Skip to main content

Advertisement

SpringerLink
Log in

Phenotype variability and natural history of X-linked myopathy with excessive autophagy

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Objective

X-linked myopathy with excessive autophagy (XMEA) linked to the VMA21 gene leads to autophagy failure with progressive vacuolation and atrophy of skeletal muscles. Current knowledge of this rare disease is limited. Our objective was to define the clinical, radiological, and natural history of XMEA.

Methods

We conducted a retrospective study collecting clinical, genetic, muscle imaging, and biopsy data of XMEA patients followed in France and reviewed the literature for additional cases.

Results

Eighteen males had genetically confirmed XMEA in France, carrying four different VMA21 variants. Mean age at disease onset was 9.4 ± 9.9 (range 1–40) years. In 14/18 patients (77.8%), onset occurred during childhood (< 15 years); however in four patients, the disease started in adulthood. Patients had anterior and medial compartment thigh muscle weakness, distal contractures (56.3%), elevated CK levels (1287.9 ± 757.8 U/l) and autophagic vacuoles with sarcolemmal features on muscle histopathology. Muscle MRI (n = 10) showed a characteristic pattern of lower limb muscle involvement. In 11 patients, outcome measures were available for an average follow-up period of 10.6 ± 9.8 years and six of them show disease progression. Mean change of functional outcomes was 0.5 ± 1.2 points for Brooke and 2.2 ± 2.5 points for Vignos score, 7/16 patients (43.8%) needed a walking aid and 3/16 (18.8%) were wheelchair-bound (median age of 40 years old, range 39–48). The variant c.164-7 T > G was associated with a later onset of symptoms. Respiratory insufficiency was common (57.1%) but cardiac involvement rare (12.5%).

Interpretation

XMEA has variable age of onset, but a characteristic clinical, histopathological, and muscle imaging presentation, guiding the diagnosis. Although slowly, motor disability progresses with time, and relevant genotype–phenotype correlations will help design future clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Ramachandran N, Munteanu I, Wang P et al (2013) VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy. Acta Neuropathol 125(3):439–457

    Article  CAS  PubMed  Google Scholar 

  2. Sugie K, Noguchi S, Kozuka Y et al (2005) Autophagic vacuoles with sarcolemmal features delineate danon disease and related myopathies. J Neuropathol Exp Neurol 64(6):513–522

    Article  CAS  PubMed  Google Scholar 

  3. Kalimo H, Savontaus M-L, Lang H et al (1988) X-Linked myopathy with excessive autophagy: a new hereditary muscle disease. Ann Neurol 23(3):258–265

    Article  CAS  PubMed  Google Scholar 

  4. Nemazanyy I, Blaauw B, Paolini C et al (2013) Defects of Vps15 in skeletal muscles lead to autophagic vacuolar myopathy and lysosomal disease. EMBO Mol Med 5(6):870–890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mercuri E, Pichiecchio A, Allsop J et al (2007) Muscle MRI in inherited neuromuscular disorders: past present, and future. J Magn Reson Imag 440:433–440

    Article  Google Scholar 

  6. Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of medical genetics and genomics and the association for molecular pathology. Genet Med 17(5):405–424

    Article  PubMed  PubMed Central  Google Scholar 

  7. Villanova M, Louboutin JP, Chateau D et al (1995) X-linked vacuolated myopathy: complement membrane attack complex on surface membrane of injured muscle fibers. Ann Neurol 37(5):637–645

    Article  CAS  PubMed  Google Scholar 

  8. Chabrol B, Figarella-Branger D, Coquet M et al (2001) X-linked myopathy with excessive autophagy: a clinicopathological study of five new families. Neuromuscul Disord 11(4):376–388

    Article  CAS  PubMed  Google Scholar 

  9. Kurashige T, Takahashi T, Yamazaki Y et al (2013) Elevated urinary β2 microglobulin in the first identified Japanese family afflicted by X-linked myopathy with excessive autophagy. Neuromuscul Disord 23(11):911–916

