Leigh syndrome

The symptoms of Leigh syndrome vary greatly from person to person. Very rarely, affected people with near-normal neurologic findings have been reported. Most people with Leigh syndrome have central nervous system and peripheral nervous system abnormalities, without involvement of other body systems.^[5]

Central nervous system abnormalities may include:^[1][5]

• Developmental delay or regression
• Nystagmus
• Ophthalmoparesis (weakness in the muscles that control eye movement)
• Optic atrophy
• Ataxia
• Dysphagia
• Retinitis pigmentosa
• Deafness

Peripheral nervous system abnormalities may include polyneuropathy and myopathy.^[1][5]

Although most people with Leigh syndrome only have neurological abnormalities, some people also have non-neurologic abnormalities. These may include:^[5]

• Distinct physical features
• Hormone abnormalities resulting in short stature or hypertrichosis
• Heart abnormalities (hypertrophic or dilated cardiomyopathy)
• Gastrointestinal symptoms such as diarrhea

Leigh syndrome can be caused by mutations in any of more than 75 different genes. Most of our genes are made up of DNA in the cell's nucleus (nuclear DNA). Some of our genes are made up of DNA in other cell structures called mitochondria (mitochondrial DNA, or mtDNA). Most people with Leigh syndrome have a mutation in nuclear DNA, and about 20% have a mutation in mtDNA.

Most genes associated with Leigh syndrome are involved in the process of energy production in mitochondria (oxidative phosphorylation). Five protein complexes, named complex I through complex IV, are involved in this process. Many of the gene mutations associated with Leigh syndrome disrupt the function of proteins in these complexes, how the complexes form, or additional steps related to energy production. Researchers believe that impaired oxidative phosphorylation may cause cells to die because they don't have enough energy. The death of brain cells likely contributes to the neurologic features of the condition, while the death of cells in other tissues may lead to additional symptoms in other parts of the body.^[2]

More information about the genes responsible for Leigh syndrome is available here on the Genetics Home Reference website.

Leigh syndrome can be inherited in different ways depending on the location of the responsible gene in each person.^[2]

It is most commonly inherited in an autosomal recessive manner.^[2] This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. Affected people inherit one mutated copy of the gene from each parent, who is referred to as a carrier. Carriers of an autosomal recessive condition typically do not have any signs or symptoms (they are unaffected). When two carriers of an autosomal recessive condition have children, each child has a:

• 25% chance to be affected
• 50% chance to be an unaffected carrier like each parent
• 25% chance to be unaffected and not a carrier

Autosomal recessive inheritance applies to most of the associated genes in nuclear gene-encoded Leigh syndrome.^[2]

In about 20% of cases, when Leigh syndrome is due to mutations in mitochondrial DNA (mitochondrial DNA-associated Leigh syndrome), it is inherited in a mitochondrial pattern.^[2] This is also called maternal inheritance. Only egg cells, but not sperm cells, pass mitochondria on to children. This means that children can inherit mtDNA mutations from their mother only. This type of Leigh syndrome can occur in every generation of a family, and can affect males and females. However, affected males do not pass the condition on to their children. The father of an affected child is not at risk of having the mtDNA mutation, but the mother of an affected child usually has the mutation and may or may not have symptoms. In some cases, an mtDNA mutation occurs for the first time in an affected person and is not inherited. This is called a de novo mutation.

In a few cases of Leigh syndrome due to mutations in nuclear DNA, inheritance is X-linked recessive.^[2] X-linked recessive conditions usually occur in males, who only have one X chromosome (and one Y chromosome). Females have two X chromosomes, so if they have a gene mutation on one of them, they still have a normal copy on their other X chromosome. For this reason, females are typically unaffected. While females can have an X-linked recessive condition, it is very rare.

If a mother is a carrier of an X-linked recessive condition and the father is not, the risk to children depends on each child's sex.

• Each son has a 50% chance to be unaffected, and a 50% chance to be affected
• Each daughter has a 50% chance to be unaffected, and a 50% chance to be an unaffected carrier

If a father has the condition and the mother is not a carrier, all sons will be unaffected, and all daughters will be unaffected carriers.

Leigh syndrome may be diagnosed by using the following criteria, defined by Rahman et al. in 1996:^[3]

• Progressive neurologic disease with motor and intellectual developmental delay
• Signs and symptoms of brainstem and/or basal ganglia disease
• Raised lactate concentration in blood and/or cerebrospinal fluid (CSF)
• The presence of one or more of the following:
  • Characteristic features on brain imaging (CT scan or MRI)
  • Typical nervous system tissue changes
  • Typical nervous system tissue changes in a similarly affected sibling

After these criteria are met and a diagnosis of Leigh syndrome is made, molecular genetic testing can then differentiate between mtDNA-associated Leigh syndrome (caused by mutations in mtDNA) and nuclear gene-encoded Leigh syndrome (caused by mutations in nuclear DNA).^[3] A diagnosis of nuclear gene-encoded Leigh syndrome can be made either by identifying a mutation in nuclear DNA, or by excluding the presence of a mutation in mtDNA.^[4]

Because not all patients have increased lactate levels, recent studies proposed new diagnostic criteria excluding the raised lactate levels as a prerequisite. The remaining criteria are similar, but add mitochondrial dysfunction as a criterion.^[3]

A diagnosis of Leigh-like syndrome may be considered in individuals who do not meet the strict diagnostic criteria but have features resembling Leigh syndrome.^[3] 

Treatment of Leigh syndrome is directed toward the specific symptoms present in each person.^[6]

Supportive care for Leigh syndrome includes treatment of acidosis, seizures, dystonia, and cardiomyopathy, and attention to nutritional status.^[4][3]

Because anesthesia can potentially aggravate respiratory symptoms and bring on respiratory failure, careful consideration should be given to its use and close monitoring prior to, during, and after its use.^[4][3]

Progression and new symptoms should be monitored regularly (typically every 6-12 months). Evaluations with a neurologist, ophthalmologist, audiologist, and cardiologist are recommended.^[4][3]

Specific treatment is possible for the three nuclear gene-encoded Leigh-like syndromes (milder conditions with similar features). These include biotin-thiamine-responsive basal ganglia disease (BTBGD), biotinidase deficiency, and coenzyme Q10 deficiency caused by mutation of PDSS2.^[4]

Leigh syndrome in general is rare and is estimated to affect about 1 in 30,000 to 1 in 40,000 people at birth. Mitochondrial DNA-associated Leigh syndrome, which is more rare than nuclear gene-encoded Leigh syndrome, is likely to occur in about 1 in 100,000 to 1 in 140,000 births.^[3]

Leigh syndrome is much more common in certain populations. For example, it occurs in approximately 1 in 2,000 newborns in the Saguenay Lac-Saint-Jean region of Quebec, Canada and in approximately 1 in 1,700 on the Faroe Islands (between Norway and Iceland).^[2]