Kearns-Sayre syndrome: signs and diagnosis

Kearns-Sayre syndrome is a rare mitochondrial disorder characterized by large deletions in mitochondrial DNA. The classic triad includes onset before age 20, chronic progressive external ophthalmoplegia (limited eye movements and ptosis), and pigmentary retinopathy. Cardiac conduction disturbances, ataxia, elevated cerebrospinal fluid protein, short stature, hearing loss, and endocrine disorders are often associated. The disease is multimodal, affecting the central nervous system, skeletal muscles, and heart. [1]

KSS is a subtype of chronic progressive external ophthalmoplegia, but is distinguished by its systemic manifestations and the risk of life-threatening arrhythmias. Early recognition is key to preventing sudden events: timely pacemaker implantation during progression of atrioventricular conduction block reduces the risk of cardiac arrest. Vision support, rehabilitation, and correction of endocrine problems are also important. [2]

Molecularly, KSS is most often caused by single, large-scale deletions of mitochondrial DNA (including a "common" deletion of approximately 4.9 kilobases), leading to energy deficiency in tissues with high energy demands. These deletions are usually sporadic, so there may be no family history. Diagnosis requires a "smart" approach: the mutation may not be detectable in the blood, but may be detected in muscle, buccal mucus, or urinary sediment. [3]

Although there is no causal therapy yet, quality of life and life expectancy depend on a competent approach: cardiac monitoring with a low threshold for device implantation, ophthalmological and auditory rehabilitation, individual physical training for mitochondrial myopathies and, in some cases, metabolic support (coenzyme Q10; folinic acid for cerebral folate deficiency). [4]

Code according to ICD-10 and ICD-11

In the ICD-10-CM (clinical modification), there is a direct code H49.81 "Kearns-Sayre syndrome"; in some contexts, G71.3 "Mitochondrial myopathy, not elsewhere classified" is also used for systemic manifestations. This is important for reporting and routing: the "ophthalmological" code reflects the key ophthalmoplegia, and the "neurological" code reflects widespread muscular and systemic symptoms. [5]

For ICD-11, orphan reference books list ICD-11: 9C82.0 (as part of hereditary neuromuscular disorders), and ICD-10 field H49.8 as "other disorders of the oculomotor muscles" (historically). When selecting codes in practice, national registries and payment rules are used as a guide, but it is advisable to additionally code complications (heart blocks, endocrinopathies). [6]

Table 1. Codes for Kearns-Sayre syndrome

System	Code	Name / Note
ICD-10-CM	H49.81	Kearns-Sayre syndrome
ICD-10-CM (add.)	G71.3	Mitochondrial myopathy, NEC (Spanish for systemic manifestations)
ICD-10 (historically)	H49.8	Other disorders of the oculomotor muscles
ICD-11 (according to Orphanet)	9C82.0	Correspondence in the section on hereditary neuromuscular diseases
Orphanet	OMIM 530000	Orphan reference entry

Epidemiology

KSS is an "ultra-rare" condition; the exact prevalence varies by country and reporting method. Most cases are sporadic, reducing the likelihood of detection through family registries. Publications and clinical series emphasize onset in childhood and adolescence, with gradual progression of ptosis and limited eye movement. [7]

No sex differences in frequency have been demonstrated, as the mitochondrial deletions typical of KSS are more often de novo. The absence of a family history does not exclude the diagnosis; on the contrary, the sporadic nature of the disorder is an argument in favor of testing for large mtDNA deletions. [8]

Cardiac complications are common and determine the prognosis. In retrospective series, a significant proportion of patients develop progressive atrioventricular block, requiring pacemaker implantation; ventricular arrhythmias have also been described, justifying the choice of an implantable cardioverter-defibrillator in a small proportion. [9]

Systemic manifestations - endocrinopathies (hypoparathyroidism, diabetes mellitus, adrenal insufficiency), hearing loss, cerebellar ataxia - are more common than thought and require active screening, even if ophthalmological symptoms dominate. [10]

Reasons

In the vast majority of cases, the syndrome is caused by single, large-scale deletions of mitochondrial DNA, disrupting the assembly of respiratory chain proteins and the synthesis of adenosine triphosphate. The most well-known "common" deletion is approximately 4.9 kilobases, but the spectrum of deletions is broad and heterogeneous across tissues (heteroplasmy). [11]

