Kearns-Sayre syndrome
Encyclopedia
Kearns–Sayre syndrome also known as oculocraniosomatic disease or Oculocraniosomatic neuromuscular disease with ragged red fibers is a mitochondrial myopathy
with a typical onset before 20 years of age. 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 eyelid movement (levator palpebrae, orbicularis oculi), and those controlling eye movement (extra-ocular muscles). This results in ptosis and ophthalmoplegia respectively. KSS involves a triad of the already described CPEO, as well as bilateral pigmentary retinopathy, and cardiac conduction abnormalities
. Other areas of involvement can include cerebellar ataxia
, proximal muscle weakness, deafness, diabetes mellitus
, growth hormone deficiency
, hypoparathyroidism
, or other endocrinopathies. In both of these diseases, muscle involvement may begin unilateral but always develops into a bilateral deficit, and the course is progressive. This discussion is limited specifically to the more severe and systemically involved variant; KSS
(abbreviated mtDNA) Since this discovery, numerous deletions in mitochondrial DNA have been linked to the development of KSS.
, or difficulty opening the eyelids, that gradually progresses to a bilateral ptosis. 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. Along with the insidious development of ptosis, eye movements eventually become limited causing a person to rely more on turning the head side to side or up and down to view objects in the peripheral visual field
. Pigmentary retinopathy: KSS results in a pigmentation of the retina
, primarily in the posterior fundus
. The appearance is described as a "salt-and-pepper" appearance. There is diffuse depigmentation of the retinal pigment epithelium with the greatest effect occurring at the macula
. This is in contrast to retinitis pigmentosa
where the pigmentation is peripheral. The appearance of the retina in KSS is similar to that seen in myotonic dystrophy
type 1 (abbreviated DM1). Modest night-blindness can be seen in patients with KSS. Visual acuity loss is usually mild and only occurs in 40-50% of patients. Cardiac conduction abnormalities: most often occurs years after the development of ptosis and ophthalmoplegia. Atrioventricular(abbreviated "AV") block is the most common cardiac conduction deficit. This often progresses to a Third-degree atrioventricular block
, which is a complete blockage of the electrical conduction from the atrium to the ventrical. Symptoms of heart block include syncope
, exercise intolerance
, and bradycardia
.Other: As characterized in Kearns' 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.
found in the single circular chromosome
measuring 16,569 base pairs in length. Among these, 13 genes encode proteins of the electron transport chain
(abbreviated "ETC"), 22 encode transfer RNA
(tRNA), and two encode the large and small subunits that form ribosomal RNA
(rRNA). The 13 proteins involved in the ETC of the mitochondrion are necessary for oxidative phosphorylation
. Mutations in these proteins results in impaired energy production by mitochondria. 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. This is one factor involved in the presentation of mitochondrial diseases.
There are other factors involved in the manifestation of a mitochondrial disease besides the size and location of a mutation. Mitochondria replicate during each cell division during gestation and throughout life. Because the mutation in mitochondrial disease most often occurs early in gestation in these diseases and only occurs in one parent mitochondria, only those mitochondria in the mutated lineage are defective. This results in an uneven distribution of dysfunctional mitochondria within each cell, and among different tissues of the body. This describes the term heteroplasmic which is characteristic of mitochondrial diseases including KSS. The distribution of mutated mtDNA in each cell, tissue, and organ, is dependent on when and where the mutation occurs. This may explain why two patients with an identical mutation in mtDNA can present with entirely different phenotypes and in turn different syndromes. A publication in 1992 by Fischel-Ghodsian et al. identified the same 4,977-bp deletion in mtDNA in two patients presenting with two entirely different diseases. One of the patients had characteristic KSS, while the other patient had a very different disease known as Pearson marrow pancreas syndrome. Complicating the matter, in some cases Pearson's syndrome has been shown to progress into KSS later in life.
More recent studies have concluded that mtDNA duplications may also play a significant role in determining what phenotype is present. Duplications of mtDNA seem to be characteristic of all cases of KSS and Pearson's syndrome, while they are absent in CPEO.
