Background

Danon disease (DD) is a rare X-linked dominant lysosomal glycogen storage disease that manifests as severe ventricular hypertrophy and heart failure [1]. Currently, detection of mutations in the lysosomal-associated membrane protein-2 (LAMP-2) gene is the gold standard for DD diagnosis [2], and endocardial biopsy is also a critical method for diagnosing it. If a genetic test is unavailable, endocardial biopsy by electron microscopy combined with clinical triad can be used for clinical diagnosis.

Cardiovascular magnetic resonance (CMR) is a rapidly evolving non-invasive imaging modality offering comprehensive, multiparametric assessment of cardiac structure and function in various clinical situations. CMR does not expose patients to ionizing radiation, and its high spatial resolution enables detailed myocardial tissue characterization [3]. Late gadolinium enhancement (LGE) CMR imaging is the most sensitive imaging technique for identifying the extent of myocardial infarction or assessing residual myocardial viability. Myocardial T1 map** is a non-invasive technology to assess the extracellular volume fraction (ECV), which reflects the degree of diffuse myocardial fibrosis by measuring myocardial and blood T1 relaxation time before and after contrast enhancement [4].

Typical DD treatments aimed at preventing sudden cardiac death and alleviate symptoms, and heart transplantation is still its sole radical treatment. In addition, in vivo study using LAMP-2 KO mice, Manso et al. attempted to rescue LAMP-2B deficiency via recombinant adeno-associated virus 9 (AAV9).The survival rate in older mice treated with gene therapy treatment was evidently improved, and a phase 1 clinical trial is currently underway to assess the safety and toxicity of this gene therapy product in human DD [5]. Small molecule-based approaches to modify the autophagy process have also been shown to have therapeutic effects in several studies [6]. Due to the low prevalence of DD, most previous studies are case reports, and multiple cases in one family are rare. The diagnostic value of CMR in DD and the cardiac efficacy of various treatments still needs to be explored. In this study, we describe the CMR characteristics of three cases of DD in a Chinese family, aiming to explore the value of multi-parameter MR characteristics in DD diagnosis and follow-up after treatment.

Case presentation

Clinical features and associated laboratory data

The three generations of the proband’s immediate family members were investigated. Clinical data, including sex, age, symptoms, electrocardiography, extracardiac presentation, and laboratory data, were collected and analysed (Table 1). Their pedigree was obtained from hospital records in Anhui Province, China. Gene sequencing verified that the proband carried the mutation c.963G > A in the LAMP-2 gene.

Table 1 Baseline characteristics, clinical presentation, and assisted testing of patients with DD
Full size table

The proband (III-1) was a 16-year-old male who had been previously reported [

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

DD:

Danon disease

LAMP-2:

Lysosomal-associated membrane protein-2

CMR:

Cardiovascular magnetic resonance

LGE:

Late gadolinium enhancement

ECV:

Extracellular volume fraction

AAV9:

Adeno-associated virus 9

WPW:

Wolf-parkinson-white

HCM:

Hypertrophic cardiomyopathy

DCM:

Dilated cardiomyopathy

References

  1. Sugie K, Noguchi S, Kozuka Y, Arikawa-Hirasawa E, Tanaka M, Yan C, et al. Autophagic vacuoles with sarcolemmal features delineate Danon disease and related myopathies. J Neuropathol Exp Neurol. 2005;64:513–22. https://doi.org/10.1093/jnen/64.6.513.

    Article  CAS  PubMed  Google Scholar 

  2. Nishino I, Fu J, Tanji K, Yamada T, Shimojo S, Koori T, et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature. 2000;406:906–10. https://doi.org/10.1038/35022604.

    Article  CAS  PubMed  Google Scholar 

  3. Arnold JR, McCann GP. Cardiovascular magnetic resonance: applications and practical considerations for the general cardiologist. Heart. 2020;106(3):174–81. https://doi.org/10.1136/heartjnl-2019-314856.

    Article  CAS  PubMed  Google Scholar 

  4. Nakamori S. Dohi, Native T1 map** and extracellular volume map** for the Assessment of diffuse myocardial fibrosis in dilated cardiomyopathy. JACC. Cardiovascular imaging. (2018) 11(1):48–59. doi: https://doi.org/10.1016/j.jcmg.2017.04.006.

  5. Manso AM, Hashem SI, Nelson BC, Gault E, Soto-Hermida A, Villarruel E, et al. Systemic AAV9.LAMP2B injection reverses metabolic and physiologic multiorgan dysfunction in a murine model of Danon disease. SCI TRANSL MED. 2020;535:eaax1744. https://doi.org/10.1126/scitranslmed.aax1744.

    Article  CAS  Google Scholar 

  6. Ng KM, Mok PY, Butler AW, Ho JC, Choi SW, Lee YK, et al. Amelioration of X-Linked related autophagy failure in Danon Disease with DNA methylation inhibitor. Circulation. 2016;134:1373–89. https://doi.org/10.1161/CIRCULATIONAHA.115.019847.

    Article  CAS  PubMed  Google Scholar 

  7. **e J, Liu Y, Wei X, et al. Relationship between fragmented QRS Complex and Left Ventricular fibrosis and function in patients with Danon Disease. Front Cardiovasc Med. 2022;9:790917. https://doi.org/10.3389/fcvm.2022.790917.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Dougu N, Joho S, Shan L, Shida T, Matsuki A, Uese K, et al. Novel LAMP-2 mutation in a family with Danon disease presenting with hypertrophic cardiomyopathy. Circ J. 2009;73:376–80. https://doi.org/10.1253/circj.cj-08-0241.