These deletions are often sporadic, meaning they arise de novo during embryogenesis; therefore, maternal inheritance of pure KSS is rare. However, related syndromes (e.g., Pearson syndrome in infants) may eventually "grow" into the KSS phenotype in survivors, reflecting a common molecular root. [12]

Mitochondrial damage affects energy-intensive tissues: the extraocular muscles are the first to react with ptosis and limited movement, the retina with the "salt-pepper" pattern of pigmentary retinopathy, the cardiac conduction system with blockades, and the cerebellum with ataxia. This explains the variety of complaints with a single diagnosis. [13]

Blood levels of mutant mtDNA can be low, so informative tissue samples such as muscle biopsy, buccal epithelium, and urinary sediment are often used to detect the deletion. A negative blood result in a typical clinical picture does not confirm the diagnosis. [14]

Risk factors

The main risk factor is the very nature of mitochondrial deletions, which arise de novo. Family history is less helpful than with maternally inherited mtDNA point mutations (for example, LHON). It is important to discuss this with families: the absence of cases in relatives is not an argument against diagnosis. [15]

Certain external factors (smoking, heavy alcohol consumption, and certain medications with mitochondrial toxicity) could theoretically worsen muscle weakness and fatigue, although direct data specifically for KSS are limited. In practice, these factors are generally avoided, based on general experience with mitochondrial myopathies. [16]

Certain endocrine and metabolic stresses (nutritional deficiency, uncorrected hormonal imbalances) impair exercise tolerance and may exacerbate complaints; therefore, early screening for endocrinopathies is included in the standard of care. [17]

Age is an important modifier: the earlier the disease manifests, the higher the likelihood of systemic progression and cardiac complications requiring proactive tactics (implantation of devices according to strict indications). [18]

Table 2. Factors influencing the manifestation and course

Category	Examples	Practical significance
Molecular	Large mtDNA deletions, heteroplasmy	Determine energy deficit and tissue variability
Age of onset	Childhood, teenagers	Higher risk of systemic manifestations
External	Smoking, heavy alcohol consumption, myotoxic drugs	We strive to exclude
Comorbidity	Endocrinopathies, deficiencies	Active screening and correction

Pathogenesis

Deletions of mtDNA disrupt the synthesis of key components of the mitochondrial respiratory chain (complexes IV), leading to a decrease in adenosine triphosphate production and an excess of reactive oxygen species. Neurons, muscle cells, and cardiac conduction cells are particularly sensitive to the "energy crisis," so they are the first to fail. [19]

The extraocular muscles are among the most energy-intensive muscle groups: energy deficiency leads to ptosis and ophthalmoparesis. Dysfunction of the photoreceptors and pigment epithelium leads to a characteristic "salt and pepper" pattern in the retina, and over time, decreased twilight vision and contrast sensitivity. [20]

In the cardiac conduction system, progressive fibrosis and energy deficit disrupt atrioventricular conduction. From the first signs (prolonged PQ, bundle branch block), the path to high degrees of block can be relatively short, so the monitoring strategy is active, with a low threshold for pacemaker implantation. [21]

Elevated CSF protein (often >100 mg/dL) reflects impaired barrier function and metabolism in neural tissue in mitochondrial dysfunction; this is a supportive but not essential criterion.[22]

Table 3. “Where does the energy deficit hit” under KSS

Fabric/system	Pathogenetic link	Clinical trace
Oculomotor muscles	Oxidative phosphorylation defect	Ptosis, limited eye movement
Retina	Photoreceptor dysfunction/PED	Pigmentary retinopathy, nyctalopia
Conduction system of the heart	Fibrosis + energy crisis	AV blocks, risk of sudden death
CNS	White matter dysfunction, increased CSF protein	Ataxia, cognitive/behavioral changes

Symptoms

The first symptoms are slowly increasing ptosis (drooping eyelids), eye fatigue in the evening, and difficulty looking up. Over time, limited eye movement (external ophthalmoplegia) develops: the person "turns their head" to look around. These symptoms often lead the patient to an ophthalmologist long before systemic problems are identified. [23]

Pigmentary retinopathy may not cause any symptoms for a long time, but early complaints include "poor" twilight vision and decreased color perception. Ophthalmoscopically, "salt-pepper" lesions are visible; optical coherence tomography reveals thinning of the retinal layers. Visual acuity often remains acceptable for a long time. [24]

