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Mitochondrion. 2019 Jan;44:58-64. doi: 10.1016/j.mito.2018.01.001. Epub 2018 Jan 4.

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

Author information

1
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.
2
Princess Margaret Hospital for Children, Perth, Australia; Children's Hospital at Westmead, Sydney, Australia.
3
Neurodevelopmental Genomics Research Group, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA.
5
Program for Inherited Metabolic Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
6
Metabolic Service, Starship Children's Hospital, Auckland, New Zealand.
7
Inherited Metabolic Diseases Clinic, Valley Children's Hospital, Madera, CA, USA.
8
Children's Mercy Hospitals and Clinics, Kansas City, MO, USA.
9
Inherited Metabolic Diseases Clinic, University of British Columbia, Vancouver, Canada.
10
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.
11
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
12
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.

Abstract

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.

KEYWORDS:

Inherited metabolic diseases; Leigh disease; Mitochondrial disease; Newborn screening; Organic acidemias; mtDNA

PMID:
29307858
DOI:
10.1016/j.mito.2018.01.001
[Indexed for MEDLINE]

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