Omar Hikmat1,2, Charalampos Tzoulis2,3, Claus Klingenberg4,5, Magnhild Rasmussen6,7, Chantal M E Tallaksen8,9, Eylert Brodtkorb10,11, Torunn Fiskerstrand12,13, Robert McFarland14, Shamima Rahman15,16, Laurence A Bindoff17,18. 1. Department of Pediatrics, Haukeland University Hospital, 5021, Bergen, Norway. 2. Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway. 3. Department of Neurology, Haukeland University Hospital, 5021, Bergen, Norway. 4. Department of Paediatric and Adolescent Medicine, University Hospital of North Norway, Tromsø, Norway. 5. Paediatric Research Group, Department of Clinical Medicine, UiT- The Arctic University of Norway, Tromsø, Norway. 6. Women and Children's Division, Department of Clinical Neurosciences for Children, Oslo University Hospital, Oslo, Norway. 7. Unit for Congenital and Hereditary Neuromuscular Disorders, Department of Neurology, Oslo University Hospital, Oslo, Norway. 8. Department of Neurology, Oslo University Hospital, Oslo, Norway. 9. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. 10. Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway. 11. Department of Neurology and Clinical Neurophysiology, St. Olav's University Hospital, Trondheim, Norway. 12. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. 13. Department of Clinical Science (K2), University of Bergen, Bergen, Norway. 14. Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School Framlington Place, Newcastle University, Newcastle upon Tyne, UK. 15. Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, UK. 16. Metabolic Unit, Great Ormond Street Hospital NHS Foundation trust, London, UK. 17. Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway. laurence.bindoff@nevro.uib.no. 18. Department of Neurology, Haukeland University Hospital, 5021, Bergen, Norway. laurence.bindoff@nevro.uib.no.
Abstract
BACKGROUND: Mitochondria play an important role in iron metabolism and haematopoietic cell homeostasis. Recent studies in mice showed that a mutation in the catalytic subunit of polymerase gamma (POLG) was associated with haematopoietic dysfunction including anaemia. The aim of this study was to analyse the frequency of anaemia in a large cohort of patients with POLG related disease. METHODS: We conducted a multi-national, retrospective study of 61 patients with confirmed, pathogenic biallelic POLG mutations from six centres, four in Norway and two in the United Kingdom. Clinical, laboratory and genetic data were collected using a structured questionnaire. Anaemia was defined as an abnormally low haemoglobin value adjusted for age and sex. Univariate survival analysis was performed using log-rank test to compare differences in survival time between categories. RESULTS: Anaemia occurred in 67% (41/61) of patients and in 23% (14/61) it was already present at clinical presentation. The frequency of anaemia in patients with early onset disease including Alpers syndrome and myocerebrohepatopathy spectrum (MCHS) was high (72%) and 35% (8/23) of these had anaemia at presentation. Survival analysis showed that the presence of anaemia was associated with a significantly worse survival (P = 0.004). CONCLUSION: Our study reveals that anaemia can be a feature of POLG-related disease. Further, we show that its presence is associated with significantly worse prognosis either because anaemia itself is impacting survival or because it reflects the presence of more serious disease. In either case, our data suggests anaemia is a marker for negative prognosis.
BACKGROUND: Mitochondria play an important role in iron metabolism and haematopoietic cell homeostasis. Recent studies in mice showed that a mutation in the catalytic subunit of polymerase gamma (POLG) was associated with haematopoietic dysfunction including anaemia. The aim of this study was to analyse the frequency of anaemia in a large cohort of patients with POLG related disease. METHODS: We conducted a multi-national, retrospective study of 61 patients with confirmed, pathogenic biallelic POLG mutations from six centres, four in Norway and two in the United Kingdom. Clinical, laboratory and genetic data were collected using a structured questionnaire. Anaemia was defined as an abnormally low haemoglobin value adjusted for age and sex. Univariate survival analysis was performed using log-rank test to compare differences in survival time between categories. RESULTS:Anaemia occurred in 67% (41/61) of patients and in 23% (14/61) it was already present at clinical presentation. The frequency of anaemia in patients with early onset disease including Alpers syndrome and myocerebrohepatopathy spectrum (MCHS) was high (72%) and 35% (8/23) of these had anaemia at presentation. Survival analysis showed that the presence of anaemia was associated with a significantly worse survival (P = 0.004). CONCLUSION: Our study reveals that anaemia can be a feature of POLG-related disease. Further, we show that its presence is associated with significantly worse prognosis either because anaemia itself is impacting survival or because it reflects the presence of more serious disease. In either case, our data suggests anaemia is a marker for negative prognosis.
Entities:
Keywords:
Alpers; Anaemia; Haematopoietic dysfunction; Iron metabolism; Mitochondria; POLG
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