FBXL4 defects are common in patients with congenital lactic acidemia and encephalomyopathic mitochondrial DNA depletion syndrome |
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| Authors: | H. Dai V.W. Zhang A.W. El‐Hattab C. Ficicioglu M. Shinawi M. Lines A. Schulze M. McNutt G. Gotway X. Tian S. Chen J. Wang W.J. Craigen L.‐J. Wong |
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| Affiliation: | 1. Baylor Genetics, Houston, TX, USA;2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;3. Division of Clinical Genetics and Metabolic Disorders, Pediatric Department, Tawam Hospital, Al‐Ain, United Arab Emirates;4. Division of Human Genetics and Metabolism, The Children's Hospital of Philadelphia, Philadelphia, PA, USA;5. Division of Genetics and Genomics, Washington University School of Medicine, St. Louis, MO, USA;6. Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada;7. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada;8. Children's Medical Center, Dallas, TX, USA |
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| Abstract: | Mutations in FBXL4 have recently been recognized to cause a mitochondrial disorder, with clinical features including early onset lactic acidosis, hypotonia, and developmental delay. FBXL4 sequence analysis was performed in 808 subjects suspected to have a mitochondrial disorder. In addition, 28 samples from patients with early onset of lactic acidosis, but without identifiable mutations in 192 genes known to cause mitochondrial diseases, were examined for FBXL4 mutations. Definitive diagnosis was made in 10 new subjects with a total of 7 novel deleterious variants; 5 null and 2 missense substitutions. All patients exhibited congenital lactic acidemia, most of them with severe encephalopathic presentation, and global developmental delay. Overall, FBXL4 defects account for at least 0.7% (6 out of 808) of subjects suspected to have a mitochondrial disorder, and as high as 14.3% (4 out of 28) in young children with congenital lactic acidosis and clinical features of mitochondrial disease. Including FBLX4 in the mitochondrial diseases panel should be particularly important for patients with congenital lactic acidosis. |
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| Keywords: | congenital lactic acidemia early onset encephalopathy FBXL4 mutations mitochondrial disorders |
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