Kearns-Sayre Syndrome (KSS) is a rare mitochondrial disorder that affects multiple systems in the body. It is characterized by a combination of symptoms, including progressive external ophthalmoplegia (paralysis or weakness of the eye muscles), pigmentary retinopathy (damage to the light-sensitive cells in the retina), and onset before the age of 20. KSS is typically caused by deletions or rearrangements of mitochondrial DNA (mtDNA).
Epidemiology
KSS is an extremely rare disorder, and comprehensive epidemiological data are limited. It is estimated to have a prevalence of approximately 1-3 cases per million individuals in the general population. KSS is considered a sporadic condition, meaning it typically occurs in individuals with no family history of the disorder. KSS can affect both males and females, and it has been reported across different ethnicities and geographic regions.
The onset of symptoms usually occurs before the age of 20, although cases with adult-onset have also been reported. KSS is a progressive disorder, and the severity and rate of progression can vary among individuals. Due to its rarity and overlap of symptoms with other mitochondrial disorders, KSS is often underdiagnosed or misdiagnosed. Some cases may remain undiagnosed or be identified later in life when additional symptoms become evident.
Anatomy
Pathophysiology
Kearns-Sayre Syndrome (KSS) is a mitochondrial disorder primarily caused by deletions or rearrangements of mitochondrial DNA (mtDNA). Mitochondria are cellular structures responsible for producing energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation. The pathophysiology of KSS is related to the dysfunction of mitochondria, particularly in tissues and organs that have high energy demands, such as the muscles and nervous system. Here is an overview of the key pathophysiological mechanisms involved in KSS:
Defective Oxidative Phosphorylation:
Deletions or rearrangements in mtDNA disrupt the normal functioning of the electron transport chain (ETC) in mitochondria. The ETC is responsible for the production of ATP through oxidative phosphorylation.
The impaired ETC function leads to a deficiency in ATP production, which is crucial for cellular energy supply. As a result, tissues and organs, especially those with high energy demands, experience energy deficits.
Mitochondrial Dysfunction:
The dysfunction of mitochondria affects multiple organ systems, including skeletal muscles, cardiac muscles, the central nervous system, and the eyes, which are particularly affected in KSS.
Skeletal Muscle: In KSS, mitochondrial dysfunction in skeletal muscles leads to the characteristic symptom of progressive external ophthalmoplegia (PEO) due to the weakness or paralysis of the eye muscles.
Cardiac Muscles: The impaired mitochondrial function can also affect the heart, leading to cardiac conduction abnormalities, arrhythmias, and progressive heart muscle weakness, which may result in heart block or heart failure.
Central Nervous System: Mitochondrial dysfunction in the brain can contribute to neurological symptoms such as ataxia (loss of muscle coordination), muscle weakness, cognitive impairment, and developmental delays.
Eyes: The retina, which has high energy demands, can be affected by mitochondrial dysfunction, leading to pigmentary retinopathy and visual disturbances.
Accumulation of mtDNA Deletions:
In KSS, there is an accumulation of mtDNA deletions within affected cells. These deletions may occur sporadically during development or as a result of defects in the maintenance and replication of mtDNA.
The exact mechanisms underlying the formation and accumulation of mtDNA deletions in KSS are not fully understood. However, they contribute to the mitochondrial dysfunction and energy deficits observed in affected tissues.
Etiology
The etiology of Kearns-Sayre Syndrome (KSS) is primarily associated with genetic abnormalities involving mitochondrial DNA (mtDNA). KSS is typically caused by deletions or rearrangements of mtDNA, specifically within the affected individual’s mitochondria. Here are the key aspects of the etiology of KSS:
Mitochondrial DNA (mtDNA) Abnormalities:
Deletions: The most common genetic abnormality in KSS is the deletion of a portion of mtDNA. These deletions can vary in size and location within the mtDNA molecule.
Rearrangements: In some cases, rearrangements of mtDNA can occur, such as duplications or inversions, contributing to the development of KSS.
Heteroplasmy: Mitochondria contain multiple copies of mtDNA, and the presence of abnormal mtDNA can vary among different tissues and cells. This variation is known as heteroplasmy, and the degree of heteroplasmy can influence the severity and clinical presentation of KSS.
Mitochondrial Inheritance:
Maternal Inheritance: Mitochondria, including their mtDNA, are primarily inherited from the mother. Therefore, KSS is inherited maternally. However, there can be exceptions, as sporadic cases with de novo mtDNA abnormalities have also been reported.
Genetic Variability:
Genetic Heterogeneity: Although mtDNA abnormalities are the most common cause of KSS, there can be genetic heterogeneity in the disorder. Rare cases of KSS have been associated with nuclear gene mutations involved in mitochondrial function.
Sporadic Cases:
While KSS is primarily inherited maternally, it can also occur sporadically without a family history of the disorder. These cases are believed to arise from de novo mutations in the mtDNA or nuclear genes involved in mitochondrial function.
Genetics
Prognostic Factors
The prognosis of Kearns-Sayre Syndrome (KSS) can vary widely among individuals and is influenced by several factors, including the age of onset, the severity of symptoms, and the involvement of various organ systems. KSS is a progressive disorder, meaning that symptoms tend to worsen over time. Here are some key aspects regarding the prognosis of KSS:
Progressive Nature: KSS is characterized by the progressive deterioration of neurological, ophthalmologic, and systemic functions. The rate of progression can vary, and the severity of symptoms may differ among affected individuals.
