Kearns Sayre syndrome

Kearns-Sayre syndrome (KSS) is a very rare multisystem mitochondrial disease defined by 3 primary findings of onset before age 20 years, atypical pigmentary retinopathy (a degenerative condition of the retina with a “salt-and-pepper” or “moth-eaten” pigmentation in the retina that lead to poor night vision and progressive vision loss, but often leaves it intact), and chronic progressive external ophthalmoplegia (CPEO) that is characterized by weakness or paralysis of the eye muscles that control eye movement (extraocular muscles) and eyelids, leading to drooping eyelids (ptosis) in one or both eyes and difficulty moving the eyes (ophthalmoplegia) ¹, ², ³, ⁴, ⁵, ⁶, ⁷, ⁸. Other associated findings in Kearns-Sayre syndrome (KSS) include heart disease such as an enlarged heart muscle (cardiomyopathy) and/or progressive arrhythmia leading to complete heart block, cerebrospinal fluid (CSF) protein greater than 100mg/dL, short stature, deafness (sensorineural hearing loss), dementia, endocrine abnormalities such as diabetes mellitus and hypoparathyroidism (a condition where the parathyroid glands produce too little parathyroid hormone (PTH), leading to low calcium levels in the blood (hypocalcemia) and high phosphorus levels) and cerebellar ataxia (a movement disorder characterized by difficulty with coordination, balance, and posture, resulting in clumsy movements, unsteady gait, slurred speech, and difficulty with fine motor skills caused by damage or dysfunction of the cerebellum) ², ⁹, ³. An important feature of Kearns-Sayre syndrome (KSS) is the presence of droopy eyelids (ptosis) in one or both eyes. Patients with Kearns-Sayre syndrome (KSS) should therefore be considered for comprehensive eye exam, heart assessment, a lumbar puncture, and a thorough neurologic assessment ⁸, ⁵.

Kearns-Sayre syndrome is the result of abnormalities in the DNA of mitochondria or mitochondrial DNA (mtDNA), a small rod-like structures found in every cell of the body that produce the energy that drives cellular functions. In about 80% of people with Kearns Sayre syndrome (KSS), genetic testing shows missing (deleted) mitochondrial DNA (mtDNA deletion). The cause of the deletion in affected individuals is unknown. The mtDNA deletions range from 1,000 to 10,000 DNA building blocks (nucleotides) that cause Kearns-Sayre syndrome (KSS) result in the loss of genes important for mitochondrial protein formation and oxidative phosphorylation. The most common deletion removes 4,997 nucleotides labeled as the “common 4977 bp deletion”, which includes twelve mitochondrial genes, accounts for more than one-third of Kearns Sayre syndrome cases ¹⁰, ¹¹, ¹². Deletions of mtDNA result in impairment of oxidative phosphorylation (a process that use oxygen to convert the energy from food into a form cells can use) and a decrease in cellular energy production. Regardless of which genes are deleted, all steps of oxidative phosphorylation are affected. Researchers have not determined how these mtDNA deletions lead to the specific signs and symptoms of Kearns-Sayre syndrome (KSS), although the features of the condition are probably related to a lack of cellular energy. It has been suggested that eyes are commonly affected by mitochondrial defects because they are especially dependent on mitochondria for energy. A lack of energy results in the brain and muscles not functioning properly and this is called an encephalomyopathy.

Most cases of Kearns-Sayre syndrome (KSS) appear to occur as the result of a new spontaneous (de novo) deletion (loss) of a large amount (typically ~25%) of mitochondrial DNA (mtDNA). Mitochondria, which are found by the hundreds in the cells of your body, particularly in your muscles and nerve tissues, are structures that carry the blueprints for regulating energy production. As opposed to the genetic instructions of cellular chromosomes (nuclear DNA [nDNA]) which are found in the nucleus of each cell, multiple copies of mitochondrial DNA (mtDNA) are found outside of the nucleus of the cell and within the mitochondria.

In extremely rare cases, deletions in mitochondrial DNA (mtDNA) may be inherited from the mother. The mitochondrial DNA (mtDNA) found in sperm cells typically break off during fertilization. As a result, it is thought that human mitochondrial DNA (mtDNA) comes only from the mother. An affected mother may pass the mitochondrial gene mutation(s) on to all her children but only her daughters will pass the mutation(s) on to their children.

Both normal and altered mtDNA can exist in the same cell, a situation known as heteroplasmy. The number of abnormal mitochondria may be outnumbered by the number of normal mitochondria. Symptoms of Kearns Sayre syndrome (KSS) may not appear in any given generation until the deletion affects a significant proportion of mitochondria. The uneven distribution of normal and altered mtDNA in different tissues can affect different organs in members of the same family. This can result in a variety of symptoms and different degrees of severity in affected family members. This can also mean that the mtDNA deletion might not be detected in some tissues such as blood or cheek swab but can be found in other tissues such as muscle biopsy, and this confirms the diagnosis.

Kearns-Sayre syndrome (KSS) is very rare. While the exact prevalence of Kearns-Sayre syndrome (KSS) is unknown, one study has reported a prevalence of 1.6 cases per 100,000 in the Finnish population ². Some researchers think that mitochondrial myopathies (muscle diseases resulting from mitochondrial dysfunction) may go unrecognized and underdiagnosed in the general population, making it difficult to determine the true frequency of disorders like Kearns-Sayre syndrome (KSS) ¹³.

