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      Acute onset of diabetes and rapid cognitive decline in a patient with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome

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          Abstract

          Summary

          Mitochondrial diseases are a group of rare diseases presenting with heterogeneous clinical, biochemical, and genetic disorders caused by mutations in the mitochondrial or nuclear genome. Multiple organs can be affected, particularly those with high energy demand. Diabetes is a common endocrine manifestation of mitochondrial diseases. The onset of mitochondrial diabetes can be latent or acute, and the presenting phenotype can be type 1- or type 2-like. Studies show that diabetes ais associated with latent progression of cognitive decline in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Herein, we report a case of rapid cognitive decline after the acute onset of diabetes in a patient with MELAS syndrome. The patient was a 36-year-old woman who was hospitalized due to hyperglycemic crisis and seizures. She was diagnosed with MELAS syndrome two years previously, and had gradually progressing dementia and hearing loss. However, following the acute onset of diabetes, she developed rapid cognitive decline and loss of ability to perform daily activities. In conclusion, the acute onset of diabetes could be an associated risk factor for rapid cognitive decline in patients with MELAS syndrome. Thus, these patients as well as healthy carriers with related genetic mutations should undergo diabetes education and screening tests. Moreover, clinicians should be aware of the possibility for acute onset of hyperglycemic crisis, particularly in the presence of triggering factors.

          Learning points
          • Diabetes is a common endocrine manifestation of mitochondrial diseases, presenting with a type 1- or type 2-like phenotype depending on the level of insulinopenia.

          • Metformin should be avoided in patients with mitochondrial diseases to prevent metformin-induced lactic acidosis.

          • Mitochondrial diabetes can manifest before or after the onset of MELAS syndrome.

          • In patients with MELAS syndrome, diabetes can initially manifest with a life-threatening severe hyperglycemic crisis and can cause rapid cognitive decline.

          • Diabetes screening tests (e.g. hemoglobin A1c, oral glucose tolerance test, or random blood glucose level measurement) should be performed either systematically or in the presence of symptoms, particularly after triggering events.

          • Genetic testing and counseling should be provided to patients and their families for the purpose of better understanding the inheritance, progression, and possible outcomes of the disease.

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          Most cited references13

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          MELAS: a nationwide prospective cohort study of 96 patients in Japan.

          MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) (OMIM 540000) is the most dominant subtype of mitochondrial myopathy. The aim of this study was to determine the prevalence, natural course, and severity of MELAS. A prospective cohort study of 96 Japanese patients with MELAS was followed between June 2003 and April 2008. Patients with MELAS were identified and enrolled based on questionnaires administered to neurologists in Japan. MELAS was defined using the Japanese diagnostic criteria for MELAS. Two follow-up questionnaires were administered to neurologists managing MELAS patients at an interval of 5years. A prevalence of at least 0.58 (95% confidential interval (CI), 0.54-0.62)/100,000 was calculated for mitochondrial myopathy, whereas the prevalence of MELAS was 0.18 (95%CI, 0.02-0.34)/100,000 in the total population. MELAS patients were divided into two sub-groups: juvenile form and adult form. Stroke-like episodes, seizure and headache were the most frequent symptoms seen in both forms of MELAS. Short stature was significantly more frequent in the juvenile form, whereas hearing loss, cortical blindness and diabetes mellitus were significantly more frequent in the adult form. According to the Japanese mitochondrial disease rating scale, MELAS patients showed rapidly increasing scores (mean±standard deviation, 12.8±8.7) within 5years from onset of the disease. According to a Kaplan-Meier analysis, the juvenile form was associated with a higher risk of death than the adult form (hazard ratio, 3.29; 95%CI, 1.32-8.20; p=0.0105). We confirmed that MELAS shows a rapid degenerative progression within a 5-year interval and that this occurs in both the juvenile and the adult forms of MELAS and follows different natural courses. This article is part of a Special Issue entitled: Biochemistry of Mitochondria. Copyright © 2011 Elsevier B.V. All rights reserved.
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            The m.3243A>G mitochondrial DNA mutation and related phenotypes. A matter of gender?

