Introduction

Kearns-Sayre Syndrome (KSS) is a rare, chronic, and progressive condition involving paralysis of the eye muscles, known as external ophthalmoplegia.¹ Patients are diagnosed based on the presence of all of the following criteria: 

• Onset of symptoms below the age of 20
• External ophthalmoplegia
• Retinitis pigmentosa (a condition causing a series of visual disturbances such as gradual vision loss, reduced night vision ability, and tunnel vision)

KSS arises due to a spontaneous mutation in mitochondrial deoxyribonucleic acid (mtDNA).¹ Apart from nuclear DNA, which presents 23 pairs of chromosomes, DNA is also found in the mitochondria, which are needed for its energy-producing function.² Mutations in mitochondrial DNA (mtDNA) in certain cell types can alter their function and the overall function of the organ they form.³

Mitochondrial DNA and its function

Structure of mtDNA

You may have heard the saying “mitochondria is the powerhouse of the cell”, but what does that mean? Mitochondria are large organelles that generate energy in the form of adenosine triphosphate (ATP), which is utilised throughout the cell for a multitude of functions.⁴ It does this via a process known as aerobic respiration, where glucose and oxygen from the blood are taken up by the cell and converted into ATP, water, and carbon dioxide.⁵

Unlike linear DNA found in the nucleus, mtDNA is a double-stranded DNA that exists in a circular structure without any end points, hence the name. However, it is still read in one direction, as in the case of linear DNA.⁶ 

Function of mtDNA

mtDNA sits in the matrix of mitochondria, the innermost compartment, and consists of 37 genes which code for 13 proteins that are essential for aerobic respiration.^6,7 The remaining genes code for transfer-ribonucleic acid (tRNA) and ribosomal RNA (rRNA), which are components used by the mitochondria to synthesise these 13 proteins.⁸

DNA and RNA structure 

RNA has a similar structure DNA where both have a sugar molecule bound to a phosphate and one of four bases.⁹ They differ in types of sugar molecules, where DNA has a deoxyribose sugar and RNA has a ribose sugar, hence their names. Furthermore, they both have either adenine, cytosine or guanine bases. However, RNA has uracil instead of DNA’s thymine. Also, RNA tends to be single-stranded whereas DNA is almost always double-stranded in its famous double helix structure.¹⁰

RNA presents a wider variety of the forms – rRNA and tRNA –  compared to DNA. Both rRNA and tRNA are single stranded RNA molecules that are folded to fulfil their functions.¹⁰ For example, rRNA is folded into a large and small subunit to make ribosomes – organelles that read genetic code in the form of messenger RNA (mRNA) and synthesise proteins. tRNA is folded into a clover shape and binds to the mRNA as it is being read by the ribosome. Opposite the mRNA binding site is an amino acid molecule, which is a subunit of a protein. As the mRNA is read and more tRNA binds, the amino acids bind together and form a chain, eventually creating the primary structure of a protein.¹¹

Role of mtDNA in cellular energy production

Unlike nuclear DNA, which is inherited from both biological parents, mtDNA is passed down solely via maternal inheritance.⁶ This is because during fertilisation, only the sperm’s nuclear DNA is transferred into the ovum; the zygote’s mitochondria (from the ovum) are the source of all mtDNA in the offspring. 

The proteins the mtDNA codes for are required for its function in ATP production; therefore, any mutations or defects in the synthesis of these proteins can lead to defects in ATP production. Some examples of cellular processes that require ATP are:¹²

• DNA replication 
• Signalling within the cell 
• Muscle contraction 
• Transport of ions and other molecules 
• Neurotransmission - signalling between neurons 

Mitochondrial DNA deletions in KSS

The type of mutation that occurs in KSS is an example of large-scale deletion, where base-pairs are removed, thus removing sections of the genetic code.¹³ This can involve the removal of about 1,100 to 10,000 bases, resulting in defects in the synthesis of proteins, rRNA or tRNA. This hinders the ability of the mitochondria to produce sufficient amounts of ATP. ATP plays a crucial role in muscle contraction and neuronal signalling; therefore, when these mutations spontaneously occur in these cell and tissue types, they give rise to the vision and eye movement symptoms seen in KSS.

Kearns-Sayre syndrome overview

Diagnostic criteria

For a patient to be diagnosed with KSS, the following criteria must be met:¹ 

• Present symptoms before the age of 20 
• External ophthalmoplegia: presents with drooping of the eyelids and impaired eye movement and coordination 
• Retinitis pigmentosa: various visual defects including reduced night vision, diminished visual acuity and vision field narrowing 
• Have at least one of the following: dementia, deafness, stunted growth, cerebellar ataxia, complete heart block, endocrine (hormone) abnormalities, or high protein in the cerebrospinal fluid

Investigations

The types of investigations that a clinician will carry out largely depend on the symptoms.¹ These include: 

• Electrocardiogram: to check for heart block and other heart abnormalities 
• Lumbar puncture: a procedure where a needle is inserted into the lower spinal canal to take a sample of the cerebrospinal fluid and check it for protein elevation
• Eye test: to test for diminishment in vision or visual field defects 
• Magnetic resonance imaging (MRI scan): to screen for any abnormalities in the central nervous system, as KSS affects neurons 
• Next-generation sequencing (NGS) of mtDNA: in suspected KSS, white blood cells are sampled from a blood draw to look for mtDNA mutations associated with KSS. If these come back negative or inconclusive, muscle cells are tested

Treatment and management

Currently, there are no approved therapies to treat KSS directly, but there have been some promising results from an intervention known as Mitochondrial Augmentation Therapy (MAT).¹⁴ This is where donated, healthy mitochondria are implanted into the patient’s stem cells so that newly regenerated cells function normally with complete mtDNA. This therapy has shown improved functions of the central nervous system, but further research must be done before this therapy can be used.

• Current treatment options mainly revolve around symptom control and increasing quality of life 
• Patients with cardiac symptoms may need pacemakers to manage their heart block and yearly ECGs and monitoring¹ 
• Folic acid supplements are recommended for patients with a low amount of cerebrospinal fluid 
• Hormonal imbalances can be treated with hormone replacement therapy (HRT), depending on the affected hormone or endocrine gland 
• Patients presenting with hearing loss may benefit from cochlear implants

Summary

• KSS is a rare disease caused by spontaneously occurring deletion of mtDNA 
• These deletions remove a large portion of the mitochondrial genetic code and interfere with the production of mitochondrial proteins that are involved in aerobic respiration 
• Reduced aerobic respiration results in the reduction of ATP production, which is essential for cellular function 
• KSS patients present with the onset of symptoms before the age of 20, paralysis of eye muscles, visual disturbances (known as retinitis pigmentosa), and other affected systems, including the heart, muscles, hormones, and the central nervous system 
• Diagnosis is confirmed by next-generation sequencing of mtDNA and depends on the symptoms presented by the patient 
• There are currently no treatments available to rectify the mtDNA deletions associated with KSS directly, but new research involving MAT shows evidence of improving symptoms 
• Current treatments aim to improve and manage associated symptoms