Genética da doença de Parkinson no Brasil : revisão sistemática de formas monogênicas

Background: Increasing numbers of mutations causing monogenic forms of Parkinson's disease (PD) have been described, mostly among patients in Europe and North America. Since genetic architecture varies between different populations, studying the specific genetic profile of Brazilian patients is essential for improving genetic counseling and for selecting patients for clinical trials. Objective: We conducted a systematic review to identify genetic studies on Brazilian patients and to set a background for future studies on monogenic forms of PD in Brazil. Methods: We searched MEDLINE, EMBASE and Web of Science from inception to December 2019 using terms for "Parkinson's disease", "genetics" and "Brazil". Two independent reviewers extracted the data. For the genes LRRK2 and PRKN, the estimated prevalence was calculated for each study, and a meta-analysis was performed. Results: A total of 32 studies were included, comprising 94 Brazilian patients with PD with a causative mutation, identified from among 2,872 screened patients (3.2%). PRKN mutations were causative of PD in 48 patients out of 576 (8.3%). LRRK2 mutations were identified in 40 out of 1,556 patients (2.5%), and p.G2019S was the most common mutation (2.2%). Conclusions: PRKN is the most common autosomal recessive cause of PD, and LRRK2 is the most common autosomal dominant form. We observed that there was a lack of robust epidemiological studies on PD genetics in Brazil and, especially, that the diversity of Brazil’s population had not been considered.Introdução: Um número crescente de mutações causando formas monogênicas de doença de Parkinson (DP) tem sido descrito, principalmente entre pacientes da Europa e da América do Norte. Como a arquitetura genética varia entre diferentes populações, entender os perfis genéticos específicos de pacientes brasileiros é essencial para um melhor aconselhamento genético e para a seleção de participantes para ensaios clínicos. Objetivo: Revisão sistemática para identificar estudos genéticos brasileiros na área e definir o cenário para estudos futuros das formas monogênicas de DP no Brasil. Métodos: Nós pesquisamos as bases de dados MEDLINE, EMBASE e Web of Science desde a criação até dezembro de 2019, usando termos para “Parkinson’s disease”, “genetics” e “Brazil”. A extração de dados foi feita por dois revisores independentes. Para os genes LRRK2 e PRKN, calculamos a prevalência estimada para cada estudo e realizamos uma meta-análise. Resultados: Um total de 32 estudos foram incluídos e 94 pacientes brasileiros com DP com mutações causativas foram identificados em 2872 pacientes avaliados (3.2%). As mutações no PRKN causaram DP em 48 de 576 pacientes (8.3%). As mutações no LRRK2 foram identificadas em 40 de 1566 pacientes (2.5%), sendo a mutação mais comum a p.G2019S (2.2%). Conclusões: As mutações na PRKN são a causa mais comum de DP autossômica recessiva, e as mutações no LRRK2 a causa mais comum de DP autossômica dominante. Nós observamos uma falta de estudos epidemiológicos robustos em genética de DP, especialmente por não levar em conta a diversidade de nossa população

Caracterização fenotípica e genotípica de parkinsonismo e distonia familiares no ambulatório de distúrbios de movimento do Hospital das Clínicas da Universidade Federal de Minas Gerais

