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Leigh syndrome
This rare condition affects the central nervous system, impairing motor, sensory, and cognitive functions. It results from mitochondrial dysfunction, disrupting the body's energy production. Most commonly, it appears in infants and young children, but can also manifest later in life.
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Overview
Leigh syndrome is a rare and severe neurological disorder that generally presents in infants and young children, though it can sometimes manifest later in childhood or even adulthood. It is a progressive condition, meaning that symptoms typically worsen over time. The primary characteristic of Leigh syndrome is the presence of specific lesions (damaged areas) in the brain, particularly in regions involved in movement and sensation [PMID:36577319]. These brain changes can be observed through imaging techniques like MRI.
The disorder is classified as a mitochondrial disease because it results from an impaired ability of the mitochondria - often called the 'powerhouses' of the cells - to produce energy. This energy is crucial for normal cell function, especially in high-energy-demand organs like the brain, muscles, and heart. The lack of adequate energy leads to widespread cellular dysfunction, causing the varied symptoms observed in affected individuals.
Symptoms & clinical features
The symptoms of Leigh syndrome vary widely in severity and age of onset, but generally involve progressive neurological decline. In infants, the first signs may include feeding difficulties, vomiting, irritability, and continuous crying. Developmental milestones, such as sitting or walking, may be delayed or lost (psychomotor regression) [PMID:36577319].
Other common symptoms can include hypotonia (poor muscle tone), ataxia (problems with coordination and balance), spasticity (stiff muscles), and dystonia (involuntary muscle contractions). Eye movement abnormalities, such as nystagmus (rapid, uncontrolled eye movements) or ophthalmoplegia (paralysis of eye muscles), are also frequently observed. Breathing difficulties, such as apnoea (temporary cessation of breathing), and heart problems like hypertrophic cardiomyopathy (thickening of the heart muscle) can occur [PMID:32139886]. Seizures are also a potential feature of the condition.
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Affected organs
Leigh syndrome predominantly affects the central nervous system, specifically the brain and spinal cord. Characteristic lesions are often found in brain regions such as the brainstem, basal ganglia, and thalamus, which are critical for controlling movement, sensation, and vital functions like breathing.
Beyond the brain, other organs can be affected due to the systemic nature of mitochondrial dysfunction. Muscles can be weakened (myopathy), and the heart may develop cardiomyopathy. Some individuals may experience issues with the liver, kidneys, or gastrointestinal system, although these are typically less common or severe than the neurological manifestations.
Risks & severity
Leigh syndrome is a severe condition, and its progression can vary significantly among individuals. The prognosis is often poor, especially for those with an early onset, with many children not surviving beyond early childhood. However, some individuals with milder forms or later onset may have a more prolonged course.
While the exact prevalence is not well established globally, research suggests it affects approximately 1 in 36,000 live births. The lifetime risks associated with Leigh syndrome include progressive neurological decline, respiratory failure, and heart complications. The age of onset typically falls within the first year of life, but it can range from birth to adulthood. The severity of the disease is influenced by the specific genetic cause and the extent of mitochondrial impairment.
Genetic causes
Leigh syndrome is a genetically heterogeneous disorder, meaning it can be caused by pathogenic variants in many different genes. These genes are involved in the function of mitochondria, specifically in the process of oxidative phosphorylation, which is how cells generate most of their energy. The condition can result from issues in the nuclear DNA (inherited from both parents) or in the mitochondrial DNA (inherited from the mother).
Two specific genes associated with Leigh syndrome are NDUFS4 and SURF1. Pathogenic variants in NDUFS4 disrupt the assembly or function of Complex I of the mitochondrial respiratory chain, which is essential for energy production. Similarly, pathogenic variants in SURF1 affect the assembly of Complex IV (cytochrome c oxidase), another crucial component of the respiratory chain. Both lead to inefficient energy production and cause the neurological damage characteristic of Leigh syndrome.
- NDUFS4 NADH:ubiquinone oxidoreductase subunit S4
- SURF1 SURF1 cytochrome c oxidase assembly factor
Inheritance pattern
Leigh syndrome is most commonly inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of a pathogenic variant - one from each parent - to develop the condition. Parents who carry one copy of the pathogenic variant are known as carriers; they typically do not show symptoms themselves because they have one working copy of the gene.
