Análise do ritmo de atividade e repouso e do perfil de melatonina em pacientes com doença de Fabry
Data
2018-03-29
Autores
Vallim, Julia Ribeiro da Silva 
Orientadores
D'Almeida, Vania
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Introdução: A Doença de Fabry é causada por mutação no gene GLA, cuja consequência é o acúmulo de glicoesfingolípidos no interior dos lisossomos. A sintomatologia clássica da doença se desenvolve nas primeiras décadas de vida e abrange manifestações dermatológicas, neurológicas, oculares, cardíacas e renais. Já a manifestação não clássica é mais tardia e se restringe ao comprometimento do coração e dos rins. Além dos sintomas, os pacientes apresentam alterações comportamentais do ciclo sono/vigília, como sonolência diurna excessiva, distúrbios respiratórios do sono e movimento periódico de membros inferiores. A propensão ao sono é regulada por um componente homeostático e um componente circadiano, que é rítmico, oscila com uma periodicidade de aproximadamente 24 horas, sincronizado por pistas ambientais, e é orquestrado pelo sistema de temporização. Esse sistema pode ser avaliado por marcadores de ritmicidade biológica, como o ritmo de atividade e repouso e variação de temperatura corporal, assim como pelo ritmo endógeno de cronobióticos, como a biossíntese de melatonina. As alterações do ciclo sono/vigília observadas nos pacientes diagnosticados com Doença de Fabry podem estar relacionadas com uma modificação da ordem temporal interna e consequente modificação no padrão diário de melatonina, e talvez, na manifestação de outros ritmos. Objetivo: Avaliar o efeito da disfunção lisossômica na Doença de Fabry sobre os ritmos de atividade e repouso e de melatonina. Métodos:. Estudo do tipo caso-controle conduzido na cidade de São Paulo, aprovado pelo Comitê de Ética em Pesquisa da Universidade Federal de São Paulo. Foram recrutados 16 pacientes com variante clássica (11 em terapia de reposição enzimática, 10 mulheres) e 7 pacientes com variante não clássica (4 em terapia de reposição enzimática, 6 mulheres) com média de idade de 36,4 ± 3,0 anos e de 44,0 ± 4,6 anos, respectivamente. O grupo controle foi pareado por gênero e idade, sendo composto por 14 indivíduos (10 mulheres), com média de idade de 42,4 ± 3,2 anos. Foi feita uma avaliação por meio de três questionários (escala de sonolência diurna, identificação de cronotipo de Horne e índice de qualidade de sono), atividade e temperatura corporal periférica foram determinados por no mínimo 10 dias de uso do actígrafo e dosagem de 6-sulfatoximelatonina (segunda urina da manhã até 19:00 – Dia; 19:00 até a primeira urina da manhã do dia seguinte - Noite) e melatonina (19:00 às 21:30), na urina e saliva respectivamente. Resultados: O grupo controle apresentou porcentagem de carga excretada de 6-sulfatoximelatonina maior durante a noite que durante o dia. O grupo Fabry com a variante não clássica apresentou um aumento de excreção deste metabólito durante o dia quando comparado com grupo controle, enquanto no grupo Fabry com a variante clássica a oscilação observada no grupo controle estava ausente. Foi encontrado um aumento de período de temperatura corporal periférica entre o grupo Fabry com a variante clássica e o grupo controle. Não foram encontradas diferenças entre os grupos para os outros parâmetros avaliados. Conclusão: Esses resultados mostram que há uma alteração rítmica no perfil de 6-sulfatoximelatonina na Doença de Fabry, evidenciada pelas modificações de carga excretada deste metabólito observada nos pacientes.
