Overview

Kearns-Sayre syndrome (KSS) is a mitochondrial disease that causes multi-system failure. Ptosis is the first sign to be diagnosed and the condition affects a variety of organs including the eyes, muscles, heart, liver, kidneys, pancreas, thyroid and parathyroid glands, and peripheral and central neurological systems. The pacemaker can be given for cardiac problems.

It is thought that systemic administration of coenzyme Q10 slows down the progression of the disease.
After cardiac pacing, no other treatment has been proven to be beneficial; hence, treatment options remain supportive and require continuous monitoring and follow-up.

Currently, the only ways to help these people are through effective diagnosis and disease-modifying treatments.

Introduction

What is Kearns Sayre syndrome?

The triad of chronic progressive external ophthalmoplegia, pigmentary retinopathy, and at least one of the following: cardiac conduction defects, cerebellar ataxia, or an elevated CSF protein level (≥100 mg/dl) that manifests before the age of 20 is known as Kearns-Sayre syndrome (KSS), a rare mitochondrial myopathy that was initially identified by Kearns and Sayre in 1958.^2,4,5

Etiology

Impaired respiratory chain function or oxidative phosphorylation in the mitochondria causes mitochondrial myopathies.
Point mutations or deletions in mitochondrial DNA cause mitochondrial myopathies, and individuals with KSS usually have 45–75% deletions of total mitochondrial DNA, including mutations or deletions that are too tiny to be detected.²

In cells with unusual mitochondria, compensatory growth of mitochondria takes place when cellular energy production drops below a specific threshold. Abnormal clusters of distorted and enlarged mitochondria appear as bright red staining material with modified Gomori trichrome staining, hence the term "ragged red fibres".

Prevalence

Because this illness is transmitted from the mother, the afflicted mother passes it on to her offspring, who in turn pass it on to future generations. Males and females are therefore equally impacted.³ It manifests before the youngster turns twenty years old.⁴

Signs and symptoms

It can take years for cardiac issues to manifest. The syndrome's initial symptom, bilateral ptosis occurs in early childhood, while the remaining symptoms may not show up for years.⁶ Upon fundoscopic inspection, several pigmentary alterations (early stage, salt-and-pepper-like look) were observed throughout the retinas of both eyes.

Sensorineural deafness, muscle weakness, ataxia, dementia, nystagmus, developmental delay or regression, mental retardation, scoliosis, ptosis, ophthalmoplegia, pigmentary retinopathy, cardiac conduction defects and/or cardiomyopathy, and endocrine disorders are typical clinical features of KSS.

Lactic acidosis is often caused by elevated serum lactate and pyruvate levels. Increased protein in the CSF is indicative of CNS injury, and intracranial degenerations are frequent.³

There can be bilateral facial paralysis, myopathy, dystonia, and bulbar symptoms such as dysarthria and nasal regurgitation. Other characteristics include bilateral sensorineural deafness, dementia, cataracts, proximal renal tubular acidosis, skeletal muscular weakness (proximal more than distal), endocrinopathies (such as diabetes, growth retardation/short stature, and hypoparathyroidism), and exercise intolerance.

Diagnostic criteria

KSS diagnosis criteria include the following: at least one of the following conditions, in addition to the triad of progressive external ophthalmoplegia, pigmentary retinopathy, and beginning before the age of 20: cerebellar symptoms, cardiac block, or protein levels in the CSF fluid exceeding 1000 mg/L.

Nearly all individuals with muscle disease exhibit cytochrome c oxidase (COX) negative fibres, ragged red fibres (RRF), or ragged blue fibres (RBF). About 90% of KSS patients have a single large-scale deletion that can be found using a Southern blot or long-range polymerase chain reaction.¹

Clinical impressions can be used to diagnose KSS by looking for common and identifiable symptoms in the patient, such as bilateral ptosis of eyelid drooping.³

Treatment and limitations

Patients with mitochondrial myopathies, such as KSS, may experience life-threatening problems and sensitivity to certain anaesthetic drugs and muscle relaxants, necessitating a cautious approach during anaesthesia. Since KSS affects multiple organs and the symptoms mainly appear in children, anaesthetic management should be taken into account for both diagnosis and operation.

