Prevalence of 15 mitochondrial DNA mutations among type 2 diabetic patients with or without clinical characteristics of maternally inherited diabetes and deafness / Prevalência de 15 mutações no DNA mitocondrial entre pacientes diabéticos tipo 2 com ou sem características clínicas de diabetes e surdez herdados maternalmente

The aim of the present study is to investigate the prevalence of ten described mitochondrial DNA (mtDNA) mutations in patients with type 2 diabetes, and search for new mutations in four mtDNA genes in a subgroup of patients with characteristics of maternally inherited diabetes and deafness (MIDD). These mutations were investigated in 407 type 2 diabetic patients without characteristics of mitochondrial diabetes ("classical" type 2 diabetes group) and in 38 type 2 diabetic patients with characteristics suggestive of MIDD. Through sequencing of four mtDNA genes in MIDD patients, we selected five others potentially pathogenic mutations that were also screened in the remaining patients. Overall, the frequency of the fifteen analyzed mutations was 36.84 percent in the MIDD group and 2.45 percent in the "classical" type 2 diabetes group (p < 0.001). In conclusion, our study reinforces the importance of mtDNA mutations in the pathogenesis of MIDD.

Os objetivos deste estudo foram investigar a prevalência de dez mutações conhecidas no DNA mitocondrial (mtDNA) em pacientes com diabetes tipo 2, e procurar por novas mutações em quatro genes mitocondriais em um subgrupo de pacientes com características de MIDD (Maternally Inherited Diabetes and Deafness). Estas mutações foram investigadas em 407 pacientes diabéticos tipo 2 sem características de diabetes mitocondrial (grupo de diabetes tipo 2 clássico) e em 38 pacientes com diabetes tipo 2 e com características sugestivas de MIDD. Através do seqüenciamento de quatro genes mitocondriais nos pacientes com MIDD, selecionou-se cinco outras mutações potencialmente patogênicas que também foram investigadas no restante dos pacientes. De uma forma geral, a freqüência total das 15 mutações analisadas foi de 36,8 por cento no grupo de pacientes com MIDD e de 2,4 por cento no grupo de diabetes tipo 2 clássico (p < 0,001). Em conclusão, nosso estudo reforça a importância de mutações mitocondriais na patogênese do MIDD.

Long-term Clinical Follow-up of Patients with A3243G Mitochondrial tRNA Mutation : Clinical Phenotype and Natural Course / 대한소아신경학회지

PURPOSE:Mitochondrial disorder is a progressive disease, but there are no specific treatment modalities to prevent the progression. Also, there has been little understanding on the pattern of disease progression nor natural history. The aim of this study was to elucidate the initial clinical phenotypes, patterns of the disease progression, and its natural history of the patients with mitochondrial A3243G mutation. METHODS:Among the patients with biochemically or genetically confirmed mitochondrial disorders, 7 patients with A3243G mutation were included in a 7 year follow-up observation(range: 3-11 years). We classified the patients into two groups by the initial clinical presentations:systemic and neurologic onset. They were clinically evaluated with serial brain MRI and MRS for the evaluation of the disease evolution patterns. RESULTS:The clinical manifestations of mitochondrial A3243G mutation were extremely variable; seizure, headache, dementia, myopathy, sensorineural hearing loss, external ophthalmoplegia, diabetes mellitus, cardiomyopathy, easy fatigability, and short stature. Among the 7 patients, 4 patients initially presented neurologic symptom such as seizure(3) and headache(1), and 3 patients systemic symptoms such as DM(2) and easy fatigability(1). All the patients with neurologic onset showed relentless progression with recurrent stroke- like episodes and intractable seizures, and finally fell into be functionally dependent states or death. All the patients with systemic onset showed clinically silent periods for 3-10 years, and still they were in functionally independent states despite subsequent neurologic symptoms. CONCLUSION:We could find out the relationship between initial clinical phenotypes and final outcomes in mitochondrial A3243G mutation. However, the population is small in this study so that a larger scaled analysis is needed.