Kearns-Sayre syndrome (KSS) onset is typically before the age of 20, but symptoms may appear during infancy or adulthood. Eye abnormalities and developmental delays are often observed before the age of five. Kearns-Sayre syndrome is characterized by progressive limitation of eye movements until there is complete immobility (progressive external ophthalmoplegia), accompanied by eyelid droop (ptosis). Kearns-Sayre syndrome is also associated with abnormal accumulation of pigmented material on the membrane lining the eyes called pigmentary retinopathy, which results from breakdown (degeneration) of the light-sensing tissue at the back of the eye (the retina) that gives it a speckled and streaked appearance. The pigmentary retinopathy may cause loss of vision. Kearns-Sayre syndrome may be associated with pigmentary retinopathy similar to that seen in patients with retinitis pigmentosa ¹⁴. Additional symptoms may include mild skeletal muscle weakness in the limbs, heart block (a cardiac conduction defect), short stature, hearing loss (deafness), abnormally high levels of protein in the cerebrospinal fluid (CSF) with protein concentration greater than 100 mg/dL, an inability to coordinate voluntary movements (ataxia), impaired cognitive function (dementia), kidney problems and diabetes mellitus. Seizures are infrequent. Affected individuals often have short stature. Several endocrine disorders can be associated with Kearns-Sayre syndrome, including delayed sexual maturation, hypothyroidism, and growth hormone deficiency ¹⁵.

When the muscle cells of affected individuals are stained and viewed under a microscope, these cells usually appear abnormal. The abnormal muscle cells contain an excess of structures called mitochondria and are known as ragged-red fibers.

A related condition called ophthalmoplegia-plus may be diagnosed if an individual has many of the signs and symptoms of Kearns-Sayre syndrome but not all the criteria are met.

There is currently no effective way to treat mitochondria abnormalities in Kearns-Sayre syndrome. Treatment is generally symptomatic and supportive ¹⁶. Management of Kearns-Sayre syndrome involves multiple specialties depending on the organs involved. The most essential is a regular and long-term follow-up with cardiologists. Conduction problems of heart impulse like heart block may be treated with a pacemaker. Other consultations may include audiology, ophthalmology, endocrinology, neurology, and neuropsychiatry. Hearing aids may be required. There is typically no treatment for limitation in eye movement. Endocrinology abnormalities can be treated with drugs.

Figure 1. Kearns-Sayre syndrome

Footnotes: 12-year-old boy with painless, progressive ptosis over 3 years. School photos denoting progressive ptosis and lost of upper lid crease. The patient denied symptoms of double vision (diplopia), weakness, or speech/swallow troubles. He was healthy as a young child.

Figure 2. Pigmentary retinopathy

Footnotes: 9-year-old Moroccan boy, the second of 3 children with 2nd degree of consanguineous parents, came in a standard medical screening in a primary school. He presented with 3 years past medical history of bilateral ptosis and fainting. General examination found short stature. Visual acuity was 20/100 in the right eye and 20/80 in the left eye. Ocular motility examination revealed partial external ophthalmoplegia with mild limitations in gaze in all directions. The pupillary light reflex was present. Intraocular pressure was good in both eyes. Slit-lamp biomicroscopic examination found a calm anterior segment. After dilatation, funduscopy of the right eye (A) and the left eye (B) showed bilateral atypical pigmentary retinopathy with macular dystrophy.

Figure 3. “Salt-and-pepper” or “moth-eaten” pigmentation of the retina

Footnotes: Fluorescein angiography found areas of hyper- and hypofluorescence called “aspect of salt and pepper”

What is mitochondria?

You have mitochondria present in every cell of your body except red blood cells. Mitochondria are membrane-bound cell organelles (mitochondrion, singular) within your cells, often called the “powerhouses” of the cell, in which a process called oxidative phosphorylation converts the energy from food you eat into a form called adenosine triphosphate (ATP) that your cells can use ¹⁹. Mitochondria use oxygen to break down glucose and other nutrients, releasing energy that is then stored in ATP (adenosine triphosphate). Your mitochondria also contain their own DNA known as mitochondrial DNA (mtDNA), which is essential for the normal function of these structures and is different from the DNA in your other cells nucleus.

The mitochondria in the cells throughout your body are responsible for creating more than 90% of the energy needed by your body to sustain life and support organ function. When mitochondria fail, less and less energy is generated within the cell. Cell injury and even cell death follow. If this process is repeated throughout the body, whole organ systems begin to fail – people get sick, and even die. The parts of the body, such as the heart, brain, muscles and lungs, requiring the greatest amounts of energy are the most affected. Mitochondrial disease is difficult to diagnose, because it affects each individual differently. Symptoms can include seizures, strokes, severe developmental delays, inability to walk, talk, see, and digest food combined with a host of other complications. If three or more organ systems are involved, mitochondrial disease should be suspected.

Chemical energy produced by the mitochondria is stored in a small molecule called adenosine triphosphate (ATP). Mitochondria contain their own small chromosomes. Generally, mitochondria, and therefore mitochondrial DNA, are inherited only from the mother. Problems with mitochondria, the structures that produce energy for all cells, have been linked to the development of Parkinson’s disease.

Mitochondria play a fundamental role in cell physiology; mitochondria organelles are involved in a variety of processes, including bioenergetics, various metabolic pathways, including crucial anabolic and catabolic reactions, such as ATP (adenosine triphosphate) synthesis, the tricarboxylic acid cycle (citric acid cycle or Kreb cycle), and biosynthetic processes, and govern fundamental cellular actions, including proliferation, immunity, and autophagy. Mitochondrial damage and malfunction have been related to the pathogenesis of a large number of human pathologies, such as mitochondrial diseases, neurodegenerative diseases, cancer, cardiovascular diseases, metabolic disorders, and aging. The participation of mitochondria in the redox equilibrium and redox signaling of the cell is also pivotal. Modification of the redox state and increased reactive oxygen species (ROS) production within mitochondria have major consequences for both mitochondrial and extramitochondrial processes and, ultimately, modulate fundamental cellular phenomena such as autophagy and apoptosis.

