Kearns-Sayre Syndrome

The mitochondrial genome is a 16569 base-pair closed circular loop of double-stranded DNA found in multiple copies within the mitochondrial matrix. The mitochondrial genome encodes the genetic information for the 13 polypeptide subunits essential for the process of oxidative phosphorylation. In addition, mitochondrial DNA (mtDNA) encodes 2 ribosomal RNA genes and 22 transfer RNA (tRNA) genes necessary for the intramitochondrial synthesis of these 13 polypeptides. The genome was first sequenced in its entirety in 1981,[12] and this "Cambridge Sequence" was subject to minor revisions in 1999.[13] The mitochondrial genome is remarkably concise, containing little noncoding capacity and no introns. mtDNA is inherited almost exclusively through the maternal lineage, with only a single report of paternal inheritance.[14]

Located within the mitochondrial matrix, and lacking the efficient repair mechanisms available to nuclear DNA, mtDNA has a relatively high rate of mutation. Most of these mutations are inconsequential; however, a stable, replicative mutant mtDNA is sometimes produced. This is not necessarily a problem for the cell or tissue because multiple copies of mtDNA are present in each cell (in oocytes, this is in the region of 100,000 copies per cell), and both wild type and mutated mtDNA can coexist, a situation known as heteroplasmy. Disease only ensues when the proportion of mutated to wild-type mtDNA exceeds a tissue-specific threshold. This is usually in excess of 65% mutated mtDNA but can widely vary between tissues and individuals. Thus, the level of mutant heteroplasmy is an important determinant of the clinical presentation of mitochondrial disease; however, other factors, such as nuclear genetic background, must also be considered.

A study by Lin et al suggested that in cases of mitochondrial DNA heteroplasmy, the mitochondrial unfolded protein response leads to the propagation or maintenance of deleterious mitochondrial DNA. A transcriptional response triggered by defects in oxidative phosphorylation (which are themselves caused by deletion of mitochondrial DNA, such as that found in Kearns-Sayre syndrome), the mitochondrial unfolded protein response is involved in promoting the recovery and regeneration of defective mitochondria.[15]

Kearns-Sayre syndrome (OMIM #530000) occurs as a result of large-scale single deletions (or rearrangements) of mitochondrial DNA (mtDNA), which are usually not inherited but occur spontaneously, probably at the germ-cell level or very early in embryonic development.[16, 17] The risk of maternal transmission has been estimated to be approximately 1 in 24.[18] The deletions vary in size and location on the mitochondrial genome in different individuals, although a common deletion of 4.9kB is present in at least a third of patients with Kearns-Sayre syndrome.

How can a heterogeneous group of mitochondrial deletions lead to a similar phenotype? The proposed mechanism is based on the knowledge that transcription of mtDNA is polycistronic, which means that all genes encoded on the heavy and light strands are transcribed as 2 large precursor RNA strands. These subsequently cleave into separate RNA strands, including transfer RNA strands. A deletion anywhere in the mitochondrial genome may affect transcription or translation of genes that were not affected by the deletion.

An identical deletion has been identified in patients with 2 other conditions: Pearson syndrome, which is a sideroblastic anemia of childhood, pancytopenia, and exocrine pancreatic failure, and chronic progressive external ophthalmoplegia (CPEO), which consists of external ophthalmoplegia, bilateral ptosis, and proximal myopathy.[7] Mitochondrial deletions in CPEO tend to be localized in muscle tissue; in Pearson syndrome, mutations occur in hematopoietic cells, explaining the different clinical phenotypes.

Neither size nor location of the deletion alone determines clinical phenotype. Instead, the phenotype appears to be determined by the relative amounts of deleted and wild-type mtDNA. Very high levels of deleted mtDNA in all tissues are likely to cause Pearson syndrome, in which the dominant feature is pancytopenia. Lower levels of deleted mtDNA cause Kearns-Sayre syndrome. In CPEO, deleted mtDNA may be detected only in muscle tissue. CPEO and Kearns-Sayre syndrome vary in the location and percentage of mtDNA deletion.[19] Exceptions are recognized, and survivors of the pancytopenic crisis of Pearson syndrome can also develop Kearns-Sayre syndrome.

Frequency

International

Kearns-Sayre syndrome is a rare disorder. Marked heterogeneity and various types of inheritance have been observed. By 1992, authors had described 226 cases.

Two studies have provided congruent information on the prevalence of large-scale mitochondrial deletions in the adult population. Remes et al estimated a prevalence of 1.6 cases per 100,000 population in a Finnish population (6 patients, only 3 of whom fulfilled the clinical criteria for Kearns-Sayre syndrome).[20] Schaefer et al estimated a prevalence of 1.17 cases per 100,000 population of large-scale mitochondrial deletions in North East England; however, the proportion of patients with Kearns-Sayre syndrome is not stated.[21]

Mortality/Morbidity

Although Kearns-Sayre syndrome probably reduces life expectancy, no numerical data are available. Morbidity depends on severity and the number of systems or organs involved, which widely varies from patient to patient. Heart block is a significant and preventable cause of mortality.