It's critical to look into the causes of vocal fold palsy and how thyroplasty can help with these uncommon mitochondrial disorders.⁷

Pacemaker insertion should be looked into prior to anaesthesia because cardiac symptoms are the most significant prognostic factor and full atrioventricular block (AVB) is the leading cause of mortality in individuals with KSS.² Careful evaluation is required because muscle weakness and anaesthesia sensitivity may make weaning off a ventilator challenging.

Almost all cardiac involvement has been confined to the conducting tissues, not the myocardium. Development of a cardiac conduction deficiency may result in syncope, heart failure, and sudden cardiac death in up to 57% of patients, with a mortality rate of 20%.² As the illness gradually advances to AVB, a preventive pacemaker placement has been advocated.²

Throughout the perioperative phase, neuromuscular blocking medications are utilised without incident. Although it is preferable to avoid using muscle relaxants if they are not necessary, they can be given in modest, progressive dosages while being monitored by neuromuscular monitoring equipment.

When infection or acidosis is evident, surgery should be postponed if at all possible. Avoid shivering, hypoxia, starvation, hypotension, and discomfort following surgery.²

For mtDNA problems, there are currently no rehabilitative treatments available. The goal of the current therapeutic approaches is to maintain the patient's overall health rather than correct, eradicate, or make up for the detrimental mtDNA mutations.

The largest obstacle to restorative therapy for KSS patients is the difficulty of changing mtDNA sequences in mammalian cells, which is extremely different from nuclear DNA (nDNA).³

Only mitochondrial replacement treatments that target future generations can correct mtDNA sequences in this manner.
Genetic counselling is useful in such cases.

nDNA from an intact nucleus, meiotic spindle-chromosome complex, pronucleus, or polar body is transferred in techniques like mitochondrial replacement surgery that can enhance the quality of life.

To create an enucleated donor ovum with wild-type mtDNA, the nDNA is extracted from an ovum with mutant maternal mtDNA.³

Arginine therapy

Since arginine functions as a nitric oxide donor, stroke-like episodes are believed to be caused by aberrant nitric oxide flux. Arginine is known to alleviate KSS symptoms.³

Furthermore, it has been observed that mitochondrial illnesses result in lower levels of plasma arginine since the manufacture of citrulline, the precursor of arginine, is an ATP-dependent process.

Arginine has been utilized as an acute intravenous (IV) treatment and oral prophylactic since 2005.

Folinic Acid Therapy

Since the brain is the organ most impacted by folate insufficiency, the effects of folinic acid therapy have been investigated. Since folic acid plays a crucial role in brain function, folic acid therapy is highly recommended for KSS patients.

A crucial methylating substance for healthy brain metabolism is folate.³

The upcoming therapies for patients with Kearns-Sayre syndrome may aim to either stop the replication of mutant mtDNA or encourage the replication of wild-type mtDNA.

Assistance in Therapy Longevity is increased by treating symptoms or complications related to the heart, muscles, hearing, eyes, diabetes, and other organs.⁴

Although the effects are temporary, vitamin supplements and the administration of Coenzyme Q10 (CoQ10, Ubidecarenone, Ubiquinone)are beneficial in individual cases of Kearns-Sayre syndrome (KSS). Coenzyme Q10 serves as an electron carrier between flavoproteins and cellular respiration.⁴

Adult dosage: 150–300 mg/dPO split by day and time; paediatric dosage: 30 Alternatively, 3 mg/kg/d PO divided in 2–3 doses, or 100 mg/d PO divided in 2 doses.

The eyelid can be mechanically raised in patients with apo neurogenic ptosis by surgically shortening the levator muscles, however, exposure can cause ocular injury. Ptosis correction surgery should only be performed in facilities with ophthalmic surgical specialists.

If there is severe dysphagia, surgical treatment of cricopharyngeal achalasia (incomplete opening of the upper esophageal sphincter) may be required.

Insertion of a gastrostomy is another option. For people who are completely deaf, cochlear implants may be an option.⁴
By surgically rectifying the typically severe blepharoptosis that characterises this illness, plastic surgeons can aid in the therapy of this condition.⁶

Conclusion

Patients who appear with ptosis or chronic progressive ophthalmoplegia must be appropriately sent to cardiologists, endocrinologists, and ophthalmologists due to the pleiotropic nature of this condition, which involves multiple organs.
The fact that this disease is phenotypically heterogeneous is one of its most difficult problems; therefore, understanding the relationships between these patients would raise the likelihood of increasing survival.