Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Musculoskeletal Disorders
Published in: BMC Musculoskeletal Disorders 1/2017

Open Access 01-12-2017 | Case report

Pure exercise intolerance and ophthalmoplegia associated with the m.12,294G > A mutation in the MT-TL2 gene: a case report

Authors: Patrick Soldath, Karen Lindhardt Madsen, Astrid Emilie Buch, Morten Duno, Flemming Wibrand, John Vissing

Published in: BMC Musculoskeletal Disorders | Issue 1/2017

Login to get access

Abstract

Background

Pure exercise intolerance associated with exclusive affection of skeletal muscle is a very rare phenotype of patients with mitochondrial myopathy. Moreover, the exercise intolerance in these rare patients is yet not well explored, as most of known cases have not been assessed by objective testing, but only by interview. We report a patient with a mitochondrial DNA (mtDNA) mutation that gives rise to an exclusive myopathy associated with exercise intolerance and ophthalmoplegia. We quantified the patient’s exercise intolerance through detailed exercise testing.

Case presentation

A 39-year-old man presented with exercise intolerance and chronic progressive external ophthalmoplegia. Sequencing of the entire mtDNA identified a m.12,294G > A mutation in the MT-TL2 gene. The mutation was heteroplasmic in skeletal muscle (75%) while undetectable in blood, urinary sediment, and buccal mucosa as well as in tissues from the patient’s mother. The mutation affected a highly conserved site in the anticodon stem of the mitochondrial transfer RNA Leucine (CUN) molecule and lead to a severe combined respiratory chain defect. Exercise physiological studies in the patient demonstrated a significantly reduced maximal oxygen uptake of 20.4 ml O2 × min−1 × kg−1 (about half of normal) as well as threefold elevated lactate/pyruvate ratios.

