Incidence and predictors of total mortality in 267 adults presenting with mitochondrial diseases
Corresponding Author
Constantinos Papadopoulos
APHP, Pitié-Salpêtrère Hospital, Nord/Est/Ile de France Neuromuscular Reference Center, Myology Institute, Paris, France
First Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
Correspondence
Constantinos Papadopoulos, First Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Email: [email protected]
Search for more papers by this authorKarim Wahbi
APHP, Cochin Hospital, Cardiology Department, FILNEMUS, Paris-Descartes, Sorbonne Paris Cité University, Paris, France
INSERM Unit 970, Paris Cardiovascular Research Centre (PARCC), Paris, France
Search for more papers by this authorAnthony Behin
APHP, Pitié-Salpêtrère Hospital, Nord/Est/Ile de France Neuromuscular Reference Center, Myology Institute, Paris, France
Search for more papers by this authorWulfran Bougouin
INSERM Unit 970, Paris Cardiovascular Research Centre (PARCC), Paris, France
Medical Intensive Care Unit, AP-HP, Cochin Hospital, Paris, France
Search for more papers by this authorTanya Stojkovic
APHP, Pitié-Salpêtrère Hospital, Nord/Est/Ile de France Neuromuscular Reference Center, Myology Institute, Paris, France
Search for more papers by this authorSarah Leonard-Louis
APHP, Pitié-Salpêtrère Hospital, Nord/Est/Ile de France Neuromuscular Reference Center, Myology Institute, Paris, France
Search for more papers by this authorNawal Berber
APHP, Pitié-Salpêtrère Hospital, Nord/Est/Ile de France Neuromuscular Reference Center, Myology Institute, Paris, France
Search for more papers by this authorAnne Lombès
INSERM, UMRS 975, APHP, Cochin Hospital, Paris, France
Search for more papers by this authorDenis Duboc
APHP, Cochin Hospital, Cardiology Department, FILNEMUS, Paris-Descartes, Sorbonne Paris Cité University, Paris, France
Search for more papers by this authorClaude Jardel
Biochemistry Department and Genetic Center, APHP, Pitié-Salpêtrière Hospital, Paris, France
Inserm U 1016, CNRS UMR 8104, Institut Cochin, Paris, France
GRC-UPMC Neuro-métabolisme, Université Pierre et Marie Curie, Paris, France
Search for more papers by this authorBruno Eymard
APHP, Pitié-Salpêtrère Hospital, Nord/Est/Ile de France Neuromuscular Reference Center, Myology Institute, Paris, France
Search for more papers by this authorPascal Laforêt
APHP, Raymond-Poincaré Teaching Hospital, Neurology department, Nord/Est/Ile de France Neuromuscular Reference Center, Garches, France
Search for more papers by this authorCorresponding Author
Constantinos Papadopoulos
APHP, Pitié-Salpêtrère Hospital, Nord/Est/Ile de France Neuromuscular Reference Center, Myology Institute, Paris, France
First Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
Correspondence
Constantinos Papadopoulos, First Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Email: [email protected]
Search for more papers by this authorKarim Wahbi
APHP, Cochin Hospital, Cardiology Department, FILNEMUS, Paris-Descartes, Sorbonne Paris Cité University, Paris, France
INSERM Unit 970, Paris Cardiovascular Research Centre (PARCC), Paris, France
Search for more papers by this authorAnthony Behin
APHP, Pitié-Salpêtrère Hospital, Nord/Est/Ile de France Neuromuscular Reference Center, Myology Institute, Paris, France
Search for more papers by this authorWulfran Bougouin
INSERM Unit 970, Paris Cardiovascular Research Centre (PARCC), Paris, France
Medical Intensive Care Unit, AP-HP, Cochin Hospital, Paris, France
Search for more papers by this authorTanya Stojkovic
APHP, Pitié-Salpêtrère Hospital, Nord/Est/Ile de France Neuromuscular Reference Center, Myology Institute, Paris, France
Search for more papers by this authorSarah Leonard-Louis
APHP, Pitié-Salpêtrère Hospital, Nord/Est/Ile de France Neuromuscular Reference Center, Myology Institute, Paris, France
Search for more papers by this authorNawal Berber
APHP, Pitié-Salpêtrère Hospital, Nord/Est/Ile de France Neuromuscular Reference Center, Myology Institute, Paris, France
