Kearns-Sayre Syndrome

Kearns-Sayre syndrome (KSS) is a rare genetic condition that affects many parts of the body, especially the eyes, muscles, and heart. It is caused by changes (mutations) in the DNA of mitochondria, which are the tiny "energy factories" inside our cells. Because the mitochondria cannot produce enough energy, organs and tissues that require a lot of energy to function properly begin to fail. Symptoms usually appear before the age of 20, often starting in childhood or adolescence. One of the most noticeable effects of KSS is on the eyes. Patients typically develop drooping eyelids (ptosis) and weakness or paralysis of the eye muscles, making it difficult to move the eyes. It also causes a condition called pigmentary retinopathy, which damages the light-sensing tissue at the back of the eye, leading to difficulty seeing in the dark and progressive vision loss. Beyond the eyes, KSS can cause a wide range of other issues, including hearing loss, muscle weakness, balance and coordination problems, and short stature. Importantly, KSS can affect the heart's electrical system, leading to irregular heartbeats or heart block, which requires careful monitoring by a doctor. While there is currently no cure for Kearns-Sayre syndrome, various treatments and supportive therapies are available to help manage the symptoms. Regular check-ups with a team of specialists, including eye doctors, heart doctors, and neurologists, are essential to monitor the condition, prevent complications, and maintain the best possible quality of life.

Condition category: Mitochondrial Disorder

Prevalence: Less than 1 in 100,000

Inheritance patterns: Mitochondrial (sporadic deletions)

Age of onset: Onset before 20 years of age, often in childhood or adolescence

Clinical overview: Kearns-Sayre syndrome (KSS) is a rare, multisystem mitochondrial encephalomyopathy characterized by a classic clinical triad: onset before 20 years of age, chronic progressive external ophthalmoplegia (CPEO), and pigmentary retinopathy. It is classified as a single large-scale mitochondrial DNA deletion syndrome (SLSMDS), sharing overlapping phenotypic features with other mitochondrial disorders such as Pearson syndrome and CPEO-plus. The condition is designated by OMIM number 530000 and Orphanet number 480. The clinical significance of KSS lies in its widespread and progressive impact on tissues with high energy demands, particularly the eyes, heart, skeletal muscle, and central nervous system. In addition to the defining triad, patients must exhibit at least one of the following key features: cardiac conduction block, elevated cerebrospinal fluid (CSF) protein levels (greater than 100 mg/dL), or cerebellar ataxia. Other common manifestations include sensorineural deafness, short stature, endocrine abnormalities (such as diabetes mellitus and hypoparathyroidism), and cognitive impairment. The progressive nature of KSS requires comprehensive, multidisciplinary management. The potential for life-threatening cardiac conduction defects, which can rapidly progress to complete heart block, necessitates vigilant cardiac monitoring. While the disease causes significant morbidity through visual loss, muscle weakness, and neurological decline, early diagnosis and supportive interventions can improve the quality of life and prognosis for affected individuals.

Patient and family guide: Kearns-Sayre syndrome (KSS) is a rare genetic condition that affects many parts of the body, especially the eyes, muscles, and heart. It is caused by changes (mutations) in the DNA of mitochondria, which are the tiny "energy factories" inside our cells. Because the mitochondria cannot produce enough energy, organs and tissues that require a lot of energy to function properly begin to fail. Symptoms usually appear before the age of 20, often starting in childhood or adolescence. One of the most noticeable effects of KSS is on the eyes. Patients typically develop drooping eyelids (ptosis) and weakness or paralysis of the eye muscles, making it difficult to move the eyes. It also causes a condition called pigmentary retinopathy, which damages the light-sensing tissue at the back of the eye, leading to difficulty seeing in the dark and progressive vision loss. Beyond the eyes, KSS can cause a wide range of other issues, including hearing loss, muscle weakness, balance and coordination problems, and short stature. Importantly, KSS can affect the heart's electrical system, leading to irregular heartbeats or heart block, which requires careful monitoring by a doctor. While there is currently no cure for Kearns-Sayre syndrome, various treatments and supportive therapies are available to help manage the symptoms. Regular check-ups with a team of specialists, including eye doctors, heart doctors, and neurologists, are essential to monitor the condition, prevent complications, and maintain the best possible quality of life.

