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NARP / Leigh syndrome (m.8993)
This condition can manifest with a range of symptoms, including muscle weakness, developmental delay, and neurological problems. It is caused by a specific change in mitochondrial DNA and affects individuals differently depending on how many mitochondria carry the change.
Overview
NARP, which stands for Neuropathy, Ataxia, and Retinitis Pigmentosa, and Leigh syndrome are two forms of a single mitochondrial disease spectrum caused by the m.8993 genetic change. Mitochondrial conditions affect the mitochondria, which are small structures within cells responsible for producing most of the energy needed for the body's functions [PMID:33671181]. When mitochondria do not work correctly, cells, especially those in high-energy demand organs like the brain, muscles, and eyes, can be significantly impacted.
This specific m.8993 genetic change can lead to a spectrum of clinical presentations. Individuals with a lower proportion of affected mitochondria may experience NARP syndrome, typically starting in late childhood or adulthood. Those with a higher proportion often develop Leigh syndrome, a more severe form that usually appears in infancy or early childhood. Both conditions are progressive, meaning symptoms tend to worsen over time.
Symptoms & clinical features
The symptoms of NARP syndrome often include sensory neuropathy (nerve damage causing numbness, tingling, or pain), ataxia (problems with balance and coordination), and retinitis pigmentosa (a progressive eye condition leading to vision loss) [PMID:33671181]. Individuals may also experience muscle weakness, learning difficulties, and seizures. Fatigue is a common complaint due to the energy production issues.
Leigh syndrome, the more severe end of the spectrum, typically presents in early childhood. Symptoms can include developmental delay or regression, hypotonia (poor muscle tone), and problems with movement control. Neurological issues such as seizures, difficulty swallowing, breathing problems, and vision or hearing loss are also common. Affected children may experience episodes of worsening symptoms, often triggered by illness, which can be life-threatening.
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Affected organs
NARP / Leigh syndrome primarily affects organs with high energy demands. The central nervous system, including the brain and spinal cord, is significantly impacted, leading to neurological symptoms such as ataxia, developmental delay, and seizures. Muscles are also commonly affected, resulting in weakness and hypotonia.
Other organs that can be involved include the eyes, with retinitis pigmentosa affecting vision, and the peripheral nerves, causing neuropathy. In more severe cases, issues with the heart, kidneys, and liver can also arise, reflecting the widespread role of mitochondria in cellular function.
Risks & severity
The severity of NARP / Leigh syndrome (m.8993) is highly variable, largely depending on the proportion of mitochondria within a person's cells that carry the m.8993 genetic change. This is known as heteroplasmy [PMID:33671181]. A higher percentage of affected mitochondria generally leads to more severe symptoms and an earlier onset, typically presenting as Leigh syndrome in infancy or early childhood. Lower percentages are usually associated with NARP syndrome, with symptoms emerging in late childhood or adulthood.
As a progressive condition, symptoms generally worsen over time. The prognosis varies significantly, with some individuals experiencing a relatively stable course, while others face significant neurological decline and life-threatening complications. Regular monitoring and supportive care are crucial in managing the condition and its progression.
Genetic causes
NARP / Leigh syndrome (m.8993) is caused by a specific genetic change, m.8993T>G, located in the MT-ATP6 gene within mitochondrial DNA [PMID:19459207]. Unlike most genes, which are found in the nucleus of a cell, MT-ATP6 is located in the mitochondrial genome. The MT-ATP6 gene provides instructions for making a protein component of ATP synthase, a critical enzyme complex responsible for producing adenosine triphosphate (ATP), the primary energy currency of the cell.
The m.8993T>G change disrupts the normal function of ATP synthase, leading to a reduction in the cell's ability to produce energy efficiently. This energy deficit particularly affects tissues with high energy requirements, such as the brain and muscles, leading to the diverse symptoms seen in NARP / Leigh syndrome. The severity of the condition depends on the percentage of mitochondria carrying this particular genetic change within the cells.