Systemic manifestations: cerebellar ataxia (unsteadiness of gait), myopathic fatigue, sensorineural hearing loss, short stature, endocrinopathies (diabetes mellitus, hypoparathyroidism, adrenal insufficiency). Cerebrospinal fluid may contain elevated protein. These signs suggest to the physician that the problem is not an "isolated ocular pathology." [25]

The most dangerous symptoms are cardiac: a feeling of "heart stopping," dizziness, and fainting spells. These reflect increasing conduction disturbances and require immediate evaluation by a cardiologist familiar with mitochondrial diseases. [26]

Table 4. Common clinical signs of KSS

Block	Examples
Ophthalmology	Ptosis, limited eye movements, salt-and-pepper appearance in the fundus
Neuro	Ataxia, fatigue, increased protein in CSF
Heart	Prolonged PQ, blocks, syncope
Endocrinology/ENT	Short stature, hypoparathyroidism/DM, sensorineural hearing loss

Classification, forms and stages

KSS is considered as part of syndromes of single large mtDNA deletions: this includes isolated chronic progressive external ophthalmoplegia (CPEO), familial CPEO, and the KSS spectrum. KSS is a "more systemic" pole, where retinopathy and extraocular lesions, primarily of the heart and central nervous system, are added to ophthalmology. [27]

Based on the course of the disease, the following stages are conventionally distinguished: the early ophthalmologic phase (ptosis, CPEO), the stage of systemic spread (retinopathy, ataxia, endocrine changes), and the stage of complications (conduction disorders, severe hearing loss, balance problems). This "practical" staging helps plan the frequency of screenings. [28]

Based on organ dominance, a distinction is made between the "ophthalmologically dominant" variant, the "cardiac" variant (with early conduction disturbances), and the "neuroendocrine" profile. In reality, the phenotypes overlap, so the approach is always individualized. [29]

KSS can occur after "survival" of Pearson syndrome in infants; with age, pancytopenia resolves, and CPEO and retinopathy—the classic phenotype of KSS—come to the fore. This knowledge is important for the long-term follow-up of such children. [30]

Table 5. KSS in the mtDNA deletion continuum

Position in the spectrum	Key Features	Comment
Isolated CPEO	Ptosis, ophthalmoparesis, without retinopathy	Often local muscle symptoms
CSS	CPEO + retinopathy + systemic signs	Risk of atrioventricular block, increased protein in CSF
After Pearson	Evolution from hematological phenotype to KSS	Requires alertness

Complications and consequences

The main threat is progressive atrioventricular block, even to the point of completeness, with the risk of sudden death. Cardiology societies recommend a low threshold for pacemaker implantation as the degree of block worsens or bifascicular block is present; in some cases, a cardioverter-defibrillator is considered (for ventricular arrhythmias). [31]

Ophthalmologic complications include severe ptosis (impairing vision, causing a "head" posture), persistent ophthalmoplegia, and progression of retinopathy. Surgical techniques (e.g., eyelid suspension to the frontalis muscle) are possible but require experience due to muscle weakness and the risk of incomplete eyelid closure. [32]

Neurological sequelae include chronic ataxia, fatigue, and cognitive difficulties. Hearing loss is progressive and requires early hearing aid treatment; in cases of severe hearing loss, cochlear implantation is considered. Endocrinopathies impair quality of life and require corrective protocols. [33]

The psychosocial burden is significant: limitations in driving, work, and education; the need to coordinate care with several specialists. Active rehabilitation, technical assistance, and support from patient communities reduce the burden on the family. [34]

When to see a doctor

Immediately - if fainting, severe dizziness, episodes of visual "failures," or sudden worsening of ptosis occur. These events may reflect progression of heart block or retinal complications and require urgent evaluation. [35]

Reasons for a scheduled visit include increasing eye fatigue and limited mobility, deterioration of twilight vision, sound hyposensitivity, and signs of endocrine changes (thirst/weight loss, seizures associated with hypocalcemia). The sooner a multidisciplinary approach is established, the safer the course of the disease. [36]

Parents of children with ptosis and “salt-pepper” retinopathy, especially if the onset is before the age of 20, should discuss the possibility of KSS with an ophthalmologist and neurologist and refer them for mitochondrial diagnostics in order not to miss the necessary cardiac screening. [37]