Vision and Eye Muscle Weakness: Visual impairment due to pigmentary retinopathy and progressive external ophthalmoplegia (PEO) is a significant feature of KSS. Over time, visual acuity may decline, and the limitation of eye movement can become more pronounced.
Neurological Manifestations: Neurological symptoms, such as muscle weakness, ataxia, and cognitive impairments, may worsen with disease progression. Mobility and coordination can be affected, leading to increased dependency on assistive devices for mobility.
Cardiac Involvement: Cardiac conduction abnormalities and cardiomyopathy can contribute to the overall prognosis of KSS. Severe cardiac manifestations may lead to heart failure, which can have a significant impact on an individual’s health and prognosis.
Systemic Complications: KSS can involve various organ systems, such as the endocrine, gastrointestinal, renal, and respiratory systems. The severity and progression of these complications can affect the overall prognosis and quality of life.
Lifespan: The lifespan of individuals with KSS can vary. In some cases, the condition can significantly impact life expectancy. However, it’s important to note that with proper management of symptoms and complications, individuals with KSS can live into adulthood and beyond.
Clinical History
Clinical history
The clinical presentation and history of Kearns-Sayre Syndrome (KSS) can vary among affected individuals. The onset of symptoms usually occurs before the age of 20, although adult-onset cases have also been reported. Here are the key aspects of the clinical history of KSS:
Progressive External Ophthalmoplegia (PEO):
PEO is one of the hallmark features of KSS. It is characterized by weakness or paralysis of the muscles that control eye movements, leading to difficulty moving the eyes. This can result in a fixed or limited gaze and drooping eyelids (ptosis).
The onset of PEO can be gradual, and individuals may initially notice difficulty with eye movements or drooping eyelids. Over time, the eye muscle weakness tends to progress, contributing to the characteristic fixed gaze.
Pigmentary Retinopathy:
Pigmentary retinopathy refers to degenerative changes in the retina, which is the light-sensitive layer at the back of the eye. These changes can lead to visual impairments and affect vision.
Symptoms of pigmentary retinopathy can include decreased visual acuity, difficulty seeing in low light conditions (night blindness), impaired color vision, and the presence of dark pigmented patches or changes in the retina.
Neurological Symptoms:
KSS can involve the central nervous system, leading to various neurological symptoms. These can include muscle weakness, ataxia (lack of muscle coordination), tremors, and balance difficulties.
Some individuals with KSS may also experience cognitive impairment, including learning disabilities or intellectual disability. Developmental delays may be observed in childhood-onset cases.
Cardiac Involvement:
Cardiac manifestations can occur in KSS and may include conduction abnormalities, such as heart block or arrhythmias. Progressive cardiac muscle weakness can lead to heart failure in some individuals.
Symptoms related to cardiac involvement can vary and may include fatigue, shortness of breath, chest pain, and palpitations.
Endocrine and Systemic Involvement:
KSS can affect various endocrine organs, leading to endocrine dysfunction. This can include hormonal imbalances, such as growth hormone deficiency, thyroid dysfunction, or diabetes mellitus.
Other systemic features that may be observed in KSS include hearing loss, gastrointestinal dysmotility, kidney dysfunction, and respiratory muscle weakness.
Physical Examination
Physical examination
The physical examination of an individual with Kearns-Sayre Syndrome (KSS) aims to assess the specific clinical features and manifestations associated with the condition. Here are some key aspects that may be evaluated during a physical examination:
Ophthalmologic Examination:
Assessment of eye movement and extraocular muscle function: The examiner will observe for any limitations or weakness in eye movements, particularly in vertical and lateral gaze. They may also check for ptosis (drooping eyelids).
Evaluation of visual acuity and color vision: Testing of visual acuity and color perception may be performed to assess the extent of visual impairment due to pigmentary retinopathy.
Cardiac Examination:
Assessment of heart sounds: The healthcare provider will listen to the heart sounds to check for any abnormalities, such as heart murmurs or irregular rhythms.
Monitoring of heart rate and rhythm: The pulse will be assessed, and an electrocardiogram (ECG) may be performed to evaluate the electrical conduction system of the heart and identify any arrhythmias or conduction abnormalities.
Evaluation of signs of heart failure: The provider may look for signs of fluid overload, such as jugular venous distention, peripheral edema, or abnormal lung sounds.
Neurologic Examination:
Evaluation of muscle strength: The examiner may assess muscle strength and detect any weakness or muscle wasting.
Assessment of coordination and balance: Tests such as finger-nose-finger, heel-to-shin, or Romberg’s test may be performed to evaluate coordination and balance.
Examination of reflexes: Deep tendon reflexes, such as the knee-jerk reflex, may be assessed to evaluate the function of the nervous system.
Other Systemic Examination:
Assessment of growth and development: The healthcare provider may evaluate growth parameters and developmental milestones, particularly in pediatric cases.
Evaluation of other organ systems: Depending on the individual’s symptoms and clinical history, the examination may include specific assessments related to endocrine, gastrointestinal, renal, or respiratory function.
Age group
Associated comorbidity
Associated activity
Acuity of presentation
Differential Diagnoses
Differential diagnosis
When considering the differential diagnosis of Kearns-Sayre Syndrome (KSS), it is important to assess other conditions that can present with similar clinical features. Here are some potential differential diagnoses to consider:
Mitochondrial Disorders:
Chronic Progressive External Ophthalmoplegia (CPEO): CPEO is a mitochondrial disorder characterized by progressive weakness of the eye muscles, leading to ptosis and ophthalmoplegia. While CPEO shares some similarities with KSS, it typically lacks additional features such as cardiac conduction abnormalities and pigmentary retinopathy.
Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS): MELAS is a mitochondrial disorder characterized by episodes of stroke-like symptoms, including seizures, hemiparesis, and encephalopathy. It can also involve ophthalmoplegia, but it is usually associated with other distinct clinical features.
Other Mitochondrial Deletion Syndromes:
Pearson Syndrome: Pearson syndrome is a rare mitochondrial disorder characterized by anemia, pancreatic dysfunction, and bone marrow failure in infancy. It can later present with symptoms overlapping with KSS, including ophthalmoplegia and multisystem involvement.
Leigh Syndrome: Leigh syndrome is a progressive neurodegenerative disorder often presenting in infancy or early childhood with neurological symptoms, including developmental regression, movement disorders, and respiratory problems. It can also feature ophthalmoplegia and multisystem involvement.
Progressive External Ophthalmoplegia Plus (PEO+):
PEO+ refers to a group of disorders characterized by progressive weakness of the eye muscles (external ophthalmoplegia) along with additional clinical features such as muscle weakness, ataxia, peripheral neuropathy, or other systemic manifestations. These conditions may have genetic or acquired causes and can resemble KSS.
Other Neuromuscular Disorders:
Myasthenia Gravis: Myasthenia gravis is an autoimmune disorder characterized by muscle weakness and fatigability, including oculomotor involvement. It can present with ophthalmoplegia, ptosis, and fluctuating muscle weakness, which may resemble KSS.
Muscular Dystrophies: Certain muscular dystrophies, such as limb-girdle muscular dystrophy or oculopharyngeal muscular dystrophy, can involve ophthalmoplegia and muscle weakness, leading to a resemblance with KSS.
Laboratory Studies
Imaging Studies
Procedures
Histologic Findings
Staging
Treatment Paradigm
Currently, there is no cure for Kearns-Sayre Syndrome (KSS) as it is a progressive mitochondrial disorder. Treatment primarily focuses on managing the symptoms and complications associated with the condition. The management of KSS typically involves a multidisciplinary approach and may include the following:
Ophthalmologic Care:
Regular ophthalmologic evaluations are important to monitor the progression of visual impairments and provide appropriate interventions.
Corrective lenses or visual aids may be prescribed to improve visual acuity and accommodate for specific visual deficits.
Cardiac Management:
Individuals with KSS may require monitoring and management of cardiac conduction abnormalities or arrhythmias.
Treatment options may include medications to regulate heart rate and rhythm or the placement of a pacemaker or implantable cardioverter-defibrillator (ICD) to address severe cardiac conduction disturbances.
Neurological Support:
Physical therapy, occupational therapy, and speech therapy may be beneficial in managing neurological symptoms, improving muscle strength, coordination, and communication abilities.
Assistive devices, such as braces, walkers, or wheelchairs, may be recommended to enhance mobility and independence.
Endocrine Management:
Regular monitoring of endocrine function, including thyroid hormone levels, glucose levels, and growth hormone status, is important.
Hormone replacement therapy or other interventions may be prescribed to address specific endocrine dysfunctions.
Symptomatic Treatment:
Pharmacological interventions may be utilized to manage specific symptoms such as muscle weakness, tremors, or other neurological manifestations.
Supportive care may involve addressing gastrointestinal dysmotility, hearing loss, respiratory muscle weakness, or other systemic complications as they arise.
Psychological and Emotional Support:
Counseling or support groups may be beneficial for individuals and their families to cope with the challenges and emotional impact of living with a chronic, progressive condition.
Kearns-Sayre Syndrome (KSS) is a rare mitochondrial disorder that affects multiple systems in the body. It is characterized by a combination of symptoms, including progressive external ophthalmoplegia (paralysis or weakness of the eye muscles), pigmentary retinopathy (damage to the light-sensitive cells in the retina), and onset before the age of 20. KSS is typically caused by deletions or rearrangements of mitochondrial DNA (mtDNA).
KSS is an extremely rare disorder, and comprehensive epidemiological data are limited. It is estimated to have a prevalence of approximately 1-3 cases per million individuals in the general population. KSS is considered a sporadic condition, meaning it typically occurs in individuals with no family history of the disorder. KSS can affect both males and females, and it has been reported across different ethnicities and geographic regions.
The onset of symptoms usually occurs before the age of 20, although cases with adult-onset have also been reported. KSS is a progressive disorder, and the severity and rate of progression can vary among individuals. Due to its rarity and overlap of symptoms with other mitochondrial disorders, KSS is often underdiagnosed or misdiagnosed. Some cases may remain undiagnosed or be identified later in life when additional symptoms become evident.
Kearns-Sayre Syndrome (KSS) is a mitochondrial disorder primarily caused by deletions or rearrangements of mitochondrial DNA (mtDNA). Mitochondria are cellular structures responsible for producing energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation. The pathophysiology of KSS is related to the dysfunction of mitochondria, particularly in tissues and organs that have high energy demands, such as the muscles and nervous system. Here is an overview of the key pathophysiological mechanisms involved in KSS:
Defective Oxidative Phosphorylation:
Deletions or rearrangements in mtDNA disrupt the normal functioning of the electron transport chain (ETC) in mitochondria. The ETC is responsible for the production of ATP through oxidative phosphorylation.
