NORD gratefully acknowledges Patrick Lestienne, Directeur de Recherches a l'Institut National de la Sante et de la Recherche Medicale (INSERM), Universite Victor Segalen Bordeaux 2, France, for assistance in the preparation of this report.
Kearns-Sayre syndrome (KSS) is a rare neuromuscular disorder characterized by three primary findings: progressive paralysis of certain eye muscles (chronic progressive external ophthalmoplegia [CPEO]); abnormal accumulation of colored (pigmented) material on the nerve-rich membrane lining the eyes (atypical retinitis pigmentosa), leading to chronic inflammation, progressive degeneration, and wearing away of certain eye structures (pigmentary degeneration of the retina); and heart disease (cardiomyopathy) such as heart block. Other findings may include muscle weakness, short stature, hearing loss, and/or the loss of ability to coordinate voluntary movements (ataxia) due to problems affecting part of the brain (cerebellum). In some cases, KSS may be associated with other disorders and/or conditions.
KSS belongs (in part) to a group of rare neuromuscular disorders known as mitochondrial encephalomyopathies. Mitochondrial encephalomyopathies are disorders in which a defect in genetic material arises from a part of the cell structure that releases energy (mitochondria), causing the brain and muscles to function improperly (encephalomyopathies). In these disorders, abnormally high numbers of defective mitochondria are present. In approximately 80 percent of cases of KSS, tests will reveal missing genetic material (deletion) involving the unique DNA in mitochondria (mtDNA).
The three primary findings in KSS are progressive paralysis of certain eye muscles (chronic progressive external ophthalmoplegia [CPEO]); abnormal accumulation of colored (pigmented) material on the nerve-rich membrane lining the eyes (atypical retinitis pigmentosa), leading to chronic inflammation, progressive degeneration, and wearing away of certain eye structures (pigmentary degeneration of the retina); and heart disease (cardiomyopathy) such as heart block. Symptoms of this disorder are usually apparent before the age of 20 years.
In most cases, the first physical characteristic of this disorder 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 (CPEO). 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 KSS 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 KSS experience profound visual problems.
The third primary finding in people with KSS 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 KSS may also exhibit a variety of other physical characteristics and symptoms. The number and severity of these symptoms may vary greatly from case to case; in some cases, individuals may exhibit a partial or incomplete form of the disorder. The additional physical characteristics and symptoms associated with KSS may include developmental delays; short stature (dwarfism); diminished muscle tone (hypotonia); hearing loss, eventually leading to deafness; mental retardation; 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, KSS 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 KSS 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 KSS and endocrine abnormalities is not fully understood. (For more information on these disorders, choose “diabetes mellitus,” or “hypoparathyroidism” as your search terms in the Rare Disease Database.)
On rare occasions, KSS may also be associated with other disorders or conditions including absence of certain reflexes, kidney (renal) abnormalities, and/or peripheral neuropathy. peripheral neuropathy is a rare 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. (For more information on this disorder, choose “peripheral neuropathy” as your search term in the Rare Disease Database.)
The exact cause of KSS is now established in most cases. Most cases appear to occur as the result of a new spontaneous deletion of a large amount of genetic material found in the DNA of mitochondria (mtDNA). Mitochondria, which are found by the hundreds in the cells of the body, particularly in muscle and nerve tissue, carry the blueprints for regulating energy production. As opposed to the genetic instructions of cellular chromosomes (autosomal DNA), which are found within the nucleus of each cell, mitochondrial genetic instructions are found outside of the nucleus of the cell in the cytoplasm.
In extremely rare cases, these deletions in mitochondrial genetic material may be inherited from the mother. The genetic instructions for mitochondria (mtDNA) found in sperm cells typically break off during fertilization. As a result, it is thought that human mtDNA comes from the mother. An affected mother may pass the mutation(s) on to all her children but only her daughters will pass the mutation(s) on to their children.
Both normal and mutated mtDNA can exist in the same cell, a situation known as heteroplasmy. The number of defective mitochondria may be out-numbered by the number of normal mitochondria. Symptoms of KSS may not appear in any given generation until the deletion affects a significant proportion of mitochondria. The uneven distribution of normal and mutant mtDNA in different tissues can affect different organs in members of the same family. This can result in a variety of symptoms in affected family members.
KSS is a rare neuromuscular mitochondrial disorder that affects males and females in equal numbers. Onset is typically before the age of 20; however, symptoms may appear during infancy or adulthood. Eye abnormalities and developmental delays are often observed before the age of five.
Some researchers believe that mitochondrial myopathies may go unrecognized and underdiagnosed in the general population, making it difficult to determine the true frequency of disorders like KSS.
The diagnosis of KSS may be suspected when the three primary characteristics associated with this disorder occur in association with one another. 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 KSS may be confirmed by a thorough clinical evaluation and a variety of specialized tests.
Such specialized tests may include an electrocardiogram 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 certain cerebrospinal fluid (CSF) proteins. In some cases of 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 cases, a CT scan or tomography may be used to identify abnormal accumulation of calcium in and/or lesions affecting certain areas of the brain.
Treatment of heart problems in KSS may require a pacemaker for atrioventricular (AV) block or drug therapy to regulate the heartbeat (antiarrhythymic drug therapy).
Surgery may be used to correct visual problems; in some cases, whether or not surgery helps to improve vision often depends on how far the retinal changes have advanced. Various devices may help to improve impaired vision in affected individuals. The specific devices and/or surgical treatment techniques used will depend upon the severity and specific combination of visual abnormalities present.
Separate treatment options for associated disorders (e.g., diabetes mellitus or hypoparathyroidism) may be necessary. In some cases, treatment may include hormone replacement therapies. Other treatments will depend on the specific conditions present.
Genetic counseling may be of benefit 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.
The U.S. Food and Drug Administration (FDA) has granted Orphan Drug designation to CoQ10 (UbiQGel) for the treatment of KSS and other mitochondrial cytopathies. UbiQGel is produced by the Tishcon Corporation of Westbury, New York.
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 KSS.
Ibedenone, Thiamine, Vitamin E (antioxidant), and dichloroacetate may be also used but their effects have not yet been scientifically validated.
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