Assuntos
Amiloidose , Mieloma Múltiplo/complicações , Recidiva Local de Neoplasia , Complicações Pós-Operatórias , Neoplasias Torácicas , Procedimentos Cirúrgicos Torácicos/efeitos adversos , Idoso , Amiloide/análise , Amiloidose/etiologia , Amiloidose/patologia , Amiloidose/fisiopatologia , Proteína de Bence Jones/urina , Diagnóstico Diferencial , Dissecação , Humanos , Biópsia Guiada por Imagem/métodos , Cadeias Leves de Imunoglobulina/sangue , Masculino , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/fisiopatologia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/radioterapia , Plasmocitoma/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/radioterapia , Neoplasias Torácicas/etiologia , Neoplasias Torácicas/patologia , Neoplasias Torácicas/fisiopatologia , Procedimentos Cirúrgicos Torácicos/métodos , Tomografia Computadorizada por Raios X/métodos , Resultado do TratamentoAssuntos
Anemia Hemolítica Autoimune/complicações , Histiocitose Sinusal/complicações , Linfoma de Zona Marginal Tipo Células B/complicações , Anemia Hemolítica Autoimune/diagnóstico , Antígenos CD20/metabolismo , Histiocitose Sinusal/diagnóstico , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Members of two seemingly unrelated kindreds of Arab Moslem origin presented with pronounced early onset spastic paraparesis of upper and lower limbs, mild intellectual disability, kyphosis, pectus carinatum and hypertrichosis. METHODS: The authors performed neurological and developmental examinations on the affected individuals. The authors conducted whole genome linkage and haplotype analyses, followed by sequencing of candidate genes; RNA and protein expression studies; and finally proof of principle investigations on knockdown morpholino oligonucleotide injected zebrafish. RESULTS: The authors characterise a novel form of autosomal recessive complex hereditary spastic paraparesis (CHSP). MRI studies of brain and spinal cord were normal. Within a single significantly linked locus the authors ultimately identified a homozygous missense mutation c.1146A>T (p.K382N) in the vacuolar protein sorting 37A (Vps37A) gene, fully penetrant and segregating with the disease in both families. Mobility was significantly reduced in Vps37A knockdown morpholino oligonucleotide injected zebrafish, supporting the causal relationship between mutations in this gene and the phenotype described in the patients of this study. CONCLUSIONS: The authors provide evidence for the involvement of Vps37A, a member of the endosomal sorting complex required for transport (ESCRT) system, in upper motor neuron disease. The ESCRT system has been shown to play a central role in intracellular trafficking, in the maturation of multivesicular bodies and the sorting of ubiquitinated membrane proteins into internal luminal vesicles. Further investigation of mechanisms by which dysfunction of this gene causes CHSP will contribute to the understanding of intracellular trafficking of vesicles by the ESCRT machinery and its relevance to CHSP.