Leigh syndrome

Leigh syndrome, also known as Leigh’s disease, is a degenerative disorder affecting the brain of infants and young children (although adults can be affected too). The most common form of mitochondrial disease in childhood, it affects the central nervous system and can lead to a range of severe, often life-limiting problems including swallowing, breathing, metabolic, balance and mobility difficulties.

As one of the most severe forms of mitochondrial disease, Leigh syndrome can be life-limiting and usually requires specialised care and support. Below you can find information on symptoms, causes and help available for families affected by Leigh syndrome in the UK.

What is Leigh syndrome?

Leigh’s disease is a rare genetic disorder that primarily affects the brain and spinal cord. It’s one of a number of different types of mitochondrial diseases, a group of conditions which result from failures in the mitochondria – the energy-producing structures in our cells. Leigh syndrome is caused by mutations in either mitochondrial DNA or nuclear DNA, which impair the body’s ability to produce energy.

The disorder usually presents within the first year of life, typically after the age of six months, but can also appear in older children. In rare cases, symptoms may not appear until early adulthood or may progress gradually during childhood. However, these instances are uncommon. One of the key features of this mitochondrial disease is the loss of previously acquired motor or intellectual skills, often triggered by a minor illness such as a cold, cough or tummy bug.

The condition is progressive, meaning symptoms worsen over time, and it can lead to significant physical and neurological disabilities. While there is currently no cure, early diagnosis and supportive treatments can help to manage symptoms.

What are the symptoms of Leigh syndrome?

Symptoms can vary depending on the age of onset and the specific gene mutation involved, but may include:

• delayed development or regression
• poor muscle tone (hypotonia)
• movement disorders (dystonia) or difficulty with coordination (ataxia)
• trouble breathing (dyspnea) or swallowing
• feeding difficulties
• seizures
• lactic acidosis (excess lactic acid in the body)
• vision and hearing loss.

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 causes Leigh syndrome?

An estimate of the incidence of Leigh syndrome, reported in Leigh syndrome: Clinical Features and Biochemical and DNA Abnormalities by Professor David Thorburn, PhD (Melbourne, Australia), is approximately one in 77,000 births, or one in 40,000 births when including Leigh-like disease (a milder form often not confirmed by imaging or autopsy). However, this figure may be an underestimate, as mitochondrial diseases are frequently under-diagnosed or misdiagnosed.

It can be caused by mutations in more than 75 different genes affecting mitochondrial function. These include nuclear genes (within the nuclear DNA) or mitochondrial genes (within the mitochondrial DNA).

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 / MT01 / MPV17 / MRPL3 / MRPS22 / MTFMT / 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 / SERAC1 / 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-FMT / MT-ND1 / MT-ND2 / MT-ND3 / MT-ND4 / MT-ND5 / MTND6 / MT-TI / MT-TK / MT-TL1 / MT-TV / MT-TW

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 most commonly also referred to as Leigh’s disease, especially in older medical literature. Other terms include:

• Subacute necrotising encephalomyelopathy (SNE)
• Mitochondrial Leigh disease.

Research into Leigh syndrome

Here’s what current research tells us

One paper 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 showed how the disease can progress, resulting in:

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

According to another paper, 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.

The Leigh Syndrome International Consortium

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.

Support for Leigh syndrome

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 inheritance patterns and support future family planning.

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.

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.