Abstract
Introduction: Mitochondrial diseases are a clinically, biochemically and genetically heterogeneous group of disorders with a variable age of onset and rate of disease progression. It might therefore be expected that this variation be reflected in the age and cause of death. However, to date, little has been reported regarding the ‘end-of-life’ period and causes of death in mitochondrial disease patients. For some specific syndromes, the associated clinical problems might predict the cause of death, but for many patients, it remains difficult to provide an accurate prognosis.
Aims: To describe a retrospective cohort of adult mitochondrial disease patients who had attended the NHS Highly Specialised Services for Rare Mitochondrial Diseases in Newcastle upon Tyne (UK), evaluate life expectancy and causes of death and assess the consequences for daily patient care.
Methods: All deceased adult patients cared for at this centre over a period of 10 years were included in the study. Patient history, data on laboratory findings, biochemical investigations and genetic studies were analysed retrospectively.
Results: A total of 30 adult mitochondrial patients died within the time period of the study. The main mitochondrial disease-related causes of death in this patient cohort were respiratory failure, cardiac failure and acute cerebral incidents such as seizures and strokes. In almost half of the patients, the cause of death remained unknown. Based on our study, we present recommendations regarding the care of patients with mitochondrial disease.
Competing interests: None declared
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Arpa J, Cruz-Martínez A, Campos Y et al (2003) Prevalence and progression of mitochondrial diseases: a study of 50 patients. Muscle Nerve 28:690–695
Ashizawa T, Subramony SH (2001) What is Kearns–Sayre syndrome after all? Arch Neurol 58:1053–1054
Bates M, Hollingsworth KG, Newman JH et al (2013) Concentric hypertrophic remodelling and subendocardial dysfunction in mitochondrial DNA point mutation carriers. Eur Heart J Cardiovasc Imaging 14:650–658
Benditt JO, Boitano LJ (2013) Pulmonary issues in patients with chronic neuromuscular disease. Am J Respir Crit Care Med 187:1046–1055
Berenberg RA, Pellock JM, DiMauro S et al (1977) Lumping or splitting? “Ophthalmoplegia-plus” or Kearns–Sayre syndrome? Ann Neurol 1:37–54
Caballero PE, Candela MS, Alvarez CI et al (2007) Chronic progressive external ophthalmoplegia: a report of 6 cases and a review of the literature. Neurologist 13:33–36
Chawla S, Coku J, Forbes T et al (2008) Kearns–Sayre syndrome presenting as complete heart block. Pediatr Cardiol 29:659–662
Coenen MJ, van den Heuvel LP, Nijtmans LG et al (1999) SURFEIT-1 gene analysis and two-dimensional blue native gel electrophoresis in cytochrome c oxidase deficiency. Biochem Biophys Res Commun 265:339–344
de Vries MC, Rodenburg RJ, Morava E et al (2007) Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations. Eur J Pediatr 166:229–234
DiMauro S, Schon EA (2003) Mitochondrial respiratory-chain diseases. N Engl J Med 348:2656–2668
Finsterer J, Kothari S (2014) Cardiac manifestations of primary mitochondrial disorders. Int J Cardiol 177:754–763
Greden JF (2001) The burden of disease for treatment-resistant depression. J Clin Psychiatry 62:26–31
Herrero-Martín MD, Avuso T, Tuñón MT et al (2010) A MELAS/MERRF phenotype associated with the mitochondrial DNA 5521G>A mutation. J Neurol Neurosurg Psychiatry 81:471–472
Huang CC, Kuo HC, Chu CC et al (2002) Clinical phenotype, prognosis and mitochondrial DNA mutation load in mitochondrial encephalomyopathies. J Biomed Sci 9:527–533
Hudson G, Schaefer AM, Taylor RW et al (2007) Mutation of the linker region of the Polymerase γ-1 (POLG1) gene associated with progressive external Ophthalmoplegia and Parkinsonism. Arch Neurol 64:553–557
Kato H, Uchigata M, Iijima M et al (2006) Fatal cerebral hemorrhage in mitochondrial encephalomyopathy. Clinical and pathological data of a case. J Neurol 253:529–530
Katsanos KH, Pappas CJ, Patsouras D et al (2002) Alarming atrioventricular block and mitral valve prolapse in the Kearns–Sayre syndrome. Int J Cardiol 83:179–181
Klopstock T, Jaksch M, Gasser T (1999) Age and cause of death in mitochondrial diseases. Neurology 53:855–857
Limongelli G, Tome-Esteban M, Dejthevaporn C et al (2010) Prevalence and natural history of heart disease in adults with primary mitochondrial respiratory chain disease. Eur J Heart Fail 12:114–121
Majamaa K, Moilanen JS, Uimonen S et al (1998) Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population. Am J Hum Genet 63:447–454
Majamaa-Voltti K, Turkka J, Kortelainen ML et al (2008) Causes of death in pedigrees with the 3243A>G mutation in mitochondrial DNA. J Neurol Neurosurg Psychiatry 79:209–211
Mancuso M, Filosto M, Oh SJ et al (2004) A novel polymerase c mutation in a family with ophthalmoplegia, neuropathy, and Parkinsonism. Arch Neurol 61:1777–1779