    Article  PubMed  Google Scholar 

  10. Crockett CD, Ruggieri A, Gujrati M et al (2014) Late adult-onset of X-linked myopathy with excessive autophagy. Muscle Nerve 50(1):138–144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ruggieri A, Ramachandran N, Wang P et al (2015) Non-coding VMA21 deletions cause X-linked myopathy with excessive autophagy. Neuromuscul Disord 25(3):207–211

    Article  CAS  PubMed  Google Scholar 

  12. Mercier S, Magot A, Caillon F et al (2015) Muscle magnetic resonance imaging abnormalities in X-linked myopathy with excessive autophagy. Muscle Nerve 52(4):673–680

    Article  CAS  PubMed  Google Scholar 

  13. Rao S, Chandra S, Narayanappa G (2019) X-linked myopathy with excessive autophagy; a case report. Neurol India 67(5):1344

    Article  PubMed  Google Scholar 

  14. Cotta A, Carvalho E, da Cunha-Junior AL et al (2020) Clinical, imaging, morphologic, and molecular features of X-linked VMA21-related myopathy in two unrelated Brazilian families. J Neurol Sci 415:116977

    Article  CAS  PubMed  Google Scholar 

  15. Alon T, Sadeh M, Lev D, Dabby R (2021) X-linked myopathy with excessive autophagy: first report of an Israeli family presenting with late onset lower limb girdle weakness. Neuromuscul Disord 31(9):854–858

    Article  PubMed  Google Scholar 

  16. Yang J, Chen D, Feng L et al (2022) X-linked myopathy with excessive autophagy due to a mutation in VMA21 gene: the first case in China. Neurol Sci 43(3):2137–2139

    Article  PubMed  Google Scholar 

  17. Pegat A, Streichenberger N, Lacoste N et al (2022) Novel intronic mutation in VMA21 causing severe phenotype of X-linked myopathy with excessive autophagy—case report. Genes (Basel) 13(12):2245

    Article  CAS  PubMed  Google Scholar 

  18. Ishizaki M, Kobayashi M, Adachi K et al (2018) Female dystrophinopathy: review of current literature. Neuromuscul Disord 28(7):572–581

    Article  PubMed  Google Scholar 

  19. Kishnani PS, Hwu WL, Mandel H et al (2006) A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr 148(5):671-676.e2

    Article  PubMed  Google Scholar 

  20. Sugie K, Yamamoto A, Murayama K et al (2002) Clinicopathological features of genetically confirmed Danon disease. Neurology 58(12):1773–1778

    Article  CAS  PubMed  Google Scholar 

  21. Cocchiararo I, Cattaneo O, Rajendran J et al (2023) Identification of a muscle-specific isoform of VMA21 as a potent actor in X-linked myopathy with excessive autophagy pathogenesis. Hum Mol Genet 26(3):312–318

    Google Scholar 

  22. Hobson-Webb LD, DeArmey S, Kishnani PS (2011) The clinical and electrodiagnostic characteristics of Pompe disease with post-enzyme replacement therapy findings. Clin Neurophysiol 122(11):2312–2317

    Article  PubMed  Google Scholar 

  23. Dowling JJ, Moore SA, Kalimo H, Minassian BA (2015) X-linked myopathy with excessive autophagy: a failure of self-eating. Acta Neuropathol 129(3):383–390

    Article  PubMed  Google Scholar 

  24. Tasca G, Iannaccone E, Monforte M et al (2012) Muscle MRI in becker muscular dystrophy. Neuromuscul Disord 22(SUPPL. 2):S100–S106

    Article  PubMed  Google Scholar 

  25. Fischer D, Hafner P, Rubino D et al (2016) The 6-minute walk test, motor function measure and quantitative thigh muscle MRI in Becker muscular dystrophy: a cross-sectional study. Neuromuscul Disord 26(7):414–422

    Article  PubMed  Google Scholar 

  26. Munteanu I, Ramachandran N, Ruggieri A et al (2015) Congenital autophagic vacuolar myopathy is allelic to X-linked myopathy with excessive autophagy. Neurology 84(16):1714–1716

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Frédéric Fer for assistance with developing the R code to generate a heatmap of the MRI muscle involvement.

The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. MS is supported by a clinician scientist INSERM position (CIHU INSERM).