A literature review by Imamura et al involving 112 patients with arrhythmia-associated Kearns-Sayre syndrome found that arrhythmia first manifested as bundle branch block, which then evolved into atrioventricular block (AVB) and, in about 50% of the group, subsequently progressed to complete AVB.[22]

A study by Wiseman et al, using the National (Nationwide) Inpatient Sample database, found that out of 640 hospital admissions for Kearns-Sayre syndrome, 2.3% involved patients with ventricular arrhythmia (VA) or dysrhythmic cardiac arrest (dCA). Rates of VA and dCA were higher in individuals with conduction abnormalities. On discharge, a pacemaker (with or without a defibrillator) was present in about 70% of patients with Kearns-Sayre syndrome and conduction abnormality.[23]

Race

Kearns-Sayre syndrome has no known racial predilection.

Sex

Kearns-Sayre syndrome has no known sex predilection.

Age

Part of the characterization of Kearns-Sayre syndrome is onset in individuals younger than 20 years.

The following are noted in patients with Kearns-Sayre syndrome (KSS):

• Muscle weakness

  • Chronic and progressive decreased eye movements and ptosis

  • Dysphagia

  • Skeletal muscle weakness (proximal more than distal) and exercise intolerance

• CNS dysfunction

  • Ataxia

  • Dementia, encephalopathy, or specific focal neuropsychological deficits

  • Deafness

  • Night blindness

• Cardiac disease

  • Syncope

  • Palpitations

• Symptoms of endocrine dysfunction

  • Diabetes mellitus

  • Menstrual irregularities, delayed puberty

  • Poor growth, failure to thrive

  • Seizures due to hypocalcemia (hypoparathyroidism)

In patients with Kearns-Sayre syndrome, signs are as follows:

• Muscle weakness

  • Proximal myopathy (difficulty rising from a squat)

  • Ptosis (usually bilateral but may be symmetrical initially)

  • External ophthalmoplegia (as is seen in the image below)

    Bilateral ptosis and external ophthalmoplegia. Top: patient looking straight ahead. Below: patient is being asked to look in the direction of the arrow in each case. Restriction of eye movements in each direction is demonstrated.

• CNS dysfunction

  • Retinitis pigmentosa

  • Cerebellar ataxia

  • Cognitive deficits[8]

  • Cataracts

  • Encephalopathy (in acute presentation with lactic acidosis)

• Cardiac

  • Bradycardia

  • Congestive cardiac failure

• Endocrine

  • Short stature (38% of affected individuals)

  • Hypogonadism (20% of affected individuals)

  • Other (eg, signs of hypothyroidism)

See the list below:

• Kearns-Sayre syndrome occurs secondary to deletions in mtDNA (see Pathophysiology).

The following studies are indicated in Kearns-Sayre syndrome (KSS):

• Urine measurements of pH, protein, glucose, and amino acid levels are indicated.

• Serum creatinine kinase level may be within the reference range or moderately elevated.

• Blood lactate and pyruvate are usually elevated. Cerebrospinal fluid (CSF) lactate levels are elevated even if blood lactate levels are within the reference range.[9] CSF protein levels are very frequently elevated.

• In young children, single large-scale deletions may be detectable in blood. Alternatively, diagnosis may be established by muscle biopsy with histochemistry and mtDNA analysis for major rearrangements.[10]

• Screening is recommended to exclude the endocrinologic abnormalities that occur in many patients.[11] Measure serum electrolyte, glucose, calcium, magnesium, and plasma cortisol levels, as well as thyroid function.

MRI of the brain may reveal subcortical white matter lesions (hyperintense on T2 and fluid attenuation inversion recovery [FLAIR], may be bilateral) along with involvement of thalamus, basal ganglia, and brainstem.

Cerebral and cerebellar atrophy may be present.[24, 25]

Spinal involvement on imaging may be underreported in Kearns-Sayre syndrome. One small study of 11 patients with the syndrome who underwent spinal cord imaging showed, in six individuals, involvement of gray matter, white matter, or both.[26]

See the list below:

• ECG reveals cardiac conduction defects; measurement of the PR interval is indicated.[27]

• Echocardiography is used to look for cardiomyopathy.

• Electroretinography helps assess retinal degeneration.

• Audiometry helps detect sensorineural deafness.

• Electroencephalography during period of encephalopathy reveals generalized slow wave activity.

• Electromyography and nerve conduction findings may be normal or may show mild myopathy with or without neuropathy.

See the list below:

• Perform a lumbar puncture and measure protein and lactate levels in the CSF.

• Muscle biopsy may reveal ragged red fibers (as is shown in the image below).

  Modified Gomori Trichrome stain showing ragged red fibres. These show red staining round the periphery as well as within the sarcoplasm, giving a speckled appearance. Of the two affected muscle fibres pictured here, the one on the right shows a more extreme degree of mitochondrial proliferation and also some degeneration/vacuolation than the one on the left.

• Muscle histochemistry (as is shown in the image below) reveals deficiency of cytochrome c oxidase.

