Dataset Information

A Patient with MELAS Syndrome Carried an M.3243A>G Mutation in Mitochondrial DNA and Multiple Nuclear Genetic Variants: A Case Report.

ABSTRACT: We discuss the involvement of nuclear genetic variants correlating to observed phenotype in this case study. In January 2020, the 19-year-old boy from Nantong, Jiangsu Province, China with epilepsy symptom was identified to have myelin loss in the motor and sensory nerves in the electromyogram examination. Brain magnetic resonance imaging (MRI) demonstrated high-intensity areas of small multifocal gray matter regions in the bilateral temporal, parietal, and occipital lobes. In the serum of the patient, the levels of lactate dehydrogenase (LDH) and lactic acid were higher than the normal range values in multiple tests. By subsequent whole exome sequencing (WES) including analysis of the mitochondrial genome, the patient was revealed to carry an m.3243A>G mutation in mitochondria MTTL1 gene which was confirmed by direct Sanger sequencing analysis. Thus, disease of the patient was diagnosed as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. According to WES analysis, the patient also carried multiple homozygous variants, which correlating to myelinloss and epilepsy in nuclear genes. The peripheral neuropathy of the patient carrying single mitochondrial m.3243A>G mutation could be caused by multiple nuclear DNA defect.

SUBMITTER: Chu X

PROVIDER: S-EPMC9874192 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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A Patient with MELAS Syndrome Carried an M.3243A>G Mutation in Mitochondrial DNA and Multiple Nuclear Genetic Variants: A Case Report.

Chu Xin X Dai Jie J Cui Hengxiang H Shen Hailin H Wu Qi Q Zhu Xiangyang X Zhu Baofeng B

Iranian journal of public health 20221201 12

We discuss the involvement of nuclear genetic variants correlating to observed phenotype in this case study. In January 2020, the 19-year-old boy from Nantong, Jiangsu Province, China with epilepsy symptom was identified to have myelin loss in the motor and sensory nerves in the electromyogram examination. Brain magnetic resonance imaging (MRI) demonstrated high-intensity areas of small multifocal gray matter regions in the bilateral temporal, parietal, and occipital lobes. In the serum of the p ...[more]

PMID: 36742238

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Project description:The m.3243A>G mutation in the mitochondrial gene MT-TL1 leads to a wide clinical spectrum ranging from asymptomatic carriers to MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) at the severe end. Diabetes mellitus (DM) occurs in mitochondrial diseases, with the m.3243A>G mutation being the most common mutation associated with mitochondrial DM. The pathogenesis of mitochondrial DM remains largely unknown, with previous studies suggesting that impaired insulin secretion is the major factor. In this study we used stable isotope infusion techniques to assess glucose metabolism in vivo and under physiological conditions in 5 diabetic and 11 non-diabetic adults with the m.3243A>G mutation and 10 healthy adult controls. Our results revealed increased glucose production due to increased gluconeogenesis in both diabetic and non-diabetic subjects with the m.3243A>G mutation. In addition, diabetic subjects demonstrated insulin resistance and relative insulin deficiency, resulting in an inability to increase glucose oxidation which can explain the development of DM in these subjects. Non-diabetic subjects showed normal insulin sensitivity; and therefore, they were able to increase their glucose oxidation rate. The ability to increase glucose utilization can act as a compensatory mechanism that explains why these subjects do not have DM despite the higher rate of glucose production. These results suggest that increased gluconeogenesis is not enough to cause DM and the occurrence of combined insulin resistance and relative insulin deficiency are needed to develop DM in individuals with the m.3243A>G mutation. Therefore, multiple defects in insulin and glucose metabolism are required for DM to occur in individuals with mitochondrial diseases. The results of this study uncover previously undocumented alterations in glucose metabolism in individuals with the m.3243A>G mutation that contribute significantly to our understanding of the pathogenesis of mitochondrial DM and can have significant implications for its management.

Project description:BACKGROUND:Stroke-like episodes (SLEs) in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with m.3243A?>?G mutation usually develop in the cerebral cortex. Few reports have documented SLEs in the cerebellum. The clinical neuroimaging features of cerebellar SLEs have not been fully investigated. We report distinctive features of cerebellar stroke-like lesions (SLLs) in a case of MELAS with m.3243A?>?G mutation. CASE PRESENTATION:A 47-year-old Japanese man with type-2 diabetes presented to our hospital with acute onset of aphasia. A brain MRI obtained on admission (day 1) showed increased diffusion-weighted imaging (DWI)/fluid-attenuated inversion recovery (FLAIR) signal in the left anterolateral temporal lobe, which subsequently spread along the cortex posteriorly accompanied by a new lesion in the right anterior temporal lobe. The patient was initially treated with acyclovir and subsequently with immunotherapy. However, on day 45, cerebellar ataxia developed. The brain MRI showed extensive increased DWI/FLAIR signals in the cerebellum along the folia without involvement of deep cerebellar nucleus or cerebellar peduncle; SLLs were incongruent with a vascular territory, similarly to classic cerebral SLLs. Apparent diffusion coefficient (ADC) map did not show reduction in ADC values in the affected folia. Genomic analysis revealed m.3243A?>?G mutation (heteroplasmy in leukocytes, 17%), confirming the diagnosis of MELAS. After the treatment with taurine (12,000?mg/day), L-arginine (12,000?mg/day), vitamin B1 (100?mg/day), and carnitine (3000?mg/day), the patient became able to follow simple commands, and he was transferred to a rehabilitation center on day 146. The follow-up MRI showed diffuse brain atrophy, including the cerebellum. CONCLUSIONS:SLLs develop in the cerebellum in MELAS with m.3243A?>?G mutation. The neuroimaging similarities to cerebral SLLs suggest the presence of the common pathophysiological mechanisms underlying both SLEs, which include microangiopathy and increased susceptibility of the cortex to metabolic derangements.

Dataset Information

A Patient with MELAS Syndrome Carried an M.3243A>G Mutation in Mitochondrial DNA and Multiple Nuclear Genetic Variants: A Case Report.

Publications

A Patient with MELAS Syndrome Carried an M.3243A>G Mutation in Mitochondrial DNA and Multiple Nuclear Genetic Variants: A Case Report.

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