Symptoms and clinical features: The clinical presentation of Kearns-Sayre syndrome is progressive and multisystemic, typically beginning before the age of 20. In the early stages, the initial symptoms are most commonly related to the eyes. Patients frequently present with isolated ptosis (drooping eyelids) and impaired night vision (nyctalopia) due to the early onset of pigmentary retinopathy. Mild exercise intolerance and fatigue may also be present as early signs of mitochondrial myopathy. During the intermediate stages, the ocular symptoms progress to chronic progressive external ophthalmoplegia (CPEO), characterized by symmetric paralysis of the extraocular muscles, which can cause blurred or double vision. The ptosis often worsens, requiring patients to tilt their heads back to see. Systemic features begin to emerge, including proximal limb muscle weakness, sensorineural hearing loss, and endocrine abnormalities such as short stature, delayed puberty, diabetes mellitus, or hypoparathyroidism. Neurological symptoms like cerebellar ataxia (unsteadiness and coordination problems) and mild cognitive difficulties may also become apparent. In the advanced stages, the disease can lead to severe and potentially life-threatening complications. Cardiac involvement becomes a major concern, with the development of cardiac conduction defects that can rapidly progress to complete heart block or cardiomyopathy. Neurological decline may manifest as severe ataxia, dysarthria, dysphagia (difficulty swallowing), tremor, and progressive cognitive impairment or dementia. Visual acuity may significantly deteriorate due to advanced retinopathy. Renal tubular dysfunction and severe muscle wasting can also occur, profoundly impacting the patient's quality of life and requiring extensive supportive care.

Molecular pathology: Kearns-Sayre syndrome is a mitochondrial encephalomyopathy caused by large-scale deletions in mitochondrial DNA (mtDNA). These deletions result in the loss of essential genes required for mitochondrial protein formation and the oxidative phosphorylation (OXPHOS) pathway. The most common 4977 bp deletion removes 12 mitochondrial genes, which encode subunits of the respiratory chain complexes (Complex I, IV, and V) and several transfer RNAs (tRNAs). The normal function of these mitochondrial genes is to produce proteins critical for cellular energy production via oxidative phosphorylation, converting oxygen and nutrients into ATP. When these genes are deleted, the synthesis of respiratory chain complexes is impaired, leading to a severe decrease in cellular energy production. Regardless of the specific genes deleted, all steps of oxidative phosphorylation are affected due to the loss of essential tRNAs required for mitochondrial translation. The downstream cellular effects are most pronounced in tissues with high energy demands, such as the central nervous system, skeletal muscle, heart, and eyes. The lack of cellular energy leads to cellular dysfunction and degeneration. In muscle tissue, this manifests as the proliferation of abnormal mitochondria, visible as ragged-red fibers. In the eyes, the high energy dependence of the retinal pigment epithelium and extraocular muscles makes them particularly susceptible to mitochondrial defects, leading to pigmentary retinopathy and progressive external ophthalmoplegia. The disease is characterized by heteroplasmy, meaning both normal and deleted mtDNA coexist, and symptoms appear when the proportion of mutant mtDNA exceeds a critical threshold in specific tissues.

Genetics: Kearns-Sayre syndrome is primarily caused by large-scale deletions in mitochondrial DNA (mtDNA). Approximately 90% of KSS cases are sporadic, arising from de novo somatic mutations that occur after conception. These deletions range in size from 1.1 to 10 kilobases (kb). The most frequent genetic alteration is the "common 4977 bp deletion," which accounts for more than one-third of cases and removes 12 mitochondrial genes. Because the mutations occur in mtDNA, the rare inherited cases follow a mitochondrial or maternal inheritance pattern. Mothers carrying the mutation can pass it to their children, but fathers cannot. The risk of a woman carrying a large-scale mtDNA deletion transmitting it to her offspring is estimated to be less than 4%. Exceptional cases of KSS without a typical large mtDNA deletion may be due to point mutations in mtDNA encompassing tRNA genes or mutations in nuclear genes involved in mtDNA maintenance, such as RRM2B, which follow an autosomal recessive inheritance pattern. Genotype-phenotype correlations in KSS are complex due to heteroplasmy, where a single cell can harbor both deleted (mutant) and normal (wild-type) mtDNA molecules. The clinical severity and specific tissue involvement depend on the proportion of mutant mtDNA in a given organ. The threshold for symptom manifestation varies by tissue; for example, it is about 60% for skeletal striated muscle. The specific genes lost in the deletion do not strictly dictate the phenotype, as the loss of any essential mitochondrial genes impairs the entire oxidative phosphorylation process.