Conclusion

The findings of our study support that the m.12,294G > A mutation is pathogenic. Likely, the mutation arose sporadically in early embryogenesis after differentiation of the mesoderm into muscle progenitor cells, leading to a pure myopathic phenotype.
Literature
1.
2.
Lott MT, Leipzig JN, Derbeneva O, Xie HM, Chalkia D, Sarmady M, Procaccio V, Wallace DC. mtDNA Variation and Analysis Using Mitomap and Mitomaster. Curr Protoc Bioinformatics. 2013;44:1 23 21–6.
3.
Old SL, Johnson MA. Methods of microphotometric assay of succinate dehydrogenase and cytochrome c oxidase activities for use on human skeletal muscle. Histochem J. 1989;21(9–10):545–55.CrossRefPubMed
4.
Larsen S, Nielsen J, Hansen CN, Nielsen LB, Wibrand F, Stride N, Schroder HD, Boushel R, Helge JW, Dela F, et al. Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects. J Physiol. 2012;590(14):3349–60.CrossRefPubMedPubMedCentral
5.
Rafiq J, Duno M, Ostergaard E, Ravn K, Vissing CR, Wibrand F, Vissing J. Exercise intolerance and Myoglobinuria associated with a novel maternally inherited MT-ND1 mutation. JIMD Rep. 2016;25:65–70.
6.
7.
Kleinle S, Wiesmann U, Superti-Furga A, Krahenbuhl S, Boltshauser E, Reichen J, Liechti-Gallati S. Detection and characterization of mitochondrial DNA rearrangements in Pearson and Kearns-Sayre syndromes by long PCR. Hum Genet. 1997;100(5–6):643–50.CrossRefPubMed
8.
Parson W, Strobl C, Huber G, Zimmermann B, Gomes SM, Souto L, Fendt L, Delport R, Langit R, Wootton S, et al. Evaluation of next generation mtGenome sequencing using the ion torrent personal genome machine (PGM). Forensic Sci Int Genet. 2013;7(5):543–9.CrossRefPubMedPubMedCentral
9.
Jeppesen TD, Schwartz M, Olsen DB, Vissing J. Oxidative capacity correlates with muscle mutation load in mitochondrial myopathy. Ann Neurol. 2003;54(1):86–92.CrossRefPubMed
10.
Jeppesen TD, Duno M, Risom L, Wibrand F, Rafiq J, Krag T, Jakobsen J, Andersen H, Vissing J. A novel de novo mutation of the mitochondrial tRNAlys gene mt.8340G>a associated with pure myopathy. Neuromuscul Disord. 2014;24(2):162–6.CrossRefPubMed
11.
Jeppesen TD, Schwartz M, Olsen DB, Wibrand F, Krag T, Duno M, Hauerslev S, Vissing J. Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy. Brain. 2006;129(Pt 12):3402–12.CrossRefPubMed
12.
Wasserman K, Beaver WL, Davis JA, Pu JZ, Heber D, Whipp BJ. Lactate, pyruvate, and lactate-to-pyruvate ratio during exercise and recovery. J Appl Physiol (1985). 1985;59(3):935–40.
13.
Jackson MJ, Schaefer JA, Johnson MA, Morris AA, Turnbull DM, Bindoff LA. Presentation and clinical investigation of mitochondrial respiratory chain disease. A study of 51 patients. Brain. 1995;118(Pt 2):339–57.CrossRefPubMed
14.
McFarland R, Elson JL, Taylor RW, Howell N, Turnbull DM. Assigning pathogenicity to mitochondrial tRNA mutations: when “definitely maybe” is not good enough. Trends Genet. 2004;20(12):591–6.CrossRefPubMed
15.
Yarham JW, Al-Dosary M, Blakely EL, Alston CL, Taylor RW, Elson JL, McFarland R. A comparative analysis approach to determining the pathogenicity of mitochondrial tRNA mutations. Hum Mutat. 2011;32(11):1319–25.CrossRefPubMed
16.
Yarham JW, Elson JL, Blakely EL, McFarland R, Taylor RW. Mitochondrial tRNA mutations and disease. Wiley Interdiscip Rev RNA. 2010;1(2):304–24.CrossRefPubMed
17.
Elson JL, Swalwell H, Blakely EL, McFarland R, Taylor RW, Turnbull DM. Pathogenic mitochondrial tRNA mutations--which mutations are inherited and why? Hum Mutat. 2009;30(11):E984–92.CrossRefPubMed
18.
Blakely EL, Yarham JW, Alston CL, Craig K, Poulton J, Brierley C, Park SM, Dean A, Xuereb JH, Anderson KN, et al. Pathogenic mitochondrial tRNA point mutations: nine novel mutations affirm their importance as a cause of mitochondrial disease. Hum Mutat. 2013;34(9):1260–8.CrossRefPubMedPubMedCentral
19.
Pulkes T, Liolitsa D, Nelson IP, Hanna MG. Classical mitochondrial phenotypes without mtDNA mutations: the possible role of nuclear genes. Neurology. 2003;61(8):1144–7.CrossRefPubMed
20.
Hiniker A, Wong LJ, Berven S, Truong CK, Adesina AM, Margeta M. Axial mitochondrial myopathy in a patient with rapidly progressive adult-onset scoliosis. Acta Neuropathol Commun. 2014;2:137.CrossRefPubMedPubMedCentral
21.
Moraes CT, DiMauro S, Zeviani M, Lombes A, Shanske S, Miranda AF, Nakase H, Bonilla E, Werneck LC, Servidei S, et al. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med. 1989;320(20):1293–9.CrossRefPubMed
22.
Vissing J, Salamon MB, Arlien-Soborg P, Norby S, Manta P, DiMauro S, Schmalbruch H. A new mitochondrial tRNA(Met) gene mutation in a patient with dystrophic muscle and exercise intolerance. Neurology. 1998;50(6):1875–8.CrossRefPubMed
23.
Vissing CR, Duno M, Olesen JH, Rafiq J, Risom L, Christensen E, Wibrand F, Vissing J. Recurrent myoglobinuria and deranged acylcarnitines due to a mutation in the mtDNA MT-CO2 gene. Neurology. 2013;80(20):1908–10.CrossRefPubMed
24.
Born AP, Duno M, Rafiq J, Risom L, Wibrand F, Ostergaard E, Vissing J. A mitochondrial tRNA(Met) mutation causing developmental delay, exercise intolerance and limb girdle phenotype with onset in early childhood. Eur J Paediatr Neurol. 2015;19(1):69–71.CrossRefPubMed
Metadata
Title
Pure exercise intolerance and ophthalmoplegia associated with the m.12,294G > A mutation in the MT-TL2 gene: a case report
Authors
Patrick Soldath
Karen Lindhardt Madsen
Astrid Emilie Buch
Morten Duno
Flemming Wibrand
John Vissing
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2017
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/s12891-017-1781-0

Other articles of this Issue 1/2017

BMC Musculoskeletal Disorders 1/2017 Go to the issue

Research article

Patient and surgical factors affecting procedure duration and revision risk due to deep infection in primary total knee arthroplasty

Research article

Risk factors for first hospitalization due to meniscal lesions - a population-based cohort study with 30 years of follow-up

Research article

Pain, pain intensity and pain disability in high school students are differently associated with physical activity, screening hours and sleep

Study protocol

The preventive effect of the bounding exercise programme on hamstring injuries in amateur soccer players: the design of a randomized controlled trial

Research article

Subtrochanteric shortening osteotomy during cementless total hip arthroplasty in young patients with severe developmental dysplasia of the hip

Research article

GIT1 gene deletion delays chondrocyte differentiation and healing of tibial plateau fracture through suppressing proliferation and apoptosis of chondrocyte