Chronic Progressive External Ophthalmoplegia (CPEO) And Kearns-­Sayre Syndrome

Chronic progressive external ophthalmoplegia (CPEO) and Kearn-Syre syndrome are mitochondrial diseases, where mutations or deletions in mitochondrial DNA (mtDNA) lead to defects in the oxidative phosphorylation pathways necessary for the production of ATP through the respiratory chain. The ratio between wild type and mutated mtDNA within a cell or tissue determines the severity of the mitochondrial disease. When the mutated DNA reaches about 70-80% compared to wild type, mitochondrial function becomes affected (threshold effect). This phenomenon can be dynamic and change during a lifetime, since mitochondrial DNA is replicated independently of the cell cycle. 

The consequences of mitochondrial defects become most apparent in muscles, due to the high energy consumption in these tissues. The mitochondria concentration is especially high in the extraocular muscles, allowing early detection of mitochondrial disease by eye movement examinations. 

CPEO Signs and Symptoms

Disease onset usually lies in young adulthood (mean 17.5 years) and manifests by conjugated horizontal and vertical gaze palsy. Asymmetrically affected eye muscles are observed when the eye axes are not aligned and the patients suffer with diplopia or oscillopsia during head movements and walking. Progression of the disease eventually leads to complete ophthalmoplegia without any eye movements (“staring eyes”). In contrast to PSP the impairment of eye movements cannot be overcome by the head-impulse test because this dysfunction is infranuclear and not supranuclear as in PSP.

Kearn-Sayre syndrome Signs and Symptoms

CPEO is part of the Kearn-Sayre syndrome, which is a multisystem disorder affecting the central nervous system due to a large-scale mtDNA deletion. Disease onset usually lies before the age of 20 years and manifests itself by cerebellar ataxia, pigmentary retinopathy and may include cardiac conduction block in some cases. Typically elevated cerebrospinal fluid protein levels are detectable. In addition other neurological problems, such as proximal myopathy, exercise intolerance, ptosis, oropharyngeal and esophageal dysfunction, sensorineural hearing loss, dementia and choroid plexus dysfunction may be present. 

Diagnosis

Diagnosis is reached by muscle biopsies and genetic analysis of the mtDNA mutation. During progression of the disease ocular motor examination reveals a gradually increasing impairment of all eye movements, which are asymmetrical and cannot be overcome by the head-impulse test because the dysfunction is infranuclear rather than supranuclear as in PSP.

Observable ocular motor disorders

  • Asymmetrical impairment of eye movements that cannot be overcome by the head-impulse test, often accompanied with bilateral ptosis.

References

Strupp M, et al. (2014) Central ocular motor disorders, including gaze palsy and nystagmus. J Neurol 261(2):542-558. PubMed