Kearns-Sayre Syndrome

Etiology

Approximately 90% cases of KSS are sporadic, arising from a large-scale 1.1 to 10 kilobase deletion of mitochondrial DNA, with the most common deletion labeled as the “common 4977 bp deletion”, accounting for more than one-third of cases.[4][5][6]

Epidemiology

KSS is very rare. While the exact prevalence of this condition is unknown, one study has reported a prevalence of 1.6 cases per 100,000 in the Finnish population.

Pathophysiology

In KSS muscle fibers stains demonstrate ragged red fibers like in other mitochondrial myopathies.

Postmortem ophthalmic pathology reveals atrophy of the retinal pigment epithelium and outer retina accompanied by the aberrant pigment in all layers of the sensory retina most marked posteriorly, in contrast to the preservation of peripheral retinal rods and cones. This pattern of photoreceptor degeneration led to the theory that the primary defect producing the retinopathy of KSS is in the retinal pigment epithelium.

Furthermore, postmortem neuropathology of patients with KSS can sometimes be associated with severe demyelination of the white matter tracts of the brain. It is not known why the loss of myelin occurs.[7][8][9]

History and Physical

Patients with KSS will have the following clinical manifestations:

Chronic Progressive External Ophthalmoplegia

Mitochondrial myopathy characterized by drooping of the eyelids (ptosis) and paralysis of the extraocular muscles (ophthalmoplegia).

Pigmentary Retinopathy

In patients with pigmentary retinopathy, there is a migration of retinal pigment epithelial (RPE) cells or macrophages containing melanin into the retina. Hence, pigmentary retinopathy is the final common outcome of many retinal and chorioretinal disorders and often a common manifestation of numerous metabolic and neurodegenerative diseases.

Retinitis pigmentosa is the name given to a large group of hereditary retinal degenerations that share the common feature of progressive damage to the photoreceptor–pigment epithelial complex. Pigmentary retinopathy can mimic retinitis pigmentosa phenotypically because of the presence of characteristic pigmentary changes in the retina. Moreover, visual symptoms in retinitis pigmentosa such as night blindness or diminished visual acuity can also be manifest in pigmentary retinopathy. However, they are generally mild and occur in only about 40% to 50% of patients.

The pattern of retinal involvement and electrophysiologic tests can assist differentiate between them apart. Pigmentary retinopathy initially involves the posterior fundus (e.g., peripapillary zone), whereas retinitis pigmentosa initially affects the peripheral and mid-peripheral retina. Furthermore, in pigmentary retinopathy, there is a diffuse depigmentation of the retinal pigment epithelium with a characteristic mottled “salt-and-pepper” pattern of pigment clumping, in contrast to “Bone spicule” pigment formation in retinitis pigmentosa. Distinctive ancillary findings in retinitis pigmentosa are pallor of the optic disc, attenuation of retinal vessels, visual field defects, and posterior cataract.

Electroretinography (ERG) is usually normal or mildly abnormal in pigmentary retinopathy, whereas the ERG analysis demonstrates severely depressed or extinguished scotopic responses and less severely reduced photonic cone responses compared to retinitis pigmentosa.

Cardiac Conduction Disturbances

Patients with KSS may develop cardiac conduction disorders at any time. Abnormalities range from simple PR interval prolongation to infranodal high-degree atrioventricular (AV) block. This predisposes the patients to stroke or sudden death from the direct effects of an arrhythmia or a cardiac embolus.

Non-Ocular Muscle Weakness

In some patients with KSS, the facial muscles can become affected. The involvement of orbicularis oculi muscles affects the ability to close the eyelids tightly, whereas the involvement of the frontalis muscle hinders the opening of already ptotic eyelids.

Occasionally, patients experience dysphagia when the muscles of mastication get involved.

With the progression of the disease, weakness of the neck and shoulder muscles can develop as well as the mild weakness of the extremities muscles.

Non-muscular Neurologic Dysfunction

The following abnormalities could be observed: cerebellar ataxia, sensorineural hearing loss, neuropathy, and impaired intellectual function.

