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Research Letter |

Clinical and Pathological Features of Mitochondrial DNA Deletion Disease Following Antiretroviral Treatment FREE

Brendan A. I. Payne, PhD, FRCPath1,2; Kristian Gardner, MSc1; Emma L. Blakely, PhD3; Paul Maddison, MD, FRCP4; Rita Horvath, MD, PhD1; Robert W. Taylor, PhD, FRCPath3; Patrick F. Chinnery, PhD, FRCP1
[+] Author Affiliations
1Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, England
2Department of Infection and Tropical Medicine, Royal Victoria Infirmary, Newcastle-upon-Tyne, England
3Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle-upon-Tyne, England
4Royal Derby Hospital, Derby, England
JAMA Neurol. 2015;72(5):603-605. doi:10.1001/jamaneurol.2015.0150.
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Published online

Certain nucleoside analog reverse transcriptase inhibitor (NRTI) antiretroviral drugs used to treat human immunodeficiency virus (HIV) infection lead to accelerated accumulation of somatic mitochondrial DNA (mtDNA) mutations.1 The clinical significance of this observation is unclear but a delayed-onset phenotype would be expected, perhaps years after the relevant drug exposure.

In our national mitochondrial diagnostic reference service, we have been referred several HIV-infected patients with neuromuscular symptoms where a mitochondrial etiology was suspected clinically, and investigations confirmed the presence of a mitochondrial myopathy, developing years after exposure to potentially mitochondrially toxic NRTIs. In this retrospective case series, we describe the clinical, histochemical, molecular, and imaging findings of the first 4 such patients.

Ethical approval for this study was obtained from the Newcastle and North Tyneside Local Research Ethics Committee, and written consent was obtained from patients.

The clinicopathological characteristics are summarized in the Table. Patient 1 presented with progressive ataxia, with a background of sensorineural deafness and insulin-dependent diabetes mellitus with associated nephropathy requiring continuous ambulatory peritoneal dialysis. At the time of referral, HIV infection was treated with didanosine, lamivudine, and nevirapine for 8 years. Following assessment, didanosine was switched to abacavir. Magnetic resonance imaging of the brain revealed volume loss and periventricular and deep white matter signal change; however, these features were generalized rather than localized to the cerebellum. Proton magnetic resonance spectroscopy findings of the brain were normal. Sequential cytochrome C oxidase (COX)–succinate dehydrogenase (SDH) histochemical reactions revealed 30% COX-deficient fibers with approximately 10% of fibers showing SDH hyperintensity, suggestive of mitochondrial proliferation (Figure). Molecular analyses of skeletal muscle mtDNA showed increased mtDNA copy number and evidence of multiple mtDNA deletions amplified by long-range polymerase chain reaction assays.2 A screen of nuclear genes (POLG, POLG2, PEO1, RRM2B, SLC25A4,and TK2) associated with mtDNA maintenance disorders revealed no mutations.

Table Graphic Jump LocationTable.  Summary of Clinicopathological Features
Place holder to copy figure label and caption
Figure.
Muscle Biopsy Findings in Patient 1

Oxidative enzyme histochemistry, including cytochrome C oxidase (A, original magnification ×10) and cytochrome C oxidase–succinate dehydrogenase (B, original magnification ×10) reactions in patient 1 (P), reveals numerous cytochrome C oxidase–deficient, ragged-red fibers. C, The 9.9-kb and 16.0-kb long-range polymerase chain reaction assays confirm the presence of multiple mitochondrial DNA deletions and loss of full-length, wild-type mitochondrial DNA molecules in patient 1 muscle compared with an age-matched control (C) individual.

Graphic Jump Location

Patients 2, 3, and 4 presented with myalgia, with or without mildly elevated creatine kinase (patient 2, 564 IU/L; patient 3, 841 IU/L; and patient 4, normal <320 IU/L; to convert serum creatine kinase to microkatals per liter, multiply by 0.0167). All had extensive past antiretroviral exposure including multiple polymerase γ–inhibiting NRTIs.3 Findings from nerve conduction studies revealed mild axonal sensorimotor neuropathy. Cytochrome C oxidase–SDH histochemistry revealed mosaic patterns (15%, 12%, and 1% for patients 2, 3, and 4, respectively) of COX deficiency. Phosphorus magnetic resonance spectroscopy of soleus muscle was performed in patients 3 and 4 and showed significant reduction in the maximal rate of postexertional adenosine triphosphate resynthesis. On molecular analyses (patients 3 and 4), mtDNA copy number in muscle was normal but large-scale mtDNA deletions were detected (not shown).

We describe 4 adults with treated HIV infection and evidence of mitochondrial dysfunction. Patients 1, 2, and 3 had significant levels of COX-deficient skeletal muscle fibers consistent with mitochondrial myopathy. Although the overall frequency of COX-deficient fibers in patient 4 was low, the presence of somatic mtDNA mutations and abnormal muscle bioenergetics suggests he also had a mild mitochondrial myopathy. What is the likely cause of these findings?