Deletions of mtDNA in KSS vary in size (1.3-8kb), as well as position in the mitochondrial genome. The most common deletion is 4.9kb and spans from position 8469 to position 13147 on the genome
. This deletion is present in approximately 1/3 of people with KSS
, fourth nerve palsy
, sixth nerve palsy
). Initially, imaging studies are often performed to rule out more common pathologies. Diagnosis is confirmed with muscle biopsy of the orbicularis muscle, and may be supplemented with PCR determination of mtDNA mutations. Biopsy findings: The orbicularis oculi muscle is chosen because of its high concentration of mitochondria, and the preferential distribution of mutated mitochondria in these cells. Cross-section of muscle fibers stained with Gömöri trichrome stain
is viewed using light microscopy. In muscle fibers containing high ratios of the mutated mitochondria, there is a higher concentration of mitochondria in an attempt to compensate for the decreased efficiency of energy production. This gives these fibers a darker red color, causing the overall appearance of the biopsy to be described as "ragged red fibers."
and pyruvate levels usually are elevated as a result of increased anaerobic metabolism and a decreased ratio of ATP
:ADP
. CSF analysis shows an elevated protein level, usually >100 mg/dl, as well as an elevated lactate level.
One study described a patient with KSS who had reduced serum levels of coenzyme Q10. Administration of 60–120 mg of Coenzyme Q10 for 3 months resulted in normalization of lactate
and pyruvate levels, improvement of previously diagnosed first degree AV block, and improvement of ocular movements.
A screening EKG is recommended in all patients presenting with CPEO. In KSS, implantation of pacemaker
is advised following the development of significant conduction disease, even in asymptomatic patients.
Screening for endocrinologic disorders should be performed, including measuring serum glucose levels
, thyroid function tests
, calcium and magnesium levels, and serum electrolyte
levels. Hyperaldosteronism
is seen in 3% of KSS patients.
Mitochondrial myopathy
Mitochondrial myopathy is a type of myopathy associated with mitochondrial disease. On biopsy, the muscle tissue of patients with this disease usually demonstrate "ragged red" muscle fibers...
with a typical onset before 20 years of age. KSS is a more severe syndromic variant of chronic progressive external ophthalmoplegia
Chronic progressive external ophthalmoplegia
Chronic progressive external ophthalmoplegia , also known as progressive external ophthalmoplegia , is a type of eye movement disorder. It is often the only feature of mitochondrial disease, in which case the term CPEO may be given as the diagnosis...
(abbreviated CPEO), a syndrome that is characterized by isolated involvement of the muscles controlling eyelid movement (levator palpebrae, orbicularis oculi), and those controlling eye movement (extra-ocular muscles). This results in ptosis and ophthalmoplegia respectively. KSS involves a triad of the already described CPEO, as well as bilateral pigmentary retinopathy, and cardiac conduction abnormalities
Heart block
A heart block can be a blockage at any level of the electrical conduction system of the heart .* Blocks that occur within the sinoatrial node are described as SA nodal blocks....
. Other areas of involvement can include cerebellar ataxia
Cerebellar ataxia
Cerebellar ataxia is a form of ataxia originating in the cerebellum.-References:...
, proximal muscle weakness, deafness, diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
, growth hormone deficiency
Growth hormone deficiency
Growth hormone deficiency is a medical condition in which the body does not produce enough growth hormone . Growth hormone, also called somatotropin, is a polypeptide hormone which stimulates growth and cell reproduction...
, hypoparathyroidism
Hypoparathyroidism
Hypoparathyroidism is decreased function of the parathyroid glands with under production of parathyroid hormone. This can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany , and several other symptoms...
, or other endocrinopathies. In both of these diseases, muscle involvement may begin unilateral but always develops into a bilateral deficit, and the course is progressive. This discussion is limited specifically to the more severe and systemically involved variant; KSS
History
This 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, MD., and George Pomeroy Sayre, MD. A second case was published in 1960 by Jager and co-authors reporting these symptoms in a 13-year old boy. 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. Kearns published a defining case in 1965 describing 9 unrelated cases with this triad. In 1988, the first connection was made between KSS and large-scale deletions of muscle mitochondrial DNAMitochondrial DNA
Mitochondrial DNA is the DNA located in organelles called mitochondria, structures within eukaryotic cells that convert the chemical energy from food into a form that cells can use, adenosine triphosphate...
