Brain Advance Access originally published online on April 17, 2007
Brain 2007 130(6):1516-1524; doi:10.1093/brain/awm067
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Chronic progressive ophthalmoplegia with large-scale mtDNA rearrangement: can we predict progression?
1Inserm, U582, Paris F-75013, France, 2Université Pierre et Marie Curie-Paris6, IFR14, Paris F-75013, France, 3AP-HP, hôpital Robert Debré, Centre de référence des Maladies Héréditaires du Métabolisme, Paris F-75020, France, 4Institut de Myologie, hôpital Pitié-Salpêtrière Paris, F-75013, France and 5AP-HP, hôpital Pitié-Salpêtrière, Biochimie, Paris F-75013, France
Corresponding to: Dr Anne Lombès, Inserm U582, Institut de Myologie, Groupe hospitalier Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75013 Paris Cedex, France E-mail: a.lombes{at}myologie.chups.jussieu.fr
The prognosis of chronic progressive ophthalmoplegia with large-scale mitochondrial DNA (mtDNA) may strikingly vary from mild slowly progressive myopathy to severe multi-organ involvement. Evaluation of the disease course at the beginning of the disease is reputed impossible. To address the existence of predictive prognostic clues of these diseases, we classified 69 patients with chronic progressive ophthalmoplegia and large size mtDNA deletion into two groups according to the presence of manifestations from brain, inner ear or retina. These manifestations were present in 29 patients (CPEO/+N group) and absent in 40 patients (CPEO/–N group). We retrospectively established the clinical history of the patients and characterized their genetic alteration (amount of residual normal mtDNA molecules, site, size and percentage of the mtDNA deletion in 116 DNA samples from muscle, blood, urinary and buccal cells).
In both clinical groups, the disease was progressive and heart conduction defects were frequent. We show that the CPEO/+N phenotype segregated with severe prognosis in term of rate of progression, multi-organs involvement and rate of survival. Age at onset appeared a predictive factor. The risk to develop a CPEO/+N phenotype was high when onset was before 9 years of age and low when onset was after 20 years of age. The presence and proportion of the mtDNA deletion in blood was also significantly associated with the CPEO/+N phenotype.
This study is the first to establish the natural history of chronic ophthalmoplegia with mtDNA deletion in a large series of patients and to look for parameters potentially predictive of the patients’ clinical course.
Key Words: mitochondrial disease; deletion; Kearns–Sayre syndrome; CPEO; natural history
Abbreviations: CPEO, chronic progressive ophthalmoplegia; mtDNA, mitochondrial DNA
Received October 23, 2006. Revised February 14, 2007. Accepted March 12, 2007.