            The m.3243A>G "MELAS" (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) mutation is one of the most common point mutations of the mitochondrial DNA, but its phenotypic variability is incompletely understood. The aim of this study was to revise the phenotypic spectrum associated with the mitochondrial m.3243A>G mutation in 126 Italian carriers of the mutation, by a retrospective, database-based study ("Nation-wide Italian Collaborative Network of Mitochondrial Diseases"). Our results confirmed the high clinical heterogeneity of the m.3243A>G mutation. Hearing loss and diabetes were the most frequent clinical features, followed by stroke-like episodes. "MIDD" (maternally-inherited diabetes and deafness) and "PEO" (progressive external ophthalmoplegia) are nosographic terms without any real prognostic value, because these patients may be even more prone to the development of multisystem complications such as stroke-like episodes and heart involvement. The "MELAS" acronym is convincing and useful to denote patients with histological, biochemical and/or molecular evidence of mitochondrial disease who experience stroke-like episodes. Of note, we observed for the first time that male gender could represent a risk factor for the development of stroke-like episodes in Italian m.3243A>G carriers. Gender effect is not a new concept in mitochondrial medicine, but it has never been observed in MELAS. A better elucidation of the complex network linking mitochondrial dysfunction, apoptosis, estrogen effects and stroke-like episodes may hold therapeutic promises.
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              Mitochondrial diabetes: molecular mechanisms and clinical presentation.

              Mutations in mitochondrial DNA (mtDNA) associate with various disease states. A few mtDNA mutations strongly associate with diabetes, with the most common mutation being the A3243G mutation in the mitochondrial DNA-encoded tRNA(Leu,UUR) gene. This article describes clinical characteristics of mitochondrial diabetes and its molecular diagnosis. Furthermore, it outlines recent developments in the pathophysiological and molecular mechanisms leading to a diabetic state. A gradual development of pancreatic beta-cell dysfunction upon aging, rather than insulin resistance, is the main mechanism in developing glucose intolerance. Carriers of the A3243G mutation show during a hyperglycemic clamp at 10 mmol/l glucose a marked reduction in first- and second-phase insulin secretion compared with noncarriers. The molecular mechanism by which the A3243G mutation affects insulin secretion may involve an attenuation of cytosolic ADP/ATP levels leading to a resetting of the glucose sensor in the pancreatic beta-cell, such as in maturity-onset diabetes of the young (MODY)-2 patients with mutations in glucokinase. Unlike in MODY2, which is a nonprogressive form of diabetes, mitochondrial diabetes does show a pronounced age-dependent deterioration of pancreatic function indicating involvement of additional processes. Furthermore, one would expect that all mtDNA mutations that affect ATP synthesis lead to diabetes. This is in contrast to clinical observations. The origin of the age-dependent deterioration of pancreatic function in carriers of the A3243G mutation and the contribution of ATP and other mitochondrion-derived factors such as reactive oxygen species to the development of diabetes is discussed.

                Author and article information

                Journal
                Endocrinol Diabetes Metab Case Rep
                Endocrinol Diabetes Metab Case Rep
                EDM
                Endocrinology, Diabetes & Metabolism Case Reports
                Bioscientifica Ltd (Bristol )
                2052-0573
                22 March 2023
                2023
                : 2023
                : 2
                : 22-0416
                Affiliations
                [1 ]Department of Endocrinology , University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
                [2 ]Department of Endocrinology , University Medical Center at Ho Chi Minh City, Ho Chi Minh City, Vietnam
                [3 ]Department of Imaging , University Medical Center at Ho Chi Minh City, Ho Chi Minh City, Vietnam
                Author notes
                Correspondence should be addressed to P T Ma; Email: matungphat@ 123456ump.edu.vn
                Author information
                http://orcid.org/0000-0003-4036-9876
                http://orcid.org/0000-0003-1715-0323
                Article
                EDM220416
                10.1530/EDM-22-0416
                10241238
                37073829
                22e57bf7-3d2c-47d7-9f67-bbfaffd94e0e
                © the author(s)

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..

                History
                : 27 December 2022
                : 22 March 2023
                Categories
                Adult
                Female
                White
                United States
                Pancreas
                Diabetes
                Unique/Unexpected Symptoms or Presentations of a Disease
                Unique/Unexpected Symptoms or Presentations of a Disease

                adult,female,white,united states,pancreas,diabetes,unique/unexpected symptoms or presentations of a disease,april,2023

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