Biochemical signatures mimicking multiple carboxylase deficiency in children with mutations in MT-ATP6.

Autor: Larson AA; Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO, USA; Inherited Metabolic Diseases Clinic, Children's Hospital Colorado, Aurora, CO, USA. Electronic address: austin.larson@ucdenver.edu., Balasubramaniam S; Princess Margaret Hospital for Children, Perth, Australia; Children's Hospital at Westmead, Sydney, Australia., Christodoulou J; Neurodevelopmental Genomics Research Group, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia., Burrage LC; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA., Marom R; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA., Graham BH; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA., Diaz GA; Program for Inherited Metabolic Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Glamuzina E; Metabolic Service, Starship Children's Hospital, Auckland, New Zealand., Hauser N; Inherited Metabolic Diseases Clinic, Valley Children's Hospital, Madera, CA, USA., Heese B; Children's Mercy Hospitals and Clinics, Kansas City, MO, USA., Horvath G; Inherited Metabolic Diseases Clinic, University of British Columbia, Vancouver, Canada., Mattman A; Inherited Metabolic Diseases Clinic, University of British Columbia, Vancouver, Canada., van Karnebeek C; Inherited Metabolic Diseases Clinic, University of British Columbia, Vancouver, Canada; Centre for Molecular Medicine and Therapeutics, Department of Pediatrics, University of British Columbia, Vancouver, Canada., Lane Rutledge S; Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA., Williamson A; Program for Inherited Metabolic Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Estrella L; Program for Inherited Metabolic Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Van Hove JKL; Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO, USA; Inherited Metabolic Diseases Clinic, Children's Hospital Colorado, Aurora, CO, USA., Weisfeld-Adams JD; Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO, USA; Inherited Metabolic Diseases Clinic, Children's Hospital Colorado, Aurora, CO, USA.
Jazyk: angličtina
Zdroj: Mitochondrion [Mitochondrion] 2019 Jan; Vol. 44, pp. 58-64. Date of Electronic Publication: 2018 Jan 04.
DOI: 10.1016/j.mito.2018.01.001
Abstrakt: Elevations of specific acylcarnitines in blood reflect carboxylase deficiencies, and have utility in newborn screening for life-threatening organic acidemias and other inherited metabolic diseases. In this report, we describe a newly-identified association of biochemical features of multiple carboxylase deficiency in individuals harboring mitochondrial DNA (mtDNA) mutations in MT-ATP6 and in whom organic acidemias and multiple carboxylase deficiencies were excluded. Using retrospective chart review, we identified eleven individuals with abnormally elevated propionylcarnitine (C3) or hydroxyisovalerylcarnitine (C5OH) with mutations in MT-ATP6, most commonly m.8993T>G in high heteroplasmy or homoplasmy. Most patients were ascertained on newborn screening; most had normal enzymatic or molecular genetic testing to exclude biotinidase and holocarboxylase synthetase deficiencies. MT-ATP6 is associated with some cases of Leigh disease; clinical outcomes in our cohort ranged from death from neurodegenerative disease in early childhood to clinically and developmentally normal after several years of follow-up. These cases expand the biochemical phenotype associated with MT-ATP6 mutations, especially m.8993T>G, to include acylcarnitine abnormalities mimicking carboxylase deficiency states. Clinicians should be aware of this association and its implications for newborn screening, and consider mtDNA sequencing in patients exhibiting similar acylcarnitine abnormalities that are biotin-unresponsive and in whom other enzymatic deficiencies have been excluded.
(Copyright © 2018 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)
Databáze: MEDLINE
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