When diagnosing KSS, the observation schedule is recorded in writing: ophthalmologist, cardiologist (ECG/Holter), neurologist/endocrinologist, audiologist - with agreed-upon deadlines and triggers for unscheduled visits. [38]

Diagnostics

Step 1. Clinical hypothesis. Onset before age 20, ptosis and gradually limited eye movements, pigmentary retinopathy (“salt and pepper”), ± ataxia/hearing loss are already sufficient to suspect KSS and initiate the cardiac and molecular route. [39]

Step 2. Baseline tests. Ophthalmologic examinations (OCT, fundus photography), ECG and 24-hour Holter monitoring (search for prolongation of PQ, blocks), baseline laboratory markers (lactate/pyruvic acid), and, if possible, cerebrospinal fluid (often protein >100 mg/dL). These data confirm the systemic nature of the disease. [40]

Step 3. Genetics. Search for large mtDNA deletions in informative tissues: blood + urinary sediment/buccal mucus; if negative and highly suspected, muscle biopsy with molecular analysis. Important to remember: negative blood does not rule out KSS. [41]

Step 4. Additional verification. Muscle biopsy "as indicated" with Gomori staining (ragged-red fibers) and respiratory chain activity; ophthalmologic and audiologic profiles; endocrine screening. Result: a personalized monitoring and treatment plan. [42]

Table 6. Diagnostic route for suspected KSS

Stage	What are we doing?	For what
Clinic	Age of onset, ptosis, ophthalmoplegia, retinopathy	Run a mitochondrial search
Base	OCT, ECG/Holter, lactate, ± CSF protein	Confirmation of systemicity
Genetics	mtDNA deletions in blood and alternative tissues	Verification of the cause
According to the readings	Muscle biopsy, audio/endocrine screening	Risk and Plan Mapping

Differential diagnosis

Most often, KSS must be differentiated from isolated CPEO (ophthalmoplegia without retinopathy and systemic signs) and from inflammatory myositis with ptosis: in KSS, muscle pain and elevated inflammatory markers are absent, and ophthalmoplegia progresses slowly. Molecular testing resolves the dispute. [43]

Hereditary pigmentary retinopathies without ophthalmoplegia distinguish KSS from other hereditary pigmentary retinopathies without ophthalmoplegia by early ptosis/limited eye movements and systemic symptoms. Myasthenia gravis can mimic ophthalmoplegia, but it is characterized by fluctuations and positive pharmacological tests, whereas in KSS, weakness is more stable. [44]

Cardiac manifestations require differentiation from primary cardiomyopathies and channelopathies. Clues include the association with ophthalmoplegia, retinopathy, and elevated CSF protein, as well as proven mtDNA deletion. [45]

Finally, survivors of Pearson syndrome in infancy may develop the KSS phenotype in adolescence - this is an "evolutionary" lineage that is important for pediatricians and geneticists to understand. [46]

Table 7. How KSS differs from “similar” states

State	What do they have in common?	What is the difference?
Isolated CPEO	Ptosis, ophthalmoplegia	No retinopathy or systemic signs
Myasthenia gravis	Ptosis, diplopia	Fluctuations, positive pharmaceutical tests, autoantibodies
Primary retinopathies	Changes in the fundus of the eye	No ophthalmoplegia/systemic signs
Cardiac channelopathies	Brady/tachyarrhythmias	No ophthalmological or cerebrospinal fluid signs

Treatment

The treatment strategy for KSS is to prevent dangerous events and support organ function. At the initial visit, a baseline ECG is recorded and regular Holter monitoring is initiated; if signs of conduction progression (second/third degree atrioventricular block, bifascicular block) are detected, the issue of pacemaker implantation is addressed proactively. For ventricular arrhythmias, an implantable cardioverter-defibrillator is considered in some patients. [47]

Ophthalmologic management includes conservative measures (eyelid lift with tape, custom-made frames) and surgical techniques for interfering ptosis—most commonly, frontal eyelid suspension. The choice of method depends on the residual levator function and the risk of incomplete palpebral fissure closure, which is important due to corneal dryness associated with ophthalmoplegia. [48]

Auditory rehabilitation begins early: hearing aids and, in cases of severe hearing loss, cochlear implantation. This improves quality of life and prevents secondary cognitive and social consequences of sensorineural hearing loss. [49]