In people with mitochondrial disease, the parts of the body, such as the heart, brain, muscles and lungs, requiring the greatest amounts of energy are the most affected ²⁰. Based upon recent epidemiological studies, mitochondrial disorders affect at least 1 in 8000 of the general population ²¹. Mitochondrial disease is difficult to diagnose, because it affects each individual differently. Symptoms can include seizures, strokes, severe developmental delays, inability to walk, talk, see, and digest food combined with a host of other complications. If three or more organ systems are involved, mitochondrial disease should be suspected.

Figure 4. Mitochondria cell

What is mitochondrial disease?

Footnote: Clinical features and the organs affected by mitochondrial diseases.

Figure 6. Mitochondrial diseases signs and symptoms

Are mitochondrial diseases difficult to diagnose?

Yes. Because mitochondrial diseases affect so many different organs and tissues of your body, and you may have many different symptoms, mitochondrial diseases can be difficult to diagnose. There’s no single laboratory test that can diagnose a mitochondrial disease. This is why a referral to a medical facility with physicians who specialize in these diseases is critical to making the diagnosis.

Kearns-Sayre syndrome causes

Kearns Sayre syndrome (KSS) belongs in part to a group of rare mitochondrial disorders known as mitochondrial encephalomyopathies. In these disorders there is a change (mutation) in a gene in the mitochondria, the cell structure that produces energy in the form of adenosine triphosphate (ATP). In about 80% of people with Kearns Sayre syndrome (KSS), genetic testing shows missing (deleted) mitochondrial DNA (mtDNA deletion). The cause of the deletion in affected individuals is unknown. The mtDNA deletions range from 1,000 to 10,000 DNA building blocks (nucleotides) that cause Kearns-Sayre syndrome (KSS) result in the loss of genes important for mitochondrial protein formation and oxidative phosphorylation. The most common deletion removes 4,997 nucleotides labeled as the “common 4977 bp deletion”, which includes twelve mitochondrial genes, accounts for more than one-third of Kearns Sayre syndrome cases ¹⁰, ¹¹, ¹². Deletions of mtDNA result in impairment of oxidative phosphorylation (a process that use oxygen to convert the energy from food into a form cells can use) and a decrease in cellular energy production. Regardless of which genes are deleted, all steps of oxidative phosphorylation are affected. Researchers have not determined how these mtDNA deletions lead to the specific signs and symptoms of Kearns-Sayre syndrome (KSS), although the features of the condition are probably related to a lack of cellular energy. It has been suggested that eyes are commonly affected by mitochondrial defects because they are especially dependent on mitochondria for energy. A lack of energy results in the brain and muscles not functioning properly and this is called an encephalomyopathy.

Most cases of Kearns-Sayre syndrome (KSS) appear to occur as the result of a new spontaneous (de novo) deletion (loss) of a large amount (typically ~25%) of mitochondrial DNA (mtDNA). Mitochondria, which are found by the hundreds in the cells of your body, particularly in your muscles and nerve tissues, are structures that carry the blueprints for regulating energy production. As opposed to the genetic instructions of cellular chromosomes (nuclear DNA [nDNA]) which are found in the nucleus of each cell, multiple copies of mitochondrial DNA (mtDNA) are found outside of the nucleus of the cell and within the mitochondria.

In extremely rare cases, deletions in mitochondrial DNA (mtDNA) may be inherited from the mother. The mitochondrial DNA (mtDNA) found in sperm cells typically break off during fertilization. As a result, it is thought that human mitochondrial DNA (mtDNA) comes only from the mother. An affected mother may pass the mitochondrial gene mutation(s) on to all her children but only her daughters will pass the mutation(s) on to their children.

Both normal and altered mtDNA can exist in the same cell, a situation known as heteroplasmy. The number of abnormal mitochondria may be outnumbered by the number of normal mitochondria. Symptoms of Kearns Sayre syndrome (KSS) may not appear in any given generation until the deletion affects a significant proportion of mitochondria. The uneven distribution of normal and altered mtDNA in different tissues can affect different organs in members of the same family. This can result in a variety of symptoms and different degrees of severity in affected family members. This can also mean that the mtDNA deletion might not be detected in some tissues such as blood or cheek swab but can be found in other tissues such as muscle biopsy, and this confirms the diagnosis.

Inheritance pattern

Kearns-Sayre syndrome is generally not inherited but arises from new spontaneous (de novo) mutations in the body’s cells that occur after conception. This alteration is called a somatic mutation and is present only in certain cells.

In about 15% of Kearns-Sayre syndrome cases, it may follow an autosomal dominant or autosomal recessive inheritance pattern ²³. Autosomal dominant inheritance means a single copy of a mutated gene on one of the numbered (not sex) chromosomes is enough to cause a genetic condition. With autosomal dominant inheritance, a child of an affected parent has a 50% chance of inheriting the mutated gene and thus the condition. Autosomal recessive inheritance describes a pattern where two copies of a mutated gene, one inherited from each parent, are needed to cause a genetic disorder. This means if a child inherits only one mutated gene, they are a carrier but don’t have the disease.

