Atsuko Imai-Okazaki1, Yoshihito Kishita2, Masakazu Kohda2, Yosuke Mizuno3, Takuya Fushimi4, Ayako Matsunaga4, Yukiko Yatsuka2, Tomoko Hirata5, Hiroko Harashima6, Atsuhito Takeda7, Akihiro Nakaya8, Yasushi Sakata9, Shigetoyo Kogaki10, Akira Ohtake11, Kei Murayama4, Yasushi Okazaki12. 1. Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Department of Genome Informatics, Osaka University Graduate School of Medicine, Osaka, Japan; Division of Genomic Medicine Research, Medical Genomics Center, National Center for Global Health and Medicine, Tokyo, Japan. 2. Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan. 3. Division of Analytical Science, Biomedical Research Center Hidaka Brunch, Saitama Medical University, Saitama, Japan. 4. Department of Metabolism, Chiba Children's Hospital, Chiba, Japan. 5. Laboratory for Comprehensive Genomic Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan. 6. Department of Pediatrics, Saitama Medical University, Saitama, Japan. 7. Department of Pediatrics, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan. 8. Department of Genome Informatics, Osaka University Graduate School of Medicine, Osaka, Japan. 9. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan. 10. Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan. 11. Department of Pediatrics, Saitama Medical University, Saitama, Japan; Center for Intractable Diseases, Saitama Medical University Hospital, Saitama, Japan. 12. Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Laboratory for Comprehensive Genomic Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan. Electronic address: ya-okazaki@juntendo.ac.jp.
Abstract
BACKGROUND: Cardiomyopathy is a reported indicator of poor prognosis in children with mitochondrial disease. However, the association between prognosis and the genetic background of cardiomyopathy in children with mitochondrial disease has yet to be fully elucidated. METHODS AND RESULTS: Of 137 children with mitochondrial disease whose genetic diagnosis was made between 2004 and 2018, 29 had mitochondrial cardiomyopathy (21%). After a median follow-up of 35 months, the overall survival rate was significantly lower in patients with cardiomyopathy than in those without (p < 0.001). Ten-year Kaplan-Meier estimates of overall survival were 18 and 67%, respectively. Among the 21 cardiomyopathy patients who died, two died within one month of birth (COQ4 in one patient, and COX10 in one patient), ten died within one year (BOLA3 in three patients, QRSL1 in two patients, large chromosomal deletions in two patients, MT-ATP6/8 in one patient, MT-TL1 in one patient, and TAZ gene in one patient), and nine died after one year (MT-ND5 in three patients, MT-TL1 in three patients, ACAD9 in one patient, KARS in one patient, and MT-TV in one patient). In the three patients with mitochondrial DNA mutations whose cardiac tissues were available, high heteroplasmy rates in the cardiac tissue were observed for m.8528T>C (90%, died at 2 months of age) and m.3243A>G (90 and 80%, died at 12 and 13 years of age, respectively). CONCLUSIONS: In children with mitochondrial disease, cardiomyopathy was common (21%) and was associated with increased mortality. Genetic analysis coupled with detailed phenotyping could be useful for prognosis.
BACKGROUND:Cardiomyopathy is a reported indicator of poor prognosis in children with mitochondrial disease. However, the association between prognosis and the genetic background of cardiomyopathy in children with mitochondrial disease has yet to be fully elucidated. METHODS AND RESULTS: Of 137 children with mitochondrial disease whose genetic diagnosis was made between 2004 and 2018, 29 had mitochondrial cardiomyopathy (21%). After a median follow-up of 35 months, the overall survival rate was significantly lower in patients with cardiomyopathy than in those without (p < 0.001). Ten-year Kaplan-Meier estimates of overall survival were 18 and 67%, respectively. Among the 21 cardiomyopathypatients who died, two died within one month of birth (COQ4 in one patient, and COX10 in one patient), ten died within one year (BOLA3 in three patients, QRSL1 in two patients, large chromosomal deletions in two patients, MT-ATP6/8 in one patient, MT-TL1 in one patient, and TAZ gene in one patient), and nine died after one year (MT-ND5 in three patients, MT-TL1 in three patients, ACAD9 in one patient, KARS in one patient, and MT-TV in one patient). In the three patients with mitochondrial DNA mutations whose cardiac tissues were available, high heteroplasmy rates in the cardiac tissue were observed for m.8528T>C (90%, died at 2 months of age) and m.3243A>G (90 and 80%, died at 12 and 13 years of age, respectively). CONCLUSIONS: In children with mitochondrial disease, cardiomyopathy was common (21%) and was associated with increased mortality. Genetic analysis coupled with detailed phenotyping could be useful for prognosis.
Authors: Débora da Luz Scheffer; Adriana Ann Garcia; Lucia Lee; Daria Mochly-Rosen; Julio Cesar Batista Ferreira Journal: Antioxid Redox Signal Date: 2022-04-18 Impact factor: 7.468
Authors: Cristina Mazzaccara; Bruno Mirra; Ferdinando Barretta; Martina Caiazza; Barbara Lombardo; Olga Scudiero; Nadia Tinto; Giuseppe Limongelli; Giulia Frisso Journal: Int J Mol Sci Date: 2021-05-27 Impact factor: 6.208