Association Between Heteroplasmy Level Of The Mitochondrial TRNA^Leu(UUR) A3243G Mutation And Clinical Features In A Chinese Family With Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, And Stroke-like Episodes Syndrome

BackgroundMitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS) is the most common form of mitochondrial diseases and caused by an A-to-G transition mutation at position 3243 of the mitochondrial genome. However, the correlation between heteroplasmic mutations and clinical characteristics of hereditary MELAS syndrome is unclear.The purpose of this study is to investigate the clinical manifestation, biochemically detected data, and radiographic features of a pedigree with suspected MELAS syndrome, and to explore the correlations between the clinical features and the mutant heteroplasmy levels of mitochondrial genome.Materials and methodsA case analysis based on hereditary family surgery was performed at Enliang Hospital of Anshan, Taian County, and biochemical tests and gene diagnosis were performed at the Department of Laboratory and Institute of Neurology, the First Affiliated Hospital of China Medical University, between March and September,2009. The personal details, histories of stroke-like episodes and seizures within the proband and 12 members in the maternal lineage of the family were collected. Routine blood examinations and plasma lactate levels before and after movements of these family members were detected followed with cephalic MRI examinations. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing were used to detect and validate the m.3243A>G point mutation in mitochondrial genome, and real-time PCR were used to quantify the mutation proportion of m.3243A>G. Analyze the correlation of clinical behaviors and biochemical outcomes, as well as imaging data with heteroplasmic mutations in family members with typical and atypical MELAS syndrome.ResultsTypical symptoms of MELAS include seizures, stroke-like episodes and hyperlactacidemia etc. and atypical symptoms such as growth failure, exercise intolerance, fevers and migraines. Many of these symptoms were observed on several members in the pedigree. Cephalic MRI findings performed during episode periods were in accord with the typical radiographic features of MELAS and cerebellar atrophy were commonly observed. Family members on the maternal side all harbored the point mutation on 3243 site in mitochondrial genome. Meanwhile, patients with higher heteroplasmy levels relatively manifested more typically and severely according to the clinical observation.The age of first-onset convulsion was negatively correlated with level of heteroplasmic mutation (r=-0.852, P<0.05), but lactic acid was positively correlated with mutation levels (before movement:r=0.945, P<0.001; after movement:r=0.945, P< 0.001).ConclusionsThe pedigree we encountered in our clinical practice was diagnosed with maternal inheritance of MELAS syndrome. The main cause can be attributed to a mitochondrial m.3243A>G mutation. The mutant heteroplasmy levels are positively associated with genetic relationship, seizure anticipation, plasma lactate data and other clinical features.