Chronic progressive external ophthalmoplegia
Encyclopedia
Chronic progressive external ophthalmoplegia (CPEO), also known as progressive external ophthalmoplegia (PEO), is a type of eye movement disorder. It is often the only feature of mitochondrial disease
, in which case the term CPEO may be given as the diagnosis
. In other people suffering from mitochondrial disease, CPEO occurs as part of a syndrome
involving more than one part of the body, such as Kearns-Sayre syndrome
. Occasionally CPEO may be caused by conditions other than mitochondrial diseases.
, occurring in an estimated two-thirds of all cases of mitochondrial myopathy. Patients typically present with ptosis
(drooping eyelids). Other diseases like Graves' disease
, myasthenia gravis
and glioma that may cause an external ophthalmoplegia must be ruled out.
While progressive external ophthalmoplegia may be a symptom of numerous diseases, we will be focusing on CPEO as the primary disease state caused by mitochondrial abnormalities. Kearns-Sayre syndrome
(KSS), which at times is referred to as a severe form of CPEO with pigmentary retinopathy, complete heart block and occurs before the age of 20, will not be included in this discussion.
is often unnoticed by the patient until the lids droop to the point of producing a visual field defect. Often, patients will tilt the head backwards to adjust for the slowly progressing ptosis of the lids. In addition, as the ptosis becomes complete, the patients will use the frontalis (forehead) muscle to help elevate the lids. The ptosis is typically bilateral, but may be unilateral for a period of months to years before the fellow lid becomes involved.
Ophthalmoplegia or the inability/difficulty to move the eye is usually symmetrical. As such, double vision is not often a complaint of these patients. In fact, the progressive ophthalmoplegia is often unnoticed till decreased ocular motility limits peripheral vision. Often someone else will point out the ocular disturbance to the patient. Patients will move their heads to adjust for the lost of peripheral vision caused by inability to abduct or adduct the eye. All directions of gaze are affected, however, downward gaze appears to be best spared. This is in contrast to Progressive Supranuclear Palsy
(PSP) which typically affects vertical gaze and spares horizontal gaze.
Mild visual impairment was seen in 95% of patients that were evaluated using the Visual Function Index (VF-14).
The ciliary muscles that control the lens shape and the iris muscles are often unaffected by CPEO.
Additional symptoms are variable, and may include exercise intolerance, cataracts, hearing loss, sensory axonal neuropathy, ataxia, clinical depression, hypogonadism and parkinsonism.
(ATP). Deletions or mutations to segments of mtDNA lead to defective function of oxidative phosphorylation. This may be made evident in highly oxidative tissues like skeletal muscle and heart tissue. However, extraocular muscles contain a volume of mitochondria that is several times greater than any other muscle group. As such, this results in the preferential ocular symptoms of CPEO.
Multiple mtDNA abnormalities exist which cause CPEO. One mutation is located in a conserved region of mitochondrial tRNA at nucleotide 3243 in which there is an A to G nucleotide transition. This mutation is associated with both CPEO and Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).
A common deletion found in one-third of CPEO patients is a 4,977 base pair segment found between a 13 base pair repeat.
The mtDNA that is affected maybe a single or multiple point deletion, with associated nuclear DNA deletions. One study showed that mtDNA deletion seen in CPEO patients also had an associated nuclear DNA deletion of the Twinkle gene which encodes specific mitochondrial protein; Twinkle.
Whether a tissue is affected is correlated with the amount of oxidative demands in relation to the amount of mtDNA deletion.
In most cases, PEO occurs due to a sporadic deletion or duplication within the mitochondrial DNA. However, transmission from the mother to the progeny appears only in few cases. Both autosomal dominant and autosomal recessive inheritance can occur, autosomal recessive inheritance being more severe. Dominant and recessive forms of PEO can be caused by genetic mutations in the ANT1
, POLG
, POLG2
and PEO1
genes.
CPEO is diagnosed via muscle biopsy. On examination of muscle fibers stained with Gömöri trichrome stain
, one can see an accumulation of enlarged mitochondria. This produces a dark red staining of the muscle fibers given the name “ragged red fibers”. While ragged red fibers are seen in normal aging, amounts in excess of normal aging give a diagnosis of a mitochondrial myopathy.
Polymerase Chain Reaction (PCR), from a sample of blood or muscle tissue can determine a mutation of the mtDNA.
Elevated acetylcholine receptor antibody level which is typically seen in myasthenia gravis has been seen in certain patients of mitochondrial associated ophthalmoplegia.
It is important to have a dilated eye exam to determine if there is pigmentary retinopathy that may signify KSS which is associated with cardiac abnormalities.
Experimental treatment with tetracycline has been used to improve ocular motility in one patient. Coenyzme Q10 has also been used to treat this condition . However, most neuro-ophthalmologists do not ascribe to any treatment.
Ptosis associated with CPEO may be corrected with surgery to raise the lids, however due to weakness of the orbicularis oculi muscles, care must be taken not to raise the lids in excess causing an inability to close the lids. This results in an exposure keratopathy. Therefore, rarely should lid surgery be performed and only by a neuro-ophthalmologist familiar with the disease.