The impaired ETC function leads to a deficiency in ATP production, which is crucial for cellular energy supply. As a result, tissues and organs, especially those with high energy demands, experience energy deficits.
Mitochondrial Dysfunction:
The dysfunction of mitochondria affects multiple organ systems, including skeletal muscles, cardiac muscles, the central nervous system, and the eyes, which are particularly affected in KSS.
Skeletal Muscle: In KSS, mitochondrial dysfunction in skeletal muscles leads to the characteristic symptom of progressive external ophthalmoplegia (PEO) due to the weakness or paralysis of the eye muscles.
Cardiac Muscles: The impaired mitochondrial function can also affect the heart, leading to cardiac conduction abnormalities, arrhythmias, and progressive heart muscle weakness, which may result in heart block or heart failure.
Central Nervous System: Mitochondrial dysfunction in the brain can contribute to neurological symptoms such as ataxia (loss of muscle coordination), muscle weakness, cognitive impairment, and developmental delays.
Eyes: The retina, which has high energy demands, can be affected by mitochondrial dysfunction, leading to pigmentary retinopathy and visual disturbances.
Accumulation of mtDNA Deletions:
In KSS, there is an accumulation of mtDNA deletions within affected cells. These deletions may occur sporadically during development or as a result of defects in the maintenance and replication of mtDNA.
The exact mechanisms underlying the formation and accumulation of mtDNA deletions in KSS are not fully understood. However, they contribute to the mitochondrial dysfunction and energy deficits observed in affected tissues.
The etiology of Kearns-Sayre Syndrome (KSS) is primarily associated with genetic abnormalities involving mitochondrial DNA (mtDNA). KSS is typically caused by deletions or rearrangements of mtDNA, specifically within the affected individual’s mitochondria. Here are the key aspects of the etiology of KSS:
Mitochondrial DNA (mtDNA) Abnormalities:
Deletions: The most common genetic abnormality in KSS is the deletion of a portion of mtDNA. These deletions can vary in size and location within the mtDNA molecule.
Rearrangements: In some cases, rearrangements of mtDNA can occur, such as duplications or inversions, contributing to the development of KSS.
Heteroplasmy: Mitochondria contain multiple copies of mtDNA, and the presence of abnormal mtDNA can vary among different tissues and cells. This variation is known as heteroplasmy, and the degree of heteroplasmy can influence the severity and clinical presentation of KSS.
Mitochondrial Inheritance:
Maternal Inheritance: Mitochondria, including their mtDNA, are primarily inherited from the mother. Therefore, KSS is inherited maternally. However, there can be exceptions, as sporadic cases with de novo mtDNA abnormalities have also been reported.
Genetic Variability:
Genetic Heterogeneity: Although mtDNA abnormalities are the most common cause of KSS, there can be genetic heterogeneity in the disorder. Rare cases of KSS have been associated with nuclear gene mutations involved in mitochondrial function.
Sporadic Cases:
While KSS is primarily inherited maternally, it can also occur sporadically without a family history of the disorder. These cases are believed to arise from de novo mutations in the mtDNA or nuclear genes involved in mitochondrial function.
The prognosis of Kearns-Sayre Syndrome (KSS) can vary widely among individuals and is influenced by several factors, including the age of onset, the severity of symptoms, and the involvement of various organ systems. KSS is a progressive disorder, meaning that symptoms tend to worsen over time. Here are some key aspects regarding the prognosis of KSS:
Progressive Nature: KSS is characterized by the progressive deterioration of neurological, ophthalmologic, and systemic functions. The rate of progression can vary, and the severity of symptoms may differ among affected individuals.
Vision and Eye Muscle Weakness: Visual impairment due to pigmentary retinopathy and progressive external ophthalmoplegia (PEO) is a significant feature of KSS. Over time, visual acuity may decline, and the limitation of eye movement can become more pronounced.
Neurological Manifestations: Neurological symptoms, such as muscle weakness, ataxia, and cognitive impairments, may worsen with disease progression. Mobility and coordination can be affected, leading to increased dependency on assistive devices for mobility.
Cardiac Involvement: Cardiac conduction abnormalities and cardiomyopathy can contribute to the overall prognosis of KSS. Severe cardiac manifestations may lead to heart failure, which can have a significant impact on an individual’s health and prognosis.
Systemic Complications: KSS can involve various organ systems, such as the endocrine, gastrointestinal, renal, and respiratory systems. The severity and progression of these complications can affect the overall prognosis and quality of life.
Lifespan: The lifespan of individuals with KSS can vary. In some cases, the condition can significantly impact life expectancy. However, it’s important to note that with proper management of symptoms and complications, individuals with KSS can live into adulthood and beyond.
Clinical history
The clinical presentation and history of Kearns-Sayre Syndrome (KSS) can vary among affected individuals. The onset of symptoms usually occurs before the age of 20, although adult-onset cases have also been reported. Here are the key aspects of the clinical history of KSS:
Progressive External Ophthalmoplegia (PEO):
PEO is one of the hallmark features of KSS. It is characterized by weakness or paralysis of the muscles that control eye movements, leading to difficulty moving the eyes. This can result in a fixed or limited gaze and drooping eyelids (ptosis).
The onset of PEO can be gradual, and individuals may initially notice difficulty with eye movements or drooping eyelids. Over time, the eye muscle weakness tends to progress, contributing to the characteristic fixed gaze.
