Leigh Syndrome

What else is it called?

  • Leigh Disease
  • Necrotising Encephalomyelopathy (of Leigh)
  • Subacute Necrotising Encephalomyelopathy
  • SNE

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What causes it?

Leigh Syndrome is usually characterised by a degeneration of the nervous system. This is caused by a failure of energy production in the mitochondria of brain cells. Mitochondria are the cell’s ‘batteries’ and produce energy in the form of ATP (adenosine triphosphate), mainly through a process using specific enzymes. This process is called oxidative phosphorylation (OXPHOS). Energy is produced by burning sugars or fats within the mitochondria. The final pathway for generating energy for fuels is known as the respiratory chain which is located within the wall of the mitochondria. Problems within the respiratory chain can lead to a lack of energy and lead to a build-up of the things that would usually be burnt. For example, from the carbohydrates there will be an accumulation of lactic acid (lactic acidosis). Due to all parts of the body requiring energy to function, Leigh Syndrome is a multisystem disorder.

How common is it?

We do not know exactly how many people are affected by Leigh Syndrome. This disorder affects at least 1 in 40,000 newborns. It is more common in certain populations such as the Saguenay Lac-Saint-Jean region of Quebec (1 in 2,000) and in the Faroe Islands (1 in 1,700).

What are the signs and symptoms?

Patients with Leigh Syndrome usually develop symptoms in the first months of life, although in some cases onset of symptoms may not be until later in childhood or even (occasionally) in adulthood.

The classical form of Leigh Syndrome begins with symptoms usually appearing before the age of 2 years. The initial symptoms can include a loss of previously acquired skills such as head control and the ability to suck. There can also be a loss of appetite, vomiting, general irritability and abnormal crying. If onset is later in childhood, the symptoms that may occur are difficulties in articulating words, a loss of intellectual skills and difficulty co-ordinating movements (ataxia). As the disease progresses further symptoms may include generalised weakness, lack of muscle tone (hypotonia), clumsiness and tremors. Individuals may develop problems with their breathing and sometimes with swallowing. Visual problems that can occur may include rapid eye movement (nystagmus), crossed eyes (strabismus) and degeneration of the nerve in the eyes (optic atrophy). Further neurological development is delayed. Other organs which may be affected are the heart (hypertrophic cardiomyopathy – the heart is abnormally enlarged) and the kidneys.

Symptoms in the adult form usually begin during adolescence or adulthood with disturbances to the vision such as blurring, colour-blindness and/or progressive loss of vision. This is due to the degeneration of the optic nerves (optic atrophy). Later in mid-life other symptoms may appear, including difficulties co-ordinating movements (ataxia), muscle spasm, seizures and dementia.

How is it diagnosed?

The underlying cause of Leigh Disease is an inherited defect of energy production. Patients may have a biochemical defect in one or more of the OXPHOS enzyme complexes (complex I, II, III, IV or V) or in the enzyme PDH (pyruvate dehydrogenase). Tests that may be used to confirm the diagnosis including measuring lactate levels in blood and CSF (cerebrospinal fluid), magnetic resonance imaging (MRI) of the brain, and muscle and skin biopsies to measure the activities of the OXPHOS and PDH enzymes. In the UK, samples are sent off to one of two specialist centres and can take up to six weeks for the results to be returned

Can it be treated?

Unfortunately, there is no curative treatment for Leigh Disease. Some doctors may try one of a number of vitamin cofactors (such as biotin, thiamine, riboflavin and coenzyme Q10) because very occasionally a patient may improve with vitamin therapy. Sodium bicarbonate may be helpful if there are high levels of lactate in the blood. This may need to be given intravenously in the acute setting but is sometimes given by mouth if the patient has persistent lactic acidosis. Individuals with a deficiency of the PDH enzyme may be recommended to have a high fat, low carbohydrate (ketogenic) diet. Other treatment aims are supportive, to provide relief from difficult symptoms, for example drugs may be needed to control seizures or muscle spasms or to reduce nausea and vomiting.

Prognosis is extremely variable and does not appear to be closely correlated with the underlying biochemical or genetic defect. There tends to be a stepwise decline in function over the years, with periods of plateau or even improvement followed by periods of loss of skills. Loss of skills may follow intercurrent infections, or be triggered by some general anaesthetics, so children with Leigh Disease should only be anaesthetised in a specialist centre by anaesthetists experienced in managing patients with mitochondrial disorders. For some patients (particularly those with early onset) there may be rapid progression of disease leading to death within a few years of diagnosis, but other patients may survive into adulthood. It is difficult to predict the likely pattern of disease progression in individual cases at the time of diagnosis, although this may become clearer in the ensuing months. Progression of the adult form tends to be much slower than in the classical form that begins in infancy.

Several research groups in the UK and around the world are actively trying to find cures for Leigh Syndrome and other mitochondrial disorders.

Do my family need to be tested?

The enzyme defect is inherited through the genes from the parents in one of a number of different ways, depending on the precise genetic defect in the individual. It is thought that most cases of Leigh Syndrome are inherited from the genes of the parents by a method called autosomal recessive inheritance. This is when a child inherits a gene for the disease from both parents. If a child receives one normal gene and one gene with the disease, the child will be a carrier for the disease and usually does not show any symptoms. The risk of transmitting the disease from a couple who are both carriers is 25%, there is a 50% chance that their child will be a carrier and there is a 25% chance that the child would be genetically normal. This risk is the same for each pregnancy.

Approximately 20% of cases of Leigh Syndrome are caused by defects in genes located within the mitochondria. These genes are collectively known as the mitochondrial genome or mitochondrial DNA (mtDNA). The mtDNA is only passed down from mothers to their children because mtDNA from the sperm is not passed on to the fertilised egg. Defects in mtDNA are described as being maternally inherited. This means that girls will always pass on a defect in the mtDNA and boys will never pass on a defect in their mtDNA to their children.

The final way that Leigh Syndrome may be inherited is by X-linked inheritance. This applies to some cases of PDH deficiency. X-linked inheritance occurs when the disease genes are coded on the X-chromosome. Females have two X chromosomes and any disease trait that is on one of the X chromosomes is usually compensated by the other normal X chromosome. Males have one X and one Y chromosome; because there is only one X chromosome the disease is usually expressed, and therefore male children will have the disease.

 

Relevant Organisations

References

References are available on request. Please contact Helen Morris by phoning 0845 241 2173 or emailing helen@metabolicsupportuk.org [Resource Library No: LEM001].

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