When two carriers have children, there is a 25% chance with each pregnancy that their child will inherit two pathogenic variants and develop Leigh syndrome. There is a 50% chance the child will be a carrier like their parents, and a 25% chance the child will inherit two working copies of the gene and not be affected or a carrier. In some cases, Leigh syndrome can also be inherited through X-linked or mitochondrial inheritance patterns, depending on the specific gene involved.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosing Leigh syndrome often begins with a clinical suspicion based on the characteristic neurological symptoms and developmental regression. Brain imaging, particularly MRI, plays a crucial role in diagnosis by revealing the typical lesions in the basal ganglia, brainstem, or cerebellum. Metabolic tests, such as elevated lactate levels in blood or cerebrospinal fluid, can also support the diagnosis by indicating impaired energy metabolism.
Genetic testing is the definitive method to confirm a diagnosis of Leigh syndrome and identify the specific causative gene. This can involve gene panels, whole exome sequencing, or whole genome sequencing, available through the NHS Genomic Medicine Service (GMS). Referral for genetic testing is typically made by a paediatric neurologist or a clinical genetics specialist. The NHS Genomic Test Directory lists relevant R-codes for testing, such as R301 'Mitochondrial disease - nuclear DNA'. A genetic counsellor can provide support and explain the implications of genetic test results.
Management & lifestyle
The management of Leigh syndrome is primarily supportive, aiming to alleviate symptoms and improve quality of life, as there is currently no cure. A multidisciplinary team of specialists, including neurologists, metabolic specialists, physiotherapists, occupational therapists, and speech and language therapists, is usually involved in care.
Treatments may include medications to manage symptoms such as seizures or spasticity. Nutritional support, including dietary modifications or supplements, might be recommended to address metabolic imbalances, though evidence for their effectiveness is limited for some. Regular monitoring of respiratory and cardiac function is important, and interventions like respiratory support may be necessary. Genetic counselling is vital for affected families to understand the inheritance pattern and risks for future pregnancies.
UK care pathway
In the UK, individuals suspected of having Leigh syndrome would typically be referred to specialist services within the NHS. This pathway often starts with a paediatrician or neurologist. If a mitochondrial disorder is suspected, a referral to a Clinical Genetics service or a specialist metabolic centre would be made for further evaluation and genetic testing. The NHS Genomic Medicine Service provides comprehensive genetic testing through R-codes such as R301 (for nuclear DNA-related mitochondrial disorders), facilitating a precise diagnosis.
Genetic counsellors play a crucial role in this pathway, offering information and support to families about the genetic basis of the condition, inheritance patterns, and reproductive options. They can also help coordinate care and access to relevant support groups.
Frequently asked questions
What is the typical age of onset for Leigh syndrome?
Leigh syndrome most commonly presents in infancy, usually within the first year of life. However, it can occasionally appear later in childhood or even during adulthood, though these cases are less common.
Is Leigh syndrome inherited?
Yes, Leigh syndrome is typically an inherited condition. Most often, it follows an autosomal recessive inheritance pattern, meaning a child inherits a pathogenic gene variant from both parents, who are usually carriers. Other inheritance patterns, such as X-linked or mitochondrial inheritance, can occur depending on the specific gene involved.
Can Leigh syndrome be cured?
Currently, there is no cure for Leigh syndrome. Management focuses on supportive care to ease symptoms, improve quality of life, and address complications. This often involves a team of specialists to manage neurological, respiratory, and cardiac issues.
How is Leigh syndrome diagnosed?
Diagnosis involves a combination of clinical assessment of symptoms, brain imaging (MRI) to look for characteristic lesions, metabolic tests (like lactate levels), and crucially, genetic testing to identify the specific genetic cause. Genetic testing is available through the NHS Genomic Medicine Service.
What kind of support is available for families affected by Leigh syndrome in the UK?
Families in the UK can access support through specialist NHS services, including Clinical Genetics teams and metabolic centres. Genetic counsellors offer vital information and emotional support. Patient advocacy groups and charities also provide resources and community support for those affected by mitochondrial diseases.