Pigmentary Retinopathy:
Pigmentary retinopathy refers to degenerative changes in the retina, which is the light-sensitive layer at the back of the eye. These changes can lead to visual impairments and affect vision.
Symptoms of pigmentary retinopathy can include decreased visual acuity, difficulty seeing in low light conditions (night blindness), impaired color vision, and the presence of dark pigmented patches or changes in the retina.
Neurological Symptoms:
KSS can involve the central nervous system, leading to various neurological symptoms. These can include muscle weakness, ataxia (lack of muscle coordination), tremors, and balance difficulties.
Some individuals with KSS may also experience cognitive impairment, including learning disabilities or intellectual disability. Developmental delays may be observed in childhood-onset cases.
Cardiac Involvement:
Cardiac manifestations can occur in KSS and may include conduction abnormalities, such as heart block or arrhythmias. Progressive cardiac muscle weakness can lead to heart failure in some individuals.
Symptoms related to cardiac involvement can vary and may include fatigue, shortness of breath, chest pain, and palpitations.
Endocrine and Systemic Involvement:
KSS can affect various endocrine organs, leading to endocrine dysfunction. This can include hormonal imbalances, such as growth hormone deficiency, thyroid dysfunction, or diabetes mellitus.
Other systemic features that may be observed in KSS include hearing loss, gastrointestinal dysmotility, kidney dysfunction, and respiratory muscle weakness.
Physical examination
The physical examination of an individual with Kearns-Sayre Syndrome (KSS) aims to assess the specific clinical features and manifestations associated with the condition. Here are some key aspects that may be evaluated during a physical examination:
Ophthalmologic Examination:
Assessment of eye movement and extraocular muscle function: The examiner will observe for any limitations or weakness in eye movements, particularly in vertical and lateral gaze. They may also check for ptosis (drooping eyelids).
Evaluation of visual acuity and color vision: Testing of visual acuity and color perception may be performed to assess the extent of visual impairment due to pigmentary retinopathy.
Cardiac Examination:
Assessment of heart sounds: The healthcare provider will listen to the heart sounds to check for any abnormalities, such as heart murmurs or irregular rhythms.
Monitoring of heart rate and rhythm: The pulse will be assessed, and an electrocardiogram (ECG) may be performed to evaluate the electrical conduction system of the heart and identify any arrhythmias or conduction abnormalities.
Evaluation of signs of heart failure: The provider may look for signs of fluid overload, such as jugular venous distention, peripheral edema, or abnormal lung sounds.
Neurologic Examination:
Evaluation of muscle strength: The examiner may assess muscle strength and detect any weakness or muscle wasting.
Assessment of coordination and balance: Tests such as finger-nose-finger, heel-to-shin, or Romberg’s test may be performed to evaluate coordination and balance.
Examination of reflexes: Deep tendon reflexes, such as the knee-jerk reflex, may be assessed to evaluate the function of the nervous system.
Other Systemic Examination:
Assessment of growth and development: The healthcare provider may evaluate growth parameters and developmental milestones, particularly in pediatric cases.
Evaluation of other organ systems: Depending on the individual’s symptoms and clinical history, the examination may include specific assessments related to endocrine, gastrointestinal, renal, or respiratory function.
Differential diagnosis
When considering the differential diagnosis of Kearns-Sayre Syndrome (KSS), it is important to assess other conditions that can present with similar clinical features. Here are some potential differential diagnoses to consider:
Mitochondrial Disorders:
Chronic Progressive External Ophthalmoplegia (CPEO): CPEO is a mitochondrial disorder characterized by progressive weakness of the eye muscles, leading to ptosis and ophthalmoplegia. While CPEO shares some similarities with KSS, it typically lacks additional features such as cardiac conduction abnormalities and pigmentary retinopathy.
Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS): MELAS is a mitochondrial disorder characterized by episodes of stroke-like symptoms, including seizures, hemiparesis, and encephalopathy. It can also involve ophthalmoplegia, but it is usually associated with other distinct clinical features.
Other Mitochondrial Deletion Syndromes:
Pearson Syndrome: Pearson syndrome is a rare mitochondrial disorder characterized by anemia, pancreatic dysfunction, and bone marrow failure in infancy. It can later present with symptoms overlapping with KSS, including ophthalmoplegia and multisystem involvement.
Leigh Syndrome: Leigh syndrome is a progressive neurodegenerative disorder often presenting in infancy or early childhood with neurological symptoms, including developmental regression, movement disorders, and respiratory problems. It can also feature ophthalmoplegia and multisystem involvement.
Progressive External Ophthalmoplegia Plus (PEO+):
PEO+ refers to a group of disorders characterized by progressive weakness of the eye muscles (external ophthalmoplegia) along with additional clinical features such as muscle weakness, ataxia, peripheral neuropathy, or other systemic manifestations. These conditions may have genetic or acquired causes and can resemble KSS.
Other Neuromuscular Disorders:
Myasthenia Gravis: Myasthenia gravis is an autoimmune disorder characterized by muscle weakness and fatigability, including oculomotor involvement. It can present with ophthalmoplegia, ptosis, and fluctuating muscle weakness, which may resemble KSS.
Muscular Dystrophies: Certain muscular dystrophies, such as limb-girdle muscular dystrophy or oculopharyngeal muscular dystrophy, can involve ophthalmoplegia and muscle weakness, leading to a resemblance with KSS.
