Kearns Sayre Syndrome: Symptoms, Types, Causes and Treatment

Kearns Sayre Syndrome (KSS) is a rare, multisystem mitochondrial disorder with a distinctive range of symptoms that often appear in childhood or adolescence. While its hallmark features affect the eyes, heart, and muscles, KSS can impact almost every organ system, leading to a complex clinical picture that challenges both patients and clinicians. Understanding the symptoms, types, causes, and treatment options of KSS is vital for effective management and improving quality of life.

Symptoms of Kearns Sayre Syndrome

Kearns Sayre Syndrome is known for its wide-ranging and progressive symptoms. While some features are considered “classic” and form the diagnostic triad, patients may experience a diverse array of manifestations affecting multiple body systems. Early recognition of these symptoms can lead to timely diagnosis and improved management.

Symptom	Description	Common Onset	Source(s)
Ophthalmoplegia	Weakness/paralysis of eye muscles	Childhood/Teens	2 3 5
Ptosis	Drooping eyelids	Childhood	2 3 5
Retinopathy	Pigmentary retinal degeneration	Childhood/Teens	2 3 5 9
Heart Block	Electrical cardiac conduction defects	Teens/Young Adult	2 3 10 12
Hearing Loss	Bilateral sensorineural deafness	Childhood/Teens	5 12
Muscle Weakness	Skeletal muscle weakness, exercise fatigue	Variable	7 12
Endocrinopathy	Diabetes, thyroid, gonadal failure	Variable	8 12
Ataxia	Unsteady gait, poor coordination	Childhood/Teens	2 3 7
Renal Issues	Tubular acidosis, electrolyte imbalances	Childhood	1 8
Growth Issues	Short stature	Childhood	8

Table 1: Key Symptoms of Kearns Sayre Syndrome

Overview of Major Symptoms

KSS presents with a highly variable constellation of symptoms, but several stand out as central to the diagnosis.

Classic Triad: The Hallmarks of KSS

• Progressive External Ophthalmoplegia: This refers to a gradual weakening or paralysis of the eye muscles, leading to difficulty moving the eyes and often resulting in double vision. Bilateral ptosis (drooping eyelids) is often present, and these symptoms typically emerge before age 20 2 3 5.
• Pigmentary Retinopathy: This is a degeneration of the retina that gives a mottled, speckled appearance on examination and can lead to vision loss over time 2 3 5 9.
• Cardiac Conduction Defects: Abnormalities in the electrical signaling of the heart can manifest as heart block, which can be life-threatening if not managed appropriately 2 3 10 12.

Additional Neurological and Muscular Features

• Ataxia: Problems with balance and coordination, resulting in an unsteady, wide-based gait 2 3 7.
• Muscle Weakness & Fatigue: This can be generalized or proximal, affecting daily activities and exercise tolerance 7 12.
• Sensorineural Hearing Loss: Hearing impairment due to nerve involvement is increasingly recognized in KSS 5 12.

Endocrine, Renal, and Growth Manifestations

• Endocrinopathies: Patients may develop diabetes mellitus, thyroid dysfunction, gonadal failure, and other hormonal disturbances. Short stature is also commonly reported, likely due to a combination of endocrine and metabolic issues 8 12.
• Renal Tubular Acidosis: Some patients, particularly children, present with kidney-related symptoms such as renal tubular acidosis, leading to electrolyte imbalances and tetany (muscle spasms) 1 8.

Less Common and Rare Symptoms

• Deafness, Gut Dysmotility, Corneal Edema, and Retinoschisis: Additional rare features, including problems with the gastrointestinal tract, sensorineural deafness, and retinal splitting (retinoschisis), have been described in case reports 5.
• Skeletal and Dental Abnormalities: Arachnodactyly (long, slender fingers), high-arched palate, severe myopia, and tooth/bone calcification issues may occur in some individuals 4 8.

Types of Kearns Sayre Syndrome

While KSS is traditionally considered a single clinical entity, increasing evidence points to a spectrum of related disorders and variable expression, partly due to genetic diversity and phenotypic variability.