In extremely rare cases, Kearns-Sayre syndrome is inherited in a mitochondrial pattern from the mother, which is also known as maternal inheritance. This pattern of inheritance applies to genes contained in mitochondrial DNA (mtDNA). Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, children can only inherit Kearns Sayre syndrome (KSS) resulting from mtDNA mutations from their mother. Kearns Sayre syndrome (KSS) can appear in every generation of a family and can affect both males and females, but fathers do not pass traits associated with changes in mtDNA to their children.

The children of males with Kearns-Sayre syndrome are not at risk ¹⁵.

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://abgc.learningbuilder.com/Search/Public/MemberRole/Verification) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (https://clinics.acmg.net/) has a searchable database of medical genetics clinic services in the United States.

Kearns-Sayre syndrome symptoms

Kearns Sayre syndrome signs and symptoms are usually apparent before the age of 20 years. The 3 primary findings in Kearns Sayre syndrome (KSS) are ³, ¹³:

1. Chronic progressive external ophthalmoplegia (CPEO) which is weakness or paralysis of the external eye muscles (extraocular muscles) resulting in impaired eye movement and drooping eyelids (ptosis).
2. Pigmentary retinopathy, a condition caused by the breakdown (degeneration) of the light-sensing tissue at the back of the eye (retina) with a “salt-and-pepper” or “moth-eaten” pigmentation in the retina that lead to poor night vision and progressive vision loss, but often leaves it intact. This pigmentary retinopathy feature distinguishes Kearns Sayre syndrome (KSS) from chronic progressive external ophthalmoplegia (CPEO).
3. These symptoms typically develop before 20 years of age. Unlike isolated chronic progressive external ophthalmoplegia (CPEO) that commonly presents at the third or fourth decade of life, patients with Kearns–Sayre syndrome typically have symptom onset before age 20 as well as at least one of the following features ⁵:
   • heart disease such as complete heart block, cardiomyopathy and/or progressive arrhythmia,
   • cerebellar ataxia,
   • dementia,
   • deafness,
   • short stature,
   • endocrine abnormalities,
   • cerebrospinal fluid (CSF) protein of more than 100 mg/dL.

Patients with Kearns-Sayre syndrome (KSS) typically present within the first two decades of life with signs of and symptoms due to bilateral, progressive drooping eyelids (ptosis) and weakness or paralysis of the external eye muscles that control eye movement (external ophthalmoplegia). Most Kearns-Sayre syndrome (KSS) cases are sporadic with a negative family history, although inherited forms have been rarely described. Serial examination of old photos can be invaluable in establishing the chronic, progressive nature of the disease. Although the ophthalmoplegia (weakness or paralysis of the external eye muscles that control eye movement) may be less severe than the drooping eyelids (ptosis) at presentation, it usually becomes progressively worse over a period of years. The systemic manifestations typically follow a similar pattern of chronic progressive worsening, in particular the heart conduction defects ultimate result in complete heart block, which has been described up to 8 years after diagnosis ²⁴. Despite the presence of retinopathy, visual acuity is often preserved, although severe macular involvement and poor vision have been described ²⁵.

It is essential to perform an electrocardiogram (ECG) on Kearns–Sayre syndrome patients to rule out a complete heart block. Endocrine abnormalities affecting the adrenals, parathyroid, and hypothalamus can present with diabetes mellitus, growth hormone deficiency, and short stature ²⁶, ²⁷. Orbicularis oculi muscle weakness can impair eyelid closure, and frontalis weakness can affect eyelid elevation. Difficulty swallowing (dysphagia) is a rare presentation of Kearns–Sayre syndrome and may result from upper esophageal sphincter dysfunction and reduced peristalsis in the pharynx and upper esophagus, as observed in a manometric study of a case report ²⁸.

Other signs and symptoms of Kearns Sayre syndrome (KSS) may include:

• Short stature and/or difficulty growing and gaining weight (failure to thrive), which in most people is the first physical characteristic of this disorder
• Drooping of the upper eyelid (ptosis) due to weakness of one of the muscles of the eyelid (levator palpebrae superioris) which is usually seen during childhood or adolescence
• Inability to move the eyes due to the progressive weakness of the muscles involved in coordinating eye movements (CPEO)

Eventually, the eye muscles weakness may extend to other parts of your body and result in the following symptoms:

• Weakness of the face, throat (pharynx), neck and/or shoulders which may lead to:
  • Speech difficulties (dysarthria)
  • Swallowing difficulties (dysphagia)
• Progressive weaknesses of the upper arms and legs, resulting in problems with coordinating movement and balance (ataxia)
• Visual problems (may be severe in about 40% of people with Kearns Sayre syndrome (KSS)) that may include:
  • Visual difficulties caused by the abnormal accumulation of colored (pigmented) material and progressive degeneration of the retina (pigmentary degeneration of the retina)
    • This degenerative process may eventually affect the optic nerve (optic atrophy), the layers of membranes behind the retina (choroid) and/or the tough, white outer covering of the eyeball (sclera) and may result in:
      • night blindness (nyctalopia)
      • rapid, involuntary eye movements (nystagmus)
      • decrease in the sharpness of vision (visual acuity)
  • Abnormal clouding of the front portion of the eyeball (cornea) which rarely may also contribute to nystagmus and decreased visual acuity
• Heart problems that may include:
  • Dilated cardiomyopathy (enlarged heart muscle)
  • Abnormal heart rhythm (arrhythmias) and heart block of variable severity due to an abnormal conduction system (abnormalities of the electrical signals that control the heartbeat)

Normal heart has 4 chambers. The 2 upper chambers are known as atria are separated from each other by a fibrous partition known as the atrial septum. The 2 lower chambers known as ventricles are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles.

