRK2 mutations in Portuguese PD patients, a comprehensive screening of LRRK2 mutations in a consecutively recruited cohort of familial PD probands was performed. Findings were evaluated in a larger PD cohort and in controls, ascertained at the Movements Disorders Outpatient Clinic of the Hospital de Santa Maria in Lisbon. A case-control cross-sectional study was designed to compare the motor and non-motor clinical phenotype between PD patients carrying a LRRK2 gene mutation and PD patients with no mutations identified, matched for age of onset, disease duration and gender. The primary outcome was the Movement Disorders Society- Unified Parkinson’s disease Rating Scale (MDS-UPDRS) part III (motor part) and secondary outcomes concerned other questionnaires and scales for the study of motor and nonmotor symptoms in PD. Retrospective data on motor and nonmotor symptoms was additionally collected and analyzed. A logistic regression model was used to identify PD patients carrying LRRK2 mutations. For the evaluation of the use of neuromelanin-Magnetic Resonance imaging (Neuromelanin-MRI) as biomarker in LRRK2-related PD, we performed a comparative imaging study between PD patients carrying an LRRK2 mutation vs. controls with no known neurodegenerative disorder and PD patients with no mutations identified. Results Sixty-eight studies from 32 countries were included in the systematic review on reported G2019S frequency in different PD populations. Heterogeneity in frequency in different PD populations was observed, ranging from 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. Sixty-one familial PD probands were included in the analysis of the entire LRRK2 coding region and respective exon-intron boundaries. The G2019S mutation was found in 16.4% of the probands, the R1441H mutation in 3.3% and five novel coding LRRK2 variants were identified, each in one patient. Identified mutations were tested in additional familial and sporadic patients, and together with previous results, we found a frequency of G2019S carriers of 14% for familial cases (12/86) and 3.5% for sporadic cases (8/226). The five novel coding variants were absent from 191 sporadic PD patients. No mutations or novel variants were identified in 138 control individuals. For studying the LRRK2 associated clinical phenotype, 342 PD patients were additionally screened for LRRK2 mutations. 24 PD patients carrying a LRRK2 mutation (20 G2019S, 4 R1441H) and 48 PD controls with no mutations identified were included in the case-control cross-sectional study. With a mean disease duration of 16.0±8.7 years, PD patients with a LRRK2 mutation presented no significant difference in MDS-UPDRS III and significantly less frequent nocturia when compared with PD patients with no mutations identified. REM sleep behavior disorder (RBD) related symptoms were significantly less reported in PD patients carrying a LRRK2 mutation. The Odds Ratio of a PD patient not carrying a LRRK2 mutation was 7.96 if RBD related symptoms were ever reported. Neuromelanin-MRI was performed in 13 PD patients with a LRRK2 mutation (10 G2019S, 3 R1441H), in 13 PD patients with no LRRK2 mutations identified and in 10 controls with no known neurodegenerative disorder. The SN neuromelanin signal area was significantly decreased in both LRRK2-related PD and PD patients with no LRRK2 mutations when compared to controls. There was no significant difference in neuromelanin signal areas between PD groups with and without LRRK2 mutations. The neuromelanin-MRI area measurement had a 92.3% sensitivity and 100% specificity in discriminating LRRK2-related PD patients from controls. Conclusions Worldwide frequencies of G2019S LRRK2 PD mutation carriers are heterogeneous and highly variable, reflecting differences in populations and possible methodological discrepancies. In order to improve accuracy in reporting, recommendations on the methods of selection of participants and on the definition of familial PD are made. Concerning Portugal, our comprehensive genetic screening study confirms G2019S as the most important genetic cause of PD known so far in Portuguese PD patients and supports R1441H as pathogenic. Together with our first study, our results show that Portugal has one of the highest frequencies of G2019S PD carriers in Europe. Concerning LRRK2-related PD clinical expression, our results confirm that also for patients with long disease duration, the LRRK2-associated motor phenotype largely overlaps with idiopathic Parkinson’s disease. Nocturia and RBD were significantly less frequent in LRRK2-PD patients and emerged as main differences to be further investigated. Neuromelanin-MR images of the SN can accurately differentiate LRRK2-related PD from control individuals. Our results may have important implications for clinical practice, counseling, molecular and clinical research, in preclinical, prodromal and post diagnostic phases of the disease. |
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