Congenital ACTA1-associated homozygous nemaline myopathy: case report

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Abstract

Nemaline myopathies are a heterogeneous group of congenital structural myopathies characterized by rod-shaped inclusions in the sarcoplasm and/or nuclei of muscle fibers. Pathogenic variants in the ACTA1 gene represent the second most frequent cause of nemaline myopathies, with 90 % exhibiting autosomal dominant inheritance. Homozygous pathogenic variants typically are manifested by severe infantile phenotype 2B, whereas the phenotypic spectrum of mild and moderate forms has yet to be systematically categorized.

This article presents an 8-year-old patient with homozygous actinopathy (NM_001100.4(ACTA1):c.661G>C (p.Val221Leu)) corresponding to the typical phenotype of congenital myopathy-2A. Distinctive features of this case were the presence of distal hand joint hypermobility, rimmed vacuolar changes on histological analysis, and abnormal white matter signal intensity on neuroimaging. Magnetic resonance pattern of fatty infiltration and edematous changes in the pelvic girdle and lower extremity muscles were also presented. Combined inheritance of pathogenic homozygous variants in the COQ8A gene (formerly ADCK3) (NM_020247.5(COQ8A):c.1189G>A (p.Val397Met)) required differential diagnosis with primary coenzyme Q10 deficiency, which may involve skeletal muscle pathology.

About the authors

Minh Duc Tran

N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia

Email: epistaxis@mail.ru
ORCID iD: 0000-0002-3146-0822
Russian Federation, 1 Ostrovityanova St., Moscow 117513

S. N. Bardakov

S.M. Kirov Military Medical Academy, Ministry of Defense of Russia

Author for correspondence.
Email: epistaxis@mail.ru
ORCID iD: 0000-0002-3804-6245
Russian Federation, 6 Akademika Lebedeva St., Saint Petersburg 194044

A. M. Emelin

Petrovsky Russian Scientific Center of Surgery

Email: epistaxis@mail.ru
ORCID iD: 0000-0003-4109-0105
Russian Federation, 2 Abrikosovskiy per., Moscow 119991

A. A. Titova

Kazan (Volga Region) Federal University

Email: epistaxis@mail.ru
ORCID iD: 0000-0002-5608-7809
Russian Federation, 18 Kremlyovskaya St., Kazan 420008

I. V. Dmitrochenko

S.M. Kirov Military Medical Academy, Ministry of Defense of Russia

Email: epistaxis@mail.ru
ORCID iD: 0000-0002-2903-9107
Russian Federation, 6 Akademika Lebedeva St., Saint Petersburg 194044

V. A. Tsargush

My Medical Center Advanced Technologies LLC

Email: epistaxis@mail.ru
ORCID iD: 0000-0002-5459-986X
Russian Federation, Build. 1, 5A Olimpiyskiy pr-kt, Sirius Urban-Type Settlement, Federal Territory “Sirius”, Krasnodar Krai 354340

D. O. Binnatova

Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia

Email: epistaxis@mail.ru
ORCID iD: 0009-0006-8863-1158
Russian Federation, 2 Litovskaya St., Saint Petersburg 194100

I. A. Yakovlev

Genotarget LLC

Email: epistaxis@mail.ru
ORCID iD: 0000-0001-8127-4078
Russian Federation, Build. 2, 32 Krylatskie Kholmy St., Moscow 121614

A. A. Isaev

Artgen Biotech PJSC; Genetico PJSC

Email: epistaxis@mail.ru
ORCID iD: 0000-0001-5848-5117
Russian Federation, 3 Gubkina St., Moscow 119333; Build. 1, 3 Gubkina St., Moscow 119333, Russia

R. V. Deev

Petrovsky Russian Scientific Center of Surgery

Email: epistaxis@mail.ru
ORCID iD: 0000-0001-8389-3841
Russian Federation, 2 Abrikosovskiy per., Moscow 119991