(abbreviated mtDNA) Since this discovery, numerous deletions in mitochondrial DNA have been linked to the development of KSS.
Etiology
Kearns–Sayre syndrome occurs spontaneously in the majority of cases. In some cases it has been shown to be inherited through mitochondrial, autosomal dominant, or autosomal recessive inheritance. There is no predilection for race or sex, and there are no known risk factors. As of 1992 there were only 226 cases reported in published literature.Signs and Symptoms
Individuals with KSS present initially in a similar way to those with typical CPEO. Onset is in the first and second decades of life. The first symptom of this disease is a unilateral ptosisPtosis
Ptosis refers to droopiness of a body part. Specifically, it can refer to:* Ptosis * Ptosis * Enteroptosis * Gastroptosis...
, or difficulty opening the eyelids, that gradually progresses to a bilateral ptosis. 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. Along with the insidious development of ptosis, eye movements eventually become limited causing a person to rely more on turning the head side to side or up and down to view objects in the peripheral visual field
Visual field
The term visual field is sometimes used as a synonym to field of view, though they do not designate the same thing. The visual field is the "spatial array of visual sensations available to observation in introspectionist psychological experiments", while 'field of view' "refers to the physical...
. Pigmentary retinopathy: KSS results in a pigmentation of the retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
, primarily in the posterior fundus
Fundus (eye)
The fundus of the eye is the interior surface of the eye, opposite the lens, and includes the retina, optic disc, macula and fovea, and posterior pole. The fundus can be viewed with an ophthalmoscope. The term may also be inclusive of Bruch's membrane and the choroid.The color of the fundus varies...
. The appearance is described as a "salt-and-pepper" appearance. There is diffuse depigmentation of the retinal pigment epithelium with the greatest effect occurring at the macula
Macula
The macula or macula lutea is an oval-shaped highly pigmented yellow spot near the center of the retina of the human eye. It has a diameter of around 5 mm and is often histologically defined as having two or more layers of ganglion cells...
. This is in contrast to retinitis pigmentosa
Retinitis pigmentosa
Retinitis pigmentosa is a group of genetic eye conditions that leads to incurable blindness. In the progression of symptoms for RP, night blindness generally precedes tunnel vision by years or even decades. Many people with RP do not become legally blind until their 40s or 50s and retain some...
where the pigmentation is peripheral. The appearance of the retina in KSS is similar to that seen in myotonic dystrophy
Myotonic dystrophy
Myotonic dystrophy is a chronic, slowly progressing, highly variable inherited multisystemic disease. It is characterized by wasting of the muscles , cataracts, heart conduction defects, endocrine changes, and myotonia. Myotonic dystrophy can occur in patients of any age...
type 1 (abbreviated DM1). Modest night-blindness can be seen in patients with KSS. Visual acuity loss is usually mild and only occurs in 40-50% of patients. Cardiac conduction abnormalities: most often occurs years after the development of ptosis and ophthalmoplegia. Atrioventricular(abbreviated "AV") block is the most common cardiac conduction deficit. This often progresses to a Third-degree atrioventricular block
Third degree heart block
-Presentation:Third-degree AV block, also known as complete heart block, is a medical condition in which the impulse generated in the SA node in the atrium does not propagate to the ventricles....
, which is a complete blockage of the electrical conduction from the atrium to the ventrical. Symptoms of heart block include syncope
Syncope (medicine)
Syncope , the medical term for fainting, is precisely defined as a transient loss of consciousness and postural tone characterized by rapid onset, short duration, and spontaneous recovery due to global cerebral hypoperfusion that most often results from hypotension.Many forms of syncope are...
, exercise intolerance
Exercise intolerance
Exercise intolerance is a condition where the patient is unable to do physical exercise at the level or for the duration that would be expected of someone in his or her general physical condition, or experiences unusually severe post-exercise pain, fatigue, or other negative effects...
