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Highly asymmetrical distribution of muscle wasting correlates to the heteroplasmy in a patient carrying a large-scale mitochondrial DNA deletion: a novel pathophysiological mechanism for explaining asymmetry in mitochondrial myopathies

  • Author Footnotes
    1 Equal contribution.
    M. Masingue
    Correspondence
    Corresponding authors at: Centre de Référence de Pathologie Neuromusculaire, CHU La Pitié-Salpêtrière, APHP, Paris, 75013, France.
    Footnotes
    1 Equal contribution.
    Affiliations
    Reference Center for Neuromuscular Disorders Nord/Est/Ile de France, Neuromuscular Morphology Unit, Institut de Myologie, CHU Pitié-Salpêtrière, APHP, Paris, France
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  • Author Footnotes
    1 Equal contribution.
    B. Rucheton
    Footnotes
    1 Equal contribution.
    Affiliations
    UF de Biochimie des maladies neurométaboliques et neurodégénératives, Service de Biochimie Métabolique, AP-HP, Paris, France
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  • C. Bris
    Affiliations
    Department of Genetics, Angers Hospital, Angers, France

    Université Angers, MitoLab Team, UMR CNRS 6015 - INSERM U1083, Institut MitoVasc, SFR ICAT, Angers, France
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  • N.B. Romero
    Affiliations
    Reference Center for Neuromuscular Disorders Nord/Est/Ile de France, Neuromuscular Morphology Unit, Institut de Myologie, CHU Pitié-Salpêtrière, APHP, Paris, France

    Université Sorbonne, UPMC Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, CHU Pitié-Salpêtrière, Paris, France
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  • V. Procaccio
    Affiliations
    Department of Genetics, Angers Hospital, Angers, France

    Université Angers, MitoLab Team, UMR CNRS 6015 - INSERM U1083, Institut MitoVasc, SFR ICAT, Angers, France
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  • B Eymard
    Correspondence
    Corresponding authors at: Centre de Référence de Pathologie Neuromusculaire, CHU La Pitié-Salpêtrière, APHP, Paris, 75013, France.
    Affiliations
    Reference Center for Neuromuscular Disorders Nord/Est/Ile de France, Neuromuscular Morphology Unit, Institut de Myologie, CHU Pitié-Salpêtrière, APHP, Paris, France
    Search for articles by this author
  • Author Footnotes
    1 Equal contribution.
Published:October 26, 2022DOI:https://doi.org/10.1016/j.nmd.2022.10.006

      Highlights

      • Heteroplasmy varies not only in different organs but within different muscles
      • heteroplasmy explains asymmetrical muscle involvement in mitochondrial myopathies
      • heteroplasmy is the second elucidated mechanism in asymmetrical myopathies

      Abstract

      Mitochondrial diseases are a heterogeneous group of pathologies, caused by missense mutations, sporadic large-scale deletions of mitochondrial DNA (mtDNA) or mutations of nuclear maintenance genes. We report the case of a patient in whom extended muscle pathology, biochemical and genetic mtDNA analyses have proven to be essential to elucidate a unique asymmetrical myopathic presentation. From the age of 34 years on, the patient has presented with oculomotor disorders, right facial peripheral palsy and predominantly left upper limb muscle weakness and atrophy. By contrast, he displayed no motor weakness on the right hemi-body, and no sensory symptoms, cerebellar syndrome, hypoacusis, or parkinsonism. Cardiac function was normal. CK levels were elevated (671 UI/L). Electroneuromyography (ENMG) and muscle MRI showed diffuse myogenic alterations, more pronounced on the left side muscles. Biopsy of the left deltoid muscle showed multiple mitochondrial defects, whereas in the right deltoid, mitochondrial defects were much less marked. Extended mitochondrial biochemical and molecular workup revealed a unique mtDNA deletion, with a 63.4% heteroplasmy load in the left deltoid, versus 8.1% in the right one. This case demonstrates that, in mitochondrial myopathies, heteroplasmy levels may drastically vary for the same type of muscle, rising the hypothesis of a new pathophysiological mechanism explaining asymmetry in hereditary myopathies.