    Article  CAS  PubMed  Google Scholar 

  9. Sugie K, Yamamoto A, Murayama K, Oh SJ, Takahashi M, Mora M, et al. Clinicopathological features of genetically confirmed Danon disease. Neurology. 2002;58:1773–8. https://doi.org/10.1212/wnl.58.12.1773.

    Article  CAS  PubMed  Google Scholar 

  10. Schorderet DF, Cottet S, Lobrinus JA, Borruat FX, Balmer A, Munier FL. Retinopathy in Danon disease. Arch Ophthalmol. 2007;125:231–6. https://doi.org/10.1001/archopht.125.2.231.

    Article  CAS  PubMed  Google Scholar 

  11. López-Sainz Á, Salazar-Mendiguchía J, García-Álvarez A, Campuzano Larrea O, López-Garrido M, García-Guereta L et al. Clinical findings and prognosis of Danon Disease. An analysis of the spanish Multicenter Danon Registry. Rev Esp Cardiol (Engl Ed). (2019) 72:479–86. doi: https://doi.org/10.1016/j.rec.2018.04.035.

  12. Guo S, Zhou L, Wang R, Lv Z, Xu H, Han B, et al. Danon disease: two patients with atrial fibrillation in a single family and review of the literature. Exp Ther Med. 2019;18:1527–32. https://doi.org/10.3892/etm.2019.7777.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Cetin H, Wöhrer A, Rittelmeyer I, Gencik M, Zulehner G, Zimprich F, et al. The c.65-2A > G splice site mutation is associated with a mild phenotype in Danon disease due to the transcription of normal LAMP2 mRNA. Clin Genet. 2016;90:366–71. https://doi.org/10.1111/cge.12724.

    Article  CAS  PubMed  Google Scholar 

  14. Wei X, Zhao L, **e J, Liu Y, Du Z, Zhong X, et al. Cardiac phenotype characterization at MRI in patients with Danon Disease: a retrospective Multicenter Case Series. Radiology. 2021;299:303–10. https://doi.org/10.1148/radiol.2021203996.

    Article  PubMed  Google Scholar 

  15. Taylor MRG, Ku L, Slavov D, Cavanaugh J, Boucek M, Zhu X, et al. Danon disease presenting with dilated cardiomyopathy and a complex phenotype. J Hum Genet. 2007;52:830–5. https://doi.org/10.1007/s10038-007-0184-8.

    Article  PubMed  Google Scholar 

  16. Lotan D, Salazar-Mendiguchía J, Mogensen J, Rathore F, Anastasakis A, Kaski J, et al. Clinical Profile of Cardiac involvement in Danon Disease: a Multicenter European Registry. Circ Genom Precis Med. 2020;13:e003117. https://doi.org/10.1161/CIRCGEN.120.003117.

    Article  CAS  PubMed  Google Scholar 

  17. Rigolli M, Kahn AM, Brambatti M, Contijoch FJ, Adler ED. Cardiac magnetic resonance imaging in Danon Disease Cardiomyopathy. JACC Cardiovasc Imaging. 2021;14:514–6. https://doi.org/10.1016/j.jcmg.2020.08.011.

    Article  PubMed  Google Scholar 

  18. Zhou N, Cui J, Zhao W, Jiang Y, Zhu W, Tang L, et al. A family with Danon disease caused by a splice site mutation in LAMP2 that generates a truncated protein. Mol Genet Genomic Med. 2019;7:e561. https://doi.org/10.1002/mgg3.561.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pöyhönen P, Hiippala A, Ollila L, Kaasalainen T, Hänninen H, Heliö T, et al. Cardiovascular magnetic resonance findings in patients with PRKAG2 gene mutations. J Cardiovasc Magn Reson. 2015;17:89. https://doi.org/10.1186/s12968-015-0192-3.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors acknowledge **uzheng Yue(Philips Healthcare, Bei**g, China)and Yinsu Zhu(Department of Radiology, The First Affiliated Hospital of Nan**g Medical University). for assistance with the English editing.

Funding

No.

Author information

Author notes

  1. Yang Zhang and Ren Zhao contributed equally to this article and are co-first authors

Authors and Affiliations

  1. Department of Radiology, Fuyang People’s Hospital, Fuyang, 236000, Anhui, China

    Yang Zhang & Yushan Yuan

  2. Department of Cardiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China

    Ren Zhao

  3. Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China

    Yongqiang Yu, Bin Liu & **aohu Li

  4. Research Center of Clinical Medical Imaging, Hefei, 230032, Anhui Province, China

    Yongqiang Yu, Bin Liu & **aohu Li

  5. Department of Radiology, First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei, 230022, Anhui, China

    Bin Liu & **aohu Li

Authors
  1. Yang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ren Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yushan Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yongqiang Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. **aohu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XL contributed to the study planning and conduct, and the article writing. YZ, RZ, YY, and XL contributed to the patient enrolment process. YZ and YY contributed to the data analysis. BL and XL contributed to the study design and take responsibility for the overall content as guarantors. All authors contributed to the article and approved the submitted version.

Corresponding authors

Correspondence to Bin Liu or **aohu Li.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The studies involving human participants were reviewed and approved by Fuyang People’s Hospital Ethics Committee (2021-56). The patients/participants provided their written informed consent to participate in this study. All procedures were conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Consent for publication

Not applicable in the declarations section.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Additional File 1:

CARE Checklist of information to include when writing a case report

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Y., Zhao, R., Yuan, Y. et al. Clinical manifestations and MRI features of Danon disease: a case series. BMC Cardiovasc Disord 23, 397 (2023). https://doi.org/10.1186/s12872-023-03356-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12872-023-03356-y

Keywords