References

  1. Nowak K.J., Ravenscroft G., Laing N.G. Skeletal muscle α-actin diseases (actinopathies): pathology and mechanisms. Acta Neuropathol 2013;125:19–32. doi: 10.1007/s00401-012-1019-z
  2. Sewry C.A., Laitila J.M., Wallgren-Pettersson C. Nemaline myopathies: a current view. J Muscle Res Cell Motil 2019;40:111–26. doi: 10.1007/s10974-019-09519-9
  3. Moreno C.A.M., Abath Neto O., Donkervoort S. et al. Clinical and histologic findings in ACTA1-related nemaline myopathy: case series and review of the literature. Pediatric Neurol 2017;75:11–6. doi: 10.1016/j.pediatrneurol.2017.04.002
  4. Labasse C., Brochier G., Taratuto A.L. et al. Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies. Acta Neuropathol Commun 2022;10:101. doi: 10.1186/s40478-022-01400-0
  5. Wallgren-Pettersson C., Laing N.G. 109th ENMC International Workshop: 5th workshop on nemaline myopathy, 11th–13th October 2002, Naarden, The Netherlands. Neuromusc Disord 2003;13:501–7. doi: 10.1016/s0960-8966(03)00007-5
  6. Nowak K.J., Wattanasirichaigoon D., Goebel H.H. et al. Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy. Nat Genet 1999;23:208–12. doi: 10.1038/13837
  7. Sparrow J.C., Nowak K.J., Durling H.J. et al. Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1). Neuromusc Disord 2003;13:519–31. doi: 10.1016/s0960-8966(03)00101-9
  8. Laing N.G., Clarke N.F., Dye D.E. et al. Actin mutations are one cause of congenital fibre type disproportion. Ann Neurol 2004;56:689–94. doi: 10.1002/ana.20260
  9. Kaindl A.M., Rüschendorf F., Krause S. et al. Missense mutations of ACTA1 cause dominant congenital myopathy with cores. J Med Genet 2004;41:842–8. doi: 10.1136/jmg.2004.020271
  10. Malfatti E., Romero N.B. Nemaline myopathies: sate of the art. Rev Neurol 2016;172:614–9. doi: 10.1016/j.neurol.2016.08.004
  11. Vandebrouck A., Domazetovska A., Mokbel N. et al. In vitro analysis of rod composition and actin dynamics in inherited myopathies. J Neuropathol Exp Neurol 2010;69:429–41. doi: 10.1097/NEN.0b013e3181d892c6
  12. Nowak K.J., Sewry C.A., Navarro C. et al. Nemaline myopathy caused by absence of alpha-skeletal muscle actin. Ann Neurol 2007;61:175–84. doi: 10.1002/ana.21035
  13. Laitila J., Wallgren-Pettersson C. Recent advances in nemaline myopathy. Neuromusc Disord 2021;31:955–67. doi: 10.1016/j.nmd.2021.07.012
  14. Zukosky K., Meilleur K., Traynor B.J. et al. Association of a novel ACTA1 mutation with a dominant progressive scapuloperoneal myopathy in an extended family. JAMA Neurol 2015;72:68–98. doi: 10.1001/jamaneurol.2015.37
  15. O’Grady G.L., Best H.A., Oates E.C. et al. Recessive ACTA1 variant causes congenital muscular dystrophy with rigid spine. Eur J Hum Genet 2015;23:883–6. doi: 10.1038/ejhg.2014.169
  16. Castiglioni C., Cassandrini D., Fattori F. et al. Muscle magnetic resonance imaging and histopathology in ACTA1-related congenital nemaline myopathy. Muscle Nerve 2014;50:1011–6. doi: 10.1002/mus.24353
  17. Hernandez-Lain A., Cantero D., Camacho-Salas A. et al. Autosomal dominant distal myopathy with nemaline rods due to p.Glu197Asp mutation in ACTA1. Neuromusc Disord 2019;29:247–50. doi: 10.1016/j.nmd.2018.12.001