The quantitative analysis the number of mitochondrial DNA copy using real-time PCR and mitochondrial tRNA mutation analysis at position 3243 in Korean gestational diabetes mellitus / 대한산부인과학회지

OBJECTIVE: Mitochondrial gene mutations may play a role in the development of gestational diabetes mellitus. This study has assisted to confirm the relationship between the mitochondrial DNA copy number and the GDM. METHODS: Peripheral blood samples were collected from 68 patients with GDM and from 79 controls. For the quantification of mtDNA content, a comparative analysis was performed by the amplification of endogenous control (nuclear DNA, 28S rRNA). The mitochondrial A3243G mutation analysis performed. RESULTS: The ratio of mtDNA/28S rRNA was 1.2053 +/- 0.8307 in GDM patients and 1.7975 +/- 1.1355 in control group (p=0.0004), respectively. Among 68 GDM patients, the mutation in tRNA nt 3243 was detected in only one subject. The A3243G mutation in tRNA- Leu gene, implicated in GDM was reported in 1 of 68 (1.47%) but not in controls. CONCLUSION: In this investigation, blood samples from GDM patients using the real-time polymerase chain reaction will be applied to confirm the relationship between the mitochondrial DNA copy number and the GDM. It is hypothesized that this method will help to predict GDM, and aid in developing early diagnostic methods and treatment modalities.

MELAS Syndrome Presenting as Occipital Brain Infarct: Case Report / 대한뇌혈관외과학회지

MELAS syndrome is characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. A 14-year-old male presented with symptoms that resemble stroke including headache, seizure, visual disturbance and slight left hemiparesis. Laboratory investigation showed elevated lactate level in the blood. Brain computed tomography and magnetic resonance image revealed acute infarction in the right occipitoparietal lobe, which was not restricted to a specific vascular territory. Magnetic resonance spectroscopy showed decreased N-acetyl aspartate and increased lactate level in the affected lobe. A molecular genetic analysis identified A3243G point mutation in the peripheral blood leukocytes and confirmed MELAS syndrome. We describe clinical, radiological and molecular genetic findings in the patient with MELAS syndrome presenting occipital brain infarct.

MELAS : Clinical Features according to Genetic Characteristics / 대한소아신경학회지

PURPOSE: This study was performed to estimate the frequency of mitochondrial DNA (mtDNA) A3243G point mutation in MELAS(mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) of our population and to identify the clinical or laboratory variables suggesting MELAS with mtDNA A3243G tRNA mutation. METHODS: Thirty-one patients were included, diagnosed with MELAS in Seoul National University Children's Hospital between Jan. 1993 and Aug. 2002. Seventeen males and fourteen females were included. Mean age of onset was 7.66 years old and mean duration of follow-up was 4.8 years. Brain MRI was performed in all and muscle biopsy was performed on eleven cases. A3243G point mutation was analyzed by PCR/RFLP using DNA from blood and/or muscle tissue. RESULTS: A3243G point mutation was detected in 15(15/31, 48.4%). Mean age of onset was 10.52 years old in A3243G (+) group, and 4.77 years in(-)group. Eight in A3243G (+) group and 2 in(-)group revealed the history of migraine(53.3%, 12.5%, respectively, P value, 0.015). Ten in (+) group and 4 in(-)group experienced recurrent attacks of stroke or transient ischemic attack(TIA)(83.3%, 40.0%, P value=0.02). The lactate level was significantly different between two groups; 2.39 in (+) group, 1.42 in(-)group. Additionally, stroke or TIA as an initial symptom, a history of diabetes or hearing impairment was frequently associated in A3243G (+) group. In brain MR, A3243G (+) group tended to be more frequently involved at posterior cerebral cortex than at basal ganglia. On muscle biopsy, ragged red fibers were detected in 4 patients (4/6) in A3243G (+) group, and 3 (3/5) in(-)group. CONCLUSION: In our populations, A3243G mitochondrial tRNA mutation was responsible genetic defect in 48.3% of MELAS patients, less frequent than other populations. On clinical point of view, older age of onset, recurrent TIA including migraine and lactate concentration higher than 2 times of upper margin of reference value were highly suggestive of A3243G point mutation. MELAS is characterized by various clinical or genetic heterogeneity, so further large scale prospective study will be needed to identify the other genetic causes of them.