Leigh syndrome

Leigh syndrome, also called Leigh’s disease, is a rare inherited condition that damages the brain and nervous system, usually in infants and young children. It’s caused by faults in the mitochondria, the parts of our cells that produce energy. There’s currently no cure, but specialist care can help manage symptoms. This page explains the symptoms, causes, inheritance, diagnosis, treatment and outlook, and where UK families can find support.

What is Leigh syndrome?

Leigh syndrome is a degenerative disorder of the brain and central nervous system, and the most common way mitochondrial disease presents in childhood. It affects infants and young children most often, although older children and adults can be affected too.

Mitochondria are the structures in our cells that turn food and oxygen into energy. When they fail, the organs that need the most energy, such as the brain, nerves and muscles, are affected first. In Leigh syndrome, changes in either mitochondrial DNA or nuclear DNA reduce the body’s ability to produce energy. The damage typically shows on MRI as areas of change in the brain, particularly the basal ganglia and brainstem.

The condition is progressive, so symptoms tend to worsen over time. A key feature is the loss of skills a child had already gained, such as sitting, walking or talking. This often happens during or after a minor illness such as a cold, cough or tummy bug.

What are other names for Leigh syndrome?

Leigh syndrome is named after a British neuropsychiatrist called Archibald Denis Leigh who first described the condition back in 1951. It’s also referred to as:

• Leigh’s disease (the older, and still very common term)
• Subacute necrotising encephalomyelopathy (SNE)
• Mitochondrial Leigh disease

Leigh-like disease is a milder or less typical presentation that doesn’t meet every diagnostic criterion, for example when imaging or post-mortem findings are not confirmed. It’s sometimes counted separately in research.

What are the symptoms of Leigh syndrome?

Symptoms usually begin in the first year of life and vary with the age of onset and the gene involved. The most common early signs are developmental delay or loss of skills, low muscle tone (hypotonia) and poor weight gain. Symptoms then tend to worsen, and neurological function becomes more severely affected over time.

Infants and young children (most common)

• Missed milestones or loss of skills
• Floppiness (hypotonia)
• Feeding and swallowing difficulties
• Poor weight gain
• Vomiting
• Irritability
• Seizures
• Breathing difficulties
• Abnormal eye movements

Older children

• Slower or stepwise loss of skills
• Movement problems such as dystonia or poor co-ordination (ataxia)
• Speech and learning difficulties
• Vision or hearing loss

Adolescents and adults (very rare)

• Slowly progressing neurological problems, often with movement, balance or vision difficulties

Other features can include high lactic acid in the blood (lactic acidosis), which doctors check for in diagnosis.

As Leigh syndrome progresses, neurological functions become more severely impaired.

The symptoms of the adult-onset form of Leigh syndrome (a very rare form of the disorder) generally begin during adolescence or early adulthood. The neurological problems associated with the disease progress slowly in this form of the disorder.

What can trigger a decline?

Many children first lose skills, or get worse, during an illness such as a cold, a cough or a tummy bug. Fever, infection and long periods without food can put extra strain on energy production. Families are usually given an emergency care plan by their specialist team.

When to get urgent medical help

If your child has a known diagnosis, follow their emergency care plan and contact their specialist team. Call 999 or go to A&E if your child has difficulty breathing, a prolonged seizure, is unusually drowsy or hard to wake, or cannot keep fluids down.

This page cannot diagnose Leigh syndrome. If you’re worried about your child’s development, speak to your GP, health visitor or paediatrician.

What causes Leigh syndrome, and what are the types?

Leigh syndrome is caused by changes (mutations) in genes needed for mitochondria to make energy. More than 75 different genes have been linked to it. Some sit in nuclear DNA, which we inherit from both parents, and some sit in mitochondrial DNA (mtDNA), which is passed on by the mother.