Currently, there is no cure for Kearns-Sayre Syndrome (KSS) as it is a progressive mitochondrial disorder. Treatment primarily focuses on managing the symptoms and complications associated with the condition. The management of KSS typically involves a multidisciplinary approach and may include the following:
Ophthalmologic Care:
Regular ophthalmologic evaluations are important to monitor the progression of visual impairments and provide appropriate interventions.
Corrective lenses or visual aids may be prescribed to improve visual acuity and accommodate for specific visual deficits.
Cardiac Management:
Individuals with KSS may require monitoring and management of cardiac conduction abnormalities or arrhythmias.
Treatment options may include medications to regulate heart rate and rhythm or the placement of a pacemaker or implantable cardioverter-defibrillator (ICD) to address severe cardiac conduction disturbances.
Neurological Support:
Physical therapy, occupational therapy, and speech therapy may be beneficial in managing neurological symptoms, improving muscle strength, coordination, and communication abilities.
Assistive devices, such as braces, walkers, or wheelchairs, may be recommended to enhance mobility and independence.
Endocrine Management:
Regular monitoring of endocrine function, including thyroid hormone levels, glucose levels, and growth hormone status, is important.
Hormone replacement therapy or other interventions may be prescribed to address specific endocrine dysfunctions.
Symptomatic Treatment:
Pharmacological interventions may be utilized to manage specific symptoms such as muscle weakness, tremors, or other neurological manifestations.
Supportive care may involve addressing gastrointestinal dysmotility, hearing loss, respiratory muscle weakness, or other systemic complications as they arise.
Psychological and Emotional Support:
Counseling or support groups may be beneficial for individuals and their families to cope with the challenges and emotional impact of living with a chronic, progressive condition.
https://www.ncbi.nlm.nih.gov/books/NBK482341/
medtigo
Kearns-Sayre Syndrome
Updated :
May 16, 2024
Kearns-Sayre Syndrome (KSS) is a rare mitochondrial disorder that affects multiple systems in the body. It is characterized by a combination of symptoms, including progressive external ophthalmoplegia (paralysis or weakness of the eye muscles), pigmentary retinopathy (damage to the light-sensitive cells in the retina), and onset before the age of 20. KSS is typically caused by deletions or rearrangements of mitochondrial DNA (mtDNA).
KSS is an extremely rare disorder, and comprehensive epidemiological data are limited. It is estimated to have a prevalence of approximately 1-3 cases per million individuals in the general population. KSS is considered a sporadic condition, meaning it typically occurs in individuals with no family history of the disorder. KSS can affect both males and females, and it has been reported across different ethnicities and geographic regions.
The onset of symptoms usually occurs before the age of 20, although cases with adult-onset have also been reported. KSS is a progressive disorder, and the severity and rate of progression can vary among individuals. Due to its rarity and overlap of symptoms with other mitochondrial disorders, KSS is often underdiagnosed or misdiagnosed. Some cases may remain undiagnosed or be identified later in life when additional symptoms become evident.
Kearns-Sayre Syndrome (KSS) is a mitochondrial disorder primarily caused by deletions or rearrangements of mitochondrial DNA (mtDNA). Mitochondria are cellular structures responsible for producing energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation. The pathophysiology of KSS is related to the dysfunction of mitochondria, particularly in tissues and organs that have high energy demands, such as the muscles and nervous system. Here is an overview of the key pathophysiological mechanisms involved in KSS:
Defective Oxidative Phosphorylation:
Deletions or rearrangements in mtDNA disrupt the normal functioning of the electron transport chain (ETC) in mitochondria. The ETC is responsible for the production of ATP through oxidative phosphorylation.
The impaired ETC function leads to a deficiency in ATP production, which is crucial for cellular energy supply. As a result, tissues and organs, especially those with high energy demands, experience energy deficits.
Mitochondrial Dysfunction:
The dysfunction of mitochondria affects multiple organ systems, including skeletal muscles, cardiac muscles, the central nervous system, and the eyes, which are particularly affected in KSS.
Skeletal Muscle: In KSS, mitochondrial dysfunction in skeletal muscles leads to the characteristic symptom of progressive external ophthalmoplegia (PEO) due to the weakness or paralysis of the eye muscles.
Cardiac Muscles: The impaired mitochondrial function can also affect the heart, leading to cardiac conduction abnormalities, arrhythmias, and progressive heart muscle weakness, which may result in heart block or heart failure.
Central Nervous System: Mitochondrial dysfunction in the brain can contribute to neurological symptoms such as ataxia (loss of muscle coordination), muscle weakness, cognitive impairment, and developmental delays.
Eyes: The retina, which has high energy demands, can be affected by mitochondrial dysfunction, leading to pigmentary retinopathy and visual disturbances.
Accumulation of mtDNA Deletions:
In KSS, there is an accumulation of mtDNA deletions within affected cells. These deletions may occur sporadically during development or as a result of defects in the maintenance and replication of mtDNA.
The exact mechanisms underlying the formation and accumulation of mtDNA deletions in KSS are not fully understood. However, they contribute to the mitochondrial dysfunction and energy deficits observed in affected tissues.