Funding

The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. MS is supported by a clinician scientist INSERM position (CIHU INSERM).

Author information

Author notes

  1. Gorka Fernández-Eulate and Girolamo Alfieri co-first authors.

Authors and Affiliations

  1. Nord/Est/Ile-de-France Neuromuscular Diseases Reference Center, Institut de Myologie, Pitié-Salpêtrière Hospital, APHP, 47-83 Bd de L’Hôpital, 75013, Paris, France

    Gorka Fernández-Eulate, Girolamo Alfieri, Anthony Behin & Tanya Stojkovic

  2. Azienda Ospedaliera Universitaria Sant’Andrea, Rome, Italy

    Girolamo Alfieri

  3. Neuromuscular Diseases Reference Center, Neurology Department, CHU Angers, Angers, France

    Marco Spinazzi

  4. Nuclear Magnetic Resonance Laboratory, Institut de Myologie, Paris, France

    Isabelle Ackermann-Bonan

  5. Neuromuscular Diseases Reference Center “AOC”, Nerve-Muscle Unit, Pellegrin Hospital, CHU Bordeaux, Bordeaux, France

    Fanny Duval & Guilhem Solé

  6. Radiology Department, CHU de Nantes, Nantes, France

    Florence Caillon

  7. Medical Genetics Department, Neuromuscular Diseases Reference Center “AOC”, CHU Nantes, Nantes, France

    Sandra Mercier

  8. Neuromuscular Diseases Reference Center “AOC”, Laboratoire d’Explorations Fonctionnelles, CHU de Nantes, FILNEMUS, Euro-NMD, Nantes, France

    Yann Pereon & Armelle Magot

  9. Electroneuromyography and Neuromuscular Diseases Unit, PACA-Réunion-Rhône Alpes Neuromuscular Diseases Reference Center, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Lyon, France

    Antoine Pegat

  10. Neuromuscular Diseases and ALS Reference Center, FILNEMUS, CHU La Timone, APHM, Marseille, France

    Emmanuelle Salort-Campana & Brigitte Chabrol

  11. Medical Genetics Department, CHU La Timone Enfants, APHM, Aix-Marseille University, Inserm, U1251-MMG, Marseille, France

    Svetlana Gorokhova & Martin Krahn

  12. Diagnostic Genetics Laboratory, CRU Strasbourg, Strasbourg University, Strasbourg, France

    Valerie Biancalana

  13. Muscle Pathology Unit, Institut de Myologie, Nord/Est/Ile-de-France Neuromuscular Diseases Reference Center, Pitié-Salpêtrière Hospital, APHP, Paris, France

    Teresinha Evangelista

  14. Cardiomyogenetics and Molecular and Cellular Myogenetics Unit, Institut de Myologie, Pitié-Salpêtrière Hospital, APHP, Paris, France

    Corinne Metay

Authors
  1. Gorka Fernández-Eulate
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Girolamo Alfieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marco Spinazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Isabelle Ackermann-Bonan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fanny Duval
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guilhem Solé
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Florence Caillon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sandra Mercier
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yann Pereon
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Armelle Magot
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Antoine Pegat
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Emmanuelle Salort-Campana
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Brigitte Chabrol
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Svetlana Gorokhova
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Martin Krahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Valerie Biancalana
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Teresinha Evangelista
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Anthony Behin
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Corinne Metay
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Tanya Stojkovic
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Concept and design: GFE, AB, TS. Acquisition and analysis of data: GFE, GA, MS, IAB, FD, GS, FC, SM, YP, AM, AP, ESC, BC, SG, MK, VB, TE. Drafting of the manuscript and figures: GFE, GA, MS, AB, CM, TS.

Corresponding author

Correspondence to Gorka Fernández-Eulate.

Ethics declarations

Conflicts of interest

The authors declare no conflict of interest.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 74 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fernández-Eulate, G., Alfieri, G., Spinazzi, M. et al. Phenotype variability and natural history of X-linked myopathy with excessive autophagy. J Neurol (2024). https://doi.org/10.1007/s00415-024-12298-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00415-024-12298-0

Keywords

Search

Navigation