University of Oulu

Hikmat, O, Naess, K, Engvall, M, et al. Simplifying the clinical classification of polymerase gamma (POLG) disease based on age of onset; studies using a cohort of 155 cases. J Inherit Metab Dis. 2020; 43: 726– 736.

Simplifying the clinical classification of polymerase gamma (POLG) disease based on age of onset; studies using a cohort of 155 cases

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Author: Hikmat, Omar1,2; Naess, Karin3,4; Engvall, Martin3,5;
Organizations: 1Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
2Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway
3Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden
4Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
6Department of Paediatric and Adolescent Medicine, University Hospital of North Norway, Tromso, Norway
7Paediatric Research Group, Department of Clinical Medicine, UiT - The Arctic University of Norway, Tromso, Norway
8Women and Children's Division, Department of Clinical Neurosciences for Children, Oslo University Hospital, Oslo, Norway
9Unit for Congenital and Hereditary Neuromuscular Disorders, Department of Neurology, Oslo University Hospital, Oslo, Norway
10Department of Neurology, Oslo University Hospital, Oslo, Norway
11Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
12Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway
13Department of Neurology and Clinical Neurophysiology, St. Olav's University Hospital, Trondheim, Norway
14Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
15Department of Neurology, Medical Spectrum Twente, Enschede, The Netherlands
16Department of Genetics and Cell Biology, University of Maastricht, Maastricht, The Netherlands
17Department of Neurology, Sant Joan de Déu Children´s Hospital, Barcelona, Spain
18Department of Pediatric Neurology, Children's Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
19Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
20PEDEGO Research Unit, University of Oulu, Oulu, Finland
21Biocenter Oulu, University of Oulu, Oulu, Finland
22Department of Pediatric Neurology, Clinic for Children and Adolescents, Medical Research Center, Oulu University Hospital, Oulu, Finland
23Department of Pediatrics, The Queen Silvia Children's Hospital, University of Gothenburg, Gothenburg, Sweden
24Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, UK
25Metabolic Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
26Department of Neurology, Haukeland University Hospital, Bergen, Norway
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.5 MB)
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Language: English
Published: John Wiley & Sons, 2020
Publish Date: 2020-08-26


Background: Variants in POLG are one of the most common causes of inherited mitochondrial disease. Phenotypic classification of POLG disease has evolved haphazardly making it complicated and difficult to implement in everyday clinical practise. The aim of our study was to simplify the classification and facilitate better clinical recognition.

Methods: A multinational, retrospective study using data from 155 patients with POLG variants recruited from seven European countries.

Results: We describe the spectrum of clinical features associated with POLG variants in the largest known cohort of patients. While clinical features clearly form a continuum, stratifying patients simply according to age of onset—onset prior to age 12 years; onset between 12 and 40 years and onset after the age of 40 years, permitted us to identify clear phenotypic and prognostic differences. Prior to 12 years of age, liver involvement (87%), seizures (84%), and feeding difficulties (84%) were the major features. For those with onset between 12 and 40 years, ataxia (90%), peripheral neuropathy (84%), and seizures (71%) predominated, while for those with onset over 40 years, ptosis (95%), progressive external ophthalmoplegia (89%), and ataxia (58%) were the major clinical features. The earlier the onset the worse the prognosis. Patients with epilepsy and those with compound heterozygous variants carried significantly worse prognosis.

Conclusions: Based on our data, we propose a simplified POLG disease classification, which can be used to guide diagnostic investigations and predict disease course.

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Series: Journal of inherited metabolic disease
ISSN: 0141-8955
ISSN-E: 1573-2665
ISSN-L: 0141-8955
Volume: 43
Issue: 4
Pages: 726 - 736
DOI: 10.1002/jimd.12211
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
Funding: This work was supported by grants from the Western Norway Regional Health Authority (Helse‐Vest, grant no. 911944). P.I. is supported by grant from the special governmental subsidy for health sciences research of the Helsinki University Hospital. S.R. is supported by research grant funding from Great Ormond Street Hospital Children's Charity, the NIHR Great Ormond Street Hospital Biomedical Research Centre, and the Lily Foundation. I.d.C. was supported by the NeMO foundation (no.17_P19).
Dataset Reference: Supporting information:
Copyright information: © 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.