The etiology of Kearns-Sayre Syndrome (KSS) is primarily associated with genetic abnormalities involving mitochondrial DNA (mtDNA). KSS is typically caused by deletions or rearrangements of mtDNA, specifically within the affected individual’s mitochondria. Here are the key aspects of the etiology of KSS:
Mitochondrial DNA (mtDNA) Abnormalities:
Deletions: The most common genetic abnormality in KSS is the deletion of a portion of mtDNA. These deletions can vary in size and location within the mtDNA molecule.
Rearrangements: In some cases, rearrangements of mtDNA can occur, such as duplications or inversions, contributing to the development of KSS.
Heteroplasmy: Mitochondria contain multiple copies of mtDNA, and the presence of abnormal mtDNA can vary among different tissues and cells. This variation is known as heteroplasmy, and the degree of heteroplasmy can influence the severity and clinical presentation of KSS.
Mitochondrial Inheritance:
Maternal Inheritance: Mitochondria, including their mtDNA, are primarily inherited from the mother. Therefore, KSS is inherited maternally. However, there can be exceptions, as sporadic cases with de novo mtDNA abnormalities have also been reported.
Genetic Variability:
Genetic Heterogeneity: Although mtDNA abnormalities are the most common cause of KSS, there can be genetic heterogeneity in the disorder. Rare cases of KSS have been associated with nuclear gene mutations involved in mitochondrial function.
Sporadic Cases:
While KSS is primarily inherited maternally, it can also occur sporadically without a family history of the disorder. These cases are believed to arise from de novo mutations in the mtDNA or nuclear genes involved in mitochondrial function.
The prognosis of Kearns-Sayre Syndrome (KSS) can vary widely among individuals and is influenced by several factors, including the age of onset, the severity of symptoms, and the involvement of various organ systems. KSS is a progressive disorder, meaning that symptoms tend to worsen over time. Here are some key aspects regarding the prognosis of KSS:
Progressive Nature: KSS is characterized by the progressive deterioration of neurological, ophthalmologic, and systemic functions. The rate of progression can vary, and the severity of symptoms may differ among affected individuals.
Vision and Eye Muscle Weakness: Visual impairment due to pigmentary retinopathy and progressive external ophthalmoplegia (PEO) is a significant feature of KSS. Over time, visual acuity may decline, and the limitation of eye movement can become more pronounced.
Neurological Manifestations: Neurological symptoms, such as muscle weakness, ataxia, and cognitive impairments, may worsen with disease progression. Mobility and coordination can be affected, leading to increased dependency on assistive devices for mobility.
Cardiac Involvement: Cardiac conduction abnormalities and cardiomyopathy can contribute to the overall prognosis of KSS. Severe cardiac manifestations may lead to heart failure, which can have a significant impact on an individual’s health and prognosis.
Systemic Complications: KSS can involve various organ systems, such as the endocrine, gastrointestinal, renal, and respiratory systems. The severity and progression of these complications can affect the overall prognosis and quality of life.
Lifespan: The lifespan of individuals with KSS can vary. In some cases, the condition can significantly impact life expectancy. However, it’s important to note that with proper management of symptoms and complications, individuals with KSS can live into adulthood and beyond.
Clinical history
The clinical presentation and history of Kearns-Sayre Syndrome (KSS) can vary among affected individuals. The onset of symptoms usually occurs before the age of 20, although adult-onset cases have also been reported. Here are the key aspects of the clinical history of KSS:
Progressive External Ophthalmoplegia (PEO):
PEO is one of the hallmark features of KSS. It is characterized by weakness or paralysis of the muscles that control eye movements, leading to difficulty moving the eyes. This can result in a fixed or limited gaze and drooping eyelids (ptosis).
The onset of PEO can be gradual, and individuals may initially notice difficulty with eye movements or drooping eyelids. Over time, the eye muscle weakness tends to progress, contributing to the characteristic fixed gaze.
Pigmentary Retinopathy:
Pigmentary retinopathy refers to degenerative changes in the retina, which is the light-sensitive layer at the back of the eye. These changes can lead to visual impairments and affect vision.
Symptoms of pigmentary retinopathy can include decreased visual acuity, difficulty seeing in low light conditions (night blindness), impaired color vision, and the presence of dark pigmented patches or changes in the retina.
Neurological Symptoms:
KSS can involve the central nervous system, leading to various neurological symptoms. These can include muscle weakness, ataxia (lack of muscle coordination), tremors, and balance difficulties.
Some individuals with KSS may also experience cognitive impairment, including learning disabilities or intellectual disability. Developmental delays may be observed in childhood-onset cases.
Cardiac Involvement:
Cardiac manifestations can occur in KSS and may include conduction abnormalities, such as heart block or arrhythmias. Progressive cardiac muscle weakness can lead to heart failure in some individuals.
Symptoms related to cardiac involvement can vary and may include fatigue, shortness of breath, chest pain, and palpitations.
Endocrine and Systemic Involvement:
KSS can affect various endocrine organs, leading to endocrine dysfunction. This can include hormonal imbalances, such as growth hormone deficiency, thyroid dysfunction, or diabetes mellitus.
Other systemic features that may be observed in KSS include hearing loss, gastrointestinal dysmotility, kidney dysfunction, and respiratory muscle weakness.
Physical examination
The physical examination of an individual with Kearns-Sayre Syndrome (KSS) aims to assess the specific clinical features and manifestations associated with the condition. Here are some key aspects that may be evaluated during a physical examination:
Ophthalmologic Examination:
Assessment of eye movement and extraocular muscle function: The examiner will observe for any limitations or weakness in eye movements, particularly in vertical and lateral gaze. They may also check for ptosis (drooping eyelids).