Inheritance pattern
NARP / Leigh syndrome (m.8993) follows a mitochondrial inheritance pattern. This means the condition is passed down from the mother to all her children, regardless of their sex. Fathers do not pass on mitochondrial conditions to their children [PMID:19459207]. This is because mitochondria, and their DNA, are inherited exclusively from the egg cell.
An individual's mother may or may not show symptoms of NARP / Leigh syndrome herself, depending on her own level of heteroplasmy. If a mother carries the m.8993 genetic change, all her children are at risk of inheriting it. The specific symptoms and their severity in each child will depend on the proportion of affected mitochondria they inherit.
Diagnosis & testing
Diagnosing NARP / Leigh syndrome (m.8993) typically involves a combination of clinical evaluation, imaging studies, and genetic testing. Doctors may suspect the condition based on characteristic symptoms like developmental delay, neurological issues, and muscle weakness, along with specific findings on brain imaging, such as lesions in particular areas of the brain [PMID:33671181].
Confirmation of the diagnosis is usually achieved through genetic testing, specifically looking for the m.8993T>G variant in mitochondrial DNA. This can be performed using blood samples or, in some cases, tissue biopsies. In the UK, genetic testing for mitochondrial disorders may be accessed via the NHS Genomic Medicine Service, often through referral from a specialist paediatrician, neurologist, or clinical geneticist. Relevant NHS R-codes would be used for ordering these tests.
Management & lifestyle
Currently, there is no cure for NARP / Leigh syndrome (m.8993); however, management focuses on alleviating symptoms and providing supportive care to improve quality of life. Treatment plans are highly individualised, depending on the specific symptoms and their severity. This may involve a multidisciplinary team including neurologists, paediatricians, physiotherapists, occupational therapists, and dieticians.
Management strategies can include medications to control seizures, physical therapy to maintain muscle strength and mobility, and speech therapy for swallowing difficulties. Nutritional support, including specific dietary supplements like coenzyme Q10 or B vitamins, may be considered, though their effectiveness can vary. Regular monitoring for complications and prompt treatment of infections are also important aspects of care. Individuals and families affected by NARP / Leigh syndrome can access support and guidance through clinical genetics services and genetic counsellors in the UK.
UK care pathway
In the UK, individuals suspected of having NARP / Leigh syndrome (m.8993) can be referred to specialist services within the NHS Genomic Medicine Service. Referrals are typically made by general practitioners or other specialists, such as paediatricians or neurologists, to a clinical genetics team. This team can then coordinate diagnostic genetic testing, which is undertaken using specific NHS R-codes.
Following diagnosis, ongoing care is often managed by a multidisciplinary team at a specialist centre. Genetic counsellors play a vital role in providing information, emotional support, and discussing inheritance patterns and family planning options.
Frequently asked questions
What is mitochondrial DNA?
Mitochondrial DNA (mtDNA) is a small circular piece of genetic material found within mitochondria, the 'powerhouses' of our cells. Unlike the majority of our DNA, which is in the cell's nucleus, mtDNA is inherited solely from the mother.
What is heteroplasmy?
Heteroplasmy refers to the presence of more than one type of mitochondrial DNA within a cell or individual. In NARP / Leigh syndrome (m.8993), it means that some mitochondria have the genetic change, while others do not. The proportion of affected mitochondria determines the severity of the condition.
Can NARP / Leigh syndrome be prevented?
Currently, there is no known way to prevent NARP / Leigh syndrome (m.8993). However, for families with a known history, genetic counselling can provide information about inheritance risks and reproductive options.
Will my children inherit NARP / Leigh syndrome (m.8993)?
If you are a woman with the m.8993 genetic change, all your children will inherit the change, as mitochondrial DNA is passed from mother to child. The severity of the condition in your children will depend on the proportion of affected mitochondria they inherit from you.
How is NARP / Leigh syndrome (m.8993) treated?
Treatment focuses on managing symptoms and providing supportive care. This can involve medications for specific symptoms, physical and occupational therapy, dietary support, and regular monitoring by a team of specialists to address the condition's various manifestations.