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A novel TUFM homozygous variant in a child with mitochondrial cardiomyopathy expands the phenotype of combined oxidative phosphorylation deficiency 4

Authors
  • Hershkovitz, Tova1
  • Kurolap, Alina1, 2
  • Gonzaga-Jauregui, Claudia3
  • Paperna, Tamar1
  • Mory, Adi1
  • Wolf, Sarah E.3
  • Overton, John D.3
  • Shuldiner, Alan R.3
  • Saada, Ann4
  • Mandel, Hanna5
  • Baris Feldman, Hagit1, 2
  • 1 Rambam Health Care Campus, The Genetics Institute, Haifa, Israel , Haifa (Israel)
  • 2 Technion—Israel Institute of Technology, The Ruth and Bruce Rappaport Faculty of Medicine, Haifa, Israel , Haifa (Israel)
  • 3 Regeneron Genetics Center, Tarrytown, NY, USA , Tarrytown (United States)
  • 4 Hadassah-Hebrew University Medical Center, Monique and Jacques Roboh Department of Genetic Research and the Department of Genetic and Metabolic Diseases, Jerusalem, Israel , Jerusalem (Israel)
  • 5 Western Galilee Medical Center, Institute of Human Genetics and Metabolic Disorders, Naharia, Israel , Naharia (Israel)
Type
Published Article
Journal
Journal of Human Genetics
Publisher
Springer Nature
Publication Date
Mar 22, 2019
Volume
64
Issue
6
Pages
589–595
Identifiers
DOI: 10.1038/s10038-019-0592-6
Source
Springer Nature
License
Yellow

Abstract

Translation of mitochondrial-specific DNA is required for proper mitochondrial function and energy production. For this purpose, an elaborate network of dedicated molecular machinery including initiation, elongation and termination factors exists. We describe a patient with an unusual phenotype and a novel homozygous missense variant in TUFM (c.344A>C; p.His115Pro), encoding mtDNA translation elongating factor Tu (EFTu). To date, only four patients have been reported with bi-allelic mutations in TUFM, leading to combined oxidative phosphorylation deficiency 4 (COXPD4) characterized by severe early-onset lactic acidosis and progressive fatal infantile encephalopathy. The patient presented here expands the phenotypic features of TUFM-related disease, exhibiting lactic acidosis and dilated cardiomyopathy without progressive encephalopathy. This warrants the inclusion of TUFM in differential diagnosis of metabolic cardiomyopathy. Cases that further refine genotype-phenotype associations and characterize the molecular basis of mitochondrial disorders allow clinicians to predict disease prognosis, greatly impacting patient care, as well as provide families with reproductive planning options.

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