Abstract
Progressive external ophthalmoplegia (PEO), Kearns–Sayre syndrome (KSS) and Pearson syndrome are the three sporadic clinical syndromes classically associated with single large-scale deletions of mitochondrial DNA (mtDNA). PEO plus is a term frequently utilized in the clinical setting to identify patients with PEO and some degree of multisystem involvement, but a precise definition is not available. The purpose of the present study is to better define the clinical phenotypes associated with a single mtDNA deletion, by a retrospective study on a large cohort of 228 patients from the database of the “Nation-wide Italian Collaborative Network of Mitochondrial Diseases”. In our database, single deletions account for about a third of all patients with mtDNA-related disease, more than previously recognized. We elaborated new criteria for the definition of PEO and “KSS spectrum” (a category of which classic KSS represents the most severe extreme). The criteria for “KSS spectrum” include the resulting multisystem clinical features associated with the KSS features, and which therefore can predict their presence or subsequent development. With the new criteria, we were able to classify nearly all our single-deletion patients: 64.5 % PEO, 31.6 % KSS spectrum (including classic KSS 6.6 %) and 2.6 % Pearson syndrome. The deletion length was greater in KSS spectrum than in PEO, whereas heteroplasmy was inversely related with age at onset. We believe that the new phenotype definitions implemented here may contribute to a more homogeneous patient categorization, which will be useful in future cohort studies of natural history and clinical trials.
Similar content being viewed by others
References
DiMauro S, Schon EA (2003) Mitochondrial respiratory-chain diseases. N Engl J Med 348:2656–2668
Filosto M, Mancuso M (2007) Mitochondrial diseases: a nosological update. Acta Neurol Scand 115:211–221
Mancuso M, Orsucci D, Angelini CI, Bertini E, Carelli V, Comi GP, Minetti C, Moggio M, Mongini T, Servidei S, Tonin P, Toscano A, Uziel G, Bruno C, Caldarazzo Ienco E, Filosto M, Lamperti C, Martinelli D, Moroni I, Musumeci O, Pegoraro E, Ronchi D, Santorelli FM, Sauchelli D, Scarpelli M, Sciacco M, Spinazzi M, Valentino ML, Vercelli L, Zeviani M, Siciliano G (2013) Phenotypic heterogeneity of the 8344A>G mtDNA “MERRF” mutation. Neurology 80:2049–2054
Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP, Donati A, Minetti C, Moggio M, Mongini T, Servidei S, Tonin P, Toscano A, Uziel G, Bruno C, Ienco EC, Filosto M, Lamperti C, Catteruccia M, Moroni I, Musumeci O, Pegoraro E, Ronchi D, Santorelli FM, Sauchelli D, Scarpelli M, Sciacco M, Valentino ML, Vercelli L, Zeviani M, Siciliano G (2014) The m.3243A>G mitochondrial DNA mutation and related phenotypes. A matter of gender? J Neurol 261:504–510
Bernier FP, Boneh A, Dennett X, Chow CW, Cleary MA, Thorburn DR (2002) Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 59:1406–1411
Pitceathly RD, Rahman S, Hanna MG (2012) Single deletions in mitochondrial DNA—molecular mechanisms and disease phenotypes in clinical practice. Neuromuscul Disord 22:577–586
Schaefer AM, McFarland R, Blakely EL, He L, Whittaker RG, Taylor RW, Chinnery PF, Turnbull DM (2008) Prevalence of mitochondrial DNA disease in adults. Ann Neurol 63:35–39
Holt IJ, Harding AE, Morgan-Hughes JA (1988) Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331:717–719
Zeviani M, Moraes CT, DiMauro S, Nakase H, Bonilla E, Schon EA, Rowland LP (1988) Deletions of mitochondrial DNA in Kearns–Sayre syndrome. Neurology 38:1339–1346
