Advertisement

Journal of Neurology

, Volume 260, Issue 6, pp 1504–1510 | Cite as

A novel late-onset axial myopathy associated with mutations in the skeletal muscle ryanodine receptor (RYR1) gene

  • Sissel Løseth
  • Nicol C. Voermans
  • Torberg Torbergsen
  • Sue Lillis
  • Christoffer Jonsrud
  • Sigurd Lindal
  • Erik-Jan Kamsteeg
  • Martin Lammens
  • Marcus Broman
  • Gabriele Dekomien
  • Paul Maddison
  • Francesco Muntoni
  • Caroline Sewry
  • Aleksandar Radunovic
  • Marianne de Visser
  • Volker Straub
  • Baziel van Engelen
  • Heinz JungbluthEmail author
Original Communication

Abstract

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of inherited neuromuscular disorders and have been associated with a wide clinical spectrum, ranging from various congenital myopathies to the malignant hyperthermia susceptibility (MHS) trait without any associated weakness. RYR1-related myopathies are usually of early-childhood onset. Here we present 11 patients from 8 families with a late-onset axial myopathy associated with RYR1 variants. Patients presented between the third and seventh decade of life to neuromuscular centres in Norway, the Netherlands and the United Kingdom with predominant axial muscle involvement, comprising variable degrees of lumbar hyperlordosis, scapular winging and/or camptocormia. Marked myalgia was commonly associated. Serum creatine kinase levels were normal or moderately elevated. Muscle imaging showed consistent involvement of the lower paravertebral muscles and the posterior thigh. Muscle biopsy findings were often discrete, featuring variability in fibre size, increased internal nuclei and unevenness of oxidative enzyme staining, but only rarely overt cores. RYR1 sequencing revealed heterozygous missense variants, either previously associated with the MHS trait or localizing to known MHS mutational hotspots. These findings indicate that MHS-related RYR1 mutations may present later in life with prominent axial weakness but not always typical histopathological features. We propose a combined effect of RyR1 dysfunction, aging and particular vulnerability of axial muscle groups as a possible pathogenic mechanism. RYR1 is a candidate for cases with “idiopathic” camptocormia or bent spine syndrome (BSS).

Keywords

Skeletal muscle ryanodine receptor (RYR1) gene RYR1 mutations Malignant hyperthermia susceptibility (MHS) Axial myopathy Camptocormia 

Notes

Acknowledgments

The authors wish to thank all participating families. Family members gave consent to the publication of their photographs and information. Support from the National Commissioning Group (NCG) of the United Kingdom to the Dubowitz Neuromuscular Centre and Guy’s Hospital is gratefully acknowledged. We would like to thank Dr Mark Davis, Perth, Western Australia, for constructive discussions and critically reading our manuscript.

Conflicts of interest

The authors do have no conflict of interest to declare.

Supplementary material

415_2012_6817_MOESM1_ESM.doc (59 kb)
Supplementary material 1 (DOC 59 kb)

