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Comprehensive pathological and genetic investigation of three young adult myotonic dystrophy type 1 patients with sudden unexpected death

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Abstract

Objectives

The mechanism and pathological substrate of arrhythmogenic events in dystrophic myopathy type 1 (DM1) have not been fully established, especially for patients without progression of motor and/or cardiac disability. Therefore, we aimed to clarify the pathological appearance and genetic factors, other than CTG repeats in DMPK, associated with sudden cardiac death in patients with DM1.

Methods

A pathological investigation including the cardiac conduction system in the heart and whole-exome sequencing was conducted for three young adults (Patient 1; 25-year-old female, Patient 2; 35-year-old female, Patient 3; 18-year-old male) with DM1 who suffered sudden death.

Results

Only Patient 1 showed abnormal electrocardiogram findings before death. The pathological investigation showed severe fibrosis of the atrioventricular conduction system in Patient 1 and severe fatty infiltration in the right ventricle in Patient 2. Several minimal necrotic/inflammatory foci were found in both patients. Patient 3 showed no significant pathological findings. A genetic investigation showed CORIN_p.W813* and MYH2_p. R793* in Patient 1, KCNH2_p. V794D and PLEC_p. A4147T in Patient 2, and SCN5A_p.E428K and SCN3B_ p.V145L in Patient 3 as highly possible pathogenic variants.

Conclusion and relevance

The present study showed varied heart morphology in young adults with DM1 and sudden death. Synergistic effects of various genetic factors other than CTG repeats may increase the risk of sudden cardiac death in DM1 patients, even if signs of cardiac and skeletal muscle involvement are mild. Comprehensive genetic investigations, other than CTG repeat assessment, may be useful to estimate the risk of sudden cardiac death in DM1 patients.

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Data availability

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

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Acknowledgements

This work was supported in part by the JSPS KAKENHI (Grant number JP21H03211 to YH. and JP23H03759 to NN.). The authors thank Miyuki Maekawa, Misa Kusaba, and Osamu Yamamoto for their technical assistance. We thank Lisa Kreiner, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

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Authors and Affiliations

  1. Department of Legal Medicine, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan

    Yukiko Hata, Shojiro Ichimata, Koji Yoshida, Yoshiaki Yamaguchi & Naoki Nishida

  2. Tanz Centre for Research in Neurodegenerative Disease, Krembil Discovery Tower, University of Toronto, 60 Leonard Ave, Toronto, ON, M5T 0S8, Canada

    Shojiro Ichimata & Koji Yoshida

  3. Department of Laboratory Medicine and Pathobiology and Department of Medicine, University of Toronto, Toronto, ON, Canada

    Shojiro Ichimata & Koji Yoshida

  4. Department of Cardiology, Saiseikai Takaoka Hospital, 387-1 Futatsuka, Takaoka, Toyama, 933-8525, Japan

    Yoshiaki Yamaguchi

  5. Department of Pediatrics, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan

    Keiichi Hirono

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  1. Yukiko Hata
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  2. Shojiro Ichimata
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  3. Koji Yoshida
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  6. Naoki Nishida
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Contributions

YH conceptualized the study, performed the pathological and genetic investigations, acquired the samples, and wrote the original draft of the manuscript. SH performed pathological investigations and visualization. KY summarized the neurological findings. YH and KH summarized the electrocardiogram findings. NN conceptualized the study, performed pathological investigations, acquired samples, and reviewed and wrote the original draft of the manuscript.

Corresponding author

Correspondence to Naoki Nishida.

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Ethics standard

All autopsies and neuropathological investigations were performed with written consent of the legal authority under the criminal code. Written consent was obtained from the next of kin or guardian for genetic investigations and publication of anonymized data obtained through clinical characterization and scientific research. This study was performed in accordance with the ethical standards established in the 1964 Declaration of Helsinki. All experimental protocols, including the use of pathological specimens obtained at autopsies for research upon anonymization, were approved by the official ethical institutional review board of the University of Toyama (I2020006).

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Hata, Y., Ichimata, S., Yoshida, K. et al. Comprehensive pathological and genetic investigation of three young adult myotonic dystrophy type 1 patients with sudden unexpected death. J Neurol 270, 5380–5391 (2023). https://doi.org/10.1007/s00415-023-11850-8

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