Avaliação clínica e genética de uma amostra sul-brasileira de pacientes com doença de Wilson

Orientador: Prof. Dr.Helio Afonso Ghizoni TeiveCo-orientadora: Profª Drª Dominique Araújo MuzzilloTese (doutorado) - Universidade Federal do Paraná, Setor de Ciencias da Saúde, Programa de Pós-Graduaçao em Medicina Interna. Defesa : Curitiba, 29/04/2011Bibliografia: fls. 56-65Resumo: A doença de Wilson (DW), distúrbio herdado com caráter autossômico recessivo, caracteriza-se pela deficiência de excreção de cobre pelo fígado, originária de mutações do gene ATP7B. Foram descritas mais de 400 diferentes mutações causadoras da doença e existem escassas informações sobre o comportamento genético da DW no Brasil. Este estudo objetiva analisar uma amostra de 36 pacientes com DW provenientes da população sul-brasileira, avaliando as mutações ATP7B, as manifestações fenotípicas, caracterizando a região geográfico-continental da família e antepassados e comparando os padrões de manifestações geno-fenotípicas encontrados nesta casuítica com os descritos no Brasil e no mundo. A idade média no início dos sintomas foi de 23,3 ± 9,3 anos, com um atraso médio de 27,5 ± 41,9 meses para o diagnóstico definitivo. O tempo médio entre o início dos primeiros sintomas clínicos e o diagnóstico definitivo foi 18,5 ± 12,4 meses na forma neurológica; 6,7 ± 5,8 meses na hepática e; de 51 ± 59,6 meses na mista. Houve diferença estatística significativa no intervalo de tempo para o diagnóstico entre a forma hepática e as demais (p=0,02 neurológica e p=0,004 mista). Ao diagnóstico, nove pacientes (25%) apresentavam quadro clínico exclusivamente neurológico, 14 (38,9%) exclusivamente hepático, 11 (30,6%) características neurológicas e hepáticas (apresentação mista) e 2 (5,5%) eram assintomáticos. Anéis de Kayser-Fleischer foram identificados em 55,6%, com maior freqüência nos pacientes com quadro neurológico (77,8%). Dezoito pacientes desenvolveram manifestações neuro-psiquiátricas e alterações neuro-radiológicas foram observadas em 72,2% destes. Doença hepática crônica foi identificada em 68% dos pacientes com manifestação hepática. O tratamento com D-penicilamina foi instituído para 94,2% dos pacientes. Outras terapias empregadas foram os sais de zinco, combinação de drogas e transplante hepático (TH). Após o início do tratamento, 78,8% evoluíram com um quadro estável ou apresentaram melhora clínica e a taxa de sobrevida global foi de 90,1%. A quase totalidade dos pacientes apresentava ascendência européia através de pelo menos um dos seus ancestrais. Foram descritos os genótipos em 23 pacientes desta amostra. Encontraram-se 14 mutações diferentes em pelo menos um dos alelos, sendo 2 novas mutações potencialmente causadoras de doença. A substituição c.3207C>A no éxon 14 foi a mais freqüente mutação encontrada, com frequência alélica de 28,3%, seguida da mutação c.3402delC no éxon 15, com freqüência alélica de 8,7%. As duas mutações mais freqüentes respondem por 37% dos alelos estudados, indicando que estes éxons são importantes para a detecção de mutações em pacientes da população sul-brasileira. Este é o primeiro estudo que avaliou a correlação genótipo/fenótipo de pacientes com DW no sul do Brasil e possibilitou a determinação de um padrão genotípico semelhante ao europeu e diferente do previamente descrito para a população brasileira.Abstract: Wilson's disease (WD), an inherited autosomal recessive illness, is characterized by the impaired copper excretion and triggered by a mutation of the ATP7B gene. Over 400 different disease-causing mutations were already described and there are only few reports of WD genetics’ behavior in Brazil. The aim of this study was to analyze a sample of 36 WD patients from the south of Brazil, ATP7B mutations, the phenotypic features, characterizing the continental-geographical origin of relatives and ancestors and comparing the genotypic and phenotypic patterns of this study with the ones previously described in Brazil and in the world. The mean age at initial symptom presentation was 23,3 ± 9,3 years with 27,5 ± 41,9 months delay until definitive diagnosis. The mean time between the initial symptom and the definitive diagnosis was 18,5 ± 12,4 months in the neurological form; 6,5 ± 5,8 months in the hepatic one and 51 ± 59,6 months in the mixed one. There was a statistically significant difference in the delay until definitive diagnosis of the hepatic form compared to the other ones (p=0,02 neurological; p=0,004 mixed form). At presentation, nine patients (25%) presented exclusive neurological clinical features, 14 (38,9%) exclusively hepatic ones, 11 (30,6%) hepatic and neurologic ones (mixed presentation) and two (5,5%) were asymptomatic. Kayser-Fleischer rings were identified in 55,6%,with a higher frequency among those with neuropsychiatric symptoms (77,8%). Eighteen patients developed neuropsychiatric features and neuroradiological imaging abnormalities were observed in 72,2% of them. Chronic liver disease was detected in 68% of the patients with hepatic symptoms. Treatment with D-penicillamine was started with 94,2% of the patients. Other employed therapies were zinc salts, combined drugs and liver transplantation. After initiating therapy, 78,8% had a stable or improved outcome and the overall survival rate was 90,1%. Almost all patients presented European ancestry through at least one of their ancestors. The genetic profile was determined in 23 WD patients of this sample. Fourteen different mutations were found in at least one of the alleles, being two of them novel potentially disease-causing mutations. The most frequent mutation was the c.3207C>A substitution at exon 14, with an allelic frequency of 28,3%, followed by the c.3402delC at exon 15, with an allelic frequency of 8,7%. The two most frequent mutations account for 37% of the analyzed alleles, therefore indicating that these exons are important for the detection of mutations in south Brazilian WD patients. This is the first study which evaluated the genotypic/phenotypic correlation among southern Brazil WD patients and allowed the determination of a genotypic pattern similar to the European one and different from the previously ones described for the Brazilian population

