Lea Abou Haidar1,2, Robert C. Harris1,2, Panayotis Pachnis1,3, Hongli Chen1, Garrett K. Gotway3,4,5, Min Ni1,3 and Ralph J. DeBerardinis1,2,3,4 1Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, Texas 75390, USA; 2Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, Texas 75390, USA; 3Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas 75390, USA; 4Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas 75390, USA; 5Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas 75390, USA Corresponding author: ralph.deberardinisutsouthwestern.edu Abstract

Electron transport chain (ETC) disorders are a group of rare, multisystem diseases caused by impaired oxidative phosphorylation and energy production. Deficiencies in complex III (CIII), also known as ubiquinol–cytochrome c reductase, are particularly rare in humans. Ubiquinol–cytochrome c reductase core protein 2 (UQCRC2) encodes a subunit of CIII that plays a crucial role in dimerization. Several pathogenic UQCRC2 variants have been identified in patients presenting with metabolic abnormalities that include lactic acidosis, hyperammonemia, hypoglycemia, and organic aciduria. Almost all previously reported UQCRC2-deficient patients exhibited neurodevelopmental involvement, including developmental delays and structural brain anomalies. Here, we describe a girl who presented at 3 yr of age with lactic acidosis, hyperammonemia, and hypoglycemia but has not shown any evidence of neurodevelopmental dysfunction by age 15. Whole-exome sequencing revealed compound heterozygosity for two novel variants in UQCRC2: c.1189G>A; p.Gly397Arg and c.437T>C; p.Phe146Ser. Here, we discuss the patient's clinical presentation and the likely pathogenicity of these two missense variants.

Received June 8, 2023. Accepted August 25, 2023.

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