RESUMO
Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have been recently identified in families with Parkinson's disease (PD). However, the prevalence and nature of LRRK2 mutations, the polymorphism content of the gene, and the associated phenotypes remain poorly understood. We performed a comprehensive study of this gene in a large sample of families with Parkinson's disease compatible with autosomal dominant inheritance (ADPD). The full-length open reading frame and splice sites of the LRRK2 gene (51 exons) were studied by genomic sequencing in 60 probands with ADPD (83% Italian). Pathogenic mutations were identified in six probands (10%): the heterozygous p.G2019S mutation in four (6.6%), and the heterozygous p.R1441C mutation in two (3.4%) probands. A further proband carried the heterozygous p.I1371 V mutation, for which a pathogenic role could not be established with certainty. In total, 13 novel disease-unrelated variants and three intronic changes of uncertain significance were also characterized. The phenotype associated with LRRK2 pathogenic mutations is the one of typical PD, but with a broad range of onset ages (mean 55.2, range 38-68 years) and, in some cases, slow disease progression. On the basis of the comprehensive study in a large sample, we conclude that pathogenic LRRK2 mutations are frequent in ADPD, and they cluster in the C-terminal half of the encoded protein. These data have implications both for understanding the molecular mechanisms of PD, and for directing the genetic screening in clinical practice.
Assuntos
Doença de Parkinson/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/fisiologia , Adulto , Idoso , Processamento Alternativo , Sequência de Aminoácidos , Animais , Progressão da Doença , Éxons , Saúde da Família , Feminino , Genes Dominantes , Testes Genéticos , Genótipo , Heterozigoto , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Dados de Sequência Molecular , Mutação , Fases de Leitura Aberta , Linhagem , Fenótipo , Polimorfismo Genético , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de ProteínaRESUMO
We studied absorption, efficacy, and tolerability in Parkinson's disease (PD) of a new preparation of apomorphine included in a microemulsion and administered by transdermal route (Apo-MTD). Twenty-one PD patients were treated with levodopa plus oral dopamine-agonists (T0), with levodopa alone (T1), finally with levodopa plus Apo-MTD (T2). Apo-MTD provided therapeutic plasma levels for many hours, improved Unified Parkinson's Disease Rating Scale III scores, and reduced total duration of off periods compared to T0 and T1. We concluded that Apo-MTD is absorbed and demonstrates clinical efficacy and long action. Therefore, it seems a promising add-on treatment for uncontrolled prolonged off phases in PD patients, but chronic tolerability needs further study.