Moderate, supervised aerobic exercise has been shown to be safe for mitochondrial myopathies and improves muscle oxidative capacity, exercise tolerance, and daily endurance. Programs typically include cyclic endurance training (walking/cycling) 3-4 times per week for 30-45 minutes, with gradual progression. [50]

Metabolic support: Coenzyme Q10 (ubiquinone) has been shown to improve metabolic parameters and subjective endurance in some patients in observational series, although the effect is variable and not reproducible in all patients; it is prescribed as an “add-on” to basic care after a benefit/cost discussion. The evidence base is moderate. [51]

A separate situation is cerebral folate deficiency in some patients with KSS: in small series, folinic acid (levocovorin) was associated with clinical and radiological improvement, but other studies have shown no effect; there are no randomized trials. The decision is made individually, with confirmed 5-MTHF deficiency in the CSF. [52]

Endocrinological correction – according to the standards for the relevant conditions: insulin/oral hypoglycemic agents for diabetes, calcium and active vitamin D metabolites for hypoparathyroidism, replacement therapy for adrenal insufficiency. "Patient passports" with emergency plans are important. [53]

Pharmacological “sanitation” includes avoiding, if possible, drugs with potential mitochondrial toxicity (long-term ethambutol, chloramphenicol, linezolid, etc.) and caution with sedatives that depress conduction in patients at cardiac risk - always under the supervision of a cardiologist. [54]

Rehabilitation and occupational therapy focus on balance, gait, and energy-saving strategies in everyday life; ankle braces, canes, and Nordic walking are used when needed. Pacing training (load planning) reduces fatigue and decreases the frequency of breakdowns. [55]

Psychological and social support is part of the standard: information about the nature of the disease, training in recognizing dangerous symptoms (fainting), connecting with schools for the visually impaired and hearing services, coordinating parental leave, and assistance in finding employment. [56]

Table 8. Cardiostrategy for KSS - what and when

Situation	Tactics	Base
Progressive atrioventricular block (grades II-III)	Pacemaker implantation	ACC/AHA/HRS recommendations
Bifascicular block ± symptoms	Low threshold for implantation	Observation series at KSS
Ventricular arrhythmias/syncope due to dysfunction	Consider ICD	CSS Reports and Reviews

Table 9. Supportive interventions and their role

Intervention	What does it give?	Comments
Aerobic exercise	↑ oxidative capacity, ↑ endurance	Safe to observe
Coenzyme Q10	Possible improvement in metabolism/symptoms	The effect is variable
Folinic acid (in CFD)	Potential improvement of neurological manifestations	Only if there is a confirmed shortage
Ophthalmic surgery (ptosis)	Improving visual field/head posture	Experience needed due to ophthalmoplegia

Prevention

There is no primary prevention for KSS, as most mtDNA deletions are sporadic. However, secondary prevention of complications is possible: regular cardiac monitoring with a low threshold for device implantation, early auditory and ophthalmologic rehabilitation, an individualized physical therapy program, and medication management. [57]

It is important for families to understand the sporadic nature and limited heritability of KSS (as opposed to mitochondrial point mutations). Genetic counseling is useful for understanding risks and choosing family planning strategies. [58]

Lifestyle: quitting smoking, moderating alcohol consumption, sleep and nutrition, and preventing deficiencies. These measures are universal for mitochondrial diseases and do improve exercise tolerance and daily well-being. [59]

Patients and relatives are given “alarm sheets”: when to go to the hospital (fainting, severe bradycardia, sudden weakness), who to call, what documents to have with them (extracts, ECG, list of medications). [60]

Forecast

The prognosis is variable and is determined primarily by cardiac conduction and the rate of its deterioration. With timely pacemaker implantation and competent multidisciplinary support, many patients live for decades, adapting to ophthalmoplegia and retinopathy. [61]

Visual and muscular symptoms usually progress slowly. Properly selected rehabilitation and technical aids allow for independence in everyday life and study/work. [62]

Endocrinopathies and hearing loss impair quality of life, but are highly treatable if detected early. This is another argument in favor of regular screening using a checklist. [63]

Scientific developments (conditional mitochondrial "boosters," genetic approaches) are actively continuing, but the standard of care today already significantly improves outcomes if the team is in place and the patient is trained to recognize "red flags." [64]