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Chronic progressive external ophthalmoplegia
CPEO is characterised by the gradual weakening of eye muscles, leading to drooping eyelids and difficulty moving the eyes. It is typically a slowly progressing condition that can affect individuals of various ages.
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Overview
Chronic progressive external ophthalmoplegia (CPEO) is a condition that primarily affects the muscles controlling eye movement and the eyelids. The term 'ophthalmoplegia' refers to the paralysis or weakness of these eye muscles, while 'external' indicates that it affects the muscles on the outside of the eye rather than within it. 'Progressive' highlights that the symptoms tend to worsen gradually over time. This condition is part of a group of disorders known as mitochondrial diseases, which arise from problems in the mitochondria, the 'powerhouses' of our cells [PMID:31535269].
CPEO typically begins in adulthood, though in some cases, symptoms can appear during childhood. It affects individuals globally, and its exact prevalence is estimated to be around 1 in 100,000 people. While the main symptoms involve the eyes, some people with CPEO may also experience muscle weakness in other parts of the body, or other broader health issues.
Symptoms & clinical features
The most common initial symptom of CPEO is ptosis, which is the drooping of one or both eyelids. This often progresses slowly and can make it difficult to keep the eyes fully open [PMID:14555811]. Following this, individuals usually develop ophthalmoplegia, meaning they have trouble moving their eyes in different directions. This can lead to double vision (diplopia) or difficulty focusing.
Because the condition progresses gradually, the brain often adapts to the vision changes, reducing the severity of double vision for some. While eye-related symptoms are central to CPEO, some people may also experience more widespread symptoms. These can include general muscle weakness (myopathy), particularly in the limbs, difficulty swallowing (dysphagia), hearing loss, or problems with coordination (ataxia). Less commonly, heart problems (cardiomyopathy) or nerve damage (neuropathy) may occur, suggesting a broader impact of mitochondrial dysfunction.
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Affected organs
The primary organs affected in CPEO are the external eye muscles, which control eye movement, and the levator palpebrae superioris muscle, responsible for lifting the eyelids. Over time, these muscles weaken and degenerate, leading to the characteristic drooping eyelids and limited eye movement.
Beyond the eyes, CPEO can sometimes affect other muscle groups throughout the body, such as those in the arms and legs, leading to generalised muscle weakness. The heart, ears, and nervous system can also be involved in more complex forms of the disorder, reflecting the widespread role of mitochondria in cellular energy production [PMID:14555811].
Risks & severity
The severity of CPEO can vary significantly between individuals. For many, the condition remains largely confined to the eye muscles, causing visual impairment due to ptosis and ophthalmoplegia. However, for others, CPEO can be part of a broader syndrome, known as CPEO-plus or multi-systemic CPEO, where additional organs are affected.
The age of onset also varies, though symptoms typically emerge in adulthood. The progression is generally slow, often over many years or decades. While CPEO itself is not considered life-threatening in its isolated form, the more severe multi-systemic presentations can have more significant health implications, depending on which other organs are involved, such as the heart or brain. Regular monitoring helps to identify and manage these potential issues.
Genetic causes
CPEO is a mitochondrial disorder, meaning it is caused by problems within the mitochondria. Mitochondria are structures within our cells that generate most of the energy needed for cellular function. In many cases of CPEO, the condition is associated with changes in the mitochondrial DNA (mtDNA) or in nuclear genes that are essential for the health and function of mitochondria.
One significant gene implicated in CPEO is POLG. The POLG gene provides instructions for making DNA polymerase gamma, an enzyme crucial for replicating and repairing mitochondrial DNA [PMID:31535269]. Pathogenic variants in POLG can lead to widespread mitochondrial dysfunction, particularly affecting tissues like muscle that have high energy demands. This disruption in mtDNA maintenance can result in an accumulation of deletions in the mtDNA, which is a hallmark finding in many CPEO patients. Other genes are also known to be involved, but POLG is a common cause for both isolated CPEO and multi-systemic forms of the disease.
- POLG DNA polymerase gamma, catalytic subunit
Inheritance pattern
CPEO predominantly follows a mitochondrial inheritance pattern. This means the condition is passed down from the mother to all her children, regardless of their gender. Fathers do not pass on mitochondrial conditions to their children. This is because mitochondria, which contain their own DNA, are inherited almost exclusively from the egg cell during conception.
while mitochondrial inheritance is common, some forms of CPEO can also be inherited in an autosomal dominant or autosomal recessive manner, particularly when the genetic cause involves nuclear genes like POLG. In these cases, the inheritance pattern would differ, and a genetic counsellor can provide specific information based on the individual's family history and genetic findings. For maternally inherited forms, all children of an affected mother will inherit the pathogenic mitochondrial DNA, though the severity of symptoms can vary widely due to a phenomenon called heteroplasmy, where some cells may have more mutated mitochondrial DNA than others.
