RESUMO
BACKGROUND: Hirschsprung disease (HSCR) is a frequent congenital disorder with an incidence of 1 in 5000 live births, characterised by the absence of parasympathetic intramural ganglion cells in the hindgut resulting in intestinal obstruction in neonates and severe constipation in infants and adults. Intestinal neuronal dysplasia (IND) shares clinical features with HSCR but the submucosal parasympathetic plexus is affected. IND has been proposed as one of the most frequent causes of chronic constipation and is often associated with HSCR. METHODS: We examined 29 patients diagnosed with sporadic HSCR, 20 patients with IND, and 12 patients with mixed HSCR/IND for mutations in the coding regions of the RET, GDNF, EDNRB, and EDN3 genes. The entire coding regions were analysed by single strand conformational polymorphism and DNA sequencing. RESULTS: Only three RET mutations were detected in patients with HSCR. In patients with IND or a mixed HSCR/IND phenotype, no mutations in these genes were observed. While HSCR and HSCR/IND showed over representation of a specific RET polymorphism in exon 2, IND exhibited a significantly lower frequency comparable with that of controls. CONCLUSIONS: The mutation frequency found in our sporadic HSCR patients (10%) and the allelic distribution of RET polymorphisms are comparable with earlier published data. A significantly different allelic distribution in an established HSCR associated polymorphism argues against common genetic pathways for HSCR and IND.
Assuntos
Proteínas de Drosophila , Doença de Hirschsprung/genética , Mutação/genética , Fatores de Crescimento Neural , Alelos , Estudos de Casos e Controles , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial , Humanos , Proteínas do Tecido Nervoso/genética , Linhagem , Polimorfismo Conformacional de Fita Simples , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-ret , Receptores Proteína Tirosina Quinases/genética , Receptores de Endotelina/genética , Análise de Sequência de DNARESUMO
A bradykinetic form of parkinsonism, unresponsive to levo-dopa therapy developed in four patients two to eight weeks after completion of external beam irradiation (39.2 Gy to 59.4 Gy) of their intracranial neoplasm. In the absence of other causative factors, we relate the movement disorder to radiation-induced changes within the basal ganglia. At post-mortem examination one patient had putamenal gliosis and thickened vessels with loss of nigral neurons.
Assuntos
Antiparkinsonianos/uso terapêutico , Neoplasias Encefálicas/radioterapia , Irradiação Craniana/efeitos adversos , Levodopa/uso terapêutico , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/etiologia , Lesões por Radiação/etiologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Resistência a Medicamentos , Feminino , Humanos , Hipocinesia/etiologia , Masculino , Pessoa de Meia-Idade , Rigidez Muscular/etiologia , Transtornos Parkinsonianos/induzido quimicamenteRESUMO
Inactivating mutations of the RET proto-oncogene and of one of its soluble ligand molecules, glial cell line derived neurotrophic factor (GDNF), have been found in a subset of patients with Hirschsprung disease (HSCR). However, the majority of HSCR mutations remain unidentified. As normal RET function requires a multicomponent ligand complex for activation, other members of the RET ligand complex are primary candidates for these mutations. We investigated the presence of mutations in another member of the RET signalling complex, GDNF family receptor alpha-1 (GFR alpha-1), in a panel of 269 independent cases of HSCR. We identified 10 polymorphisms at the GFR alpha-1 locus. Surprisingly, however, we did not identify any sequence variants in our HSCR population that were not also present in a normal control population. Our data suggest that mutations of the GFR alpha-1 gene are not a common aetiological event in HSCR.