Wilson's disease in southern Brazil: a 40-year follow-up study

BACKGROUND: Long-term data on the clinical follow-up and the treatment effectiveness of Wilson's disease are limited because of the low disease frequency. This study evaluated a retrospective cohort of Wilson's disease patients from southern Brazil during a 40-year follow-up period. METHODS: Thirty-six Wilson's disease patients, diagnosed from 1971 to 2010, were retrospectively evaluated according to their clinical presentation, epidemiological and social features, response to therapy and outcome. RESULTS: Examining the patients' continental origins showed that 74.5% had a European ancestor. The mean age at the initial symptom presentation was 23.3 ± 9.3 years, with a delay of 27.5 ± 41.9 months until definitive diagnosis. At presentation, hepatic symptoms were predominant (38.9%), followed by mixed symptoms (hepatic and neuropsychiatric) (30.6%) and neuropsychiatric symptoms (25%). Kayser-Fleischer rings were identified in 55.6% of patients, with a higher frequency among those patients with neuropsychiatric symptoms (77.8%). Eighteen patients developed neuropsychiatric features, most commonly cerebellar syndrome. Neuroradiological imaging abnormalities were observed in 72.2% of these patients. Chronic liver disease was detected in 68% of the patients with hepatic symptoms. 94.2% of all the patients were treated with D-penicillamine for a mean time of 129.9 ± 108.3 months. Other treatments included zinc salts, combined therapy and liver transplantation. After initiating therapy, 78.8% of the patients had a stable or improved outcome, and the overall survival rate was 90.1%. CONCLUSION: This study is the first retrospective description of a population of Wilson's disease patients of mainly European continental origin who live in southern Brazil. Wilson's disease is treatable if correctly diagnosed, and an adequate quality of life can be achieved, resulting in a long overall survival

Doença de Wilson no sul do Brasil: correlação genotípica-fenotípica\ud e a descrição de duas novas mutações no gene ATP7B

OBJECTIVE:\ud \ud Wilson's disease (WD) is an inborn error of metabolism caused by abnormalities of the copper-transporting protein encoding gene ATP7B. In this study, we examined ATP7B for mutations in a group of patients living in southern Brazil.\ud \ud METHODS:\ud \ud 36 WD subjects were studied and classified according to their clinical and epidemiological data. In 23 subjects the ATP7B gene was analyzed.\ud \ud RESULTS:\ud \ud Fourteen distinct mutations were detected in at least one of the alleles. The c.3207C>A substitution at exon 14 was the most common mutation (allelic frequency=37.1%) followed by the c.3402delC at exon 15 (allelic frequency=11.4%). The mutations c.2018-2030del13 at exon 7 and c.4093InsT at exon 20 are being reported for the first time.\ud \ud CONCLUSION:\ud \ud The c.3207C>A substitution at exon 14, was the most common mutation, with an allelic frequency of 37.1%. This mutation is the most common mutation described in Europe.OBJETIVO:\ud \ud A doença de Wilson (DW) é um erro inato do metabolismo causado por abnormalidades no gene ATP7B, que codifica uma proteína transportadora de cobre. Neste estudo, avaliamos as mutações do gene ATP7B em um grupo de pacientes do sul do Brasil.\ud \ud MÉTODOS:\ud \ud Foram estudados 36 pacientes com DW e classificados do ponto de vista clínico e epidemiológico. Em 23 pacientes, o gene ATP7B foi analisado.\ud \ud RESULTADOS:\ud \ud A substituição c.3207C>A no éxon 14 foi a mutação mais comum seguida pela mutação c.3402delC no éxon 15 . A mutação c.2018-2030del13 no éxon 7 e a c.4093InsT no éxon 20 são relatadas pela primeira vez na literatura.\ud \ud CONCLUSÃO:\ud \ud A mutação do gene ATP7B, com a substituição c.3207C>A no éxon 14 foi a mais frequente. Esta mutação é a mais comumente encontrada em pacientes europeus

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Síndrome de Parsonage-Turner em paciente HIV positivo Parsonage-Turner syndrome in HIV seropositive patient

A síndrome de Parsonage-Turner é uma desordem rara de etiologia ainda indeterminada, contudo com fortes evidências de associação a infecções virais inclusive pelo vírus HIV, que afeta a cintura escapular e desencadeia dor e fraqueza da musculatura do ombro e da extremidade superior. O diagnóstico raramente é feito no início do quadro e poucos exames laboratoriais podem ser úteis, com destaque para a eletroneuromiografia. Seu tratamento é basicamente observacional e de controle dos sintomas e a recuperação é esperada na maioria dos pacientes. Por se tratar de uma enfermidade rara e de difícil diagnóstico clínico, os autores relatam o caso de um paciente com quadro clínico laboratorial compatível com a síndrome de Parsonage-Turner associada à soropositividade ao vírus da imunodeficiência adquirida.Parsonage-Turner syndrome is a rare disorder of unknown etiology, nevertheless with high evidences of association with viral infections, including HIV, which affects the shoulder girdle and unleash pain and weakness of the shoulder and upper extremity. The diagnosis is rarely made in acute setting and few diagnostic tests are helpful, except for electroneuromyography. The treatment is basically supportive and full recovery is expected in most patients. For being a rare ailment allied with difficult diagnosis, the authors report a case of a patient with clinical and laboratorial findings of Parsonage-Turner syndrome associated with acquired immunodeficiency virus seropositivity