, and bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...
.Other: As characterized in Kearns' 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
Hearing impairment
-Definition:Deafness is the inability for the ear to interpret certain or all frequencies of sound.-Environmental Situations:Deafness can be caused by environmental situations such as noise, trauma, or other ear defections...
, small stature, electroencephalographic changes, cerebellar ataxia
Cerebellar ataxia
Cerebellar ataxia is a form of ataxia originating in the cerebellum.-References:...
and elevated levels of cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
protein.
Genetics
KSS is the result of deletions in mitochondrial DNA (mtDNA) that cause a particular phenotype. mtDNA is transmitted exclusively from the mother's ovum. Mitochondrial DNA is composed of 37 genesGênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
found in the single circular chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
measuring 16,569 base pairs in length. Among these, 13 genes encode proteins of the electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
(abbreviated "ETC"), 22 encode transfer RNA
Transfer RNA
Transfer RNA is an adaptor molecule composed of RNA, typically 73 to 93 nucleotides in length, that is used in biology to bridge the three-letter genetic code in messenger RNA with the twenty-letter code of amino acids in proteins. The role of tRNA as an adaptor is best understood by...
(tRNA), and two encode the large and small subunits that form ribosomal RNA
Ribosomal RNA
Ribosomal ribonucleic acid is the RNA component of the ribosome, the enzyme that is the site of protein synthesis in all living cells. Ribosomal RNA provides a mechanism for decoding mRNA into amino acids and interacts with tRNAs during translation by providing peptidyl transferase activity...
(rRNA). The 13 proteins involved in the ETC of the mitochondrion are necessary for oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
. Mutations in these proteins results in impaired energy production by mitochondria. 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. This is one factor involved in the presentation of mitochondrial diseases.
There are other factors involved in the manifestation of a mitochondrial disease besides the size and location of a mutation. Mitochondria replicate during each cell division during gestation and throughout life. Because the mutation in mitochondrial disease most often occurs early in gestation in these diseases and only occurs in one parent mitochondria, only those mitochondria in the mutated lineage are defective. This results in an uneven distribution of dysfunctional mitochondria within each cell, and among different tissues of the body. This describes the term heteroplasmic which is characteristic of mitochondrial diseases including KSS. The distribution of mutated mtDNA in each cell, tissue, and organ, is dependent on when and where the mutation occurs. This may explain why two patients with an identical mutation in mtDNA can present with entirely different phenotypes and in turn different syndromes. A publication in 1992 by Fischel-Ghodsian et al. identified the same 4,977-bp deletion in mtDNA in two patients presenting with two entirely different diseases. One of the patients had characteristic KSS, while the other patient had a very different disease known as Pearson marrow pancreas syndrome. Complicating the matter, in some cases Pearson's syndrome has been shown to progress into KSS later in life.
More recent studies have concluded that mtDNA duplications may also play a significant role in determining what phenotype is present. Duplications of mtDNA seem to be characteristic of all cases of KSS and Pearson's syndrome, while they are absent in CPEO.
Deletions of mtDNA in KSS vary in size (1.3-8kb), as well as position in the mitochondrial genome. The most common deletion is 4.9kb and spans from position 8469 to position 13147 on the genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
. This deletion is present in approximately 1/3 of people with KSS
Diagnosis
A neuro-ophthalmologist is usually involved in the diagnosis and management of KSS. An individual should be suspected of having KSS based upon clinical exam findings. Suspicion for myopathies should be increased in patients whose ophthalmoplegia does not match a particular set of cranial nerve palsies (oculomotor nerve palsyOculomotor nerve palsy
Oculomotor nerve palsy is an eye condition resulting from damage to the third cranial nerve or a branch thereof. As the name suggests, the oculomotor nerve supplies the majority of the muscles controlling eye movements. Thus, damage to this nerve will result in the affected individual being unable...
