KSS is a more severe syndromic variant of chronic progressive external ophthalmoplegia (abbreviated CPEO), a syndrome that is characterized by isolated involvement of the muscles controlling movement of the eyelid (levator palpebrae, orbicularis oculi) and eye (extra-ocular muscles).

KSS involves a combination of the already described CPEO as well as pigmentary retinopathy in both eyes and cardiac conduction abnormalities.

Other symptoms may include cerebellar ataxia, proximal muscle weakness, deafness, diabetes mellitus, growth hormone deficiency, hypoparathyroidism, and other endocrinopathies.

As the ptosis worsens, the individual commonly extends their neck, elevating their chin in an attempt to prevent the eyelids from occluding the visual axis.

As the clinical characterization, however, was not always comprehensive the term "mitochondrial retinopathy" appears most accurate and the diagnosis of RP may have been imprecise.

[citation needed] Kearns-Sayre patients are consistently found to have cerebral folate deficiency, a syndrome in which 5-MTHF levels are decreased in the cerebrospinal fluid despite being normal in serum.

[5] Treatment with folinic acid can in some cases alleviate the associated symptoms and partially correct associated brain abnormalities, especially if started early in the course of illness.

[7] As characterized in Kearns's original publication in 1965 and in later publications, inconsistent features of KSS that may occur are weakness of facial, pharyngeal, trunk, and extremity muscles, hearing loss, small stature, electroencephalographic changes, cerebellar ataxia and elevated levels of cerebrospinal fluid protein.

[9] Although NIH and other studies estimate occurrence in the population to be 1–3 and some as high as 9 in 100,000 individuals but a failure to be referred to specialist centres and recognise the disease symptoms is common [9] KSS is the result of deletions in mitochondrial DNA (mtDNA) that cause a particular constellation of medical signs and symptoms.

[10] Mitochondrial DNA is composed of 37 genes found in the single circular chromosome measuring 16,569 base pairs in length.

This cellular energy deficit manifests most readily in tissues that rely heavily upon aerobic metabolism such as the brain, skeletal and cardiac muscles, sensory organs, and kidneys.

[13] More recent studies have concluded that mtDNA duplications may also play a significant role in determining what phenotype is present.

"[16] Blood lactate and pyruvate levels usually are elevated as a result of increased anaerobic metabolism and a decreased ratio of ATP:ADP.

In the forementioned study, regenerating muscle fibers were sampled at the original biopsy site, and it was found that they were essentially homoplasmic for wildtype mtDNA.

[20][21] The triad of CPEO, bilateral pigmentary retinopathy, and cardiac conduction abnormalities was first described in a case report of two patients in 1958 by Thomas P. Kearns (1922–2011), MD., and George Pomeroy Sayre (1911–1992), MD.

[23] Previous cases of patients with CPEO dying suddenly had been published, occasionally documented as from a cardiac dysrhythmia.

Other cases had noted a peculiar pigmentation of the retina, but none of these publications had documented these three pathologies occurring together as a genetic syndrome.