Mancuso M, Orsucci D, Ienco EC et al (2013a) Psychiatric involvement in adult patients with mitochondrial disease. Neurol Sci 34:71–74
Mancuso M, Orsucci D, Angelini C et al (2013b) Phenotypic heterogeneity of the 8344>G mtDNA “MERRF” mutation. Neurology 80:2049–2054
Marcus KA, Barends M, Morava-Kozicz E et al (2011) Early detection of myocardial dysfunction in children with mitochondrial disease: An ultrasound and two-dimensional strain echocardiography study. Mitochondrion 11:405–412
McFarland R, Turnbull DM (2009) Batteries not included: diagnosis and management of mitochondrial disease. J Intern Med 265:210–228
McFarland R, Taylor RW, Turnbull DM (2010) A neurological perspective on mitochondrial disease. Lancet Neurol 9:829–840
Morava E, van den Heuvel L, Hol F et al (2006a) Mitochondrial disease criteria: diagnostic applications in children. Neurology 67:1823–1826
Morava E, Rodenburg RJ, Hol F et al (2006b) Clinical and biochemical characteristics in patients with a high mutant load of the mitochondrial T8993G/C mutations. Am J Med Genet A 140:863–868
Morava E, Gardeitchik T, Kozicz T et al (2010) Depressive behaviour in children diagnosed with a mitochondrial disorder. Mitochondrion 10:528–533
Palmio J, Evilä A, Chapon F et al (2014) Hereditary myopathy with early respiratory failure: occurrence in various populations. J Neurol Neurosurg Psychiatry 85:345–353
Pfeiffer RF (2011) Gastrointestinal dysfunction in Parkinson’s disease. Parkinsonism Relat Disord 17:10–15
Sanger TD, Jain KD (1996) MERRF syndrome with overwhelming lactic acidosis. Pediatr Neurol 14:57–61
Schaefer AM, Phoenix C, Elson JL et al (2006) Mitochondrial disease in adults: a scale to monitor progression and treatment. Neurology 66:1932–1934
Schaefer AM, McFarland R, Blakely EL et al (2008) Prevalence of mitochondrial DNA disease in adults. Ann Neurol 63:35–39
Smeitink JA, Zeviani M, Turnbull DM et al (2006) Mitochondrial medicine: a metabolic perspective on the pathology of oxidative phosphorylation disorders. Cell Metab 3:9–13
Smits BW, Heijdra YF, Cuppen FW et al (2011) Nature and frequency of respiratory involvement in chronic progressive external ophthalmoplegia. J Neurol 258:2020–2025
Sweet D (2011) Office for National Statistics. National Records of Scotland; Northern Ireland Statistics and Research Agency. Social Trends 41 – Health data. ‘Life expectancy at birth and age 65 and infant and neonatal mortality rate United Kingdom’. http://www.ons.gov.uk/ons/index.htm
Wahbi K, Larue S, Jardel C et al (2010) Cardiac involvement is frequent in patients with the m.8344A N G mutation of mitochondrial DNA. Neurology 74:674–677
Welzing L, von Kleist-Retzow JC, Kribs A et al (2009) Rapid development of life-threatening complete atrioventricular block in Kearns–Sayre syndrome. Eur J Pediatr 168:757–775
Wortmann SB, Rodenburg RJ, Backx AP et al (2007) Early cardiac involvement in children carrying the A3243G mtDNA mutation. Acta Paediatr 96:450–451
Yilmaz A, Gdynia HJ, Ponfick M et al (2012) Cardiovascular magnetic resonance imaging (CMR) reveals characteristic pattern of myocardial damage in patients with mitochondrial myopathy. Clin Res Cardiol 101:255–261
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Shamima Rahman, FRCP, FRCPCH, PhD
Appendices
Take-Home Messages
Mitochondrial disease can cause significant morbidity and mortality.
Mitochondrial disease is incurable and ‘end-of-life’ planning should be discussed with patients appropriately.
Compliance with Ethics Guideline
Conflict of Interest
Marlieke Barends and Lotte Verschuren declare that they have no conflicts of interest. Victoria Nesbitt is a Clinical Research Associate for the Medical Research Council Mitochondrial Diseases Patient Cohort Study, UK. Eva Morava is a guest editor for the Journal of Inherited Metabolic Disease. Doug Turnbull and Robert McFarland are both PIs on the same study.
Contributions of Individual Authors
Marlieke Barends and Lotte Verschuren conducted the collection, analysis and interpretation of data and drafted the article. Eva Morava contributed to the revision of the article. Victoria Nesbitt contributed to data collection and revision of the article. Doug Turnbull contributed to the conception and design of the study and to the revision of the article. Robert McFarland was responsible for the conception and design of the audit, interpretation of data and to the revision of the article; he is the guarantor for the article.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Rights and permissions
Copyright information
© 2015 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Barends, M., Verschuren, L., Morava, E., Nesbitt, V., Turnbull, D., McFarland, R. (2015). Causes of Death in Adults with Mitochondrial Disease. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 26. JIMD Reports, vol 26. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_449
Download citation
DOI: https://doi.org/10.1007/8904_2015_449
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-49832-3
Online ISBN: 978-3-662-49833-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)