Exportado OPUSMade available in DSpace on 2019-08-13T19:08:21Z (GMT). No. of bitstreams: 1 sarahteixeira_camargos.pdf: 4298340 bytes, checksum: 6ffcd10e4cb2820095baeae4b63f912f (MD5) Previous issue date: 16O objetivo deste estudo foi fazer uma avaliação fenotípica e genotípica de pacientes com parkinsonismo e distonia de início precoce e parkinsonismo e distonia familiares. Foram atendidos no ambulatório de Movimentos Anormais do Hospital das Clínicas da UFMG 575 pacientes entre junho de 2005 e junho de 2006, dos quais 39% preenchiam critérios para parkinsonismo e 33% preenchiam critérios para distonia. Foram selecionados oito pacientes com doença deParkinson familiar de início habitual, 45 com doença de Parkinson de início precoce (PIP), 11 com distonia e parkinsonismo familiar, sete com distonia responsiva à dopa, quatro com neurodegeneração com acúmulo cerebral de ferro e 21 com distonia de início precoce e distonia familiar. Os pacientes foram caracterizados clinicamente e genes conhecidos (PRKN, PINK1, LRRK2, SNCA, GCH1, PANK2, DYT1, DYT12) foram seqüenciados de acordo com a doença dos indivíduos. Os éxons PRKN e SNCA foram dosados. Causas hereditárias puderam ser identificadas em 18,8% dos casos de distonia e parkinsonismofamiliares e de início precoce na presente série, permitindo inferir que causas não hereditárias, genes não testados ou genes ainda não descritos podem participar da etiopatogenia da doença nos casos em que o gene causador não pode ser identificado. Foram encontradas mutações novas nos genes PINK1 (del exon 7), LRRK2 (Q923H) e CGH1 (T209P). Foram também encontradas mutações jáanteriormente descritas em PRKN (W54R em heterozigose composta com V3I; heterozigose composta de 255Adel com T240M, heterozigose composta de P253R com duplicação do éxon 5 e também heterozigose simples de 255Adel e T240M), GCH1 (M211V e K224R) e PANK2 (N294I). Os indivíduos com parkinsonismo de início precoce e das demais séries de herança provável autossômico-recessiva foram selecionados para o estudo amplo do genoma a partir de single nucleotide polymorphism (SNP). Nenhuma SNP se mostrou estatisticamente relevante nos pacientes com PIP em relação aos controles. Não houve alteração estrutural (duplicação ou deleção) em nenhuma região não descrita em controles saudáveis. Foi encontrado um traço de homozigose comum em duas famílias com quadro clínico de distonia e parkinsonismo no cromossomo 2 em uma região compreendendo 1,2Mb. Os éxons codificantes dos 12 genes daregião foram seqüenciados e foi encontrada mutação segregadora de doença no gene PRKRA (P222L). O gene codifica uma proteína quinase de indução de interferon dependente de ativador de ácido ribonucléico (RNA) de dupla-fita. PRKRA ativa a quinase latente PKR no caso de estresse extracelular. Este foi, então, identificado como um novo gene causador de distonia, o primeiro com transmissão autossômico-recessiva, denominado DYT16.The aim of this study was to characterize phenotipically and genotipically patients with early onset and familiar parkinsonism and dystonia. During the period of june 2005 through june 2006, 575 patients were assisted at Movement Disorder Clinic, Minas Gerais Federal University. From all, 39% filled criteria for parkinsonism and 33% for dystonia. We selected eight familiar Parkinson disease patients, 45 earlyonset Parkinson disease patients (EOPD), 11 dystonia and parkinsonism patients, seven dopa responsive dystonia patients, four patients with diagnosis of neurodegeneration with brain iron accumulation and 21 patients with familiar dystonia and early onset dystonia. Accordingly with the phenotype, we studied the known genes PRKN, PINK1, LRRK2, SNCA, GCH1, PANK2, DYT1, DYT12. Genedosage was performed for the exons of PRKN and PINK1. Hereditary causes were identified in 18.8% of patients with parkinsonism and dystonia. We described new mutations in PINK1 gene (del exon 7), LRRK2 (Q923H) and CGH1 (T209P). We have found the described mutations in PRKN (W54R in compound heterozygous with V3I; 255Adel in compound heterozygous with T240M, P253R in compound heterozygous with exon 5 duplication, 255Adel single mutation andT240M single mutation), GCH1 (M211V e K224R) and PANK2 (N294I). Patients with early onset Parkinson disease and patients with autosomal recessive inheritance (negative for known mutations) were selected for Whole Genomic Association Study. We failed to find any SNP with significant statistical association in parkinsonian patients when compared with controls. We also failed to find structural association (deletion or duplication) in a region not previously described in healthy controls. A common homozygous track was found in two non correlatedand consanguineous families with dystonia and parkinsonism. This was located in the chromosome 2 in a region comprising 1.2Mb. The codifying exons from the 12 genes from region were sequenced and we found a mutation segregating disease at PRKA gene(P222L). The gene codifies a protein kinase, interferon-inducible double-stranded RNA-dependent activator. PRKA activates a latent PKR in case of cellular stress. We describe a new gene related to dystonia; the first with autosomal recessive inheritance, nominated DYT16. Non hereditary causes(environmental), not tested genes or not described genes might participate of the disease pathology in the cases we didnt find out the cause

Ziprasidone-related oculogyric crisis in an adult.

Introduction: Drug-induced dyskinesias arecommonside-effects of first-generation antipsychotics (FGAs) but are not usually related to second-generation antipsychotics (SGAs). Oculogyric crisis (OGC) is a disabling acute dystonia that affects extra-ocular muscles usually resulting in an upward deviation of the eyes, which lasts from minutes to hours. Case report:Wedescribe an adult patient, previously exposed to an FGA,whodevelopedOGCon 80 mg/day of ziprasidone. The movement disorder significantly improved after use of 1 mg/day of clonazepam without the need to switch to another SGA. Discussion: The clinical features of the movement disorder of our patient meet the criteria for OGC. It is, sometimes, difficult to directly correlate a drug-induced dyskinesia to a SGA due to previous exposures to FGAs. The onset of OGC after exposure to ziprasidone without simultaneous use of other antipsychotic suggests a casual relationship between the former and the movement disorder. It is possible that previous use of an FGA was a risk factor for the development of OGC. Conclusion: To the best of our knowledge, this is the first report of ziprasidone-related OGC in an adult patient. Physicians must be aware of its occurrence in order to improve care of patients treated with these agents