Type/Variant	Key Features/Distinctions	Inheritance	Source(s)
Classic KSS	Triad: ophthalmoplegia, retinopathy, heart block	Sporadic/Inherited	2 3 4 7
KSS with Endocrine	Prominent endocrine dysfunction	Sporadic	8 12
KSS with Renal	Renal tubular acidosis as presenting sign	Sporadic	1
Inherited KSS	Family clusters, variable penetrance	AD/AR patterns	4 7
Overlapping Syndromes	Features of CPEO, Pearson, etc.	Variable	6 12

Table 2: Subtypes and Variants of Kearns Sayre Syndrome

Classic Kearns Sayre Syndrome

Most cases of KSS present with the full triad of progressive external ophthalmoplegia, pigmentary retinopathy, and heart block, often with the onset of symptoms before the age of 20. This classic presentation is considered the archetype of the disorder 2 3.

Endocrine- or Renal-predominant Variants

Some individuals may first present with significant endocrine dysfunctions, such as diabetes mellitus, thyroid disease, or hypoparathyroidism, or with renal tubular acidosis. These manifestations can sometimes precede the classic ocular or cardiac symptoms, complicating diagnosis 1 8 12.

Inherited Forms and Familial Clustering

While many cases of KSS are sporadic, familial cases exhibiting autosomal dominant or autosomal recessive inheritance patterns have been documented. These tend to show variable expression, with some family members having only mild symptoms or subclinical findings 4 7.

Overlap with Other Mitochondrial Syndromes

KSS shares clinical and genetic overlap with other mitochondrial disorders, such as Chronic Progressive External Ophthalmoplegia (CPEO) and Pearson syndrome. Some patients evolve from one phenotype to another, or may initially be misclassified 6 12.

Spectrum of Phenotypic Expression

• Mild to Severe: Even within families, the severity and range of symptoms can differ widely, from isolated ophthalmoplegia to multisystem involvement.
• Unique Features: Rare presentations such as retinoschisis or prominent cardiac arrhythmias (beyond heart block) have been reported, suggesting that the clinical spectrum of KSS continues to expand 5 14.

Causes of Kearns Sayre Syndrome

Understanding the underlying causes of KSS is crucial not only for diagnosis but for future therapeutic strategies. At its core, KSS is a mitochondrial disorder, but the genetic and molecular landscape is complex.

Cause	Mechanism/Description	Type	Source(s)
mtDNA Deletions	Large-scale deletions in mitochondrial DNA	Sporadic	6 12
mtDNA Duplications	Duplicated segments of mitochondrial DNA	Sporadic	6
Nuclear Gene Mutations	Defects in genes (e.g., RRM2B) affecting mtDNA	Inherited	11
Inheritance	AD/AR patterns in rare familial cases	Genetic	4 7
Cellular Energy Deficit	Impaired oxidative phosphorylation in cells	Pathogenic	16

Table 3: Causes and Pathogenesis of Kearns Sayre Syndrome

Mitochondrial DNA (mtDNA) Rearrangements

• Large-scale Deletions: The majority of KSS cases are caused by large deletions in the mitochondrial DNA. These deletions remove key genes necessary for mitochondrial function, leading to energy deficits in affected tissues 6 12. The size and position of the deletions vary between individuals, contributing to the diversity of symptoms 12.
• Duplications: Some cases also show duplications of mtDNA, particularly in early-onset disease. The balance between deletions and duplications appears central to the pathogenesis and may influence disease severity 6.

Nuclear Gene Mutations

• RRM2B and Others: A minority of patients, especially adults, may have mutations in nuclear genes involved in mitochondrial DNA maintenance and replication, such as RRM2B. These mutations can cause multiple mtDNA deletions and a KSS phenotype, highlighting the complex genetic architecture of the disorder 11.

Inheritance Patterns

• While most cases are sporadic, involving new (de novo) mutations in mtDNA, some familial clusters have shown autosomal dominant or autosomal recessive inheritance, suggesting genetic modifiers or nuclear gene involvement 4 7 11.
• Variable Penetrance: Even within families, not all individuals carrying a mutation will develop full-blown KSS, reflecting the role of heteroplasmy (variable load of mutant mitochondria) and other modifying factors 7.

Pathophysiological Mechanism: Cellular Energy Failure

• The unifying theme in KSS is impaired mitochondrial function, leading to reduced ATP production and widespread tissue dysfunction, particularly in organs with high energy demands such as the brain, eyes, heart, and skeletal muscle 16.
• Tissue Specificity: The severity and location of symptoms often reflect the proportion of mutated mtDNA in different tissues. For example, the absence of mtDNA deletions in blood but presence in muscle can explain why some diagnostic tests may be negative unless a muscle biopsy is performed 16.