  18. Gurgel-Giannetti J., Souza L.S., Yamamoto G.L. et al. Nemaline myopathy in Brazilian рatients: molecular and clinical characterization. Int J Mol Genet 2022;23. doi: 10.3390/ijms231911995
  19. Quinzii C.M., Hirano M. Primary and secondary CoQ(10) deficiencies in humans. Biofactors 2011;37:361–5. doi: 10.1002/biof.155
  20. Quinzii C.M., Emmanuele V., Hirano M. Clinical presentations of coenzyme Q10 deficiency syndrome. Mol Syndromol 2014;5:141–6. doi: 10.1159/000360490
  21. Salviati L., Trevisson E., Doimo M., Navas P. Primary coenzyme Q10 deficiency. In: GeneReviews. Seattle, 2017.
  22. Shalata A., Edery M., Habib C. et al. Primary coenzyme Q deficiency due to novel ADCK3 variants: studies in fibroblasts and review of literature. Neurochem Res 2019;44:2372–84. doi: 10.1007/s11064-019-02786-5
  23. Haghighi A., Alvandi Z., Nilipour Y. et al. Nemaline myopathy: reclassification of previously reported variants according to ACMG guidelines, and report of novel genetic variants. Eur J Hum Genet 2023;31:1237–50. doi: 10.1038/s41431-023-01378-w
  24. Garcia-Angarita N., Kirschner J., Heiliger M. et al. Severe nemaline myopathy associated with consecutive mutations E74D and H75Y on a single ACTA1 allele. Neuromusc Disord 2009;19:481–4. doi: 10.1016/j.nmd.2009.05.001
  25. Laing N.G., Dye D.E., Wallgren-Pettersson C. et al. Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1). Hum Mutat 2009;30:1267–77. doi: 10.1002/humu.21059
  26. Auré K., Benoist J.F., Ogier de Baulny H. et al. Progression despite replacement of a myopathic form of coenzyme Q10 defect. Neurology 2004;63:727–9. doi: 10.1212/01.wnl.0000134607.76780.b2
  27. Mollet J., Delahodde A., Serre V. et al. CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures. Am J Hum Genet 2008;82:623–30. doi: 10.1016/j.ajhg.2007.12.022
  28. Meyer A.P., Yousfi S., Nicolau S. et al. Like father, like son: RNA-sequencing from a 30-year-old muscle biopsy identifies a novel splice variant in ACTA1 as the cause of an attenuated nemaline myopathy phenotype. Neuromusc Disord 2025;52:105416. doi: 10.1016/j.nmd.2025.105416
  29. Liewluck T., Sorenson E.J., Walkiewicz M.A. et al. Autosomal dominant distal myopathy due to a novel ACTA1 mutation. Neuromusc Disord 2017;27:742–6. doi: 10.1016/j.nmd.2017.05.003
  30. Perry L., Stimpson G., Singh L. et al. Muscle magnetic resonance imaging involvement patterns in nemaline myopathies. Ann Clin Transl Neurol 2023;10:1219–29. doi: 10.1002/acn3.51816
  31. Garibaldi M., Fattori F., Pennisi E.M. et al. Novel ACTA1 mutation causes late-presenting nemaline myopathy with unusual dark cores. Neuromusc Disord 2021;31:139–48. doi: 10.1016/j.nmd.2020.11.012
  32. Jungbluth H., Sewry C.A., Counsell S. et al. Magnetic resonance imaging of muscle in nemaline myopathy. Neuromusc Disord 2004;14:779–84. doi: 10.1016/j.nmd.2004.08.005
  33. Quijano-Roy S., Carlier R.Y., Fischer D. Muscle imaging in congenital myopathies. Semin Pediatr Neurol 2011;18:221–9. doi: 10.1016/j.spen.2011.10.003
  34. Saito Y., Komaki H., Hattori A. et al. Extramuscular manifestations in children with severe congenital myopathy due to ACTA1 gene mutations. Neuromusc Disord 2011;21:489–93. doi: 10.1016/j.nmd.2011.03.004
