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      Increased Peripheral Blood Heteroplasmy of the mt.3243A>G Mutation Is Associated with Earlier End-Stage Kidney Disease: A Case Report and Review of the Literature

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          Abstract

          The mitochondrial DNA mutation mt.3243A>G is most commonly associated with maternally inherited diabetes and deafness (MIM 52,000), but it has protean phenotypes including renal disease due to focal segmental glomerulosclerosis. We describe monozygotic twins who both harboured this mutation and developed ESRD. Although otherwise genetically identical, the twins differed in their peripheral blood leucocyte levels of circulating mt.3243A>G heteroplasmy: 20 versus 10%, when assessed at 42 years of age. The twin with the higher heteroplasmy load developed end-stage kidney disease 15 years earlier than her sister. A review of the published literature supports a relationship between heteroplasmy level and the age at the development of the end stage of renal failure in patients with mt.3243A>G-related kidney disease.

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          Most cited references21

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          mt DNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease

          Abstract Mitochondrial disease associated with the pathogenic m.3243A>G variant is a common, clinically heterogeneous, neurogenetic disorder. Using multiple linear regression and linear mixed modelling, we evaluated which commonly assayed tissue (blood N = 231, urine N = 235, skeletal muscle N = 77) represents the m.3243A>G mutation load and mitochondrial DNA (mtDNA) copy number most strongly associated with disease burden and progression. m.3243A>G levels are correlated in blood, muscle and urine (R 2 = 0.61–0.73). Blood heteroplasmy declines by ~2.3%/year; we have extended previously published methodology to adjust for age. In urine, males have higher mtDNA copy number and ~20% higher m.3243A>G mutation load; we present formulas to adjust for this. Blood is the most highly correlated mutation measure for disease burden and progression in m.3243A>G‐harbouring individuals; increasing age and heteroplasmy contribute (R 2 = 0.27, P  G heteroplasmy is the most convenient and reliable measure for routine clinical assessment, additional factors such as mtDNA copy number may also influence disease severity.
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            Population prevalence of the MELAS A3243G mutation.

            We aimed to establish the population prevalence of the MELAS 3243A>G mtDNA mutation in a large Caucasian-based population (n=2954; 99% Caucasian, 57% women and mean age of 66.4 years). All participants underwent comprehensive clinical evaluation including audiologic testing. We detected the 3243A>G mutation in seven subjects using standard polymerase chain reaction/restriction fragment length polymorphism methods, establishing a population prevalence of 236/100000 (0.24%; 95% CI 0.10-0.49%); much higher than previously reported. All had mild to moderate hearing loss. Our findings indicate that subjects with the 3243A>G mtDNA mutation could be markedly under-recognised in the community.
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              Clinical features and heteroplasmy in blood, urine and saliva in 34 Dutch families carrying the m.3243A > G mutation

              The m.3243A > G mutation has become known as the MELAS mutation. However, many other clinical phenotypes associated with this mutation have been described, most frequently being maternally inherited diabetes and deafness (MIDD). The m.3243A > G mutation, can be detected in virtually all tissues, however heteroplasmy differs between samples. Recent reports indicate, a preference to perform mutation analysis in urinary epithelial cells (UEC). To test this, and to study a correlation between the mutational load in different tissues with two mitochondrial scoring systems (NMDAS and NPMDS) we investigated 34 families carrying the m.3243A > G mutation. Heteroplasmy was determined in three non-invasively collected samples, namely leucocytes, UEC and buccal mucosa. We included 127 patients, of which 82 carried the m.3243A > G mutation. None of the children (n = 11) had specific complaints. In adults (n = 71), a median NMDAS score of 15 (IQR 10-24) was found. The most prevalent symptoms were hearing loss(48%), gastro-intestinal problems(42%), exercise intolerance(38%) and glucose intolerance(37%). Ten patients had neurologic involvement. Buccal mucosa had the best correlation with the NMDAS in all adults (r = 0.437,p  G mutation causes a wide variety of signs and symptoms, MIDD being far more prevalent than MELAS. Looking at the characteristics of the three non-invasively available tissues for testing heteroplasmy we confirm that UEC are the preferred sample to test.
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                Author and article information

                Journal
                NEF
                Nephron
                10.1159/issn.1660-8151
                Nephron
                S. Karger AG
                1660-8151
                2235-3186
                2020
                July 2020
                20 May 2020
                : 144
                : 7
                : 358-362
                Affiliations
                [_a] aDepartment of Endocrinology and Diabetes, Auckland City Hospital, Auckland, New Zealand
                [_b] bMolecular Pathology Laboratory, Canterbury Health Laboratories, Canterbury District Health Board, Christchurch, New Zealand
                [_c] cDepartment of Nephrology, Auckland City Hospital, Auckland, New Zealand
                [_d] dDepartment of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
                Author notes
                *Dr. James A.D. Shand, Department of Endocrinology and Diabetes, Auckland City Hospital, 2 Park Rd., Grafton, Auckland 1023 (New Zealand), jshand@adhb.govt.nz
                Article
                507732 Nephron 2020;144:358–362
                10.1159/000507732
                32434190
                6bb48373-c117-4029-b3ab-e319ed98ffda
                © 2020 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 04 November 2019
                : 05 April 2020
                Page count
                Figures: 2, Pages: 5
                Categories
                Experimental Nephrology and Genetics: Case Study of Genetic Interest

                Cardiovascular Medicine,Nephrology
                Mitochondrial disease,mt.3243A>G,Heteroplasmy,Maternally inherited diabetes and deafness,Renal replacement therapy

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