Assuntos
Análise Mutacional de DNA , Etnicidade/genética , Doença de Gaucher/genética , Glucosilceramidase/genética , Doença de Parkinson/genética , Transtornos Parkinsonianos/genética , Polimorfismo Genético/genética , Alelos , Estudos de Coortes , Efeito Fundador , Doença de Gaucher/diagnóstico , Frequência do Gene , Testes Genéticos , Humanos , Judeus/genética , Doença de Parkinson/diagnóstico , Transtornos Parkinsonianos/diagnóstico , Valores de Referência , VenezuelaRESUMO
To better understand the pathogenesis of brain dysfunction in Gaucher disease (GD), we studied brain pathology in seven subjects with type 1 GD (four also exhibited parkinsonism and dementia), three with type 2 GD and four with type 3 GD. Unique pathologic patterns of disease involving the hippocampal CA2-4 regions and layer 4b of the calcarine cortex were identified. While these findings were common to all three GD phenotypes, the extent of the changes varied depending on the severity of disease. Cerebral cortical layers 3 and 5, hippocampal CA2-4, and layer 4b were involved in all GD patients. Neuronal loss predominated in both type 2 and type 3 patients with progressive myoclonic encephalopathy, whereas patients classified as type 1 GD had only astrogliosis. Adjacent regions and lamina, including hippocampal CA1 and calcarine lamina 4a and 4c were spared of pathology, highlighting the specificity of the vulnerability of selective neurons. Elevated glucocerebrosidase expression by immunohistochemistry was found in CA2-4. Hippocampal (45)Ca(2+) uptake autoradiography in rat brain was performed demonstrating that hippocampal CA2-4 neurons, rather than CA1 neurons, were calcium-induced calcium release sensitive (CICR-sensitive). These findings match recent biochemical studies linking elevated glucosylceramide levels to sensitization of CA2-4 RyaR receptors and 300% potentiation of neuronal CICR sensitivity. In two patients with type 1 GD and parkinsonism, numerous synuclein positive inclusions, similar to brainstem-type Lewy bodies found in Parkinson disease, were also found hippocampal CA2-4 neurons. These findings argue for a common cytotoxic mechanism linking aberrant glucocerebrosidase activity, neuronal cytotoxicity, and cytotoxic Lewy body formation in GD.
Assuntos
Encéfalo/patologia , Doença de Gaucher/fisiopatologia , Neurônios/patologia , Adolescente , Idoso , Idoso de 80 Anos ou mais , Animais , Astrócitos/patologia , Autorradiografia , Radioisótopos de Cálcio/metabolismo , Criança , Pré-Escolar , Epilepsias Mioclônicas/complicações , Feminino , Doença de Gaucher/complicações , Glucosilceramidase/metabolismo , Humanos , Imuno-Histoquímica , Lactente , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Ratos , SinucleínasRESUMO
Recent studies showing an association between glucocerebrosidase deficiency and parkinsonism in Gaucher disease prompted an examination of the glucocerebrosidase gene sequence (GBA) and enzyme activity in brain samples from 57 subjects carrying the diagnosis of Parkinson disease. Alterations in GBA were identified in 12 samples (21%) and were more frequent among the younger subjects. These included eight with mutations (N370S, L444P, K198T, and R329C) and four with probable polymorphisms (T369M and E326K). Our findings suggest that mutations in glucocerebrosidase may be a risk factor for the development of parkinsonism.