      Keywords

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      References

        • Rijken NH
        • Van der Kooi EL
        • Hendriks JC
        • Van Asseldonk RJ
        • Padberg GW
        • Geurts AC
        • et al.
        Skeletal muscle imaging in facioscapulohumeral muscular dystrophy, pattern and asymmetry of individual muscle involvement.
        Neuromuscul Disord. 2014; 24: 1087-1096
        • Wang LH
        • Tawil R
        Facioscapulohumeral dystrophy.
        Curr Neurol Neurosci Rep. 2016; 16: 66
        • Hoogerwaard EM
        • Bakker E
        • Ippe lPF
        • Oosterwijk JC
        • Majoor-Krakauer DF
        • et al.
        Signs and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among carriers in the Netherlands: a cohort study.
        Lancet. 1999; 353 (–1): 2116
        • Mercier S
        • Toutain A
        • Toussaint A
        • Raynaud M, de
        • et al.
        Genetic and clinical specificity of 26 symptomatic carriers for dystrophinopathies at pediatric age. I.
        Eur J Hum Genet. 2013; 21: 855-856
        • Biancalana V
        • Scheidecker S
        • Miguet M
        • Laquerrière A
        • Romero NB
        • et al.
        Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues.
        Acta Neuropathol. 2017; 134: 889-904
        • Cocanougher BT
        • Flynn L
        • Yun P
        • Jain M
        • Waite M
        • et al.
        Adult MTM1-related myopathy carriers Classification based on deep phenotyping.
        Neurology®. 2019; 93: e1535-e1542
        • Savarese M
        • Musumeci O
        • Giugliano T
        • Rubegni A
        • Fiorillo C
        • et al.
        Novel findings associated with MTM1 suggest a higher number of female symptomatic carriers.
        Neuromuscul Disord. 2016; 26: 292-299
        • Bevilacqua JA
        • Bitoun M
        • Biancalana V
        • Oldfors A
        • Stoltenburg G
        • Claeys KG
        • et al.
        Necklace" fibers, a new histological marker of late-onset MTM1-related centronuclear myopathy.
        Acta Neuropathol. 2009; 117 (Epub 2008 Dec 16): 283-291https://doi.org/10.1007/s00401-008-0472-1
        • Guglieri M
        • Magri F
        • D'Angelo MG
        • Prelle A
        • Morandi L
        • Rodolico C
        • et al.
        Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients.
        Hum Mutat. 2008; 29: 258-266
        • Sarkozy A
        • Deschauer M
        • Carlier RY
        • Schrank B
        • Seeger J
        • Walter MC
        • et al.
        Muscle MRI findings in limb girdle muscular dystrophy type 2L.
        Neuromuscul Disord. 2012; 22: S122-S129
        • Paradas C
        • Llauger J
        • Diaz-Manera J
        • Rojas-Garcia R
        • De Luna N
        • Iturriaga C
        • et al.
        Redefining dysferlinopathy phenotypes based on clinical findings and muscle imaging studies.
        Neurology. 2010; 75: 316-323
        • Vissing J.
        Limb girdle muscular dystrophies: classification, clinical spectrum and emerging therapie.
        Curr Opin Neurol. 2016; 29 (-4): 635
        • Matthews PM
        • Benjamin D
        • Van Bakel I
        • Squier MV
        • Nicholson LVB.
        • et al.
        Muscle X-inactivation patterns and dystrophin expression in Duchenne muscular dystrophy carriers.
        Neuromusc Disord. 1995; 5: 209 220
        • Helderman-van den Enden AT
        • Ginjaar HB
        • Kneppers AL
        • Bakker E
        • Breuning MH
        • de Visser M.
        Somatic mosaicism of a point mutation in the dystrophin gene in a patient presenting with an asymmetrical muscle weakness and contractures.
        Neuromuscul Disord. 2003; 13: 317-321
        • Chinnery PC
        • DiMauro S
        • Se Shanske
        • Schon EA
        • Zeviani M
        • et al.
        Risk of developing a mitochondrial DNA deletion disorder.
        Lancet. 2004; 364: 592-599
        • Wallace DC
        • Chalkia D
        Mitochondrial DNA Genetics and the Heteroplasmy Conundrum in Evolution and disease.
        Cold Spring Harb Perspect Biol. 2013; 5: a02122
        • DiMauro S
        • Schon EA
        • Carelli V
        • Hirano M.
        The clinical maze of mitochondrial neurology.
        Nat Rev Neurol. 2013; 9: 429-444
        • Pitceathly RD1
        • Rahman S
        • Hanna MG.
        Single deletions in mitochondrial DNA–molecular mechanisms and disease phenotypes in clinical practice.
        Neuromuscul Disord. 2012; 22: 577-586
        • Wei W
        • Chinnery PF.
        Inheritance of mitochondrial DNA in humans: implications for rare and common diseases.
        J Intern Med. 2020; 287 (Epub 2020 Mar 18): 634-644https://doi.org/10.1111/joim.13047
        • Auré K
        • Fayet G
        • Leroy JP
        • Lacène E
        • Romero NB
        • Lombès A.