Search for more papers by this authorAnne Lombès
INSERM, UMRS 975, APHP, Cochin Hospital, Paris, France
Search for more papers by this authorDenis Duboc
APHP, Cochin Hospital, Cardiology Department, FILNEMUS, Paris-Descartes, Sorbonne Paris Cité University, Paris, France
Search for more papers by this authorClaude Jardel
Biochemistry Department and Genetic Center, APHP, Pitié-Salpêtrière Hospital, Paris, France
Inserm U 1016, CNRS UMR 8104, Institut Cochin, Paris, France
GRC-UPMC Neuro-métabolisme, Université Pierre et Marie Curie, Paris, France
Search for more papers by this authorBruno Eymard
APHP, Pitié-Salpêtrère Hospital, Nord/Est/Ile de France Neuromuscular Reference Center, Myology Institute, Paris, France
Search for more papers by this authorPascal Laforêt
APHP, Raymond-Poincaré Teaching Hospital, Neurology department, Nord/Est/Ile de France Neuromuscular Reference Center, Garches, France
Search for more papers by this authorFunding information: French Alliance against Myopathies
Abstract
Assessing long-term mortality and identifying predictors of death in adults with mitochondrial diseases. We retrospectively included adult patients with genetically proven mitochondrial diseases referred to our centre between January 2000 and June 2016, and collected information relative to their genetic testing, clinical assessments, and vital status. We performed single and multiple variable analyses in search of predictors of total mortality, and calculated hazard ratios (HR) and 95% confidence intervals (CI). We included 267 patients (women 59%; median age 43.3 [31.3-54.2] years), including 111 with mitochondrial DNA (mtDNA) single large-scale deletions, 65 with m.3243A>G, 24 with m.8344A>G, 32 with other mtDNA point mutations, and 36 patients with nuclear genes mutations. Over a median follow-up of 8.9 years (0.3 to 18.7), 61 patients (22.8%) died, at a median age of 50.7 (37.9-51.9) years. Primary cause of death was cardiovascular disease in 16 patients (26.2%), respiratory in 11 (18.0%), and gastrointestinal in 5 (8.1%). By multiple variable analysis, diabetes (HR 2.75; 95% CI 1.46-5.18), intraventricular cardiac conduction defects (HR 3.38; 95% CI 1.71-6.76) and focal brain involvement (HR 2.39; 95% CI 1.25-4.57) were independent predictors of death. Adult patients with mitochondrial diseases present high morbidity that can be independently predicted by the presence of diabetes, intraventricular cardiac conduction defects, and focal brain involvement.
Supporting Information
| Filename | Description |
|---|---|
| jimd12185-sup-0001-TableS1.docxWord 2007 document , 14.2 KB | Supplementary Table 1 Baseline disease manifestations and treatments according to each mutation type Values are medians [IQR] or numbers (%) of observations. |
| jimd12185-sup-0002-TableS2.docxWord 2007 document , 17.8 KB | Supplementary Table 2 Individual gene mutations in the 267 study patients aPatient also carrying a single mutation in POLG (c.2492A > G) |
| jimd12185-sup-0003-TableS3.docxWord 2007 document , 15.1 KB | Supplementary Table 3 Primary causes of death classified according to the International Classification of Diseases, 10th revision |
| jimd12185-sup-0004-TableS4.docxWord 2007 document , 15.3 KB | Supplementary Table 4 Causes of death in the entire study population and in each mutation type Values are numbers (%) of observations or medians [SD] |
| jimd12185-sup-0005-TableS5.docxWord 2007 document , 15.6 KB | Supplementary Table 5 Causes for death for each independent predictor of death |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1DiMauro S. Mitochondrial encephalomyopathies - fifty years on: the Robert Wartenberg lecture. Neurology. 2013; 81: 281-291.
- 2DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med. 2003; 348: 2656-2668.
- 3Pfeffer G, Chinnery PF. Diagnosis and treatment of mitochondrial myopathies. Ann Med. 2013; 45: 4-16.
- 4Goto Y, Horai S, Matsuoka T, et al. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation. Neurology. 1992; 42: 545-550.