Because so many genes are involved, Leigh syndrome is better thought of as a group of related conditions than a single disease. Knowing the gene matters: it can tell families how the condition is inherited, what to expect and, in a few cases, which treatment may help.

Some examples of nuclear genes associated with Leigh syndrome include:

• AARS2 / ACAD9 / ADCK3 / AIFM1 / ANT1 / BCS1L / BTD / CARS2 / C12orf65 / C10orf2 / COIII / COX10 / COX15 / DGOUK / DLAT / DLD / EARS2 / ECHS1 / ECSIT / ETHE1 / ELAC2 / FARS2 / FBXL4 / FOXRED1 / GFM1 / GFM2 / GTPBP3 / HIBCH / IARS2 / LARS / LIAS / LIPT1 / LRPPRC / MECR / MFN2 / MTO1 / MPV17 / MRPL3 / MRPS22 / MT-FMT / NARS2 / NDUFA1 / NDUFA2 / NDUFA4 / NDUFA9 / NDUFA10 / NDUFA11 / NDUFA12 / NDUFAF2 / NDUFAF3 / NDUFAF5 / NDUFAF6 / NDUFB3 / NDUFS1 / NDUFS2 / NDUFS3 / NDUFS4 / NDUFS7 / NDUFS8 / NDUFV1 / NDUFV2 / NUBPL / OPA1 / PDHA1 / PDHB / PDHX / PDP1 / PDSS2 / PET100 / PNPLA8 / PNPT1 / RARS2 / RMND1 / RRM2B / RTN4IP1 / SCO / SCO2 / SDHA / SDHB / SDHD / SDHAF1 / SERAC1 / SLC19A3 / SLC25A1 / SLC25A19 / SUCLA2 / SUCLG1 / SURF1 / TACO1 / TANGO2 / TAZ / TK2 / TMEM126B / TMEM70 / TPK1 / TRIT1 / TRMU / TRTN1 / TSFM / TTC19 / TYMP / UQCRQ / WARS2 / YARS2

Some examples of mitochondrial genes associated with the condition include:

• MT-ATP6 / MT-CO3 / MT-ND1 / MT-ND2 / MT-ND3 / MT-ND4 / MT-ND5 / MT-ND6 / MT-TI / MT-TK / MT-TL1 / MT-TV / MT-TW

Some people have symptoms of Leigh syndrome but no gene change is found, especially when testing was done before genomic sequencing was widely available. A negative result does not rule the condition out.

Is Leigh’s disease inherited?

Yes, Leigh’s disease is a genetic condition, but how it’s inherited depends on which gene is affected. In most families the parents are healthy and had no way of knowing they carried a gene change. The pattern can only be confirmed through genetic testing, so a specialist team can explain what applies to your family. You can find out more about inheritance patterns in mitochondrial disease over in our Research Zone.

How common is Leigh syndrome?

Leigh syndrome is rare. One widely cited estimate of the incidence of Leigh syndrome (Leigh syndrome: Clinical Features and Biochemical and DNA Abnormalities by S Rahman and colleagues) is one in 77,000 births or one per 40,000 births for Leigh and Leigh-like disease.

These figures may be underestimates. Mitochondrial diseases are often under-diagnosed or misdiagnosed, and some children die before a diagnosis is reached.

How is Leigh syndrome diagnosed?

Diagnosis combines a child’s symptoms with blood tests, brain imaging and genetic testing. No single test is enough on its own, which is one reason diagnosis can take time.

1. Clinical assessment. Doctors look for the typical pattern: loss of skills, weak muscle tone, movement and feeding problems and poor weight gain
2. Blood and other tests. These check for high lactic acid (lactic acidosis) and other metabolic markers
3. MRI of the brain. This often shows symmetrical changes in areas such as the basal ganglia and brainstem
4. Genetic testing. Gene panels or whole-genome or exome sequencing aim to find the exact gene change. Results can take weeks to months
5. Biopsy. Sometimes a muscle or skin sample is taken to measure how well the mitochondria work, especially if genetic testing is inconclusive

What is the outlook and life expectancy?