References

  1. 1.
    Rosenberg H, Rueffert H (2011) Clinical utility gene card for: malignant hyperthermia. Eur J Hum Genet 19(6) doi: 10.1038/ejhg.2010.248
  2. 2.
    Jungbluth H, Sewry CA, Muntoni F (2011) Core myopathies. Semin Pediatr Neurol 18(4):239–249PubMedCrossRefGoogle Scholar
  3. 3.
    Wilmshurst JM, Lillis S, Zhou H, Pillay K, Henderson H, Kress W, Muller CR, Ndondo A, Cloke V, Cullup T, Bertini E, Boennemann C, Straub V, Quinlivan R, Dowling JJ, Al-Sarraj S, Treves S, Abbs S, Manzur AY, Sewry CA, Muntoni F, Jungbluth H (2010) RYR1 mutations are a common cause of congenital myopathies with central nuclei. Ann Neurol 68(5):717–726PubMedCrossRefGoogle Scholar
  4. 4.
    Clarke NF, Waddell LB, Cooper ST, Perry M, Smith RL, Kornberg AJ, Muntoni F, Lillis S, Straub V, Bushby K, Guglieri M, King MD, Farrell MA, Marty I, Lunardi J, Monnier N, North KN (2010) Recessive mutations in RYR1 are a common cause of congenital fiber type disproportion. Hum Mutat 31(7):E1544–1550. doi: 10.1002/humu.21278 PubMedCrossRefGoogle Scholar
  5. 5.
    Klein A, Lillis S, Munteanu I, Scoto M, Zhou H, Quinlivan R, Straub V, Manzur AY, Roper H, Jeannet PY, Rakowicz W, Jones DH, Jensen UB, Wraige E, Trump N, Schara U, Lochmuller H, Sarkozy A, Kingston H, Norwood F, Damian M, Kirschner J, Longman C, Roberts M, Auer-Grumbach M, Hughes I, Bushby K, Sewry C, Robb S, Abbs S, Jungbluth H, Muntoni F (2012) Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies. Hum Mutat 33(6):981–988PubMedCrossRefGoogle Scholar
  6. 6.
    Jungbluth H, Lillis S, Zhou H, Abbs S, Sewry C, Swash M, Muntoni F (2009) Late-onset axial myopathy with cores due to a novel heterozygous dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene. Neuromuscul Disord 19(5):344–347PubMedCrossRefGoogle Scholar
  7. 7.
    Robinson R, Carpenter D, Shaw MA, Halsall J, Hopkins P (2006) Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat 27(10):977–989PubMedCrossRefGoogle Scholar
  8. 8.
    Broman M, Gehrig A, Islander G, Bodelsson M, Ranklev-Twetman E, Ruffert H, Muller CR (2009) Mutation screening of the RYR1-cDNA from peripheral B-lymphocytes in 15 Swedish malignant hyperthermia index cases. Br J Anaesth 102(5):642–649PubMedCrossRefGoogle Scholar
  9. 9.
    Groom L, Muldoon SM, Tang ZZ, Brandom BW, Bayarsaikhan M, Bina S, Lee HS, Qiu X, Sambuughin N, Dirksen RT (2011) Identical de novo mutation in the type 1 ryanodine receptor gene associated with fatal, stress-induced malignant hyperthermia in two unrelated families. Anesthesiology 115(5):938–945PubMedCrossRefGoogle Scholar
  10. 10.
    Klein A, Jungbluth H, Clement E, Lillis S, Abbs S, Munot P, Pane M, Wraige E, Schara U, Straub V, Mercuri E, Muntoni F (2011) Muscle magnetic resonance imaging in congenital myopathies due to ryanodine receptor type 1 gene mutations. Arch Neurol 68(9):1171–1179PubMedCrossRefGoogle Scholar
  11. 11.
    Jungbluth H, Davis MR, Muller C, Counsell S, Allsop J, Chattopadhyay A, Messina S, Mercuri E, Laing NG, Sewry CA, Bydder G, Muntoni F (2004) Magnetic resonance imaging of muscle in congenital myopathies associated with RYR1 mutations. Neuromuscul Disord 14(12):785–790PubMedCrossRefGoogle Scholar
  12. 12.
    Renard D, Castelnovo G, Fernandez C, De Paula AM, Penttila S, Suominen T, Udd B (2012) Camptocormia as presenting sign in myofibrillar myopathy. Neuromuscul Disord 22(11):987–989PubMedCrossRefGoogle Scholar
  13. 13.
    Lenoir T, Guedj N, Boulu P, Guigui P, Benoist M (2010) Camptocormia: the bent spine syndrome, an update. Eur Spine J 19(8):1229–1237PubMedCrossRefGoogle Scholar
  14. 14.
    Laroche M, Delisle MB, Aziza R, Lagarrigue J, Mazieres B (1995) Is camptocormia a primary muscular disease? Spine 20(9):1011–1016PubMedCrossRefGoogle Scholar
  15. 15.
    Laroche M, Cintas P (2010) Bent spine syndrome (camptocormia): a retrospective study of 63 patients. Joint Bone Spine 77(6):593–596PubMedCrossRefGoogle Scholar
  16. 16.
