Natural history of serum creatine kinase levels and motor, pulmonary, and cardiac functions in 337 patients with Duchenne muscular dystrophy: a retrospective study at a single referral center in Japan

Introduction Duchenne muscular dystrophy (DMD) is characterized by fatal progressive muscular atrophy resulting from dystrophin deficiency due to DMD gene mutations. DMD develops with symptoms of skeletal muscle weakness in early childhood; as a patient ages, muscle weakness progressively worsens and is further complicated by the involvement of the respiratory or cardiac muscles. Nonetheless, only few large-scale studies have investigated the secular changes in these symptoms from infancy to adolescence. Over recent years, with the development of DMD treatments, the need for a natural history of DMD to serve as a control for determining treatment efficacy in clinical trials has dramatically increased. The present study aimed to determine the natural history of patients with DMD and to examine the natural history of individual patients with gene mutations eligible for exon-skipping therapy by conducting a retrospective analysis of medical records of patients with DMD at a single institution in Japan. Methods Medical records of 337 patients with DMD who visited Kobe University Hospital in western Japan over a period of 30 years from their first visit until 20 years of age were examined. Data on serum creatine kinase (CK) levels, 10-meter run/walk test results and rise-from-floor test results for motor function evaluation, % forced vital capacity (%FVC) and forced expiratory volume in 1 second (%FEV1) values for respiratory function evaluation, and left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVDd) values for cardiac function evaluation were extracted. Changes in these values over time were examined. Results Serum CK levels showed a stair-step pattern of decline, with extremely high values until 6 years of age, a rapid decline from 7 to 12 years of age, and a plateau thereafter. Both the median 10-meter run/walk velocity and rise-from-floor velocity peaked at the age of 4 years and declined with age. Both the median %FVC and %FEV1 declined from the age of 11 years. The median LVEF was >60% until the age of 12 years and rapidly declined from 13 to 15 years of age. Cardiac dysfunction (LVEF <53%) occurred in approximately 80% of patients at the age of 20 years. Furthermore, examination of the relationship between gene mutations eligible for exon-skipping therapy and natural history revealed no characteristic findings. Conclusion We analyzed the natural history of patients with DMD in Japan during childhood and adolescence and showed that CK levels and motor, respiratory, and cardiac functions each exhibited unique changes over time. These findings will be useful in developing and designing new therapeutic agents for DMD and in determining their efficacy in clinical trials. ### Competing Interest Statement Masafumi Matsuo is a KNC-funded endowed chair at Kobe Gakuin University as well as a medical advisor to Daiichi Sankyo Co., Ltd. (Tokyo, Japan) and JCR Pharmaceuticals Co., Ltd. (Ashiya, Japan). Kandai Nozu received grant from Zenyaku Kogyo Co., Ltd. (Tokyo, Japan), consulting fees from Toa Eiyo Ltd. (Tokyo, Japan), Kyowa Kirin Co., Ltd. (Tokyo, Japan), and Taisho Pharmaceutical Co. Ltd. (Tokyo, Japan) and lecture fees from Sumitomo Pharma Co., Ltd. (Osaka, Japan), Chugai Pharmaceutical Co. Ltd. (Tokyo, Japan), and Kyowa Kirin Co., Ltd., and has patents for developing exon-skipping therapy for Alport syndrome patients from Daiichi Sankyo Co., Ltd. . Yasuhiro Takeshima received consulting fees from Daiichi Sankyo Co., Ltd. and Nippon Shinyaku Co., Ltd. (Tokyo, Japan), lecture fees from Nippon Shinyaku Co., Ltd., has patent from Daiichi Sankyo Co., Ltd. and participate on Advisory Board. Hiroyuki Awano received consulting fees from Daiichi Sankyo Co., Ltd., Nippon Shinyaku Co., Ltd., and Takeda Pharmaceutical Company Limited (Tokyo, Japan), and lecture fees from Nippon Shinyaku Co., Ltd., Chugai Pharmaceutical Co. Ltd., Pfizer Japan Inc. (Tokyo, Japan) and JCR Pharmaceuticals Co., Ltd. Tomoko Lee received lecture fees from Nippon Shinyaku Co., Ltd. The other authors declare that they have no known competing financial interests or personal relationships that could influence the research findings reported in the article. ### Funding Statement This work was supported in part by an intramural research grant (29-4) from the Department of Neurological and Psychiatric Disorders, National Center of Neurology and Psychiatry, and by a Grant-in-Aid for Scientific Research (19K20673) and Health and Labour Sciences Research Grant (21FC1006) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Kobe University Graduate School of Medicine gave ethical approval for this work (Approval No.:1534) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data used in this article can be obtained upon reasonable individual request to the corresponding author for their release.