Those that have diplopia as a result of asymmetric ophthalmoplegia maybe corrected with prisms or with surgery to create a better alignment of the eyes.
Mitochondrial disease
Mitochondrial diseases are a group of disorders caused by dysfunctional mitochondria, the organelles that are the "powerhouses" of the cell. Mitochondria are found in every cell of the human body except red blood cells...
, in which case the term CPEO may be given as the diagnosis
Medical diagnosis
Medical diagnosis refers both to the process of attempting to determine or identify a possible disease or disorder , and to the opinion reached by this process...
. In other people suffering from mitochondrial disease, CPEO occurs as part of a syndrome
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
involving more than one part of the body, such as Kearns-Sayre syndrome
Kearns-Sayre syndrome
Kearns–Sayre syndrome also known as oculocraniosomatic disease or Oculocraniosomatic neuromuscular disease with ragged red fibers is a mitochondrial myopathy with a typical onset before 20 years of age...
. Occasionally CPEO may be caused by conditions other than mitochondrial diseases.
Introduction
CPEO is a rare disease that may affect those of all ages, but typically manifests in the young adult years. CPEO is the most common manifestation of mitochondrial myopathyMitochondrial myopathy
Mitochondrial myopathy is a type of myopathy associated with mitochondrial disease. On biopsy, the muscle tissue of patients with this disease usually demonstrate "ragged red" muscle fibers...
, occurring in an estimated two-thirds of all cases of mitochondrial myopathy. Patients typically present with ptosis
Ptosis (eyelid)
Ptosis is a drooping of the upper or lower eyelid. The drooping may be worse after being awake longer, when the individual's muscles are tired. This condition is sometimes called "lazy eye", but that term normally refers to amblyopia...
(drooping eyelids). Other diseases like Graves' disease
Graves' disease
Graves' disease is an autoimmune disease where the thyroid is overactive, producing an excessive amount of thyroid hormones...
, myasthenia gravis
Myasthenia gravis
Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
and glioma that may cause an external ophthalmoplegia must be ruled out.
While progressive external ophthalmoplegia may be a symptom of numerous diseases, we will be focusing on CPEO as the primary disease state caused by mitochondrial abnormalities. Kearns-Sayre syndrome
Kearns-Sayre syndrome
Kearns–Sayre syndrome also known as oculocraniosomatic disease or Oculocraniosomatic neuromuscular disease with ragged red fibers is a mitochondrial myopathy with a typical onset before 20 years of age...
(KSS), which at times is referred to as a severe form of CPEO with pigmentary retinopathy, complete heart block and occurs before the age of 20, will not be included in this discussion.
Of CPEO itself
CPEO is a slowly progressing disease. The first presenting symptom of ptosisPtosis (eyelid)
Ptosis is a drooping of the upper or lower eyelid. The drooping may be worse after being awake longer, when the individual's muscles are tired. This condition is sometimes called "lazy eye", but that term normally refers to amblyopia...
is often unnoticed by the patient until the lids droop to the point of producing a visual field defect. Often, patients will tilt the head backwards to adjust for the slowly progressing ptosis of the lids. In addition, as the ptosis becomes complete, the patients will use the frontalis (forehead) muscle to help elevate the lids. The ptosis is typically bilateral, but may be unilateral for a period of months to years before the fellow lid becomes involved.
Ophthalmoplegia or the inability/difficulty to move the eye is usually symmetrical. As such, double vision is not often a complaint of these patients. In fact, the progressive ophthalmoplegia is often unnoticed till decreased ocular motility limits peripheral vision. Often someone else will point out the ocular disturbance to the patient. Patients will move their heads to adjust for the lost of peripheral vision caused by inability to abduct or adduct the eye. All directions of gaze are affected, however, downward gaze appears to be best spared. This is in contrast to Progressive Supranuclear Palsy
Progressive supranuclear palsy
Progressive supranuclear palsy is a degenerative disease involving the gradual deterioration and death of specific areas of the brain....
(PSP) which typically affects vertical gaze and spares horizontal gaze.
Occurring alongside CPEO
Weakness of extraocular muscle groups including, the orbicularis oculi muscle as well as facial and limb muscles may be present in up to 25% of patients with CPEO. As a result of the orbicularis oculi weakness, patients may suffer from exposure keratopathy (damage to cornea) from the inability to close the eyes tightly. Frontalis muscle weakness may exacerbate the ptotic lids with the inability to compensate for the ptosis. Facial muscles may be involved which lead to atrophy of facial muscle groups producing a thin, expressionless face with some having difficulty with chewing. Neck, shoulder and extremity weakness with atrophy may affect some patients and can be mild or severe.Mild visual impairment was seen in 95% of patients that were evaluated using the Visual Function Index (VF-14).
The ciliary muscles that control the lens shape and the iris muscles are often unaffected by CPEO.
