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 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.
These findings are typical of an infranuclear gaze palsy, in this case chronic, progressive external ophthalmoplegia (CPEO). These findings are typical of an infranuclear gaze palsy, in this case chronic, progressive external ophthalmoplegia (CPEO).
0.20 Bilateral ptosis when looking straight ahead. Cover test: slight exophoria. 0.30 Limited range of horizontal eye movements to the right and to the left. 0.40 Limited range of eye movements in the vertical plane for upward and downward eye movements. 1.20 ptosis. 1.40 Vestibulo-ocular reflex. It is evident that the range of eye movements driven via the vestibulo-ocular reflex is still very limited. 2.00 Vertical plane and horizontal plane. 0.0 Cover test shows a slight exophoria. 0.20 Examination of the range of horizontal eye movements shows severe limitation to the right and to the left. 0.25 Examination of the range of vertical eye movements also shows a severe impairment for upward and for downward eye movements. 0.45 Smooth pursuit is smooth, but shows a limited range of movements for horizontal and vertical eye movements. 1.05 Horizontal saccades: limited range and slowing. 1.15 Vertical saccades: slowing and limited range of movements. 1.42 Examination using the head-impulse test shows that the range of movement is still significantly limited in the horizontal and the vertical plane.
These findings are typical of an infranuclear gaze palsy, in this case chronic, progressive external ophthalmoplegia (CPEO).
Strupp M, et al. (2014) Central ocular motor disorders, including gaze palsy and nystagmus. J Neurol 261(2):542-558. PubMed