• In the mild form of heart block, the two upper chambers of the heart (atria) beat normally but the contractions of the two lower chambers (ventricles) slightly lag behind.
• In the more severe form of heart block, only a half to a quarter of the atrial beats are conducted to the ventricles.
• In complete heart block, the atria and ventricles beat separately.

In some people, heart block may lead to dizziness, blackouts (syncope), breathlessness and/or irregular heartbeats (arrhythmias). Bundle-branch block may be seen on electrocardiogram (EKG or ECG) and indicates that the arrhythmia is present; this may progress unpredictable and quickly to complete heart block.

Additional signs and symptoms of Kearns Sayre syndrome may include:

• Developmental delays
• Short stature
• Enlarged heart muscle (myocardiopathy)
• Low muscle tone (hypotonia)
• Hearing loss eventually leading to deafness
• Cognitive impairment
• Progressive memory loss
• Deterioration of intellectual abilities (dementia)
• Abnormalities of various of parts of the brain (e.g., white and gray matter, brain stem and/or cerebellum)
• Hormonal problems due to impaired function of structures and organs that secrete hormones into the blood system (multiple endocrine dysfunction) have all been reported ²⁹, ³⁰, ³¹, ³², ³³, ³⁴:
  • Low levels of parathyroid hormone (hypoparathyroidism) which can cause muscle cramps and fatigue
  • Diabetes mellitus, a condition that affects how the body processes sugar
  • Ovarian or testicular failure leading to delayed puberty (when a child’s sexual development begins later than expected) and growth hormone deficiency causing growth problems
  • Underactive thyroid (hypothyroidism) is when the thyroid gland doesn’t make enough thyroid hormones to meet your body’s needs
  • Addison’s disease also known as primary adrenal insufficiency, is a rare disorder where the adrenal glands don’t produce enough cortisol and aldosterone. These hormones (cortisol and aldosterone) are crucial for regulating blood pressure, blood sugar, and overall body functions. Primary adrenal insufficiency can lead to a range of symptoms, including fatigue, muscle weakness, weight loss, and darkening of the skin.
  • Growth hormone deficiency also known as dwarfism or pituitary dwarfism, is a condition caused by insufficient amounts of growth hormone in the body. Children with growth hormone deficiency have abnormally short stature with normal body proportions.
• Seizures are infrequent.

The relationship between Kearns Sayre syndrome (KSS) and endocrine abnormalities is not fully understood.

On rare occasions, Kearns Sayre syndrome (KSS) may also be associated with other disorders or conditions including absence of certain reflexes (peripheral neuropathy) and progressive kidney (renal) abnormalities including chronic renal failure. Peripheral neuropathy is a disorder that may affect one or several nerves of the body causing pain and weakness. Peripheral neuropathy may affect sensory, motor, reflex, or blood vessel function.

Recent publications report damage to the spinal cord (bundle of nerves that extend from the base of the brain down the center of the spine) in some affected people.

In most cases, the first physical characteristic of Kearns Sayre syndrome (KSS) is retardation of growth. In addition, drooping of the upper eyelid (ptosis) due to weakness of one of the muscles of the eyelid (levator palpebrae superioris) is also seen early during infancy. Other muscles involved in coordinating eye movements may be affected next, growing progressively weaker and eventually resulting in paralysis of certain eye movements (progressive external ophthalmoplegia). Eventually, muscle weakness may extend to other portions of the face, throat (pharynx), neck, and/or shoulders. Muscle weakness in such areas may hinder talking and/or swallowing (dysphagia). As the disease progresses, the upper arms and legs may be affected, resulting in progressive impairment of coordinated movement (ataxia) and/or a staggered or halting gait (titubation).

Most individuals with Kearns-Sayre syndrome will also have visual difficulties due to the abnormal accumulation of colored (pigmented) material on the delicate membrane that lines the eyes (atypical retinitis pigmentosa) and progressive degeneration of certain portions of the eye (pigmentary degeneration of the retina). This degenerative process may eventually affect the optic nerve (optic atrophy), the layers of membranes behind the retina (choroid), and/or the tough, white outer covering of the eyeball (sclera). In some cases, affected individuals may also experience night blindness; rapid, involuntary eye movements (nystagmus); and a decrease in the sharpness of vision (visual acuity). In rare cases, abnormal clouding of the front portion of the eyeball (cornea) may also contribute to nystagmus and decreased visual acuity. About 40 percent of people with Kearns-Sayre syndrome experience profound visual problems.

The third primary finding in people with Kearns-Sayre syndrome is an interference with the transfer of nerve impulses (conduction) that control the activity of heart muscles (heart block). The severity of such conduction abnormalities may vary among affected individuals.

The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. In the mild form of heart block, the two upper chambers of the heart (atria) beat normally, but the contractions of the two lower chambers (ventricles) slightly lag behind. In the more severe forms, only a half to a quarter of the atrial beats are conducted to the ventricles. In complete heart block, the atria and ventricles beat separately. In some cases, heart block may lead to blackouts (syncope), breathlessness, and/or irregular heartbeats (arrhythmias).

Individuals with Kearns-Sayre syndrome may also exhibit a variety of other physical characteristics and symptoms. The number and severity of these symptoms may vary greatly from patient to patient; in some people, individuals may exhibit a partial or incomplete form of the disorder. The additional physical characteristics and symptoms associated with Kearns-Sayre syndrome may include developmental delays; short stature (dwarfism); diminished muscle tone (hypotonia); hearing loss, eventually leading to deafness; cognitive impairment; progressive memory loss and deterioration of intellectual abilities (dementia), and/or abnormalities affecting various of parts of the brain (e.g., white and gray matter, brain stem, and/or cerebellum).