Endocrine Disorders

Endocrine dysfunction can be the initial presenting symptom preceding other neurological manifestations of KSS. The frequency of endocrine disturbances has been reported to range from 35% to 67%, including the following: diabetes mellitus, short stature and growth hormone insufficiency, hypogonadotropic hypogonadism, adrenal insufficiency, and primary hypoparathyroidism. Therefore, endocrinologists should be aware of possible multiple-endocrine complications and regularly screen for them, given that these are potentially treatable aspects of this disease.

Evaluation

Next-generation sequencing (NGS) of the mitochondrial DNA genome in peripheral blood leukocyte samples to identify deletions is the preferred diagnostic modality in cases of clinically suspected KSS. If blood tests for KSS are negative in patients who have a strong pretest probability of having KSS based on their phenotype, their muscle mtDNA should be sequenced as sometimes tissue-specific mutations can be missed and low levels of heteroplasmy in the blood can lead to false-negative results.

In many patients with KSS, there is an elevation of protein in the cerebrospinal fluid thus lumbar puncture with the analysis of its content should be performed.

As cerebral folate deficiency can develop in KSS and may contribute to the leukoencephalopathy as well as cognitive symptoms, measurements of spinal fluid 5-methyl-tetrahydrofolate should be obtained in all patients.

Neuroimaging cannot be used in isolation as a diagnostic modality since the findings are neither sensitive or specific enough to be considered part of the diagnostic criteria. However, as some patients develop a leukoencephalopathy, an MRI of the brain should be performed.

The central nervous system (CNS) involvement is reflected by the extent of MRI abnormalities which can include hyperintensities on fluid-attenuated inversion recovery (FLAIR) sequences in the brain stem, globus pallidus, thalamus, and white matter of the cerebrum and cerebellum.

In addition, regional abnormalities of brain metabolism can be demonstrated in patients with KSS using MR spectroscopy (MRS). These could include an increase in the lactate/creatine resonance intensity ratio (an index of impairment of oxidative metabolism) in the resting occipital cortex, as well as a significant decrease in N-acetylaspartate/creatine (a measure of neuron loss or dysfunction) in the cerebral cortex.

Cardiovascular magnetic resonance (CMR) demonstrating concentric remodeling or left ventricular hypertrophy with intramural late gadolinium enhancement (LGE) in the inferolateral wall may assist in the diagnosis of cardiomyopathy in patients with KSS.

Treatment / Management

Care for patients with KSS is primarily supportive. Folic acid supplementation in patients with low cerebrospinal fluid (CSF) is highly recommended as is hormonal replacement therapy in endocrinopathies and cardiac pacemaker placement for patients with cardiac conduction blocks. Some patients with diplopia and prisms may benefit from strabismus surgery, and frontalis slings placement surgery may also treat ptosis. Cochlear implants can be used for patients with sensorineural hearing loss.[10][11]

Surveillance includes yearly ECG, echocardiography, and 24-hour Holter monitoring (regardless of patient's age), audiometry and endocrinologic evaluation.

Future and Experimental Therapy

Since most patients with mtDNA disease harbor both mutated and wild-type mtDNA (heteroplasmy), the possibility of enhancing mitochondrial function by causing shifts in heteroplasmy through selective degradation of mutant DNA is one of the promising emerging therapies for mitochondrial disorders. Endonuclease ZFN, for instance, can reduce mutation load in a cytoplasmic hybrid model of KSS.

Zinc-finger nuclease (ZNF) binds specifically to the mutant form of mtDNA, and the FOK1 endonuclease domain cleaves the DNA molecule, which is then degraded, manipulating the ratio of mutant to a wild type of mtDNA.

The most frequently used mitochondrial antioxidant that is used for patients with KSS is CoQ 10, also known as ubiquinone.

EPI-743 is a synthetic structurally modified analog of CoQ 10 in which the bis(methoxy) groups of the quinone have been replaced with bis-methyl groups, and the tail has three rather than ten isoprenyl units. Double-blind, placebo-controlled, randomized clinical trials of EPI-743 are currently in progress for KSS.

Differential Diagnosis

CPEO must be differentiated from other disorders associated with ophthalmoplegia. These include:

• Isolated chronic progressive external ophthalmoplegia (CPEO)
• Oculopharyngeal muscular dystrophy
• Myotonic dystrophy
• Isolated oculopharyngeal myopathy
• Mendelian chronic progressive external ophthalmoplegia (CPEO)
  • associated with multiple deletions of mtDNA such as POLG