RESUMO
Approximately 3.6% of patients with Parkinson's disease develop symptoms before age 45. Early-onset Parkinson's disease (EOPD) patients have a higher familial recurrence risk than late-onset patients, and 3 main recessive EOPD genes have been described. We aimed to establish the prevalence of mutations in these genes in a UK cohort and in previous studies. We screened 136 EOPD probands from a high-ascertainment regional and community-based prevalence study for pathogenic mutations in PARK2 (parkin), PINK1, PARK7 (DJ-1), and exon 41 of LRRK2. We also carried out a systematic review, calculating the proportion of cases with pathogenic mutations in previously reported studies. We identified 5 patients with pathogenic PARK2, 1 patient with PINK1, and 1 with LRRK2 mutations. The rate of mutations overall was 5.1%. Mutations were more common in patients with age at onset (AAO) < 40 (9.5%), an affected first-degree relative (6.9%), an affected sibling (28.6%), or parental consanguinity (50%). In our study EOPD mutation carriers were more likely to present with rigidity and dystonia, and 6 of 7 mutation carriers had lower limb symptoms at onset. Our systematic review included information from >5800 unique cases. Overall, the weighted mean proportion of cases with PARK2 (parkin), PINK1, and PARK7 (DJ-1) mutations was 8.6%, 3.7%, and 0.4%, respectively. PINK1 mutations were more common in Asian subjects. The overall frequency of mutations in known EOPD genes was lower than previously estimated. Our study shows an increased likelihood of mutations in patients with lower AAO, family history, or parental consanguinity.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação/genética , Proteínas Oncogênicas/genética , Doença de Parkinson/genética , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Ubiquitina-Proteína Ligases/genética , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Doença de Parkinson/epidemiologia , Proteína Desglicase DJ-1 , Reino Unido/epidemiologiaRESUMO
The past 10 years has seen a shift in our etiological concepts of Parkinson's disease, moving from a nearly exclusively environmentally mediated disease towards a complex disorder with important genetic contributors. The identification of responsible mutations in certain genes, particularly alpha-synuclein, Parkin, PINK1, DJ-1 and LRRK2, has increased our understanding of the clinical and pathological changes underlying Parkinson's disease, with implications for patient diagnosis, management and future research. This review will outline the specific genetic advances, discuss their implications for clinical practice and hint at future directions for research into this common and disabling disease.
Assuntos
Encéfalo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Oncogênicas/genética , Doença de Parkinson/genética , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Ubiquitina-Proteína Ligases/genética , alfa-Sinucleína/genética , Ensaios Clínicos como Assunto/tendências , Genes Dominantes/genética , Genes Recessivos/genética , Predisposição Genética para Doença/genética , Predisposição Genética para Doença/prevenção & controle , Terapia Genética/métodos , Terapia Genética/tendências , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson/metabolismo , Doença de Parkinson/terapia , Proteína Desglicase DJ-1RESUMO
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Some debate still exists as to whether PD is predominantly environmental or genetic in etiology. The genetic hypothesis of PD etiology has been driven recently by the identification of a number of PD loci. This review deals with each of these loci, discussing the latest data and evidence available. Of particular interest are the recently described mutations in the PINK1 (PARK6) and LRRK2 (PARK8) genes. We also consider the impact of these latest developments on our understanding of sporadic PD and on our everyday practice with PD patients.