Diagnosis & testing
Diagnosing CPEO typically involves a combination of clinical assessment and genetic testing. A specialist, such as a neurologist or ophthalmologist, will evaluate the characteristic symptoms, including ptosis and limited eye movements. Electromyography (EMG) may be used to assess muscle function, and muscle biopsy can show characteristic ragged-red fibres, indicative of mitochondrial dysfunction.
Genetic testing is crucial for confirming a diagnosis and identifying the specific genetic cause. This testing can involve analysing mitochondrial DNA for deletions or pathogenic variants, as well as sequencing nuclear genes like POLG. In the UK, genetic testing pathways are accessed via the NHS Genomic Medicine Service (GMS) through R-codes like R142 (Adult onset mitochondrial disease). A referral from a specialist clinic, often clinical genetics or neurology, would initiate this process.
Management & lifestyle
While there is no cure for CPEO, management focuses on alleviating symptoms and addressing potential complications. For drooping eyelids (ptosis), surgical correction may be considered, though it can sometimes worsen eye movement restriction. Regular monitoring for other symptoms such as swallowing difficulties, heart problems, or hearing loss is important, especially in multi-systemic forms of the condition.
Care for individuals with CPEO often involves a multidisciplinary team, including neurologists, ophthalmologists, cardiologists, and dietitians. Genetic counsellors play a vital role in explaining the inheritance pattern, discussing prognosis, and supporting families. Avoiding certain medications that can interfere with mitochondrial function may also be recommended. Patients are supported within the NHS framework, accessing specialist services as needed.
UK care pathway
In the UK, individuals with suspected mitochondrial conditions like CPEO can access specialist care through the NHS Genomic Medicine Service (GMS). Referral to a Clinical Genetics service or specialist neurology clinic is typically the first step. These services can arrange for appropriate diagnostic genetic testing, which is covered under specific R-codes for mitochondrial disorders, such as R142 for adult-onset mitochondrial disease.
Following diagnosis, genetic counsellors are available to provide comprehensive support, explain the condition's inheritance pattern, discuss implications for family members, and help navigate the healthcare system. Ongoing management involves specialist teams who coordinate care to address the various symptoms that may arise.
Frequently asked questions
What is the main symptom of CPEO?
The primary symptom of CPEO is typically the gradual drooping of the eyelids (ptosis), followed by progressive weakness in the muscles that control eye movement, making it difficult to move the eyes in different directions.
Is CPEO always inherited from the mother?
CPEO often follows a mitochondrial inheritance pattern, meaning it is passed from mother to all her children. However, some forms caused by nuclear gene changes, such as in POLG, can be inherited in other ways, like autosomal dominant or recessive inheritance.
Can CPEO affect other parts of the body?
While CPEO primarily affects the eye muscles, some individuals can develop broader symptoms affecting other muscle groups, the heart, hearing, or the nervous system. This is sometimes referred to as 'CPEO-plus'.
How is CPEO typically diagnosed in the UK?
Diagnosis in the UK usually involves clinical evaluation by specialists like neurologists or ophthalmologists, followed by genetic testing through the NHS Genomic Medicine Service (GMS). This testing looks for specific changes in mitochondrial DNA or nuclear genes like POLG.
What kind of doctors treat CPEO?
Care for CPEO often involves a team of specialists, including neurologists for muscle and nerve issues, ophthalmologists for eye symptoms, and genetic counsellors for support and information about the genetic aspects of the condition.
References
- Ali A, Esmaeil A, Behbehani R. Mitochondrial Chronic Progressive External Ophthalmoplegia. Brain sciences. 2024. PMID: 38391710
- Birtel J, von Landenberg C, Gliem M. Mitochondrial Retinopathy. Ophthalmology. Retina. 2022. PMID: 34257060
- Nonaka I. Mitochondrial diseases. Current opinion in neurology and neurosurgery. 1992. PMID: 1392136
- Kisilevsky E, Freund P, Margolin E. Mitochondrial disorders and the eye. Survey of ophthalmology. 2020. PMID: 31783046
- Kim JY, Yang HK, Kim N. Strabismus in chronic progressive external ophthalmoplegia. Acta ophthalmologica. 2021. PMID: 33191655
- Shemesh A, Margolin E. Kearns-Sayre Syndrome. 2026. PMID: 29493966
- Danta G, Hilton RC, Lynch PG. Chronic progressive external ophthalmoplegia. Brain : a journal of neurology. 1975. PMID: 1182488
- Carruthers J. Pediatric ophthalmology. Current opinion in ophthalmology. 1996. PMID: 10165105