Department of Pediatrics and Center for Human Genomics and Precision Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
Sara M Nowinski
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, United States
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, United States
Jaya Ganesh
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
Richard J Rodenburg
Department of Pediatrics, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen, Netherlands
Joao Leandro
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
Anthony Evans
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
Hieu S Vu
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, United States
Thomas P Naidich
Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
Bruce D Gelb
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
Ralph J DeBerardinis
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, United States; Howard Hughes Medical Institute, Chevy Chase, MD, United States
Malonyl-CoA-acyl carrier protein transacylase (MCAT) is an enzyme involved in mitochondrial fatty acid synthesis (mtFAS) and catalyzes the transfer of the malonyl moiety of malonyl-CoA to the mitochondrial acyl carrier protein (ACP). Previously, we showed that loss-of-function of mtFAS genes, including Mcat, is associated with severe loss of electron transport chain (ETC) complexes in mouse immortalized skeletal myoblasts (Nowinski et al., 2020). Here, we report a proband presenting with hypotonia, failure to thrive, nystagmus, and abnormal brain MRI findings. Using whole exome sequencing, we identified biallelic variants in MCAT. Protein levels for NDUFB8 and COXII, subunits of complex I and IV respectively, were markedly reduced in lymphoblasts and fibroblasts, as well as SDHB for complex II in fibroblasts. ETC enzyme activities were decreased in parallel. Re-expression of wild-type MCAT rescued the phenotype in patient fibroblasts. This is the first report of a patient with MCAT pathogenic variants and combined oxidative phosphorylation deficiency.