Leigh syndrome is a life-limiting condition, and the course varies widely from child to child. Outcomes depend on the gene involved, the age symptoms start and how severe they are. Some children and young people live much longer, and adult-onset forms progress more slowly.

Here’s what current research tells us.

Leigh syndrome global patient registry: uniting patients and researchers worldwide using global patient data (including a handful of UK cases) shows that children are usually diagnosed at an average age of 2.8 years, with the time to diagnosis often taking 6 months to a year. Sadly, the average life expectancy is around 3.5 years.

The most common early symptoms recorded from this research were:

• Developmental delay (68%)
• Low muscle tone (hypotonia) (80%)
• Failure to thrive (71%)

An ePrint from Newcastle, entitled Natural History of Leigh Syndrome: A Study of Disease Burden and Progression, showed how the disease can progress, resulting in:

• Wheelchair use (57%)
• Tube feeding (46%)
• One-on-one support (43%)

According to the paper Natural History of Leigh Syndrome: A Study of Disease Burden and Progression, in confirmed cases of Leigh syndrome, the most common genetic causes were found to be:

• mtDNA mutations (particularly MT-ATP6, in 22.2% of cases)
• nuclear DNA mutations (56.9% of cases), with the most common being SURF1, ECHS1 and NDUFV1

How is Leigh syndrome treated?

There’s no cure yet, but care can make a real difference to comfort and quality of life. Treatment is led by a specialist team and usually includes:

• Treatable causes. A few genetic causes respond to treatments such as thiamine, biotin or a ketogenic diet, which is why a genetic diagnosis matters.
• Nutrition and feeding. Dietitian advice and, for some children, tube feeding.
• Seizures, movement and breathing. Medication and equipment to manage symptoms.
• Illness plans. Prompt treatment of infections, avoiding long periods without food, and an emergency care plan so hospital teams know what to do.
• Therapies and support. Physiotherapy, occupational therapy, speech and language therapy and appropriate equipment.
• Palliative and children’s hospice care. Offered alongside active treatment to support the child and family.

Specialist mitochondrial clinics across the UK provide diagnosis, monitoring and symptom management.

Is there any ongoing research into Leigh syndrome?

Yes. The Leigh Syndrome International Consortium unites the world’s leading scientists, clinicians and mitochondrial disease patient advocacy groups under a collaborative and inclusive approach to drive research that will advance the understanding of Leigh syndrome, uncover effective treatments and ultimately find a cure.

Although Leigh syndrome was first discovered over 70 years ago, there are significant knowledge gaps. The Consortium’s goal is to unite resources and together ‘crack the code’ on Leigh syndrome. Put simply, that means working together to understand it, define it and eventually cure it.

Find out more about the Leigh Syndrome International Consortium.

What support is available for families?

The specialist mitochondrial clinics across the UK are there to provide expert care, including diagnosis, ongoing monitoring and symptom management. Genetic counselling is also available through NHS services to help families understand how Leigh syndrome was passed on in their case and what it could mean for future children.

Here at The Lily Foundation, we understand the emotional effects of receiving a diagnosis of Leigh syndrome, and we’re here to offer practical advice, emotional support and patient advocacy for families living with the condition. We also fund critical research to help develop future treatments. Find out about all the mitochondrial disease support we offer.

Whether you or a loved one are newly diagnosed or have been living with Leigh syndrome for some time, our mitochondrial disease Q&A page is here to help answer any other questions you may have.

Living with Leigh syndrome: what families tell us

When Lucy’s son Harry was diagnosed with Leigh syndrome, her world changed overnight. Read Lucy’s story about what it’s like to live with Leigh syndrome – from the shock of diagnosis to the realities of day-to-day life, her experience offers a powerful insight into what it’s really like to care for a child with a complex, little-known condition.