In some affected individuals, Kearns-Sayre syndrome may also be associated with several disorders involving the function of structures and organs that secrete hormones into the blood system (multiple endocrine dysfunction). The most common of these disorders occurring in association with Kearns-Sayre syndrome include hypoparathyroidism, diabetes mellitus, and/or primary failure of the ovaries or testes (gonads). These disorders may result in short stature, a delay in reaching puberty, excessive fatigue, and/or muscle cramps. The relationship between Kearns-Sayre syndrome and endocrine abnormalities is not fully understood.

Kearns-Sayre syndrome diagnosis

The diagnosis of Kearns Sayre syndrome (KSS) may be suspected when the 3 primary characteristics associated with Kearns Sayre syndrome occur by the age of 20 years. These include paralysis of certain eye muscles (chronic progressive external ophthalmoplegia [CPEO]), abnormal coloration of the delicate membrane lining the eyes (atypical retinitis pigmentosa) and other changes in the structures of the eye (pigmentary degeneration of the retina) and disease affecting the heart (cardiomyopathy), especially conduction disorders (e.g., heart block). Diagnosis of Kearns Sayre syndrome (KSS) may be confirmed by a thorough clinical evaluation and a variety of specialized tests.

The specialized tests may include an electrocardiogram (ECG or EKG) to detect the presence and evaluate the severity of heart block, blood and spinal fluid lactic acid levels, a muscle biopsy to demonstrate the presence of characteristic abnormalities in muscle tissue (ragged-red fibers) and/or a spinal tap to determine whether there are elevated levels of cerebrospinal fluid (CSF) protein (>100 mg/dL) or a deficiency of folate (cerebral folate deficiency). The muscle biopsy can determine the presence of deleted mtDNA, which may not be detected in the blood sample. Kearns-Sayre Syndrome will show cytochrome C oxidase (COX) negative fibers with ragged red fibers on Gomori’s trichome stain ⁵. In some people with Kearns Sayre syndrome (KSS), the levels of other substances (i.e., serum creatine kinase, blood lactate, gamma globulin and/or pyruvate) may be elevated in the blood.

Microscopic examination of biopsy tissue samples under an electron microscope may reveal large numbers of abnormal mitochondria in skeletal and eye muscle tissue. In some people, a CT scan or tomography may be used to identify abnormal accumulation of calcium in and/or lesions affecting certain areas of the brain. MRI of the brain may also show white matter changes or changes similar to Leigh syndrome.

Figure 7. Muscle histochemistry

Footnotes: Tissue section showing the pathological abnormalities of mitochondrial disorders. (A) Hematoxylin and Eosin (HE) stain; (B) Red ragged fibers (RRF) appear on modified gomorie trichome stain suggesting abnormal subsarcolemmal accumulation of mitochondria; (C) Blue red fibers on succinate dehydrogenase (SDH) staining, suggesting an increased number of mitochondria; (D) Cytochrome C oxidase (COX) staining shows absence of enzymes of respiratory chain. (E & F) Electron micrograph showing low and high magnification of mitochondria with paracrystalline inclusions (E x10000, F x40000).

Physical exam

A comprehensive physical exam, with focus on the eye and neurological components, is crucial in identifying different types of CPEO and its associated syndromes ⁷), ³⁵. The severity of the ophthalmoplegia can be quantified by measuring the uniocular fields of fixation and ductions. The Goldmann perimeter can be used to map the range of extraocular movement (EOM) in the various fields of gaze. For example, in the right eye, the cardinal axes are 0o (lateral rectus), 67o (superior rectus), 141o (inferior oblique), 180o (medical rectus), 216o (superior oblique), and 293o (inferior rectus) ⁷). During the eye exam, one eye is occluded and the patient follows an illuminated target along each of the axes until central fixation on the target is lost ⁷). In one study ³⁶, overall mean range of extraocular movement was decreased by 73% in patients with CPEO compared to controls. The degree of ptosis can be measured by the vertical fissure height (VFH), levator function (LF), and margin-reflex distance (MRD) ³⁵.

Muscle biopsy

Biopsy of skeletal muscle can be helpful in establishing the diagnosis. Although the presence of ragged red fibers (RRF) on biopsy is not part of the current diagnostic criteria, it both supports the diagnosis and provides a tissue sample for genetic testing. Due to mitochondrial heteroplasmy and the potential uneven distribution of the genetic defect among different tissue types, biopsy is usually taken from an affected skeletal muscle.

Genetic testing

Genetic investigation for patients with suspected mitochondrial disorders should be undertaken after detailed clinical, biochemical and histopathological examination. If clinical or family history point to a specific syndrome, genetic testing may be invaluable in determining prognosis and additional studies that need to be done. Although high levels of mutations can be detected in blood, it is always advisable to use skeletal muscle for detecting mtDNA mutations, especially for deletions or mtDNA rearrangements ²². An experienced laboratory may be necessary in conducting the genetic analysis given the extensive list of potential nuclear and mitochondrial DNA involved.

Genetic testing should be coordinated with a laboratory familiar with mitochondrial diseases. The wide variety of genetic defects associated with the disease may necessitate extensive genetic testing and this should be considered when obtaining biopsies and anticipating the potential expense of obtaining a definitive genetic diagnosis.

Electroretinogram

Electroretinography and dark adaptometry are usually normal or only mildly abnormal ³⁷, ³⁸.