Additional symptoms are variable, and may include exercise intolerance, cataracts, hearing loss, sensory axonal neuropathy, ataxia, clinical depression, hypogonadism and parkinsonism.
Genetics
Mitochondrial DNA which is transmitted from the mother, encodes proteins that are critical to the respiratory chain required to produce adenosine triphosphateAdenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
(ATP). Deletions or mutations to segments of mtDNA lead to defective function of oxidative phosphorylation. This may be made evident in highly oxidative tissues like skeletal muscle and heart tissue. However, extraocular muscles contain a volume of mitochondria that is several times greater than any other muscle group. As such, this results in the preferential ocular symptoms of CPEO.
Multiple mtDNA abnormalities exist which cause CPEO. One mutation is located in a conserved region of mitochondrial tRNA at nucleotide 3243 in which there is an A to G nucleotide transition. This mutation is associated with both CPEO and Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).
A common deletion found in one-third of CPEO patients is a 4,977 base pair segment found between a 13 base pair repeat.
The mtDNA that is affected maybe a single or multiple point deletion, with associated nuclear DNA deletions. One study showed that mtDNA deletion seen in CPEO patients also had an associated nuclear DNA deletion of the Twinkle gene which encodes specific mitochondrial protein; Twinkle.
Whether a tissue is affected is correlated with the amount of oxidative demands in relation to the amount of mtDNA deletion.
In most cases, PEO occurs due to a sporadic deletion or duplication within the mitochondrial DNA. However, transmission from the mother to the progeny appears only in few cases. Both autosomal dominant and autosomal recessive inheritance can occur, autosomal recessive inheritance being more severe. Dominant and recessive forms of PEO can be caused by genetic mutations in the ANT1
ANT1
Antenna, better known as ANT1, is a television network airing in Greece and Cyprus. The alternate spelling is play on words in Greek; ena is the Greek number 1, thus ANT1 is pronounced the same as Antenna . It launched on 31 December 1989, the same year as rival Mega Channel, and is owned by...
, POLG
POLG
DNA polymerase subunit gamma is an enzyme that in humans is encoded by the POLG gene.-Functions:POLG is the gene that codes for the catalytic subunit of the mitochondrial DNA polymerase, called DNA polymerase gamma . The human POLG cDNA and gene were originally cloned mapped to chromosome 15,...
, POLG2
POLG2
DNA polymerase subunit gamma-2, mitochondrial is an protein that in humans is encoded by the POLG2 gene. The POLG2 gene encodes a 55 kDa accessory subunit protein that imparts high processivity and salt tolerance to the catalytic subunit of DNA polymerase gamma, encoded by the POLG gene. -Further...
and PEO1
PEO1
Twinkle protein, mitochondrial is a protein that in humans is encoded by the C10orf2 gene.-Further reading:...
genes.
Diagnosis
It is important to differentiate CPEO from other pathologies that may cause an ophthalmoplegia. There are specific therapies used for these pathologies.CPEO is diagnosed via muscle biopsy. On examination of muscle fibers stained with Gömöri trichrome stain
Gomori trichrome stain
Gömöri trichrome stain is a stain used on muscle tissue.It can be used to test for certain forms of mitochondrial myopathy.It is named for George Gömöri, who developed it in 1950.-External links:...
, one can see an accumulation of enlarged mitochondria. This produces a dark red staining of the muscle fibers given the name “ragged red fibers”. While ragged red fibers are seen in normal aging, amounts in excess of normal aging give a diagnosis of a mitochondrial myopathy.
Polymerase Chain Reaction (PCR), from a sample of blood or muscle tissue can determine a mutation of the mtDNA.
Elevated acetylcholine receptor antibody level which is typically seen in myasthenia gravis has been seen in certain patients of mitochondrial associated ophthalmoplegia.
It is important to have a dilated eye exam to determine if there is pigmentary retinopathy that may signify KSS which is associated with cardiac abnormalities.
Treatment
There is currently no defined treatment to ameliorate the muscle weakness of CPEO. Treatments used to treat other pathologies causing ophthalmoplegia has not been shown to be effective.Experimental treatment with tetracycline has been used to improve ocular motility in one patient. Coenyzme Q10 has also been used to treat this condition . However, most neuro-ophthalmologists do not ascribe to any treatment.
Ptosis associated with CPEO may be corrected with surgery to raise the lids, however due to weakness of the orbicularis oculi muscles, care must be taken not to raise the lids in excess causing an inability to close the lids. This results in an exposure keratopathy. Therefore, rarely should lid surgery be performed and only by a neuro-ophthalmologist familiar with the disease.
Those that have diplopia as a result of asymmetric ophthalmoplegia maybe corrected with prisms or with surgery to create a better alignment of the eyes.
External links and images
- http://www4.ocn.ne.jp/~nurophth/CPEO1.jpg
- http://webeye.ophth.uiowa.edu/eyeforum/cases/case24.htm
- http://journals.tubitak.gov.tr/medical/issues/sag-04-34-3/sag-34-3-9-0401-8.pdf