  Skeletal muscle stained for both cytochrome oxidase (COX) and succinic dehydrogenase (SDH), two mitochondrial respiratory chain enzymes. Fibers that stain only for SDH and are COX-negative appear blue. Original magnification X 50.

In patients with Kearns-Sayre syndrome, as with other mitochondrial encephalopathies, spongy degenerative changes occur in both the gray and white matter of the brain. White matter spongiosis is prominent in the cerebral hemispheres and brainstem fiber tracts in Kearns-Sayre syndrome.[28] Gray matter loss is also seen in the brainstem and Purkinje cell layer. Calcium deposits accumulate in the globus pallidus and thalamus.

Histologic studies of the heart show abnormalities of the conduction system. Large mitochondria with abnormal structure develop in both skeletal and heart muscles.

No disease-modifying therapy is available for Kearns-Sayre syndrome (KSS). Management is supportive vigilance for detection of associated problems. In the future, potential treatment in patients with Kearns-Sayre syndrome may attempt to inhibit mutant mtDNA replication or encourage replication of wild-type mtDNA.[29]

In patients with aponeurogenic ptosis, surgical shortening of levator muscles can elevate the eyelid mechanically, but exposure may lead to corneal damage. Surgery to correct ptosis should occur only in centers with specialists in ophthalmic surgical procedures.[30, 31]

Surgical management of cricopharyngeal achalasia (incomplete opening of the upper oesophageal sphincter) may be needed if significant dysphagia is present.[32] Gastrostomy insertion is also an option.

The use of cochlear implants for patients with significant deafness is under investigation.[33]

The aforementioned study by Imamura et al, which involved a case report and literature review, indicated that pacemaker implantation may not by itself be effective enough in curbing sudden death in patients with arrhythmia-associated Kearns-Sayre syndrome, with the investigators recommending implantable cardioverter defibrillators as a means of combatting mortality. They suggested that, while early afterdepolarizations (EADs) linked to bradycardia-associated QT prolongation may be suppressed via pacemakers, delayed afterdepolarizations may produce VA even in the presence of EAD suppression.[22]

All patients with Kearns-Sayre syndrome require the care of an ophthalmologist.[34] Consult with a cardiologist regarding pacemaker insertion for heart block. Additional consultations (eg, endocrinologist, neurologist, psychiatrist, neuropsychologist) may be needed, based on the status of the patient and the presence of complications. Genetic counselling is also indicated.

Supplementation with coenzyme Q10 may be indicated. Supplementation with folinic acid led to clinical and radiological improvement in a child with incomplete Kearns-Sayre syndrome, cerebral folate deficiency, and leukoencephalopathy.[35]

Exercise may help patients with myopathy. Exercise that causes concentric shortening of muscles leads to proliferation of satellite cells, the muscle cell precursors that also are involved in muscle regeneration. Satellite cells contain undetectable levels of mutant mtDNA; if they proliferate, the proportion of wild-type DNA to mutant mtDNA can beneficially increase.[36] Exercising to this extent is difficult for severely affected or young patients.

Coenzyme Q10 (CoQ10) administration and vitamin supplements have proven beneficial in individual cases of Kearns-Sayre syndrome (KSS), although effects are transient.

Treat problems associated with Kearns-Sayre syndrome as needed (eg, insulin for diabetes mellitus).

Class Summary

Supplementation with CoQ10 may support normal heart function, provide antioxidant protection, and maintain healthy gums.

Ubidecarenone (Coenzyme Q10, Ubiquinone)

Functions as electron carrier between flavoproteins and in cellular respiration.

See the list below:

• Kearns-Sayre syndrome (KSS) can involve many systems and organs. Clinicians must maintain comprehensive surveillance. Be especially alert for signs or symptoms of diabetes mellitus and for heart block; the latter may develop at any stage.

• Annual ECG, echocardiography, audiometry, and biochemistry to screen for common endocrine disturbances are recommended.[37]

See the list below:

• Heart block is a significant and preventable cause of mortality.

• Deterioration has been reported after local anesthesia with articaine.[38]

• Avoid the use of drugs known to be toxic to mitochondria, such as valproic acid, tetracyclines, biguanides, chloramphenicol, barbiturates, phenothiazines, and zidovudine.[39]

See the list below:

• Kearns-Sayre syndrome is a progressive disorder, and the prognosis for patients with the condition is poor. Death is common in the third or fourth decade of life.[40]

• Disease progression can be predicted to some extent by the size and location of the deletion and the degree of skeletal muscle heteroplasmy.[41]

• As in other mtDNA deletion disorders, women who have Kearns-Sayre syndrome have an increased risk of clinically affected offspring. The risk is currently estimated at approximately 1 per 24 births.[18] Genetic counselling is recommended so options for affected women considering pregnancy can be discussed.[42]

See the list below:

• Participation in an exercise-training program can lead to a subjective improvement in muscle-related symptoms, enhanced aerobic exercise capacity, and increased muscle strength.

• Patients can access the Kearns-Sayre Syndrome Information Page maintained by the National Institute of Neurological Disorders and Stroke for information on the disorder and support organizations.