Electrocardiogram

All patients with suspected Kearns-Sayre syndrome should be referred to a cardiologist (heart specialist) to have an electrocardiogram (ECG) to screen for heart block. A subset of patients with Kearns-Sayre syndrome may have mitral valve regurgitation and an echocardiogram may be warranted based on clinical examination and consultation with a cardiologist ²⁴.

Endocrine Evaluation

Endocrine dysfunction is common and should be evaluated in conjunction with an endocrine specialist (endocrinologist). Hypoparathyroidism, diabetes mellitus, Addison’s disease and growth hormone deficiency have all been reported ²⁹, ³⁰, ³¹, ³², ³³, ³⁴.

CSF Analysis

CSF protein greater than 1mg/ml is a potential diagnostic criterion. Elevated CSF pyruvate and lactate have also been reported ³⁹.

Auditory Testing

Auditory testing can be useful for characterizing hearing loss associated with Kearns-Sayre syndrome.

Imaging

Fluorescein angiography demonstrates retinal pigment mottling with areas of hyper and hypofluorescence as a result of interspersed retinal pigment clumping and atrophy primarily within the posterior pole. Increased choroidal fluorescence can be seen in areas of retinal pigment epithelium (RPE) atrophy ⁴⁰, ⁴¹.

Brain MRI findings are numerous and nonspecific, including white matter hyperintensity, cortical atrophy, cerebellar atrophy, and brainstem hyperintensity ⁴². MRI of the brain may reveal progressive lesions involving the brainstem, globus pallidus, thalamus and white matter of the cerebrum and cerebellum ⁴³.

Imaging of the orbit

Orbital magnetic resonance imaging (MRI) often reveals atrophy of extraocular muscles in CPEO patients ⁷). One study showed a 43% decrease in the cross-sectional area of extraocular muscles in CPEO patients compared to controls ³⁶, ⁴⁴.

Optic Coherence Tomography (OCT) may show reduced thickness of the outer retinal layer and macular central fovea as well as reduced volume of the optic nerve head and rim ⁴⁵.

Kearns-Sayre syndrome differential diagnosis

Symptoms of the following disorders can be similar to those of Kearns Sayre syndrome (KSS).

MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), is also a type of mitochondrial encephalomyopathy. The distinguishing feature in MELAS syndrome is the recurrence of stroke-like symptoms. Episodes of sudden headaches with vomiting and seizures may begin any time between the ages of five to 40 years. Muscular weakness on one side of the body (hemiparesis), blindness due to lesions in the area of the brain that regulates vision (cortical blindness) and/or impaired vision or blindness in one half of the visual field (hemianopsia) may also occur. Other features include abnormal accumulation of lactic acid in the blood (lactic acidosis), progressive dementia, deafness, diabetes and short stature.

MERRF syndrome (myoclonus epilepsy associated with ragged red fibers) also belongs to the group of mitochondrial encephalomyopathies. The distinguishing feature in MERRF syndrome is sudden, brief, jerking spasms that can affect the arms and legs (limbs) or the entire body (myoclonic seizures). Additional problems may include an abnormal accumulation of lactic acid in the blood (lactic acidosis); impaired ability to coordinate movements (ataxia); muscle weakness; difficulty speaking (dysarthria); degeneration of the optic nerve (optic atrophy); and/or rapid, involuntary movements of the eyes (nystagmus). Short stature and hearing loss are also common symptoms. The symptoms of MERRF syndrome may begin in childhood or early adult life and progressively worsen.

Leigh syndrome is also a mitochondrial encephalomyopathy. Leigh syndrome is characterized by the degeneration of the central nervous system (i.e., basal ganglia and brainstem, spinal cord and optic nerve). The symptoms of Leigh syndrome usually begin between the ages of three months and two years. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability and/or seizure activity. As Leigh syndrome progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia), and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function

The following disorder may precede the development of Kearns Sayre syndrome (KSS). It may be helpful in identifying the underlying cause of some forms of this disorder:

• Pearson marrow-pancreas syndrome is an extremely rare disorder characterized by an impaired ability of red blood cells to carry oxygen (sideroblastic anemia) requiring transfusions, dysfunction of the exocrine pancreas (impaired fat absorption), low birth weight, failure to gain weight and grow at the expected rate (failure to thrive) and/or very rarely wasting away (atrophy) or absence of the spleen (asplenia) ⁴⁶. Other symptoms may include the abnormal accumulation of connective tissue (fibrosis) in the pancreas, impaired absorption (malabsorption) of nutrients and/or an abnormal accumulation of lactic acid in the blood (lactic acidosis). Pearson marrow-pancreas syndrome may be caused by a change in the genetic material (variant) found in the DNA of mitochondria (mtDNA) that is identical to the deletions found in Kearns Sayre syndrome (KSS). Typically, young children who have had Pearson marrow-pancreas syndrome later develop Kearns Sayre syndrome (KSS) in childhood or adolescence.

Kearns-Sayre syndrome treatment

Treatment for Kearns-Sayre syndrome is generally symptomatic and supportive. There is still no cure for Kearns-Sayre syndrome (KSS).

People with Kearns Sayre syndrome (KSS) are at risk for serious heart problems including complete heart block, a condition where electrical signals in the heart don’t travel properly. This can lead to a dangerously slow heart rate or even sudden cardiac arrest. To prevent this, doctors may recommend a prophylactic pacemaker, a small device placed under the skin that helps control the heartbeat ⁴⁷. Since heart complications can be life-threatening, regular check-ups with a cardiologist (heart specialist) are essential. Surveillance includes electrocardiogram (ECG), 24-hour Holter monitoring and echocardiogram every six to 12 months and yearly audiometry and endocrine assessment are important ¹⁵. In cases of severe heart dysfunction, a heart transplant is an option ⁴⁸.