Introduction: Fabry’s disease is caused by a mutation in GLA gene, whose consequence is the accumulation of glycosphingolipids within the lysosomes. The classic symptomatology of the disease develops in the first decades of life and includes dermatological, neurological, ocular, cardiac and renal manifestations. Non-classical manifestation occurs later in life and is restricted to involvement of heart and kidneys. Besides these symptoms, the patients present behavioral changes in sleep/wake cycle such as excessive daytime sleepiness, sleep-disordered breathing and abnormal periodic leg movements. Sleep propensity is regulated by a homeostatic and a circadian component, that is rhythmic, oscillates with a periodicity of approximately, 24 hours, synchronized by environmental cues, and orchestrated by a biological clock. The clock can be assessed by markers of biological rhythmicity, as the rhythm of activity and rest and variation of body temperature, and by endogenous rhythm of chronobiotics, as melatonin biosynthesis. Behavioral manifestations of sleep/wake cycle in Fabry disease could be related to modifications in the internal temporal order, and, as a consequence, an alteration in melatonin daily profile and, maybe, in orders rhythmic manifestations. Objective: To assess the effect of lysosomal dysfunction in Fabry disease patients on activity, rest and melatonin rhythms. Methods: The investigation followed a case-control design and was approved by Institution's Ethics Committee (Universidade Federal de São Paulo). Sixteen patients with classic variant (11 on enzyme replacement therapy, 10 women) with a mean age of 36.4 ± 3.0 years and seven patients with non-classic variant (4 on enzyme replacement therapy, 6 women) with a mean age 44.0 ± 4.6 year were recruited. Control group was matched by age and gender, consisting on fourteen volunteers (10 women), with mean age of 42.4 ± 3.2 years. The volunteers answered three questionnaires (Epworth Sleepiness Scale, Morningness-eveningness questionnaire and Pittsburgh Sleep Quality Index), activity, rest and peripheral body temperature values were determined for at least ten days by actigraphy. The 6-sulfatoxymelatonin dosage in urine (second urine in the morning until 7 p.m. – Day; 7.p.m. until first urine in the next morning - Night) and melatonin on saliva (7 p.m. to 9:30 p.m.) were also performed. Results: Control group presented 6-sulfatoxymelatonin excretion load higher during the night than day. Fabry disease with non-classic variant group presented higher levels of 6-sulfatoxymelatonin during the day compared with control group, while Fabry disease with classic variant had no oscillatory pattern, which was observed for control group. Also, was found an increase in peripheral body temperature period between Fabry with classic variant and control group. No differences were found between the groups for other parameters evaluated. Conclusion: These results show a rhythm disruption on 6-sulfatoxymelatonin profile in Fabry disease patients, emphasized by differences in excretion load of this metabolite observed in patients.
Introduction: Fabry’s disease is caused by a mutation in GLA gene, whose consequence is the accumulation of glycosphingolipids within the lysosomes. The classic symptomatology of the disease develops in the first decades of life and includes dermatological, neurological, ocular, cardiac and renal manifestations. Non-classical manifestation occurs later in life and is restricted to involvement of heart and kidneys. Besides these symptoms, the patients present behavioral changes in sleep/wake cycle such as excessive daytime sleepiness, sleep-disordered breathing and abnormal periodic leg movements. Sleep propensity is regulated by a homeostatic and a circadian component, that is rhythmic, oscillates with a periodicity of approximately, 24 hours, synchronized by environmental cues, and orchestrated by a biological clock. The clock can be assessed by markers of biological rhythmicity, as the rhythm of activity and rest and variation of body temperature, and by endogenous rhythm of chronobiotics, as melatonin biosynthesis. Behavioral manifestations of sleep/wake cycle in Fabry disease could be related to modifications in the internal temporal order, and, as a consequence, an alteration in melatonin daily profile and, maybe, in orders rhythmic manifestations. Objective: To assess the effect of lysosomal dysfunction in Fabry disease patients on activity, rest and melatonin rhythms. Methods: The investigation followed a case-control design and was approved by Institution's Ethics Committee (Universidade Federal de São Paulo). Sixteen patients with classic variant (11 on enzyme replacement therapy, 10 women) with a mean age of 36.4 ± 3.0 years and seven patients with non-classic variant (4 on enzyme replacement therapy, 6 women) with a mean age 44.0 ± 4.6 year were recruited. Control group was matched by age and gender, consisting on fourteen volunteers (10 women), with mean age of 42.4 ± 3.2 years. The volunteers answered three questionnaires (Epworth Sleepiness Scale, Morningness-eveningness questionnaire and Pittsburgh Sleep Quality Index), activity, rest and peripheral body temperature values were determined for at least ten days by actigraphy. The 6-sulfatoxymelatonin dosage in urine (second urine in the morning until 7 p.m. – Day; 7.p.m. until first urine in the next morning - Night) and melatonin on saliva (7 p.m. to 9:30 p.m.) were also performed. Results: Control group presented 6-sulfatoxymelatonin excretion load higher during the night than day. Fabry disease with non-classic variant group presented higher levels of 6-sulfatoxymelatonin during the day compared with control group, while Fabry disease with classic variant had no oscillatory pattern, which was observed for control group. Also, was found an increase in peripheral body temperature period between Fabry with classic variant and control group. No differences were found between the groups for other parameters evaluated. Conclusion: These results show a rhythm disruption on 6-sulfatoxymelatonin profile in Fabry disease patients, emphasized by differences in excretion load of this metabolite observed in patients.
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Citação
VALLIM, Julia Ribeiro da Silva. Análise do ritmo de atividade e repouso e do perfil de melatonina em pacientes com doença de Fabry. 2018. 229 f. Dissertação (Mestrado em Ciências) - Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, 2018.