Objective To investigate the mutations of mitochondrial genome in a pedigree with suspected maternally inherited diabetes and deafness and to explore the correlations between the mutations and clinical features. Meth...Objective To investigate the mutations of mitochondrial genome in a pedigree with suspected maternally inherited diabetes and deafness and to explore the correlations between the mutations and clinical features. Methods Genomic DNA was isolated from blood leucocytes of each member of the pedigree. The mitochondrial genome was amplified with 24-pair primers that could cover the entire mitochondrial DNA. Direct sequencing of PCR products was used to identify any mitochondrial DNA mutations. Results Family members on the maternal side all harbored the tRNA^Lcu（UUR） A3243G mutation. The paternal side family members did not have the mutation. The age-of-onset of diabetes of the 4 maternal side family members was 15, 41, 44, and 65 years old, and their corresponding heteroplasmy level of the mutation was 34.5%, 14.9%, 14.6%, and 5.9%, respectively. The age-of-onset of diabetes and heteroplasmy level of A3243G mutation were negatively correlated with a correlation coefficient of -0.980（P=0.02）. Meanwhile, patient with high heteroplasmy level of A3243G mutation had relatively low severity of disease. Moreover, 6 reported polymorphisms and 2 new variants were found. Conclusions The main cause of diabetes in this pedigree is the tRNA^Lcu（UUR） A3243G mutation. However, other gene variants may contribute to its pathogenicity. The heteroplasmy level of the tRNA^Lcu（UUR） A3243G mutation is positively associated with earlier age-of-onset and increasing severity of diabetes.展开更多
Background： Mitochondrial diseases are a group of energy metabolic disorders with multisystem involvements. Variable clinical features present a major challenge in pediatric diagnoses. We summarized the clinical spec...Background： Mitochondrial diseases are a group of energy metabolic disorders with multisystem involvements. Variable clinical features present a major challenge in pediatric diagnoses. We summarized the clinical spectrum of m.3243A〉G mutation in Chinese pediatric patients, to define the common clinical manifestations and study the correlation between heteroplasmic degree of the mutation and clinical severity of the disease. Methods： Clinical data of one-hundred pediatric patients with symptomatic mitochondrial disease harboring m.3243A〉G mutation from 2007 to 2013 were retrospectively reviewed. Detection of m.3243A〉G mutation ratio was performed by polymerase chain reaction （PCR）-restriction fragment length polymorphism. Correlation between m.3243A〉G mutation ratio and age was evaluated. The differences in clinical symptom frequency of patients with low, middle, and high levels of mutation ratio were analyzed by Chi-square test. Results： Sixty-six patients （66%） had suffered a delayed diagnosis for an average of 2 years. The most frequent symptoms were seizures （76%）, short stature （73%）, elevated plasma lactate （70%）, abnormal magnetic resonance imaging/computed tomography （MRI/CT） changes （68%）, vomiting （55%）, decreased vision （52%）, headache （50%）, and muscle weakness （48%）. The mutation ratio was correlated negatively with onset age （r = -0.470, P 〈 0.001）. Myopathy was more frequent in patients with a high level of mutation ratio. However, patients with a low or middle level of m.3243A〉G mutation ratio were more likely to suffer hearing loss, decreased vision, and gastrointestinal disturbance than patients with a high level of mutation ratio. Conclusions： Our study showed that half of Chinese pediatric patients with m.3243A〉G mutation presented seizures, short stature, abnormal MRI/CT changes, elevated plasma lactate, vomiting, and headache. Pediatric patients with these recurrent symptoms should be considered for screening m.3243A〉G mutation. Clinical manifestations and laboratory abnormalities should be carefully monitored in patients with this point mutation.展开更多
文摘Objective To investigate the mutations of mitochondrial genome in a pedigree with suspected maternally inherited diabetes and deafness and to explore the correlations between the mutations and clinical features. Methods Genomic DNA was isolated from blood leucocytes of each member of the pedigree. The mitochondrial genome was amplified with 24-pair primers that could cover the entire mitochondrial DNA. Direct sequencing of PCR products was used to identify any mitochondrial DNA mutations. Results Family members on the maternal side all harbored the tRNA^Lcu（UUR） A3243G mutation. The paternal side family members did not have the mutation. The age-of-onset of diabetes of the 4 maternal side family members was 15, 41, 44, and 65 years old, and their corresponding heteroplasmy level of the mutation was 34.5%, 14.9%, 14.6%, and 5.9%, respectively. The age-of-onset of diabetes and heteroplasmy level of A3243G mutation were negatively correlated with a correlation coefficient of -0.980（P=0.02）. Meanwhile, patient with high heteroplasmy level of A3243G mutation had relatively low severity of disease. Moreover, 6 reported polymorphisms and 2 new variants were found. Conclusions The main cause of diabetes in this pedigree is the tRNA^Lcu（UUR） A3243G mutation. However, other gene variants may contribute to its pathogenicity. The heteroplasmy level of the tRNA^Lcu（UUR） A3243G mutation is positively associated with earlier age-of-onset and increasing severity of diabetes.
基金This study was supported by grants from National Natural Science Foundation of China （No. 81271256 and No. 81471153） and the Capital Characteristic Clinical Application Research Projects （No. Z 1311070022 13062）.
文摘Background： Mitochondrial diseases are a group of energy metabolic disorders with multisystem involvements. Variable clinical features present a major challenge in pediatric diagnoses. We summarized the clinical spectrum of m.3243A〉G mutation in Chinese pediatric patients, to define the common clinical manifestations and study the correlation between heteroplasmic degree of the mutation and clinical severity of the disease. Methods： Clinical data of one-hundred pediatric patients with symptomatic mitochondrial disease harboring m.3243A〉G mutation from 2007 to 2013 were retrospectively reviewed. Detection of m.3243A〉G mutation ratio was performed by polymerase chain reaction （PCR）-restriction fragment length polymorphism. Correlation between m.3243A〉G mutation ratio and age was evaluated. The differences in clinical symptom frequency of patients with low, middle, and high levels of mutation ratio were analyzed by Chi-square test. Results： Sixty-six patients （66%） had suffered a delayed diagnosis for an average of 2 years. The most frequent symptoms were seizures （76%）, short stature （73%）, elevated plasma lactate （70%）, abnormal magnetic resonance imaging/computed tomography （MRI/CT） changes （68%）, vomiting （55%）, decreased vision （52%）, headache （50%）, and muscle weakness （48%）. The mutation ratio was correlated negatively with onset age （r = -0.470, P 〈 0.001）. Myopathy was more frequent in patients with a high level of mutation ratio. However, patients with a low or middle level of m.3243A〉G mutation ratio were more likely to suffer hearing loss, decreased vision, and gastrointestinal disturbance than patients with a high level of mutation ratio. Conclusions： Our study showed that half of Chinese pediatric patients with m.3243A〉G mutation presented seizures, short stature, abnormal MRI/CT changes, elevated plasma lactate, vomiting, and headache. Pediatric patients with these recurrent symptoms should be considered for screening m.3243A〉G mutation. Clinical manifestations and laboratory abnormalities should be carefully monitored in patients with this point mutation.