, fourth nerve palsy
Fourth nerve palsy
Fourth nerve palsy is a condition caused by weakness or paralysis of the superior oblique muscle. This condition often causes double vision as the weakened muscle prevents the eyes from moving in the same direction....
, sixth nerve palsy
Sixth nerve palsy
Sixth nerve palsy, or abducens nerve palsy, is a disorder associated with dysfunction of cranial nerve VI , which is responsible for contracting the lateral rectus muscle to abduct the eye...
). Initially, imaging studies are often performed to rule out more common pathologies. Diagnosis is confirmed with muscle biopsy of the orbicularis muscle, and may be supplemented with PCR determination of mtDNA mutations. Biopsy findings: The orbicularis oculi muscle is chosen because of its high concentration of mitochondria, and the preferential distribution of mutated mitochondria in these cells. Cross-section of muscle fibers stained with Gömöri trichrome stain
Gomori trichrome stain
Gömöri trichrome stain is a stain used on muscle tissue.It can be used to test for certain forms of mitochondrial myopathy.It is named for George Gömöri, who developed it in 1950.-External links:...
is viewed using light microscopy. In muscle fibers containing high ratios of the mutated mitochondria, there is a higher concentration of mitochondria in an attempt to compensate for the decreased efficiency of energy production. This gives these fibers a darker red color, causing the overall appearance of the biopsy to be described as "ragged red fibers."
Laboratory Studies
Blood lactateLactate
Lactate may refer to:*The act of lactation*The conjugate base of lactic acid...
and pyruvate levels usually are elevated as a result of increased anaerobic metabolism and a decreased ratio of ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
:ADP
Adenosine diphosphate
Adenosine diphosphate, abbreviated ADP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside adenosine. ADP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase adenine....
. CSF analysis shows an elevated protein level, usually >100 mg/dl, as well as an elevated lactate level.
Management and Treatment
Currently there is no curative treatment for KSS. Because it is a rare condition, there are only case reports of treatments with very little data to support their effectiveness. Several promising discoveries have been reported which may support the discovery of new treatments with further research. Satellite cells are responsible for muscle fiber regeneration. It has been noted that mutant mtDNA is rare or undetectable in satellite cells cultured from patients with KSS. Shoubridge et al. (1997) asked the question whether wildtype mtDNA could be restored to muscle tissue by encouraging muscle regeneration. 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. Perhaps with future techniques of promoting muscle cell regeneration and satellite cell proliferation, functional status in KSS patients could be greatly improved.One study described a patient with KSS who had reduced serum levels of coenzyme Q10. Administration of 60–120 mg of Coenzyme Q10 for 3 months resulted in normalization of lactate
Lactate
Lactate may refer to:*The act of lactation*The conjugate base of lactic acid...
and pyruvate levels, improvement of previously diagnosed first degree AV block, and improvement of ocular movements.
A screening EKG is recommended in all patients presenting with CPEO. In KSS, implantation of pacemaker
Artificial pacemaker
A pacemaker is a medical device that uses electrical impulses, delivered by electrodes contacting the heart muscles, to regulate the beating of the heart...
is advised following the development of significant conduction disease, even in asymptomatic patients.
Screening for endocrinologic disorders should be performed, including measuring serum glucose levels
Blood sugar
The blood sugar concentration or blood glucose level is the amount of glucose present in the blood of a human or animal. Normally in mammals, the body maintains the blood glucose level at a reference range between about 3.6 and 5.8 mM , or 64.8 and 104.4 mg/dL...
, thyroid function tests
Thyroid function tests
Thyroid function tests is a collective term for blood tests used to check the function of the thyroid.TFTs may be requested if a patient is thought to suffer from hyperthyroidism or hypothyroidism , or to monitor the effectiveness of either thyroid-suppression or hormone replacement therapy...
, calcium and magnesium levels, and serum electrolyte
Electrolyte
In chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....
levels. Hyperaldosteronism
Hyperaldosteronism
Hyperaldosteronism, also aldosteronism, is a medical condition where too much aldosterone is produced by the adrenal glands, which can lead to lowered levels of potassium in the blood.-Types:...
is seen in 3% of KSS patients.