A common form of mitochondrial disease results from absence (or deletion) of a segment of the mitochondrial DNA (mtDNA) circle. Like most mtDNA diseases, these disorders usually exist as heteroplasmy (a mixture of normal and mutated mtDNA). The higher the percentage of deleted mtDNA in any particular tissue the more severely affected is the organ – and the patient.
Diseases due to mtDNA deletions can arise spontaneously without any known cause or they may occur because of nuclear gene defects that affect synthesis and maintenance of mtDNA.
There is a spectrum of severity of mtDNA deletion disease. The mildest affects only the muscles that move the eyes (because eye muscles contain a lot of mitochondria). This condition resulting from eye muscle weakness is called CPEO – Chronic Progressive External Ophthalmoplegia. The next degree of severity on the mtDNA deletion spectrum is when skeletal muscles including swallowing muscles are affected. In this form of mitochondrial myopathy, dysphagia (impaired swallow), limb weakness and exercise intolerance occur typically with CPEO.
Kearns-Sayre syndrome (KSS) is one of the first identified mtDNA diseases described in 1958 by an ophthalmologist and a pathologist(1). It is generally the result of a single large mtDNA deletion which is present in high enough amounts (high heteroplasmy) in multiple tissues to result in multi-organ disease with CPEO, degeneration of the back of the eye (pigmentary retinopathy), and disruption of the heart’s electrical pathways (cardiac conduction block)(2). The most severe form of mtDNA deletion disease which presents in infancy is called Pearson syndrome affecting multiple organs and the bone marrow resulting in anemia (low red blood cell count).
The most common presentation of mtDNA deletion disease is CPEO with mitochondrial myopathy. Many patients with this disorder who learn about the severe disorder KSS often assume that they have this condition and become quite depressed about their prognosis, but in fact CPEO and mitochondrial myopathy are usually much less severe than KSS. The term PEO+ is used for CPEO with myopathy and other organ system involvement. KSS is the most severe form of PEO+.
In a 2015 report on 228 patients with single mtDNA deletions enrolled in the ‘‘Nationwide Italian Collaborative Network of Mitochondrial Diseases’’, 130 had PEO with myopathy (57%) with a mean age of onset 25.8 ± 13.2 years and only 2 (1.5%) had died. Only 15 patients had classical KSS (6.6%) with onset 9.4 ± 4.8 years. There were 6 Pearson children and the rest of the patients (77 or 34%) fell in the mtDNA deletion spectrum with varying degrees of muscle, cardiac and multi-organ system involvement (3).
- Kearns TP, Sayre GP. Retinitis pigmentosa, external ophthalmophegia, and complete heart block: unusual syndrome with histologic study in one of two cases. AMA Arch Ophthalmol. 1958 Aug;60(2):280-9.
- Emmanuele V, Ganesh J, Vladutiu G, Haas R, Kerr D, Saneto RP, Cohen BH, Van Hove JLK, Scaglia F, Hoppel C, Rosales XQ, Barca E, Buchsbaum R, Thompson JL, DiMauro S, Hirano M, North American Mitochondrial Disease C. Time to harmonize mitochondrial syndrome nomenclature and classification: A consensus from the North American Mitochondrial Disease Consortium (NAMDC). Mol Genet Metab. 2022;136(2):125-31.
- Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP, Donati MA, Federico A, Minetti C, Moggio M, Mongini T, Santorelli FM, Servidei S, Tonin P, Toscano A, Bruno C, Bello L, Caldarazzo Ienco E, Cardaioli E, Catteruccia M, Da Pozzo P, Filosto M, Lamperti C, Moroni I, Musumeci O, Pegoraro E, Ronchi D, Sauchelli D, Scarpelli M, Sciacco M, Valentino ML, Vercelli L, Zeviani M, Siciliano G.J Redefining phenotypes associated with mitochondrial DNA single deletion. Neurol. 2015 May;262(5):1301-9.