People affected with Kearns Sayre syndrome (KSS) can also have various eye problems, including ptosis (droopy eyelids) and issues with the retina (the light-sensitive part at the back of the eye). Ptosis (droopy eyelids) can be surgically corrected with a frontalis suspension, although the efficacy of the procedure may wane in the later stages of the disease if the facial muscles become involved ⁶. Often ptosis recurs or progresses, requiring additional upper eyelid surgery ⁶. Patients with double vision (diplopia) may benefit from prisms or strabismus surgery (a procedure to straighten misaligned eyes) ⁶. Special vision aids or assistive devices may help people with vision loss.

Some people with Kearns Sayre syndrome (KSS) develop hearing loss. When this happens, cochlear implants (small electronic devices that help restore hearing) may be an option. An audiologist (hearing specialist) can help determine the best approach.

Kearns Sayre syndrome (KSS) can also affect other body systems leading to conditions such as:

• Diabetes mellitus (high blood sugar)
• Hypoparathyroidism (low levels of a parathyroid hormone [PTH] leading to low calcium levels in the blood (hypocalcemia) and high phosphorus levels)

These conditions are usually treated with hormone replacement therapy to help balance hormone levels in the body.

The human body needs folate to perform many functions, including cell division, growth, and the production of new red blood cells ⁴⁹. Folinic acid is chemically different to folic acid but both work in a similar way. Folic acid (vitamin B9) or folinic acid also known as leucovorin supplements may be recommended especially for people with low levels of cerebral folate (a type of folate important for brain function) or neurological symptoms like difficulty thinking or moving.

Research is exploring potential new treatments for Kearns Sayre syndrome (KSS) such as:

• Endonuclease and zinc-finger nuclease, experimental genetic therapies that might help reduce the number of damaged mitochondria
• Coenzyme Q10 also known as ubiquinone or CoQ10, a dietary supplement that acts as an antioxidant, helping protect cells from damage. Though these treatments are still being studied, some doctors may suggest Coenzyme Q10 (CoQ10) as a supplement. The U.S. Food and Drug Administration (FDA) has granted Orphan Drug designation to Coenzyme Q10 (UbiQGel) for the treatment of Kearns-Sayre syndrome and other mitochondrial cytopathies.
• L-Carnitine (a specialized amino acid) and vitamin therapy including coenzyme Q10, riboflavin, and vitamins C and K are being tested as possible treatments for mitochondrial disorders. These options may be used alone or in conjunction with one another for the treatment of mitochondrial disorders. More studies are needed to determine the long-term safety and effectiveness of these potential treatments for mitochondrial disorders such as Kearns-Sayre syndrome.

Growth hormone (GH) therapy is sometimes used to help children with Kearns Sayre syndrome (KSS) grow taller but its use is controversial. While some children with growth hormone deficiency have improved height with treatment, growth hormone (GH) therapy can also be risky because it increases the body’s demand for energy adenosine triphosphate (ATP), the fuel that powers cells. Since people with mitochondrial diseases already have trouble producing enough ATP (adenosine triphosphate), growth hormone (GH) therapy might worsen symptoms. Some patients have developed muscle weakness, trouble with balance, memory problems and even multiple organ failure after growth hormone (GH) therapy. Because of these risks, doctors carefully assess whether growth hormone (GH) treatment is appropriate for each patient. In some people, stopping growth hormone (GH) therapy has led to improvements in muscle strength, appetite and cognitive function.

People with Kearns Sayre syndrome (KSS) may have weak bones (osteoporosis) which increases the risk of fractures. Doctors may consider medications such as:

• Bisphosphonates or denosumab which may help slow down bone loss
• Teriparatide, a medication that helps build new bone

However, there isn’t enough research to prove these treatments are effective in helping people with Kearns Sayre syndrome (KSS).

Physical therapy, occupational therapy and social support services can improve quality of life.

Because Kearns Sayre syndrome (KSS) affects many parts of the body, affected people should be followed by a team of specialists including geneticists and metabolic specialists, neurologists, cardiologists, ophthalmologists, audiologists, endocrinologists, gastroenterologists and others, as needed. These specialists should work together and in a coordinated manner for the best management.

• Dilation of the upper esophageal sphincter to alleviate cricopharyngeal achalasia.
• Percutaneous endoscopic gastrostomy may improve nutritional intake and prevent aspiration pneumonia in individuals with severe dysphagia.

Since Kearns Sayre syndrome (KSS) is a genetic disorder, genetic counseling is recommended for affected individuals and their families. A team approach for infants with this disorder may also be of benefit and may include special social support and other medical services including physical and occupational therapies. Other treatment is symptomatic and supportive.

Kearns-Sayre syndrome prognosis

Kearns-Sayre syndrome is a slowly progressive disorder. The prognosis for individuals with Kearns-Sayre syndrome varies depending on the severity and the number of organs involved. Kearns-Sayre syndrome mortality depends largely on the severity of heart disease, although endocrine dysfunction has also been a cause of significant sickness and mortality in Kearns-Sayre patients. Early diagnosis and periodic electrocardiogram (ECG) are important since heart block can cause death in 20 percent of patients. Early pacemaker implantation can be of great benefit and offer a longer life expectancy in many patients.

The visual prognosis for Kearns-Sayre syndrome is relatively good. Only 40-50% of patients develop mild visual acuity disturbance or night blindness and central vision is usually preserved throughout life ⁵⁰, ²⁵, ⁴¹.

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