Clinical Characteristics of Patients With Becker Muscular Dystrophy Having Pathogenic Microvariants or Duplications

Akinori Nakamura; Tsuyoshi Matsumura; Katsuhisa Ogata; Madoka Mori-Yoshimura; Eri Takeshita; Koichi Kimura; Hajime Arahata; Yasuhiro Takeshima; Toshiaki Takahashi; Keiko Ishigaki; Hiroyuki Awano; Kazuma Sugie; Tatsuya Fujii; Hideki Oi; Hirofumi Komaki

doi:10.1212/NXG.0000000000200215

Clinical Characteristics of Patients With Becker Muscular Dystrophy Having Pathogenic Microvariants or Duplications

Neurol Genet. 2024 Dec 17;11(1):e200215. doi: 10.1212/NXG.0000000000200215. eCollection 2025 Feb.

Authors

Affiliations

¹ Department of Clinical Research and Department of Neurology, NHO Matsumoto Medical Center.
² Department of Neurology, NHO Osaka Toneyama Medical Center.
³ Department of Neurology, NHO Higashisaitama National Hospital, Hasuda.
⁴ Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira.
⁵ Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira.
⁶ Department of Laboratory Medicine/Cardiology, The Institute of Medical Science, The University of Tokyo.
⁷ Department of Neurology, Neuro-Muscular Center, NHO Omuta Hospital.
⁸ Department of Pediatrics, Hyogo Medical University, Nishinomiya.
⁹ Department of Neurology, NHO Sendai Nishitaga Hospital.
¹⁰ Department of Pediatrics, Tokyo Women's Medical University School of Medicine.
¹¹ Organization for Research Initiative and Promotion, Tottori University, Yonago.
¹² Department of Neurology, Nara Medical University, Kashihara.
¹³ Department of Pediatrics, Shiga Medical Center for Children, Moriyama; and.
¹⁴ Department of Clinical Data Science, Clinical Research and Education Promotion Division, National Center of Neurology and Psychiatry, Kodaira, Japan.

Abstract

Background and objectives: Becker muscular dystrophy (BMD) is an allelic disorder of Duchenne muscular dystrophy (DMD) in which pathogenic variants in DMD cause progressive worsening of motor dysfunction, muscle weakness and atrophy, and death due to respiratory and cardiac failure. BMD often has in-frame deletions that preserve the amino acid reading frame, but there are some cases with microvariants or duplications. In recent years, the importance of therapeutic development and care for BMD has been emphasized. Therefore, the purpose of this study was to understand the clinical characteristics of BMD patients with microvariants or duplications and to determine the genotype-phenotype relationship.

Methods: The study focused on patients with pathogenic microvariants or duplications in DMD who were ambulatory after 16 years of age or had specific muscle biopsy results between June 13, 2017, and March 31, 2023. Informed consent was obtained from the patients or their surrogates. Data concerning DMD variants, muscle biopsy findings, skeletal muscle, respiratory and cardiac function, and CNS involvement were collected and analyzed statistically.

Results: Thirty-three patients with BMD had pathogenic microvariants (missense variants, nonsense variants, splice site variants, and other microvariants), and 16 patients had in-frame duplications in DMD. Many patients with microvariants had abnormal ECG findings. The effect of variant type on patient outcomes varied. Regardless of the type of microvariant, skeletal muscle and respiratory dysfunction was more severe in mutants of the cysteine-rich/C-terminal domain than in rod domain mutants. On the other hand, there was no significant difference in the complication rate of CNS disorders among the 3 domains of dystrophin.

Discussion: Microvariant forms, in particular, tend to vary in clinical severity according to the site of the dystrophin protein mutation rather than the type of pathogenic variant. The results of this study may be useful for genetic counseling, care, and treatment of patients with BMD.

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