- 5Kaufmann P, Engelstad K, Wei Y, et al. Natural history of MELAS associated with mitochondrial DNA m.3243A.G genotype. Neurology. 2011; 77: 1965-1971.
- 6Marin-Garcia J, Goldenthal MJ. Mitochondrial cardiomyopathy: molecular and biochemical analysis. Pediatr Cardiol. 1997; 18: 251-260.
- 7Cros D, Palliyath S, DiMauro S, Ramirez C, Shamsnia M, Wizer B. Respirartory failure revealing mitochondrial myopathy in adults. Chest. 1992; 101: 824-828.
- 8Garone C, Tadesse S, Hirano M. Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy. Brain. 2011; 134: 3326-3332.
- 9Barends M, Verschuren L, Morava E, Nesbitt V, Turnbull D, McFarland R. Causes of death in adults with mitochondrial disease. JIMD Rep. 2016; 26: 103-113.
- 10Klopstock T, Jaksch M, Gasser T. Age and cause of death in mitochondrial disease. Neurology. 1999; 53: 855-857.
- 11Majamaa-Voltti K, Turkka J, Kortelainen ML, Huikuri H, Majamaa K. Causes of death in pedigrees with the 3243A>G mutation in mitochondrial DNA. J Neurol Neurosurg Psychiatry. 2008; 79: 209-211.
- 12Ng YS, Grady JP, Lax NZ, et al. Sudden adult death syndrome in m.3243A>G related mitochondrial disease: an unrecognized clinical entity in young, asymptomatic adults. Eur Heart J. 2016; 37: 2552-2259.
- 13Wahbi K, Bougouin W, Béhin A, et al. Long-term cardiac prognosis and risk stratification in 260 adults presenting with mitochondrial diseases. Eur Heart J. 2015; 36: 2886-2893.
- 14Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. Strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ. 2007; 335: 806-808.
- 15Majamaa-Voltti KA, Winqvist S, Remes AM, et al. A 3-year clinical follow-up of adult patients with 3243A>G in mitochondrial DNA. Neurology. 2006; 66: 1470-1475.
- 16Malfati E, Laforêt P, Jardel C, et al. High risk of severe cardiac adverse events in patients with mitochondrial m.3243A>G mutation. Neurology. 2013; 80: 100-105.
- 17Mancuso M, Orsucci D, Angelini C, et al. The m.3243A>G mitochondrial DNA mutation and related phenotypes. A matter of gender? J Neurol. 2014; 261: 504-510.
- 18Yatsuga S, Povalko N, Nishioka J, et al. MELAS: a nationwide prospective cohort study of 96 patients in Japan. Biochim Biophys Acta. 2012; 1820: 619-624.
- 19Neeve VC, Samuels DC, Bindoff LA, et al. What is influencing the phenotype of the common homozygous polymerase-γ mutation p.Ala467Thr? Brain. 2012; 135: 3614-3626.
- 20Aure K, Ogier de Baulny H, Laforêt P, Jardel C, Eymard B, Lombès A. Chronic progressive ophthalmoplegia with large-scale mtDNA rearrangement: can we predict progression? Brain. 2007; 130: 1516-1524.
- 21Tzoulis C, Engelsen BA, Telstad W, et al. The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases. Brain. 2006; 129: 1685-1692.
- 22Fayssoil A, Laforêt P, Bougouin W, et al. Prediction of long-term prognosis by heteroplasmy levels of the m.3243A>G mutation in patients with the mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome. Eur J Neurol. 2017; 24: 255-261.
- 23Mancuso M, Orsuci D, Angelini C, et al. Phenotypic heterogeneity of the 8344A.G mtDNA “MERRF” mutation. Neurology. 2013; 80: 2049-2054.
- 24Roglic G, Unwin N. Mortality attributable to diabetes: estimates for the year 2010. Diabetes Res Clin Pract. 2010; 87: 15-19.
- 25Roper NA, Bilous RW, Kelly WF, Unwin NC, Connolly VM. Excess mortality in a population with diabetes and the impact of material deprivation: longitudinal, population based study. BMJ. 2001; 322: 1389-1393.
- 26Parikh S, Goldstein A, Koening MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the mitochondrial medicine society. Genet Med. 2015; 17: 689-701.