Diagnostic evaluation: Clinical diagnostic criteria for Kearns-Sayre syndrome (KSS) include the classic triad of progressive external ophthalmoplegia (PEO), pigmentary retinopathy, and onset before 20 years of age. In addition, patients must have at least one of the following: cardiac conduction block, cerebrospinal fluid (CSF) protein levels above 100 mg/dL, or cerebellar ataxia. Clinical workup involves a comprehensive evaluation. Fundoscopy reveals an atypical "salt-and-pepper" pigmentary retinopathy that initially involves the posterior fundus, with diffuse depigmentation of the retinal pigment epithelium and pigment clumping. Electroretinography (ERG) often shows severely depressed or extinguished scotopic responses and reduced photopic cone responses, indicating a rod-cone retinal dystrophy. Visual field testing typically reveals normal visual fields, though peripheral vision may be compromised by ptosis. Muscle pathology plays a significant role in diagnosis. Muscle biopsy typically shows ragged-red fibers (RRF) on modified Gomori trichrome stain, ragged-blue fibers on succinate dehydrogenase (SDH) stain, and cytochrome c-oxidase (COX)-negative fibers. Diagnosis is confirmed by molecular genetic testing, specifically next-generation sequencing (NGS) of the mitochondrial DNA (mtDNA) genome, which detects large-scale deletions (1.1 to 10 kb) in clinically or morphologically affected tissues, usually skeletal muscle. Differential diagnosis includes other disorders associated with ophthalmoplegia, such as isolated chronic progressive external ophthalmoplegia (CPEO), oculopharyngeal muscular dystrophy, myotonic dystrophy, and Mendelian CPEO associated with multiple mtDNA deletions (e.g., POLG mutations). It must also be differentiated from other single large-scale mtDNA deletion syndromes like Pearson syndrome, which can occasionally progress into KSS.

Differential diagnosis: Differential diagnosis of Kearns-Sayre syndrome includes: (1) Chronic progressive external ophthalmoplegia (CPEO) — ophthalmoplegia without pigmentary retinopathy or cardiac disease. (2) Myasthenia gravis — fluctuating ptosis and ophthalmoplegia, positive antibodies, no retinal findings. (3) Oculopharyngeal muscular dystrophy — ptosis, dysphagia, later onset; PABPN1 mutations. (4) Refsum disease — pigmentary retinopathy with polyneuropathy, elevated phytanic acid. (5) Usher syndrome — RP with hearing loss but no ophthalmoplegia. (6) Abetalipoproteinemia (Bassen-Kornzweig) — pigmentary retinopathy with acanthocytosis, fat malabsorption.

Natural history: Kearns-Sayre syndrome is a progressive, multisystem disorder with an onset typically before 20 years of age, often presenting in childhood or adolescence. The initial manifestations are frequently isolated ptosis (drooping eyelids) or impaired night vision (nyctalopia). As the disease progresses over decades, new symptoms appear and existing ones slowly worsen. The progression pattern involves the gradual development of chronic progressive external ophthalmoplegia (CPEO) and pigmentary retinopathy. Over time, patients may develop severe cardiac conduction defects, which can rapidly progress to complete heart block and pose a risk of sudden death. Neurological decline is also a significant factor, with the potential development of cerebellar ataxia, sensorineural hearing loss, and cognitive impairment or dementia. Prognostic factors depend heavily on the number of organs involved and the proportion of abnormal mtDNA (heteroplasmy) in those tissues. The development of cardiac conduction abnormalities is a critical prognostic factor requiring vigilant monitoring and intervention. While the disease is progressive and can lead to significant morbidity, with appropriate supportive care and interventions such as pacemaker placement, life expectancy can be normal for many patients. A very small subset of patients may initially present with Pearson syndrome in infancy and later progress to develop KSS.