        Apoptosis in mitochondrial myopathies is linked to mitochondrial proliferation.
        Brain. 2006; 129: 1249-1259
        • Tatuch Y
        • Christodoulou J
        • Feigenbaum A
        • Clarke JT
        • Wherret J
        • Smith C
        • et al.
        Heteroplasmic mtDNA mutation (T>G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high.
        Am J Hum Genet. 1992; 50: 852-858
        • Goldstein A
        • Falk MJ
        • Adam MP
        • Ardinger HH
        • Pagon RA
        • Wallace SE
        • et al.
        Mitochondrial DNA deletion syndromes.
        University of Washington, Seattle2003 Dec 17 (GeneReviews® [Internet]Seattle (WA)1993–2020[updated 2019 Jan 31])
        • Moraes CT
        • DiMauro S
        • Zeviani M
        • Lombes A
        • Shanske S
        • Miranda AF
        • et al.
        Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome.
        N Engl J Med. 1989; 320: 1293-1299
        • Holt IJ
        • Harding AE
        • Cooper JM
        • Schapira AHV
        • Toscano A
        • Clark JB
        • et al.
        Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA.
        Ann Neurol. 1989; 26: 699-708
        • Moraes CT
        • DiMauro S
        • Zeviani M
        • Lombe`s A
        • Shanske S
        • Miranda A
        • et al.
        Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome.
        N Engl J Med. 1989; 320: 1293-1299
        • López-Gallardo E
        • López-Pérez MJ
        • Montoya J
        • Ruiz-Pesini E.
        CPEO and KSS differ in the percentage and location of the mtDNA deletion.
        Mitochondrion. 2009; 9: 314-317
        • Auré K
        • Ogier de Baulny H
        • Laforêt P
        • Jardel C
        • Eymard B
        • Lombès A.
        Chronic progressive ophthalmoplegia with large-scale mtDNA rearrangement: can we predict progression?.
        Brain. 2007; 130: 1516-1524
        • Yamashita S
        • Nishino I
        • Nonaka I
        • Goto YI.
        Genotype and phenotype analyses in 136 patients with single large-scale mitochondrial DNA deletions.
        J Hum Genet. 2008; 53 (Epub 2008 Apr 15): 598https://doi.org/10.1007/s10038-008-0289-8
        • Brockington M
        • Alsanjari N
        • Sweeney MG
        • Morgan-Hughes JA
        • Scaravilli F
        • Harding AE.
        Kearns-Sayre syndrome associated with mitochondrial DNA deletion or duplication: a molecular genetic and pathological study.
        J Neurol Sci. 1995; 131: 78-87
        • Medja F
        • Allouche S
        • Frachon P
        • Jardel C
        • Malgat M
        • Mousson de Camaret B
        • Slama A
        • Lunardi J
        • Mazat JP
        • Lombès A
        Development and implementation of standardized respiratory chain spectrophotometric assays for clinical diagnosis.
        Mitochondrion. 2009; 9: 331-339
        • Boucret L
        • Bris C
        • Seegers V
        • Goudenège D
        • Desquiret-Dumas V
        • Domin-Bernhard M
        • et al.
        Deep sequencing shows that oocytes are not prone to accumulate mtDNA heteroplasmic mutations during ovarian ageing.
        Hum Reprod. 2017; 32: 2101-2109
        • Goudenège D
        • Bris C
        • Hoffmann V
        • Desquiret-Dumas V
        • Jardel C
        • Rucheton B
        • et al.
        eKLIPse: a sensitive tool for the detection and quantification of mitochondrial DNA deletions from next-generation sequencing data.
        Genet Med. 2019; 21 (s): 1407-1416
        • López-Gallardo E
        • López-Pérez MJ
        • Montoya J
        • Ruiz-Pesini E.
        CPEO and KSS differ in the percentage and location of the mtDNA deletion.
        Mitochondrion. 2009; 9 (Epub 2009 May 4): 314-317https://doi.org/10.1016/j.mito.2009.04.005
        • Kim Y
        • Triolo M
        • Hood DA
        Impact of Aging and Exercise on Mitochondrial Quality Control in Skeletal Muscle.
        Oxid Med Cell Longev. 2017; (Epub 2017 Jun 1)
        • Lessell S
        • Hedley-Whyte ETA.
        Case records of the Massachusetts General Hospital. Weekly clinico- pathological exercises. Case 3-1985. A 33-year-old man with progressive right facial paresis and ophthalmoplegia without ptosis.
        N Engl J Med. 1985; 312: 171-177
        • Sharma NK
        • Gujrati M
        • Kumar J
        • Kattah JC.
        Chronic asymmetric progressive external ophthalmoplegia with right facial weakness: a unique presentation of mitochondrial myopathy.
        J Neurol Neurosurg Psychiatry. 2002; 73: 95
        • Cui H
        • Li F
        • Chen D
        • Wang G
        • Truong CK
        • Enns GM
        • et al.
        Comprehensive next-generation sequence analyses of the entire mitochondrial genome reveal new insights into the molecular diagnosis of mitochondrial DNA disorders.
        Genet Med. 2013; 15: 388-394