Kearns-Sayre syndrome is a rare condition that primarily affects the eyes, heart, and muscles, caused by changes in the energy-producing parts of cells called mitochondria. Most people with this condition begin experiencing symptoms before reaching their twentieth birthday, and while there is no cure, various treatments can help manage the challenges that arise.

Epidemiology

Kearns-Sayre syndrome is extremely rare across the globe. Studies have estimated that approximately 1 to 3 people out of every 100,000 individuals live with this condition.^[1] This makes it one of the uncommon mitochondrial diseases that medical professionals encounter. The condition was first described in medical literature in 1958 by two doctors, Thomas P. Kearns and George Pomeroy Sayre, after whom the syndrome is named.^[1]

One study conducted in Finland reported a prevalence of 1.6 cases per 100,000 people in the Finnish population.^[3] Because the condition is so rare, exact prevalence data from other countries and regions remains limited. The syndrome affects both males and females equally, with no particular demographic group showing higher rates of occurrence.^[1]

The defining characteristic of this syndrome from an epidemiological standpoint is that symptoms nearly always appear before a person turns 20 years old. This early onset helps distinguish Kearns-Sayre syndrome from other similar conditions that might affect the eyes and muscles later in life.^[2]

Causes

Kearns-Sayre syndrome develops due to problems with mitochondrial DNA, which is the genetic material found inside mitochondria. Mitochondria are tiny structures present in nearly every cell of your body, often described as the “energy factories” because they produce about 90% of the energy needed for your body to function and grow.^[1] These structures use oxygen to convert the nutrients from food into energy that cells can use.

The specific cause of Kearns-Sayre syndrome is a large deletion, or missing piece, of mitochondrial DNA. This deletion can range from 1,000 to 10,000 DNA building blocks, with the most common deletion removing 4,977 building blocks and including twelve mitochondrial genes.^[2] Approximately 90% of cases involve this type of large-scale deletion of mitochondrial DNA.^[3]

What makes this condition particularly unusual is that researchers do not understand why these deletions occur. The genetic changes typically happen spontaneously as a baby develops during pregnancy, occurring in the body’s cells after conception.^[2] This type of change is called a somatic mutation, meaning it appears in certain cells but was not inherited from either parent.

When mitochondrial DNA has these deletions, the genes needed for healthy mitochondrial function are lost. This results in problems with oxidative phosphorylation, the process by which mitochondria produce energy.^[2] All steps of this energy production process become affected, regardless of which specific genes were deleted. The result is that cells throughout the body cannot generate enough energy to work properly.

Because mitochondria have their own DNA that is separate from the DNA found in the cell’s nucleus, this condition follows different inheritance patterns than many other genetic disorders. Mitochondrial DNA is inherited only through the mother, because egg cells contribute mitochondria to a developing baby, but sperm cells do not.^[2] However, Kearns-Sayre syndrome is generally not passed down through families and typically occurs without any family history of the condition.^[1] In rare circumstances, it can be inherited through maternal inheritance.^[2]

Risk Factors

Unlike many other medical conditions, Kearns-Sayre syndrome does not have traditional risk factors related to lifestyle, behavior, or environmental exposures. The genetic changes that cause this syndrome typically occur randomly during fetal development, without any known triggers or preventable causes.^[1]

The primary factor associated with Kearns-Sayre syndrome is simply the spontaneous occurrence of mitochondrial DNA deletions during pregnancy. Both males and females can develop the condition equally, and it does not appear to be more common in any particular ethnic or racial group.^[1]

In the rare cases where the condition can be inherited, having a mother with mitochondrial DNA mutations could potentially increase risk. However, because most cases arise from new mutations that occur during development, having a family history of Kearns-Sayre syndrome is uncommon.^[2] Genetic testing may help families understand whether a mutation was inherited or occurred spontaneously.^[1]

Symptoms

The symptoms of Kearns-Sayre syndrome typically begin before age 20 and first affect the eyes. For a medical diagnosis of this condition, three key features must be present: onset before age 20, progressive external ophthalmoplegia (weakness or paralysis of the eye muscles), and pigmentary retinopathy (abnormal pigment changes in the light-sensing tissue at the back of the eye).^[3]

The eye-related symptoms are often the most noticeable early signs. People with Kearns-Sayre syndrome develop drooping eyelids, a condition called ptosis, which gradually worsens over time. They also experience progressive difficulty moving their eyes, which eventually leads to complete immobility of the eye muscles.^[4] The pigmentary retinopathy causes a “salt-and-pepper” appearance in the retina and can lead to difficulty seeing, especially in dark environments or low light conditions. Over time, the disease may cause vision loss or even blindness.^[1]

In addition to these three defining features, people with Kearns-Sayre syndrome must have at least one of several other symptoms. These include heart problems, specifically cardiac conduction block, which affects the electrical signals that control the heartbeat.^[3] This heart condition is particularly serious and requires close monitoring. Other qualifying symptoms include abnormally high levels of protein in the cerebrospinal fluid (the liquid that surrounds and protects the brain and spinal cord), or cerebellar ataxia, which causes problems with coordination and balance.^[2]