The genetics of the dystonias – a review based on the new classification of the dystonias

The definition and classification of the dystonias was recently revisited. In the new 2013 classification, the dystonias are subdivided in terms of their etiology according to whether they are the result of pathological changes or structural damage, have acquired causes or are inherited. As hereditary dystonias are clinically and genetically heterogeneous, we sought to classify them according to the new recently defined criteria. We observed that although the new classification is still the subject of much debate and controversy, it is easy to use in a logical and objective manner with the inherited dystonias. With the discovery of new genes, however, it remains to be seen whether the new classification will continue to be effective

Genetic evaluation for TOR1-A (DYT1) in Brazilian patients with dystonia

Several genes have been mapped in families or in sporadic cases of dystonia. TOR1-A (DYT1) gene was linked to isolated dystonia. Objective To associate clinical information of patients with dystonia with the TOR1-A gene mutations. Method Eighty-eight patients with dystonia in cervical area (focal, segmental, multifocal and generalized) were recruited at Movement Disorders Clinic of Hospital de Clínicas of the Federal University of Paraná between June of 2008 and June of 2009. They were submitted to the clinical evaluation. DNA was extract from blood and submitted at analysis to TOR1-A mutations by PCR according standard protocols. Results Two patients had c.907GAGdel mutation on TOR1-A gene. These patients, with familial history of dystonia, started his symptoms by legs and had secondary generalization. Conclusion We can suggest that analysis for TOR1-A mutations should be performed only in patients with early onset, generalized and familial dystonia

DYT6 In Brazil: Genetic Assessment and Clinical Characteristics of Patients

Background:&nbsp;Several genes associated with dystonia have been identified. A mutation in one of these, THAP1 (DYT6), is linked to isolated dystonia. The aim of this study was to assess the prevalence of THAP1 gene mutations and the clinical characteristics of patients with these mutations in a clinical population in Brazil.Methods:&nbsp;Seventy‐four patients presenting with dystonia involving the cervical muscles and without mutations in the TOR1A (DYT1) gene or any other movement disorders were recruited at a movement disorders clinic between June 2008 and June 2009. All the patients underwent clinical examination and were screened for mutations of the THAP1 gene.Results:&nbsp;Three patients had the novel p.Gln97Ter THAP1 nonsense mutation in heterozygosis. One of them had no family history of dystonia. Symptoms in this patient first appeared in his right arm, and the condition progressed to the generalized form. The other two patients belonged to the same family (cousins). Symptoms in the first patient started in her right arm at the age of 18 years and the condition progressed to the segmental form. The second patient, who carried the p.Arg169Gln missense mutation, developed dystonia in her left arm at the age of 6 years. The condition progressed to generalized dystonia.Discussion:&nbsp;We conclude that THAP1 mutations are also a cause, albeit uncommon, of segmental and generalized dystonia in the Brazilian population.</p

Amyotrophic lateral sclerosis type 8 is not a pure motor disease: evidence from a neuropsychological and behavioural study

Objective Amyotrophic lateral sclerosis type 8 (ALS8) is a familial form of motor neuron disease, with predominance of lower motor neuron degeneration, and is caused by mutation of the vesicle-associated membrane protein-associated protein B (VAPB). We aimed to compare the cognitive profile of patients with ALS8 and healthy controls (HC), and to screen for behavioural features in ALS8 patients. Methods The sample was composed of ALS8 patients (n = 22; 14 men; median age 48 years old; median disease duration 6.5 years) and HC (n = 33; 19 men; median age 48 years old). Patients and HC were matched for sex, age and educational level. Participants underwent behavioural, psychiatric (Hospital Anxiety and Depression Scale and Cambridge Behavioural Inventory-Revised) and neuropsychological assessments, focused on executive functions, visual memory, and facial emotion recognition. Results ALS8 patients exhibited subtle deficits in executive functions. Compared to controls, ALS8 patients were significantly impaired in measures of flexibility and inhibitory control. ALS8 patients and HC did not differ in scores of facial emotion recognition. There was clinically relevant anxiety and depression in 36% and 27% of ALS8 patients, respectively. Behavioural disorders such as stereotypic and motor behaviours were present in more than 30% of patients. Conclusions ALS8 patients present mild executive dysfunction and behavioural changes such as mood disorders, apathy and stereotypic behaviour. Our findings suggest that ALS8 is not a pure motor disorder and it is associated with subtle cognitive and behavioural impairments266819801987CNPQ - Conselho Nacional de Desenvolvimento Científico e TecnológicoFAPEMIG - Fundação de Amparo à Pesquisa Do Estado De Minas GeraisFAPESP – Fundação de Amparo à Pesquisa Do Estado De São Paulosem informaçãosem informação2013/01766-