Evaluation of visual acuity and color vision: Testing of visual acuity and color perception may be performed to assess the extent of visual impairment due to pigmentary retinopathy.
Cardiac Examination:
Assessment of heart sounds: The healthcare provider will listen to the heart sounds to check for any abnormalities, such as heart murmurs or irregular rhythms.
Monitoring of heart rate and rhythm: The pulse will be assessed, and an electrocardiogram (ECG) may be performed to evaluate the electrical conduction system of the heart and identify any arrhythmias or conduction abnormalities.
Evaluation of signs of heart failure: The provider may look for signs of fluid overload, such as jugular venous distention, peripheral edema, or abnormal lung sounds.
Neurologic Examination:
Evaluation of muscle strength: The examiner may assess muscle strength and detect any weakness or muscle wasting.
Assessment of coordination and balance: Tests such as finger-nose-finger, heel-to-shin, or Romberg’s test may be performed to evaluate coordination and balance.
Examination of reflexes: Deep tendon reflexes, such as the knee-jerk reflex, may be assessed to evaluate the function of the nervous system.
Other Systemic Examination:
Assessment of growth and development: The healthcare provider may evaluate growth parameters and developmental milestones, particularly in pediatric cases.
Evaluation of other organ systems: Depending on the individual’s symptoms and clinical history, the examination may include specific assessments related to endocrine, gastrointestinal, renal, or respiratory function.
Differential diagnosis
When considering the differential diagnosis of Kearns-Sayre Syndrome (KSS), it is important to assess other conditions that can present with similar clinical features. Here are some potential differential diagnoses to consider:
Mitochondrial Disorders:
Chronic Progressive External Ophthalmoplegia (CPEO): CPEO is a mitochondrial disorder characterized by progressive weakness of the eye muscles, leading to ptosis and ophthalmoplegia. While CPEO shares some similarities with KSS, it typically lacks additional features such as cardiac conduction abnormalities and pigmentary retinopathy.
Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS): MELAS is a mitochondrial disorder characterized by episodes of stroke-like symptoms, including seizures, hemiparesis, and encephalopathy. It can also involve ophthalmoplegia, but it is usually associated with other distinct clinical features.
Other Mitochondrial Deletion Syndromes:
Pearson Syndrome: Pearson syndrome is a rare mitochondrial disorder characterized by anemia, pancreatic dysfunction, and bone marrow failure in infancy. It can later present with symptoms overlapping with KSS, including ophthalmoplegia and multisystem involvement.
Leigh Syndrome: Leigh syndrome is a progressive neurodegenerative disorder often presenting in infancy or early childhood with neurological symptoms, including developmental regression, movement disorders, and respiratory problems. It can also feature ophthalmoplegia and multisystem involvement.
Progressive External Ophthalmoplegia Plus (PEO+):
PEO+ refers to a group of disorders characterized by progressive weakness of the eye muscles (external ophthalmoplegia) along with additional clinical features such as muscle weakness, ataxia, peripheral neuropathy, or other systemic manifestations. These conditions may have genetic or acquired causes and can resemble KSS.
Other Neuromuscular Disorders:
Myasthenia Gravis: Myasthenia gravis is an autoimmune disorder characterized by muscle weakness and fatigability, including oculomotor involvement. It can present with ophthalmoplegia, ptosis, and fluctuating muscle weakness, which may resemble KSS.
Muscular Dystrophies: Certain muscular dystrophies, such as limb-girdle muscular dystrophy or oculopharyngeal muscular dystrophy, can involve ophthalmoplegia and muscle weakness, leading to a resemblance with KSS.
Currently, there is no cure for Kearns-Sayre Syndrome (KSS) as it is a progressive mitochondrial disorder. Treatment primarily focuses on managing the symptoms and complications associated with the condition. The management of KSS typically involves a multidisciplinary approach and may include the following:
Ophthalmologic Care:
Regular ophthalmologic evaluations are important to monitor the progression of visual impairments and provide appropriate interventions.
Corrective lenses or visual aids may be prescribed to improve visual acuity and accommodate for specific visual deficits.
Cardiac Management:
Individuals with KSS may require monitoring and management of cardiac conduction abnormalities or arrhythmias.
Treatment options may include medications to regulate heart rate and rhythm or the placement of a pacemaker or implantable cardioverter-defibrillator (ICD) to address severe cardiac conduction disturbances.
Neurological Support:
Physical therapy, occupational therapy, and speech therapy may be beneficial in managing neurological symptoms, improving muscle strength, coordination, and communication abilities.
Assistive devices, such as braces, walkers, or wheelchairs, may be recommended to enhance mobility and independence.
Endocrine Management:
Regular monitoring of endocrine function, including thyroid hormone levels, glucose levels, and growth hormone status, is important.
Hormone replacement therapy or other interventions may be prescribed to address specific endocrine dysfunctions.
Symptomatic Treatment:
Pharmacological interventions may be utilized to manage specific symptoms such as muscle weakness, tremors, or other neurological manifestations.
Supportive care may involve addressing gastrointestinal dysmotility, hearing loss, respiratory muscle weakness, or other systemic complications as they arise.
Psychological and Emotional Support:
Counseling or support groups may be beneficial for individuals and their families to cope with the challenges and emotional impact of living with a chronic, progressive condition.
https://www.ncbi.nlm.nih.gov/books/NBK482341/
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