University of Oulu

Björkman K, Vissing J, Østergaard E, et al. J Med Genet 2023; 60: 65–73.

Phenotypic spectrum and clinical course of single large-scale mitochondrial DNA deletion disease in the paediatric population : a multicentre study

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Author: Björkman, Kristoffer1,2; Vissing, John3; Østergaard, Elsebet4,5;
Organizations: 1Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
2The Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
3Copenhagen Neuromuscular Centre, Rigshospitalet, Kobenhavn, Denmark
4Department of Clinical Genetics, Rigshospitalet, Kobenhavn, Denmark
5Department of Clinical Medicine, University of Copenhagen, Kobenhavn, Denmark
6Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway
7Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway
8Department of Toxicogenomics, Unit Clinical Genomics, Maastricht University, Maastricht, The Netherlands
9Maastricht University School for Mental Health and Neuroscience, Maastricht, The Netherlands
10Center for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden
11Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
12Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
13Research Programs Unit, Stem Cells and Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
14University of Helsinki Children's Hospital, Helsinki, Finland
15Department of Clinical Chemistry, University of Gothenburg, Gothenburg, Sweden
16Department of Neurology, Neuromuscular Center, Sahlgrenska University Hospital, Gothenburg, Sweden
17Medical Research Center, Oulu University Faculty of Medicine, Oulu, Finland
18Medical Research Center, Oulu University Hospital, Oulu, Finland
19Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
20PEDEGO Research Unit, Oulu University Faculty of Medicine, Oulu, Finland
21Clinic for Children and Adolescents and Medical Research Center, Oulu University Hospital, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.4 MB)
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Language: English
Published: BMJ, 2023
Publish Date: 2023-08-10


Background: Large-scale mitochondrial DNA deletions (LMD) are a common genetic cause of mitochondrial disease and give rise to a wide range of clinical features. Lack of longitudinal data means the natural history remains unclear. This study was undertaken to describe the clinical spectrum in a large cohort of patients with paediatric disease onset.

Methods: A retrospective multicentre study was performed in patients with clinical onset <16 years of age, diagnosed and followed in seven European mitochondrial disease centres.

Results: A total of 80 patients were included. The average age at disease onset and at last examination was 10 and 31 years, respectively. The median time from disease onset to death was 11.5 years. Pearson syndrome was present in 21%, Kearns-Sayre syndrome spectrum disorder in 50% and progressive external ophthalmoplegia in 29% of patients. Haematological abnormalities were the hallmark of the disease in preschool children, while the most common presentations in older patients were ptosis and external ophthalmoplegia. Skeletal muscle involvement was found in 65% and exercise intolerance in 25% of the patients. Central nervous system involvement was frequent, with variable presence of ataxia (40%), cognitive involvement (36%) and stroke-like episodes (9%). Other common features were pigmentary retinopathy (46%), short stature (42%), hearing impairment (39%), cardiac disease (39%), diabetes mellitus (25%) and renal disease (19%).

Conclusion: Our study provides new insights into the phenotypic spectrum of childhood-onset, LMD-associated syndromes. We found a wider spectrum of more prevalent multisystem involvement compared with previous studies, most likely related to a longer time of follow-up.

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Series: Journal of medical genetics
ISSN: 0022-2593
ISSN-E: 1468-6244
ISSN-L: 0022-2593
Volume: 60
Issue: 1
Pages: 65 - 73
DOI: 10.1136/jmedgenet-2021-108006
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3123 Gynaecology and paediatrics
Funding: The study was supported by the Queen Silvia Children’s Hospital Research Foundation (KB, ND, MT), the Swedish state under an agreement between the Swedish government and the country councils (ND: ALFGBG-718681; MT: ALFGBG-427421), and the Gothenburg Society of Medicine (KB). IFMdC is funded by NeMO (nr. 20_P10).
Copyright information: © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.