Treatment of Kearns Sayre Syndrome

While there is no cure for KSS, management focuses on alleviating symptoms, preventing complications, and improving quality of life. Treatment is highly individualized and multidisciplinary, reflecting the syndrome’s wide-ranging effects.

Treatment	Purpose/Target Symptom	Outcome/Consideration	Source(s)
Pacemaker/ICD	Manage heart block, prevent sudden death	Life-saving	10 14 15
Coenzyme Q10	Support mitochondrial function	Improves symptoms	13
Endocrine Therapy	Treat diabetes, thyroid, gonadal issues	Symptom control	8 12
Renal Management	Correct acidosis/electrolyte disturbances	Prevent complications	1
Hearing Aids/Cochlear	Address hearing loss	Improves function	5 12
Physical Therapy	Maintain muscle strength, mobility	Delays progression	7 16
iPSC Therapies	Future: cell replacement for affected tissues	Experimental	16

Table 4: Management and Treatment Options for Kearns Sayre Syndrome

Cardiac Care: Pacemakers and Defibrillators

• Pacemaker Implantation: Due to the high risk of progressive heart block and sudden cardiac death, prophylactic pacemaker insertion is recommended for KSS patients with conduction abnormalities—even before symptoms develop 10 15.
• Implantable Cardioverter Defibrillators (ICDs): For patients prone to dangerous arrhythmias (e.g., ventricular tachycardia, fibrillation), ICDs may be necessary. Pacemakers alone may not prevent fatal arrhythmias in all cases 14.
• Regular Cardiac Monitoring: Ongoing electrocardiogram (ECG) and, increasingly, cardiac MRI are vital for early detection and management of cardiac involvement 10.

Mitochondrial Support: Coenzyme Q10

• CoQ10 Supplementation: Coenzyme Q10, a key mitochondrial electron carrier, may help support cellular energy production. Studies indicate improvements in muscle metabolism, neurologic symptoms, and cardiac conduction in some patients 13.
• Dosing and Response: Typical doses range from 120-150 mg/day, but individual response varies, and CoQ10 is not a cure 13.

Endocrine and Metabolic Management

• Diabetes and Thyroid Disorders: Standard therapies for diabetes and thyroid disease are applied, with careful monitoring and adjustment for each patient’s needs 8 12.
• Other Endocrine Issues: Hormone replacement and management of growth, gonadal, or adrenal insufficiencies should be guided by endocrinology specialists 8.

Renal and Electrolyte Support

• Acidosis Management: Renal tubular acidosis and related electrolyte imbalances are managed with appropriate medications and monitoring, especially in pediatric cases 1.
• Regular Laboratory Surveillance: Ongoing assessment of kidney function and electrolytes is crucial to avoid complications.

Rehabilitation and Supportive Therapies

• Physical and Occupational Therapy: These interventions help maintain mobility, muscle strength, and independence as the disease progresses 7 16.
• Hearing and Vision Support: Hearing aids, cochlear implants, and low-vision aids can significantly improve quality of life for those with sensory involvement 5 12.

Experimental and Future Therapies

• Stem Cell and iPSC Therapies: Research into patient-specific induced pluripotent stem cells (iPSC) offers hope for future cell replacement strategies, especially as mutation-free iPSCs can be derived from patient blood and differentiated into needed cell types 16.
• Gene Therapy: While not yet available, advances in mitochondrial gene editing may one day provide targeted treatments.

Conclusion

Kearns Sayre Syndrome is a devastating but fascinating example of how mitochondrial dysfunction can have profound, multisystem consequences. Early recognition and multidisciplinary management are critical for optimizing patient outcomes.

Key takeaways:

• KSS presents with a triad of ophthalmoplegia, pigmentary retinopathy, and heart block, but can affect many organ systems.
• The clinical spectrum is broad, with significant variability even within families.
• Most cases result from large-scale deletions or duplications in mitochondrial DNA, though nuclear gene defects and inherited forms exist.
• Management is supportive and multidisciplinary, focusing especially on cardiac care, metabolic support, and symptom management.
• Future therapies such as stem cell replacement and gene editing hold promise for altering the course of this challenging syndrome.

By staying informed and vigilant, clinicians and families can together provide the best care and hope for those living with Kearns Sayre Syndrome.