The studies on clinical and molecular genetic features of MELAS

Objective The aim was to study the clinical characteristics, diagnostic standards and genetic features of MELAS and try to find the association between the A3243G mtDNA mutation rate and clinical phenotypes.Methods PCR-RFLP for screening the heteroplasmic A to G transition at nucleotide 3243 of the mitochondrial tRNALeu(UUR) of blood cells and muscle, neuroradiological examination, blood level of lactic acid and muscle biopsy analyses were performed on the 272 patients suspected to be with MELAS in Beijing Children's Hospital,the Capital Medicine University, during the years of 2001-2008. Eighteen patients with molecular genetic abnormalities of mitochondrial DNA A3243G mutation were taken as the gene diagnosis group for MELAS. Four patients with ragged red fibers on muscle biopsy specimens and with the absence of A3243G mutation were taken as the pathology diagnosis group for MELAS. Comparisons of clinical, laboratorial and neuroradiologic features between two groups were performed. The A3243G point mutation in the mtDNA of blood cells was also detected in some of their parents, maternal relatives(mother and siblings) by using PCR-RFLP.Results Eighteen patients showed heteroplasmy with a mutant load of mtDNA A3243G mutation ranging from 9.0% to 50.0% in blood cells and from 42.4% to 64.8% in muscle tissues in 4 of them. The main clinical features were characterized by epilepsy,exercise intolerance, progressive dementia, fever, vomiting,vision loss, short stature and hypertrichosis on back. Stroke-like episodes were found in 7 patients. Laboratory studies revealed elevated serum lactate with levels at 4.2-10.8 mmol·L-1. Cranial CT scan showed calcifications in the bilateral basal ganglia in 9 cases and MRI showed infarct-like lesions in 11 cases, involving the lateral temporal-occipital and parietal lobes in 6 cases, the bilateral parietal -occipital lobes in 4 cases, the frontal lobes in 2 cases. The A3243G point mutation in the mtDNA of blood cells was detected in 37 persons from 14 families. The study showed the A3243G mutation was found in 5/10 of the mothers, the mutation rates were 3.0%, 5.0%,11.8%, 21.3% and 26.9%, respectively, and in 4/7 of the siblings 19.3%,33.3%,37.5% and 41.5%, respectively, all of them were asymptomatic.Conclusions MELAS was the most common maternally inherited mitochondrial disease with various clinical phenotypes and A3243G mutation of the mtDNA accounted for most MELAS in Chinese children. The proportion of mutant mtDNA was not related to the course of the disease but to the age.