  35. Ueda K., Serajee F., Huq A.M. A mutation in the ACTA1 gene manifesting nemaline myopathy with central nervous system lesions. J Clin Neurol (Seoul, Korea) 2017;13:300–2. doi: 10.3988/jcn.2017.13.3.300
  36. Shmueli O., Horn-Saban S., Chalifa-Caspi V. et al. GeneNote: whole genome expression profiles in normal human tissues. C R Biol 2003;326:1067–72. doi: 10.1016/j.crvi.2003.09.012
  37. D’Amico A., Graziano C., Pacileo G. et al. Fatal hypertrophic cardiomyopathy and nemaline myopathy associated with ACTA1 K336E mutation. Neuromusc Disord 2006;16:548–52. doi: 10.1016/j.nmd.2006.07.005
  38. Zambon A.A., Abel F., Linnane B. et al. Troponin-T type 1 (TNNT1)-related nemaline myopathy: unique respiratory phenotype and muscle pathology findings. Neuromusc Disord 2022;32:245–54. doi: 10.1016/j.nmd.2022.01.014
  39. Wallgren-Pettersson C. Congenital nemaline myopathy. A clinical follow-up of twelve patients. J Neurol Sci 1989;89:1–14. doi: 10.1016/0022-510x(89)90002-6
  40. Ryan M.M., Ilkovski B., Strickland C.D. et al. Clinical course correlates poorly with muscle pathology in nemaline myopathy. Neurology 2003;60:665–73. doi: 10.1212/01.wnl.0000046585.81304.bc
  41. Marttila M., Lehtokari V.L., Marston S. et al. Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies. Hum Mutat 2014;35:779–90. doi: 10.1002/humu.22554
  42. Malfatti E., Lehtokari V.L., Böhm J. et al. Muscle histopathology in nebulin-related nemaline myopathy: ultrastrastructural findings correlated to disease severity and genotype. Acta Neuropathol Commun 2014;2:44. doi: 10.1186/2051-5960-2-44
  43. Romero N.B., Sandaradura S.A., Clarke N.F. Recent advances in nemaline myopathy. Curr Op Neurol 2013;26:519–26. doi: 10.1097/WCO.0b013e328364d681
  44. Tajsharghi H., Ohlsson M., Palm L., Oldfors A. Myopathies associated with β-tropomyosin mutations. Neuromusc Disord 2012;22:923–33. doi: 10.1016/j.nmd.2012.05.018
  45. Maggi L., Scoto M., Cirak S., et al. Congenital myopathies – clinical features and frequency of individual subtypes diagnosed over a 5-year period in the United Kingdom. Neuromusc Disord 2013;23:195–205. doi: 10.1016/j.nmd.2013.01.004
  46. Clarke N.F., North K.N. Congenital fiber type disproportion – 30 years on. J Neuropathol Exp Neurol 2003;62:977–89. doi: 10.1093/jnen/62.10.977
  47. Donkervoort S., Chan S.H.S., Hayes L.H. et al. Cytoplasmic body pathology in severe ACTA1-related myopathy in the absence of typical nemaline rods. Neuromusc Disord 2017;27:531–6. doi: 10.1016/j.nmd.2017.02.012
  48. Traschutz A., Schirinzi T., Laugwitz L. et al. Clinico-genetic, imaging and molecular delineation of COQ8A-ataxia: a multicenter study of 59 patients. Ann Neurol 2020;88:251–63. doi: 10.1002/ana.25751
  49. Lagier-Tourenne C., Tazir M., López L.C. et al. ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency. Am J Hum Genet 2008;82:661–72. doi: 10.1016/j.ajhg.2007.12.024
  50. Nair P., Lama M., El-Hayek S. et al. COQ8A and MED25 mutations in a child with intellectual disability, microcephaly, seizures, and spastic ataxia: synergistic effect of digenic variants? Mol Syndromol 2019;9:319–23. doi: 10.1159/000494465

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