Clinical spectrum and genetic causes of mitochondrial hepatopathy phenotype in children

• Type of Material: Article
• Authors: James E Squires, UPMC Children’s Hospital of Pittsburgh; Alexander G Miethke, Cincinnati Children’s Hospital Medical Center; Alexander C Valencia, Cincinnati Children’s Hospital Medical Center; Kieran Hawthorne, Arbor Research Collaborative for Health; Lisa Henn, Arbor Research Collaborative for Health; Johan LKH Van Hove, University of Colorado, Aurora; Robert Squires, UPMC Children’s Hospital of Pittsburgh; Kevin Bove, Cincinnati Children’s Hospital Medical Center; Simon Horslen, UPMC Childrens Hosp Pittsburgh; Rohit Kohli, UPMC Children’s Hospital of Pittsburgh; Jean P Molleston, Indiana University; Rene Romero, Emory University; Estella M Alonso, Ann and Robert H. Lurie Children’s Hospital of Chicago; Jorge A Bezerra, Cincinnati Children’s Hospital Medical Center; Stephen L Guthery, University of Utah; Evelyn Hsu, University of Washington; Saul Karpen, Emory University; Kathleen M Loomes, Childrens Hospital of Philadelphia; Vicky L Ng, University of Toronto; Philip Rosenthal, University of California San Francisco; Krupa Mysore, Texas Children’s Hospital; Kasper S Wang, Children’s Hospital Los Angeles, Los Angeles; Marisa W Friederich, University of Colorado; John C Magee, University of Michigan; Ronald J Sokol, University of Colorado
• Language: English
• Date: 2023-06-01
• Publisher: Wolters Kluwer Health
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1097/HC9.0000000000000139
• Title of Journal or Parent Work: HEPATOLOGY COMMUNICATIONS
• Volume: 7
• Issue: 6
• Grant/Funding Information: Supported by the National Institute of Diabetes, Digestive, and Kidney Diseases U01 grants (DK062445 to Mt. Sinai School of Medicine, DK062497 to Cincinnati Children’s Hospital Medical Center, DK062470 to Children’s Healthcare of Atlanta, DK062481 to The Children’s Hospital of Philadelphia, DK062456 to University of Michigan, DK084536 to Riley Hospital for Children, DK084575 to Seattle Children’s Hospital, DK062500 to University of California San Francisco Children’s Hospital, DK062466 to Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center [UPMC], DK062453 to University of Colorado School of Medicine, DK084538 to Children’s Hospital Los Angeles, DK062436 to Ann and Robert H Lurie Children’s Hospital of Chicago, DK103149 to Baylor College of Medicine, DK103135 to The Hospital for Sick Children, DK103140 to University of Utah), the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Awards (UL1 TR002535 to University of Colorado Denver, UL1 TR001872 to University of California San Francisco Children’s Hospital, UL1 TR001857 to Children’s Hospital of Pittsburgh of UPMC, UL1 TR001878 to The Children’s Hospital of Philadelphia, UL1 TR000423 and UL1 RR025014 to Seattle Children’s Hospital, UL1TR002378 to Children’s Healthcare of Atlanta, UL1TR00130 to Children’s Hospital of Los Angeles), University of Colorado Foundation and Children’s Hospital Foundation to JVH and MWF, the National Institute of Diabetes and Digestive and Kidney Disease NIDDK UO1 DK072146.
• Keywords: DEFICIENCY; DISEASES; TRANSPLANTATION; BLOOD; Life Sciences & Biomedicine; Science & Technology; LACTATE; RATIO; Gastroenterology & Hepatology; DIAGNOSIS; ACUTE LIVER-FAILURE; OUTCOMES
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

BACKGROUND: Alterations in both mitochondrial DNA (mtDNA) and nuclear DNA genes affect mitochondria function, causing a range of liver-based conditions termed mitochondrial hepatopathies (MH), which are subcategorized as mtDNA depletion, RNA translation, mtDNA deletion, and enzymatic disorders. We aim to enhance the understanding of pathogenesis and natural history of MH. METHODS: We analyzed data from patients with MH phenotypes to identify genetic causes, characterize the spectrum of clinical presentation, and determine outcomes. RESULTS: Three enrollment phenotypes, that is, acute liver failure (ALF, n = 37), chronic liver disease (Chronic, n = 40), and post-liver transplant (n = 9), were analyzed. Patients with ALF were younger [median 0.8 y (range, 0.0, 9.4) vs 3.4 y (0.2, 18.6), p < 0.001] with fewer neurodevelopmental delays (40.0% vs 81.3%, p < 0.001) versus Chronic. Comprehensive testing was performed more often in Chronic than ALF (90.0% vs 43.2%); however, etiology was identified more often in ALF (81.3% vs 61.1%) with mtDNA depletion being most common (ALF: 77% vs Chronic: 41%). Of the sequenced cohort (n = 60), 63% had an identified mitochondrial disorder. Cluster analysis identified a subset without an underlying genetic etiology, despite comprehensive testing. Liver transplant-free survival was 40% at 2 years (ALF vs Chronic, 16% vs 65%, p < 0.001). Eighteen (21%) underwent transplantation. With 33 patient-years of follow-up after the transplant, 3 deaths were reported. CONCLUSIONS: Differences between ALF and Chronic MH phenotypes included age at diagnosis, systemic involvement, transplant-free survival, and genetic etiology, underscoring the need for ultra-rapid sequencing in the appropriate clinical setting. Cluster analysis revealed a group meeting enrollment criteria but without an identified genetic or enzymatic diagnosis, highlighting the need to identify other etiologies.