Kearns-Sayre Syndrome

Kearns-Sayre Syndrome

Introduction

Kearns-Sayre Syndrome (KSS) is a rare, multisystem mitochondrial disorder characterized by the triad of progressive external ophthalmoplegia, pigmentary retinopathy, and onset before age 20. It is a type of mitochondrial myopathy caused by defects in mitochondrial DNA (mtDNA).

Key Points:

  • Rare mitochondrial disorder with an estimated prevalence of 1-3 per 100,000 individuals
  • Typically presents before age 20
  • Characterized by progressive external ophthalmoplegia and pigmentary retinopathy
  • Caused by large-scale deletions or rearrangements of mitochondrial DNA
  • Multisystem disorder affecting various organs, particularly those with high energy demands
  • Progressive course with significant morbidity and reduced life expectancy

Pathophysiology

Kearns-Sayre Syndrome is caused by defects in mitochondrial DNA, which lead to dysfunction in cellular energy production. The key pathophysiological aspects include:

  1. Mitochondrial DNA Mutations:
    • Large-scale deletions (typically 1,000 to 10,000 base pairs) in mitochondrial DNA
    • These deletions are usually sporadic and not inherited
    • Deletions affect genes coding for proteins involved in oxidative phosphorylation
  2. Heteroplasmy:
    • Coexistence of normal and mutated mtDNA within cells
    • The proportion of mutated mtDNA varies among different tissues
    • Higher levels of mutated mtDNA correlate with more severe clinical manifestations
  3. Oxidative Phosphorylation Defects:
    • Impaired function of the electron transport chain complexes
    • Reduced ATP production in affected cells
    • Increased production of reactive oxygen species
  4. Tissue-Specific Effects:
    • Tissues with high energy demands (e.g., muscle, brain, heart) are most affected
    • Progressive accumulation of dysfunctional mitochondria in these tissues

The combination of energy deficiency and oxidative stress leads to progressive cellular dysfunction and tissue damage, explaining the multi-system nature and progressive course of KSS.

Clinical Presentation

Kearns-Sayre Syndrome presents with a wide range of clinical features, typically beginning before age 20. The classic triad includes:

  1. Progressive External Ophthalmoplegia (PEO):
    • Gradual, symmetric limitation of eye movements
    • Ptosis (drooping eyelids)
  2. Pigmentary Retinopathy:
    • Salt-and-pepper appearance of the retina
    • May lead to night blindness and visual field constriction
  3. Onset before age 20

Additional features may include:

  • Neurological manifestations:
    • Cerebellar ataxia
    • Cognitive impairment
    • Sensorineural hearing loss
    • Seizures
  • Cardiac abnormalities:
    • Conduction defects (e.g., heart block)
    • Cardiomyopathy
  • Endocrine dysfunction:
    • Diabetes mellitus
    • Hypoparathyroidism
    • Growth hormone deficiency
  • Muscle weakness:
    • Proximal muscle weakness
    • Exercise intolerance
  • Gastrointestinal issues:
    • Dysphagia
    • Intestinal pseudo-obstruction
  • Renal tubular acidosis

The clinical course is typically progressive, with new symptoms developing over time and existing symptoms worsening. The rate of progression can vary significantly among individuals.

Diagnosis

Diagnosis of Kearns-Sayre Syndrome involves a combination of clinical evaluation, laboratory tests, and genetic studies:

  1. Clinical Evaluation:
    • Detailed medical history, including age of onset and family history
    • Comprehensive physical and neurological examination
    • Ophthalmological assessment, including fundoscopy
  2. Laboratory Tests:
    • Serum lactate and pyruvate levels (often elevated)
    • Creatine kinase (may be normal or mildly elevated)
    • Cerebrospinal fluid protein (typically elevated > 100 mg/dL)
    • Endocrine function tests
  3. Muscle Biopsy:
    • Histological examination may show ragged red fibers
    • Enzyme histochemistry may reveal cytochrome c oxidase-deficient fibers
    • Electron microscopy may show abnormal mitochondrial morphology
  4. Genetic Testing:
    • Analysis of mitochondrial DNA for large-scale deletions
    • Next-generation sequencing for comprehensive mtDNA analysis
  5. Imaging Studies:
    • Brain MRI may show cerebral and cerebellar atrophy, white matter lesions
    • Cardiac imaging (echocardiography, cardiac MRI) to assess for cardiomyopathy
  6. Electrocardiogram (ECG):
    • To detect cardiac conduction abnormalities
  7. Audiometry:
    • To assess for sensorineural hearing loss

Diagnosis is typically based on the presence of the classic triad, supported by laboratory findings and genetic testing. However, the clinical presentation can be variable, and not all patients will exhibit all features of the classic triad.

Management

Management of Kearns-Sayre Syndrome is primarily supportive and symptomatic, as there is currently no cure for the underlying mitochondrial defect. A multidisciplinary approach is essential:

  1. Ophthalmological Management:
    • Regular ophthalmological examinations
    • Ptosis correction surgery if severe
    • Visual aids for retinopathy-related vision loss
  2. Cardiac Care:
    • Regular cardiac monitoring
    • Pacemaker implantation for conduction defects
    • Management of cardiomyopathy as per standard guidelines
  3. Neurological Management:
    • Anticonvulsants for seizure control
    • Physical therapy and occupational therapy for ataxia and muscle weakness
    • Cognitive rehabilitation for intellectual impairment
  4. Endocrine Management:
    • Hormone replacement therapy as needed (e.g., for diabetes, hypoparathyroidism)
    • Regular monitoring of endocrine function
  5. Nutritional Support:
    • Dietary modifications to optimize energy intake
    • Supplementation with coenzyme Q10, L-carnitine, and other mitochondrial cofactors (although evidence for efficacy is limited)
  6. Respiratory Support:
    • Management of respiratory insufficiency, which may include non-invasive ventilation
  7. Hearing Aids:
    • For management of sensorineural hearing loss
  8. Genetic Counseling:
    • Discuss inheritance patterns and implications for family planning

Emerging Therapies:

  • Mitochondrial replacement therapy (currently experimental)
  • Gene therapy approaches (in research phase)

Prognosis is variable, but the condition is generally progressive. Life expectancy is often reduced, with cardiac complications being a major cause of mortality. Regular follow-up with a multidisciplinary team is crucial for optimal management and early detection of complications.



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