Objectives:We report here the clini cal and genetic features of two new families with autosomal dominant progressive external ophthalmoplegia(adPEO).Patients and methods:The examination of index patients in cluded a d...Objectives:We report here the clini cal and genetic features of two new families with autosomal dominant progressive external ophthalmoplegia(adPEO).Patients and methods:The examination of index patients in cluded a detailed clinical characterisation,histological analysis of muscle biopsy specimens,and genetic testing of mitochondrial and nuclear DNA extracted from muscle an d leucocytes.Re-sults:Index patients in both famili es presented with PEO and developed other clinical disease manifestations,such as myopathy and cardiomyopathy(patient 1)and axonal neuropathy,diabetes mellitus,hearing loss,and myopathy(patient 2),later in the course of illness.Both patients had ragged red fibres on muscle histology.Southern blot of mtDNA from muscle of patient 2showed multiple deletions.In this case,a novel heterozygous mi ssense mutation F485L was identified in the nuclear encoded putative mitochondrial helicase Twinkle.The mutation cose gregated with the clinical phenotype in the family and was not detected in150control chromosomes.In the other index patient,se-quencing of ANT1,C10or f2(encoding for Twinkle),and POLG1did not reveal pathogenic muta tions.Conclusions:Our cases illustrate the clinical variability of adPEO,add a novel pathogenic mutation in Twinkl e(F485L)to the growing list of genetic abnormalities in adPEO,and rein-force the relevance of other yet unid entified genes in mtD-NA maintenance and pathogenesis of a dPEO.展开更多
文摘Objectives:We report here the clini cal and genetic features of two new families with autosomal dominant progressive external ophthalmoplegia(adPEO).Patients and methods:The examination of index patients in cluded a detailed clinical characterisation,histological analysis of muscle biopsy specimens,and genetic testing of mitochondrial and nuclear DNA extracted from muscle an d leucocytes.Re-sults:Index patients in both famili es presented with PEO and developed other clinical disease manifestations,such as myopathy and cardiomyopathy(patient 1)and axonal neuropathy,diabetes mellitus,hearing loss,and myopathy(patient 2),later in the course of illness.Both patients had ragged red fibres on muscle histology.Southern blot of mtDNA from muscle of patient 2showed multiple deletions.In this case,a novel heterozygous mi ssense mutation F485L was identified in the nuclear encoded putative mitochondrial helicase Twinkle.The mutation cose gregated with the clinical phenotype in the family and was not detected in150control chromosomes.In the other index patient,se-quencing of ANT1,C10or f2(encoding for Twinkle),and POLG1did not reveal pathogenic muta tions.Conclusions:Our cases illustrate the clinical variability of adPEO,add a novel pathogenic mutation in Twinkl e(F485L)to the growing list of genetic abnormalities in adPEO,and rein-force the relevance of other yet unid entified genes in mtD-NA maintenance and pathogenesis of a dPEO.