Many other symptoms can develop as the condition progresses. Muscle weakness is common, affecting not only the eyes but also the limbs and other parts of the body. This skeletal muscle weakness is typically mild but can impact daily activities.^[4] People with the syndrome often have short stature, meaning they are shorter than average for their age and gender.^[3]

Hearing loss is another frequent symptom, with bilateral sensorineural hearing loss affecting nearly everyone who survives into their fourth decade of life. Hearing aids may not fully correct this type of hearing loss.^[6] Cognitive problems can develop, including impaired thinking abilities, memory difficulties, and in some cases, dementia, which is a decline in mental function.^[4]

Various hormonal and metabolic problems, called endocrine abnormalities, frequently occur in people with Kearns-Sayre syndrome. These can include diabetes mellitus, problems with the parathyroid gland, growth hormone deficiency, and Addison disease.^[6] Some individuals develop kidney problems, including renal tubular acidosis, which in rare cases can progress to end-stage kidney failure requiring dialysis or transplantation.^[6] Seizures can occur but are relatively infrequent.^[4]

Prevention

Because Kearns-Sayre syndrome results from spontaneous genetic changes that occur during fetal development, there are no known methods to prevent the condition from developing. The mitochondrial DNA deletions that cause the syndrome happen randomly, and scientists have not identified any environmental factors, behaviors, or lifestyle choices that increase or decrease the likelihood of these genetic changes occurring.^[1]

For families who have a child with Kearns-Sayre syndrome, genetic counseling can be valuable for understanding the condition and discussing family planning. Since most cases arise from new mutations rather than being inherited, the risk of having another child with the same condition is generally low.^[1] However, in the rare instances where the condition involves inherited mitochondrial DNA mutations, a genetic counselor can help families understand their specific situation and any potential risks for future pregnancies.

While the syndrome itself cannot be prevented, early detection and management of complications can help prevent serious outcomes. Regular medical monitoring, particularly of heart function through electrocardiograms, is crucial for identifying heart problems before they become life-threatening.^[4] This type of vigilant medical care represents the most effective approach to preventing serious complications rather than preventing the condition itself.

Pathophysiology

The pathophysiology of Kearns-Sayre syndrome involves understanding how damaged mitochondria lead to the various symptoms experienced by patients. At the cellular level, when mitochondrial DNA has large deletions, the genes necessary for producing proteins involved in energy production are missing. This disrupts the normal process of oxidative phosphorylation, which is how cells convert nutrients and oxygen into usable energy.^[2]

When mitochondria cannot function properly, cells do not receive adequate energy to carry out their normal functions. This energy deficit affects the entire body, but it particularly impacts organs and tissues that require large amounts of energy to function. Muscles and nerve cells are especially vulnerable because they depend heavily on mitochondrial energy production.^[1] This explains why the eyes, which contain muscles that must work constantly and precisely, are often the first and most severely affected parts of the body.

In muscle tissue, the abnormal mitochondria can be seen under a microscope using special staining techniques. When muscle cells from people with Kearns-Sayre syndrome are stained and examined, they show what are called “ragged red fibers.” These are muscle cells that contain an excess of abnormal mitochondria, giving them a characteristic ragged, reddish appearance under the microscope.^[2] This finding is common in mitochondrial diseases and helps confirm the diagnosis.

The eye problems in Kearns-Sayre syndrome have a specific pathophysiology. Examination of eye tissue after death has revealed that the retinal pigment epithelium (a layer of cells that supports the retina) and the outer retina show significant deterioration. Abnormal pigment appears throughout all layers of the sensory retina, most severely toward the back of the eye. Interestingly, the rod and cone cells in the peripheral retina tend to be preserved.^[3] This pattern of damage has led researchers to believe that the primary problem in Kearns-Sayre retinopathy originates in the retinal pigment epithelium, which then causes secondary damage to the photoreceptor cells responsible for vision.

Scientists have suggested that tissues like the eyes are particularly susceptible to mitochondrial dysfunction because they are so heavily dependent on mitochondria for energy. The constant work required for eye movements and visual processing demands enormous amounts of cellular energy, making these tissues especially vulnerable when energy production is impaired.^[2]

In the brain, post-mortem examination of patients with Kearns-Sayre syndrome sometimes reveals severe loss of myelin, the fatty substance that insulates nerve fibers and allows them to transmit electrical signals efficiently. This demyelination affects the white matter tracts of the brain.^[3] Scientists do not yet fully understand why this loss of myelin occurs in Kearns-Sayre syndrome, but it likely contributes to the cognitive and neurological symptoms some patients experience.

The heart problems in Kearns-Sayre syndrome involve disruption of the heart’s electrical conduction system. The heart relies on precisely timed electrical signals to coordinate its pumping action. When the mitochondria in heart tissue cannot produce adequate energy, the cells responsible for generating and transmitting these electrical signals may fail to function properly. This can lead to various forms of heart block, where electrical signals are delayed or blocked entirely, causing abnormal heart rhythms that can be life-threatening.^[6]

Throughout the body, the multiple organ systems affected by Kearns-Sayre syndrome reflect the widespread distribution of mitochondria and the universal need for cellular energy. The severity of symptoms in any particular organ system likely relates to both the proportion of mitochondria carrying the DNA deletion in that tissue and the specific energy demands of that tissue. This explains why the condition affects multiple body systems and why symptoms can vary considerably between individuals.^[1]