Given that mitochondrial disorders presenting in adult life are rare (approximately 1 in 10 000),4 it seems likely that the patients we described have an iatrogenic disorder caused by earlier exposure to polymerase γ–inhibiting NRTIs. Although we cannot wholly exclude the possibility of a 2-hit model of NRTI exposure and a predisposing nuclear genetic defect of mtDNA maintenance, an extensive search for causative mutations in the most severely affected case failed to find a cause.

In all cases, the observed mtDNA defect comprised mtDNA deletions rather than an mtDNA depletion as reported historically.5 This argues for the importance of previous rather than current NRTI exposure.1 Therefore, we suggest that in HIV-infected patients presenting with neuromuscular symptoms, the possibility of an acquired mitochondrial defect should continue to be considered in those patients with a relevant treatment history. Those patients with historical exposure to the polymerase γ–inhibiting dideoxynucleoside analogs are particularly worthy of further investigation.

Corresponding Author: Brendan A. I. Payne, PhD, FRCPath, Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle-upon-Tyne NE1 3BZ, England (brendan.payne@ncl.ac.uk).

Author Contributions: Dr Payne had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Payne, Chinnery.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Payne, Chinnery.

Critical revision of the manuscript for important intellectual content: All authors.

Obtained funding: Payne, Taylor, Chinnery.

Administrative, technical, or material support: Taylor.

Study supervision: Payne, Chinnery.

Conflict of Interest Disclosures: None reported.

Funding/Support: Dr Payne was funded by the Medical Research Council (United Kingdom). Dr Taylor receives support from the Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z), the Medical Research Council (United Kingdom) Centre for Translational Muscle Disease Research (G0601943) and the UK National Health Service Highly Specialised Rare Mitochondrial Disorders of Adults and Children Service. Dr Chinnery receives support from the Wellcome Trust (101876/Z/13/Z and 096919Z/11/Z), the Medical Research Council (United Kingdom) Centre for Translational Muscle Disease Research (G0601943), European Union FP7 Treat Iron-Related Childhood-Onset Neurodegeneration, and the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle-upon-Tyne Hospitals National Health Service Foundation Trust and Newcastle University.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Payne  BA, Wilson  IJ, Hateley  CA,  et al.  Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. Nat Genet. 2011;43(8):806-810.
PubMed   |  Link to Article
Blakely  EL, He  L, Taylor  RW,  et al.  Mitochondrial DNA deletion in “identical” twin brothers. J Med Genet. 2004;41(2):e19.
PubMed   |  Link to Article
Lim  SE, Copeland  WC.  Differential incorporation and removal of antiviral deoxynucleotides by human DNA polymerase gamma. J Biol Chem. 2001;276(26):23616-23623.
PubMed   |  Link to Article
Schaefer  AM, McFarland  R, Blakely  EL,  et al.  Prevalence of mitochondrial DNA disease in adults. Ann Neurol. 2008;63(1):35-39.
PubMed   |  Link to Article
Arnaudo  E, Dalakas  M, Shanske  S, Moraes  CT, DiMauro  S, Schon  EA.  Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. Lancet. 1991;337(8740):508-510.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure.
Muscle Biopsy Findings in Patient 1

Oxidative enzyme histochemistry, including cytochrome C oxidase (A, original magnification ×10) and cytochrome C oxidase–succinate dehydrogenase (B, original magnification ×10) reactions in patient 1 (P), reveals numerous cytochrome C oxidase–deficient, ragged-red fibers. C, The 9.9-kb and 16.0-kb long-range polymerase chain reaction assays confirm the presence of multiple mitochondrial DNA deletions and loss of full-length, wild-type mitochondrial DNA molecules in patient 1 muscle compared with an age-matched control (C) individual.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable.  Summary of Clinicopathological Features

References

Payne  BA, Wilson  IJ, Hateley  CA,  et al.  Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. Nat Genet. 2011;43(8):806-810.
PubMed   |  Link to Article
Blakely  EL, He  L, Taylor  RW,  et al.  Mitochondrial DNA deletion in “identical” twin brothers. J Med Genet. 2004;41(2):e19.
PubMed   |  Link to Article
Lim  SE, Copeland  WC.  Differential incorporation and removal of antiviral deoxynucleotides by human DNA polymerase gamma. J Biol Chem. 2001;276(26):23616-23623.
PubMed   |  Link to Article
Schaefer  AM, McFarland  R, Blakely  EL,  et al.  Prevalence of mitochondrial DNA disease in adults. Ann Neurol. 2008;63(1):35-39.
PubMed   |  Link to Article
Arnaudo  E, Dalakas  M, Shanske  S, Moraes  CT, DiMauro  S, Schon  EA.  Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. Lancet. 1991;337(8740):508-510.
PubMed   |  Link to Article

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