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Clinical Presentation, Genetic Etiology, and Coenzyme Q10 Levels in 55 Children with Combined Enzyme Deficiencies of the Mitochondrial Respiratory Chain.

Authors
  • Naess, Karin1
  • Bruhn, Helene2
  • Stranneheim, Henrik3
  • Freyer, Christoph2
  • Wibom, Rolf2
  • Mourier, Arnaud4
  • Engvall, Martin3
  • Nennesmo, Inger5
  • Lesko, Nicole3
  • Wredenberg, Anna2
  • Wedell, Anna3
  • von Döbeln, Ulrika2
  • 1 Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. Electronic address: [email protected] , (Sweden)
  • 2 Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. , (Sweden)
  • 3 Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden. , (Sweden)
  • 4 CNRS UMR 5095, Bordeaux Cedex, France; University of Bordeaux, EPST, IBGC UMR 5095, Bordeaux Cedex, France. , (France)
  • 5 Clinical Pathology, Karolinska University Hospital, Department of Laboratory Medicine, Stockholm, Sweden. , (Sweden)
Type
Published Article
Journal
The Journal of pediatrics
Publication Date
Aug 19, 2020
Identifiers
DOI: 10.1016/j.jpeds.2020.08.025
PMID: 32827528
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

To evaluate the clinical symptoms and biochemical findings and establish the genetic etiology in a cohort of pediatric patients with combined deficiencies of the mitochondrial respiratory chain complexes. Clinical and biochemical data were collected from 55 children. All patients were subjected to sequence analysis of the entire mitochondrial genome, except when the causative mutations had been identified based on the clinical picture. Whole exome sequencing/whole genome sequencing (WES/WGS) was performed in 32 patients. Onset of disease was generally early in life (median age, 6 weeks). The most common symptoms were muscle weakness, hypotonia, and developmental delay/intellectual disability. Nonneurologic symptoms were frequent. Disease causing mutations were found in 20 different nuclear genes, and 7 patients had mutations in mitochondrial DNA. Causative variants were found in 18 of the 32 patients subjected to WES/WGS. Interestingly, many patients had low levels of coenzyme Q10 in muscle, irrespective of genetic cause. Children with combined enzyme defects display a diversity of clinical symptoms with varying age of presentation. We established the genetic diagnosis in 35 of the 55 patients (64%). The high diagnostic yield was achieved by the introduction of massive parallel sequencing, which also revealed novel genes and enabled elucidation of new disease mechanisms. Copyright © 2020 Elsevier Inc. All rights reserved.

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