Leigh syndrome: mitochondrial and nuclear gene causes, inheritance and care

Mitochondria are the structures in nearly every cell that produce the energy the cell needs to work. The NHS Rare Mitochondrial Disorders Service explains that in mitochondrial disease the mitochondria are not producing enough energy, and that the organs with the highest energy demands, such as the brain, muscle, liver, heart and kidney, are the ones most often affected.

Leigh syndrome, also called Leigh disease, is one of the recognisable patterns of mitochondrial disease. The service describes it as a severe neurological condition that typically affects the development of movement, posture and mental abilities, with children sometimes losing these skills after a period of what appeared to be normal development. It is the particular involvement of parts of the brain that control swallowing, breathing, movement and posture that gives the condition its character.

The service estimates that Leigh syndrome affects approximately 1 in 40,000 newborns, with symptoms usually starting in the first year of life. It also notes that, although extremely rare, some people do not develop symptoms until early adult life, and others have symptoms that develop more slowly through childhood.

According to the service, children with Leigh syndrome are often weak and floppy, although this may not be obvious until they are several months old. Swallowing, breathing, movement and posture may be particularly affected. Many children gain developmental skills, such as rolling or sitting independently, and then lose them again.

This developmental regression typically happens when the child is unwell with a minor illness such as a tummy bug or a cough or cold. It may be the first sign of the underlying mitochondrial problem, and other features such as recurrent vomiting and poor weight gain are often present. After recovery, some of the lost skills may return.

The pace of the condition varies. The service says children may deteriorate in this stepwise way over many years, or follow a more rapidly progressive decline over a period of months. Because the pattern differs so much between children, it is not possible to give a single description of what to expect, and the specialist team can give the most realistic picture for an individual child.

Leigh syndrome is a syndrome rather than a single-gene disorder. The service explains that variants in over 75 genes have been linked to it. These include genes in the nuclear DNA, which sits in the chromosomes in the cell nucleus, and genes in the mitochondrial DNA, which is a small separate loop of DNA inside each mitochondrion.

Most of the genes involved help to build or assemble the protein complexes of the energy-producing chain inside the mitochondrion. The service says the most common variants are found in genes needed to make complex I, with complex IV and complex V also common causes. Other variants affect the pyruvate dehydrogenase complex, coenzyme Q10, genes that make or repair mitochondrial DNA, or the machinery that imports proteins into mitochondria.

Mitochondrial genes named by the service as associated with Leigh syndrome include MT-ATP6 and several MT-ND genes. The service also notes, in its description of the related condition NARP, that children with very high levels of changed mitochondrial DNA in the ATPase genes develop Leigh syndrome.

Because so many genes can be responsible, the inheritance pattern depends on where the variant sits. The most common pattern, according to the service, is autosomal recessive. Both parents typically carry one copy of the changed gene without having symptoms, and there is a 1 in 4 chance in each pregnancy of a child inheriting both copies.

When the variant is in mitochondrial DNA the pattern is maternal. The service explains that only mothers who carry a changed mitochondrial gene can pass it on, so sons and daughters can both be affected but only daughters can pass it on to their own children. How much of the changed DNA a child receives cannot be predicted, which the service describes as the genetic bottleneck, and this makes genetic counselling more challenging.

In a small number of families the cause is a gene on the X chromosome and the condition is X-linked recessive. In that situation males are affected more often than females, and fathers cannot pass an X-linked recessive condition to their sons.

The service says that specific patterns of brain involvement on an MRI scan, together with the typical clinical findings, usually suggest the diagnosis. A lumbar puncture, which collects a sample of spinal fluid, may help to show raised lactate in the cerebrospinal fluid and to exclude other problems. Muscle biopsy is less often performed than before but can confirm that mitochondrial function is abnormal and help direct more specific genetic testing.

The service also points out more generally that diagnosis of mitochondrial disease can be difficult because it often mimics other conditions, that blood lactate can be normal in people with mitochondrial disease, and that the genetic change can be hard to find. Genetic testing of blood is the usual first step, and a muscle sample is sometimes better for finding changes in mitochondrial DNA.

Finding the exact gene matters in practice because it tells the family which inheritance pattern applies and what the chance of recurrence is, which in turn shapes the reproductive advice.

The service states that there is no specific treatment for Leigh syndrome. For mitochondrial disease in general it says treatment is usually supportive, relieving the symptoms that develop, for example treating seizures with medication. Doctors may also try to make energy production more efficient with co-factors and vitamins such as ubiquinone (coenzyme Q10), thiamine and riboflavin, and some people use a special diet, which should only be tried under the guidance of the metabolic team.

The service stresses that any metabolic stress on the body, such as an illness, can cause a worsening of mitochondrial disease, so early medical advice and treatment of any illness is important. On its general advice pages it recommends avoiding fasting and dehydration during minor illnesses and having small snacks or high-calorie drinks to hand.

It also advises that the anaesthetist should always be told about a mitochondrial diagnosis before an operation, that a list of medicines to use with caution in primary mitochondrial disease has been published and should be shown to prescribers, and that children can attend mainstream or special school depending on their needs, with teachers made aware of problems such as epilepsy, feeding difficulty or mobility.

The service says that nothing taken during pregnancy or given to a baby will prevent Leigh syndrome if the variant is present. However, once the variant in a family has been identified, a number of reproductive options can be offered for the next pregnancy.

For people living in the UK, reproductive advice can be discussed with the doctors at any of the three highly specialised mitochondrial disease centres in Newcastle, London and Oxford, and referral to a specialised mitochondrial reproductive advice clinic in Newcastle is possible for women with mitochondrial DNA variants. One option the service describes is prenatal testing with a chorionic villus biopsy, usually after 10 to 12 weeks of pregnancy, which is only suitable for people who would consider ending an affected pregnancy.

Brothers, sisters and other relatives may also wish to know whether they carry the variant. A clinical genetics team can explain who is at risk and what testing involves for the particular inheritance pattern in the family.

The sources used for this guide do not set out a single emergency rule, because every child with Leigh syndrome has an individual care plan. In general, a child with a known mitochondrial or metabolic diagnosis who becomes unusually drowsy, cannot keep fluids down, has a seizure, has trouble breathing or is clearly deteriorating during an illness needs urgent assessment. Call 999 in an emergency, use NHS 111 for urgent advice, and contact the specialist team named in the care plan early rather than late.