Morikawa Y, Matsuura N, Kakudo K, Higuchi R, Koike M, Kobayashi Y (1993) Pearson’s marrow/pancreas syndrome: a histological and genetic study. Virchows Arch A Pathol Anat Histopathol 423:227–231
Campos Y, Martin MA, Navarro C, Gordo P, Arenas J (1996) Single large-scale mitochondrial DNA deletion in a patient with mitochondrial myopathy associated with multiple symmetric lipomatosis. Neurology 47:1012–1014
Mancuso M, Orsucci D, Gori S, Ceravolo R, Siciliano G (2008) Mitochondrial DNA single deletion in a patient with postural tremor. Mov Disord 23:2098–2100
Santorelli FM, Barmada MA, Pons R, Zhang LL, DiMauro S (1996) Leigh-type neuropathology in Pearson syndrome associated with impaired ATP production and a novel mtDNA deletion. Neurology 47:1320–1323
Magalhaes PJ, Sjo O, Norby S (1996) Ocular myopathy and mitochondrial DNA deletion. A presentation of seven identified Danish patients. Acta Ophthalmol Scand Suppl 219:29–32
Kiyomoto BH, Tengan CH, Moraes CT, Oliveira AS, Gabbai AA (1997) Mitochondrial DNA defects in Brazilian patients with chronic progressive external ophthalmoplegia. J Neurol Sci 152:160–165
Vilarinho L, Santorelli FM, Cardoso ML, Coelho T, Guimaraes A, Coutinho P (1998) Mitochondrial DNA analysis in ocular myopathy. Observations in 29 Portuguese patients. Eur Neurol 39:148–153
Schroder R, Vielhaber S, Wiedemann FR, Kornblum C, Papassotiropoulos A, Broich P, Zierz S, Elger CE, Reichmann H, Seibel P, Klockgether T, Kunz WS (2000) New insights into the metabolic consequences of large-scale mtDNA deletions: a quantitative analysis of biochemical, morphological, and genetic findings in human skeletal muscle. J Neuropathol Exp Neurol 59:353–360
Lopez-Gallardo E, Lopez-Perez MJ, Montoya J, Ruiz-Pesini E (2009) CPEO and KSS differ in the percentage and location of the mtDNA deletion. Mitochondrion 9:314–317
Grady JP, Campbell G, Ratnaike T, Blakely EL, Falkous G, Nesbitt V, Schaefer AM, McNally RJ, Gorman GS, Taylor RW, Turnbull DM, McFarland R (2014) Disease progression in patients with single, large-scale mitochondrial DNA deletions. Brain 137:323–334
Yamashita S, Nishino I, Nonaka I, Goto Y (2008) Genotype and phenotype analyses in 136 patients with single large-scale mitochondrial DNA deletions. J Hum Genet 53:598–606
Broomfield A, Sweeney MG, Woodward CE, Fratter C, Morris AM, Leonard JV, Abulhoul L, Grunewald S, Clayton PT, Hanna MG, Poulton J, Rahman S (2014) Paediatric single mitochondrial DNA deletion disorders: an overlapping spectrum of disease. J Inherit Metab Dis. doi:10.1007/s10545-014-9778-4
Mancuso M, Orsucci D, Coppede F, Nesti C, Choub A, Siciliano G (2009) Diagnostic approach to mitochondrial disorders: the need for a reliable biomarker. Curr Mol Med 9:1095–1107
Filosto M, Tomelleri G, Tonin P, Scarpelli M, Vattemi G, Rizzuto N, Padovani A, Simonati A (2007) Neuropathology of mitochondrial diseases. Biosci Rep 27:23–30
Horga A, Pitceathly RD, Blake JC, Woodward CE, Zapater P, Fratter C, Mudanohwo EE, Plant GT, Houlden H, Sweeney MG, Hanna MG, Reilly MM (2014) Peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia. Brain 137:3200–3212
Acknowledgments
This work was supported by Telethon (grant number GUP09004). The patients’ association MITOCON provided the Web-platform assistance. The work of Dr Orsucci was also supported by MITOCON (http://www.mitocon.it).
Conflicts of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Mancuso, M., Orsucci, D., Angelini, C. et al. Redefining phenotypes associated with mitochondrial DNA single deletion. J Neurol 262, 1301–1309 (2015). https://doi.org/10.1007/s00415-015-7710-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-015-7710-y