    Dowling JJ, Lillis S, Amburgey K, Zhou H, Al-Sarraj S, Buk SJ, Wraige E, Chow G, Abbs S, Leber S, Lachlan K, Baralle D, Taylor A, Sewry C, Muntoni F, Jungbluth H (2011) King-Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene. Neuromuscul Disord 21(6):420–427PubMedCrossRefGoogle Scholar
  17. 17.
    Sambuughin N, Capacchione J, Blokhin A, Bayarsaikhan M, Bina S, Muldoon S (2009) The ryanodine receptor type 1 gene variants in African American men with exertional rhabdomyolysis and malignant hyperthermia susceptibility. Clin Genet 76(6):564–568PubMedCrossRefGoogle Scholar
  18. 18.
    Guis S, Figarella-Branger D, Monnier N, Bendahan D, Kozak-Ribbens G, Mattei JP, Lunardi J, Cozzone PJ, Pellissier JF (2004) Multiminicore disease in a family susceptible to malignant hyperthermia: histology, in vitro contracture tests, and genetic characterization. Arch Neurol 61(1):106–113PubMedCrossRefGoogle Scholar
  19. 19.
    Rosenberg H, Davis M, James D, Pollock N, Stowell K (2007) Malignant hyperthermia. Orphanet J Rare Dis 2:21PubMedCrossRefGoogle Scholar
  20. 20.
    Andersson DC, Betzenhauser MJ, Reiken S, Meli AC, Umanskaya A, Xie W, Shiomi T, Zalk R, Lacampagne A, Marks AR (2011) Ryanodine receptor oxidation causes intracellular calcium leak and muscle weakness in aging. Cell Metab 14(2):196–207PubMedCrossRefGoogle Scholar
  21. 21.
    Dowling JJ, Arbogast S, Hur J, Nelson DD, McEvoy A, Waugh T, Marty I, Lunardi J, Brooks SV, Kuwada JY, Ferreiro A (2012) Oxidative stress and successful antioxidant treatment in models of RYR1-related myopathy. Brain 135(Pt 4):1115–1127PubMedCrossRefGoogle Scholar
  22. 22.
    Arbogast S, Beuvin M, Fraysse B, Zhou H, Muntoni F, Ferreiro A (2009) Oxidative stress in SEPN1-related myopathy: from pathophysiology to treatment. Ann Neurol 65(6):677–686PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Sissel Løseth
    • 1
    • 2
  • Nicol C. Voermans
    • 3
  • Torberg Torbergsen
    • 1
  • Sue Lillis
    • 4
  • Christoffer Jonsrud
    • 5
  • Sigurd Lindal
    • 6
    • 7
  • Erik-Jan Kamsteeg
    • 8
  • Martin Lammens
    • 9
  • Marcus Broman
    • 10
  • Gabriele Dekomien
    • 11
  • Paul Maddison
    • 12
  • Francesco Muntoni
    • 13
  • Caroline Sewry
    • 13
  • Aleksandar Radunovic
    • 14
  • Marianne de Visser
    • 15
  • Volker Straub
    • 16
  • Baziel van Engelen
    • 3
  • Heinz Jungbluth
    • 17
    • 18
    • 19
    Email author
  1. 1.Department of Neurology and NeurophysiologyUniversity Hospital of North NorwayTromsøNorway
  2. 2.Department of Clinical MedicineUniversity of TromsøTromsøNorway
  3. 3.Department of NeurologyRadboud University Nijmegen Medical CentreNijmegenThe Netherlands
  4. 4.Diagnostic DNA Laboratory, GSTS PathologyLondonUK
  5. 5.Department of Medical GeneticsUniversity Hospital of North NorwayTromsøNorway
  6. 6.Department of PathologyUniversity Hospital of North NorwayTromsøNorway
  7. 7.Department of Medical BiologyUniversity of TromsøTromsøNorway
  8. 8.Department of Human GeneticsRadboud University Nijmegen Medical CentreNijmegenThe Netherlands
  9. 9.Department of PathologyRadboud University Nijmegen Medical CentreNijmegenThe Netherlands
  10. 10.Department of Anaesthesiology and Intensive CareSkåne University Hospital LundMalmøSweden
  11. 11.Department of Human GeneticsRuhr UniversityBochumGermany
  12. 12.Department of NeurologyNottingham University HospitalsNottinghamUK
  13. 13.Dubowitz Neuromuscular Centre, ICHLondonUK
  14. 14.Department of NeurologyRoyal London HospitalLondonUK
  15. 15.Department of NeurologyAcademic Medical CentreAmsterdamThe Netherlands
  16. 16.Institute of Genetic Medicine, International Centre for LifeUniversity of Newcastle upon TyneNewcastle upon TyneUK
  17. 17.Clinical Neuroscience Division, IOPKing’s CollegeLondonUK
  18. 18.Department of Paediatric Neurology, Neuromuscular, ServiceEvelina Children’s Hospital, St Thomas’ HospitalLondonUK
  19. 19.Children’s Neurosciences CentreSt Thomas’ HospitalLondonUK

Personalised recommendations