Management and treatment research: ### Current management and supportive care Kearns-Sayre syndrome (KSS) is a mitochondrial disorder, most often caused by a large deletion in mitochondrial DNA. There is currently no treatment that corrects the underlying mitochondrial DNA change. Care focuses on regular monitoring, prevention of complications, treatment of symptoms, and coordination among specialists. Cardiac care is especially important because KSS can cause progressive problems with the heart’s electrical conduction system. These problems can lead to slow heart rhythms and, in some cases, serious cardiac events. Monitoring may include electrocardiograms (ECGs), echocardiograms, and ambulatory rhythm monitoring, such as a Holter monitor. A cardiologist determines how often testing is needed. A permanent pacemaker may be recommended for significant conduction disease. Some people may also need an implantable cardioverter-defibrillator (ICD), depending on their heart findings and individual risk. Other supportive care may include: - **Eye care:** Regular ophthalmology follow-up for pigmentary retinopathy, reduced vision, cataracts, ptosis (drooping eyelids), and eye-movement problems. Ptosis surgery, including a frontalis sling procedure, may be considered when eyelid drooping blocks vision, although recurrence and complications can occur. - **Hearing support:** Hearing aids or cochlear implants may help some people with sensorineural hearing loss. - **Endocrine care:** Regular screening for diabetes, hypoparathyroidism, thyroid disease, growth concerns, and other hormone-related complications. Treatment may include insulin, calcium and vitamin D, or hormone replacement when needed. - **Neurologic and rehabilitation support:** Physical therapy, occupational therapy, mobility aids, and support for weakness, ataxia (difficulty with balance and coordination), swallowing problems, or fatigue. - **Nutrition and metabolic care:** Assessment of nutrition, energy needs, and muscle symptoms. Vitamins and “mitochondrial supplements” are sometimes used, but evidence that they change the course of KSS is limited. - **Folinic acid:** This may be considered under specialist guidance for people with documented low cerebrospinal-fluid folate or cerebral folate deficiency. ### Approved therapies There are no approved disease-modifying therapies specifically for Kearns-Sayre syndrome. Treatment remains focused on early detection and management of cardiac, endocrine, vision, hearing, and neurologic complications. ### Investigational therapies There are no KSS-specific investigational treatment programs in the current treatment pipeline. Research in mitochondrial diseases more broadly is exploring approaches intended to support mitochondrial function or address mitochondrial DNA abnormalities. These approaches remain experimental and are not established treatments for KSS. ### Clinical trial and registry participation Currently recruiting studies relevant to people with KSS are registries and natural-history studies rather than interventional treatment trials. These studies collect information about symptoms, genetic findings, disease progression, and biological samples. Participation may help researchers better understand mitochondrial disease and may support future research. - **NCT05554835** — Global Registry and Natural History Study for Mitochondrial Disorders - **NCT01694940** — North American Mitochondrial Disease Consortium Patient Registry and Biorepository (NAMDC) - **NCT02435940** — Inherited Retinal Degenerative Disease Registry Eligibility criteria vary by study. A mitochondrial disease specialist, retina specialist, or study coordinator can help families determine whether a registry is appropriate.

Outlook: The prognosis for Kearns-Sayre syndrome varies depending on the severity of the symptoms, the number of organs involved, and the proportion of abnormal mitochondrial DNA (heteroplasmy) in the affected tissues. The disease is progressive, meaning symptoms typically worsen over time, and new organ systems may become involved. Visual outcomes are often poor due to progressive pigmentary retinopathy and ophthalmoplegia, which can significantly impact daily functioning and independence. Quality of life considerations are paramount, as patients may face multiple challenges including vision loss, hearing impairment, muscle weakness, and neurological decline. The potential for sudden, life-threatening cardiac conduction blocks requires lifelong monitoring and often the placement of a pacemaker. However, with appropriate, proactive, and multidisciplinary supportive care, many patients can manage their symptoms effectively, and life expectancy can be normal. Early intervention and regular surveillance are critical to preventing severe complications and improving overall outcomes.

Epidemiology: Kearns-Sayre syndrome is a very rare disorder. The exact prevalence is unknown, but it has been estimated at approximately 1 to 3 cases per 100,000 individuals in the general population. One specific epidemiological study reported a prevalence of 1.6 cases per 100,000 in the Finnish population. The condition affects both males and females equally. Because the vast majority of cases arise from sporadic, de novo somatic mutations in mitochondrial DNA that occur after conception, there are no specific geographic or ethnic variations strongly associated with the syndrome. Inherited cases are extremely rare and follow a maternal inheritance pattern.

Selected references: 1. Goldstein A, Falk MJ. Single Large-Scale Mitochondrial DNA Deletion Syndromes. GeneReviews. 2003 [updated 2023]. PMID: 20301382 2. Shemesh A, et al. Kearns-Sayre Syndrome. StatPearls. 2023. PMID: 29939687 3. Yamashita S, et al. Genotype and phenotype analyses in 136 patients with single large-scale mitochondrial DNA deletions. J Hum Genet. 2008. PMID: 18414798 4. Broomfield A, et al. Paediatric single mitochondrial DNA deletion disorders: an observational study of 34 patients. J Inherit Metab Dis. 2015. PMID: 25547604 5. Mancuso M, et al. Clinical features and mutation burden in single large-scale mtDNA deletion syndromes. J Neurol. 2015. PMID: 25680637 6. Porteous WK, et al. Bioenergetic consequences of accumulating the common 4977-bp mitochondrial DNA deletion. Eur J Biochem. 1998. PMID: 9799113