Leigh syndrome

What causes Leigh syndrome?

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.

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

Last updated on 05-01-20

How might Leigh syndrome be diagnosed?

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

  • 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). 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.

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.

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.

Last updated on 05-01-20

How is Leigh syndrome inherited?

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

It is most commonly inherited in an autosomal recessive manner. 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.

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. 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. 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.

Last updated on 05-01-20

If a family has a child with Leigh syndrome, what is the risk of future children being affected? Is this condition inherited from the mother or father?

Leigh syndrome can be inherited as either an autosomal recessive trait, an X-linked recessive trait, or as a mutation found within the mitochondrial DNA.

In autosomal recessive inheritance, a person inherits mutations in two genes, one from the father and one from the mother. If an individual receives one normal gene and one gene for the disease, the person will be a carrier and usually does not show symptoms. The risk for two carrier parents to both pass on the gene mutation and, therefore, have an affected child is 25% with each pregnancy. There is also a 50% risk in each pregnancy of having a child who is also a carrier; and a 25% of having a child that is neither affected nor a carrier.

In X-linked recessive disorders, a person can also inherit the condition from either parent. Females have two X chromosomes, but males have an X and a Y chromosome. In females, disease traits on the X chromosome can be masked by the normal gene on the other X chromosome. Since males only have one X chromosome, they will show features of the disease if they inherit a gene mutation on the X chromosome. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a 50% risk of passing on the carrier condition to their daughters, and a 50% chance of transmitting the disease to their sons.

In some cases, Leigh syndrome may be inherited from the mother as a mutation found within the mitochondrial DNA (mtDNA). All human mtDNA comes from the mother. Thus, an affected mother will pass the traits to all of her children, but only the daughters will pass the mutation(s) onto the next generation.

The genetic mutations that are present in the mtDNA may outnumber the normal copies of the genes. Symptoms may not occur until mutations are present in a significant percentage of the mitochondria. The uneven distribution of normal and mutant mtDNA in different tissues of the body can affect different organ systems in individuals from the same family and can result in a variety of symptoms in affected family members.

A genetics professional can help determine how Leigh syndrome is being transmitted in a particular family.

Last updated on 05-01-20

Am I at risk to be a carrier of Leigh syndrome if my maternal half sister has an affected son?

If your maternal half sister has a son with Leigh syndrome, there is a chance you carry a mutation responsible for Leigh syndrome. However, the chance depends on the genetic status of your sister and the inheritance pattern of Leigh syndrome in your sister's family. (Detailed information about how Leigh syndrome may be inherited is provided below or may be viewed on our website here.) For example:

  • If your nephew has mitochondrial DNA-associated Leigh syndrome and your sister has an mtDNA mutation, you and your mother are also at risk. A child always shares the same mtDNA with his/her maternal siblings and mother.
  • If your nephew has nuclear gene-encoded Leigh syndrome and it is inherited in an autosomal recessive manner, there is a chance you are a carrier if your sister inherited her mutation from your mother. If so, your chance to be a carrier of autosomal recessive Leigh syndrome would be 50%. If your sister inherited her mutation from her father, it is assumed you are not at risk to be a carrier (since you have different fathers).
  • If your nephew has nuclear gene-encoded Leigh syndrome and it is inherited in an X-linked recessive manner, there is a 50% chance you are a carrier for this type of Leigh syndrome. This is assuming that your sister's X chromosome with the mutation was inherited from your mother. If it was inherited from her father, he would have likely been affected with Leigh syndrome.

The genetics of Leigh syndrome, particularly mitochondrial DNA-associated Leigh syndrome, is very complex. Identifying the mode of inheritance in each family is necessary to learn about who is at risk to be a carrier and who is at risk to be affected.

Genetic testing of affected family members can confirm the mode of inheritance in a particular family. Carrier testing for at-risk relatives is then possible if the disease-causing mutation in a person or family has been identified. If a specific mutation causing Leigh syndrome cannot be identified and more than one family member is affected, a genetics professional may be able to take an "educated guess" about the inheritance mode based on careful evaluation of the family history.

People with personal questions and concerns about the inheritance of Leigh syndrome and risks to family members are strongly encouraged to speak with a genetic counselor or other genetics professional.

Last updated on 05-01-20

What is Leigh syndrome?

Leigh syndrome is a rare, inherited neurodegenerative condition. It usually becomes apparent in infancy, often after a viral infection. Rarely, it begins in the teenage or adult years. Signs and symptoms usually progress rapidly. Early symptoms may include poor sucking ability; loss of head control and motor skills; loss of appetite; vomiting; and seizures. As the condition progresses, symptoms may include weakness and lack of muscle tone; spasticity; movement disorders; cerebellar ataxia; and peripheral neuropathy. Complications can lead to impairment of respiratory, heart and kidney function. The term "Leigh-like syndrome" is often used for people with features that are strongly suggestive of Leigh syndrome but who do not meet the diagnostic criteria.

The inheritance of Leigh syndrome depends on where the responsible gene is located in each case. This is because it can be due to mutations in either mitochondrial DNA or nuclear DNA:

Treatment is based on the symptoms present and depends on the type of Leigh syndrome a person has. While life expectancy depends on the cause of Leigh syndrome in each person, most do not survive past mid-childhood or adolescence.

Last updated on 05-01-20

What tests are considered when diagnosing Leigh syndrome?

Tests that may be useful in diagnosing Leigh syndrome include, measuring lactic acid concentration in body fluids (i.e., blood, urine, and/or cerebrospinal fluid, the fluid that surrounds the brain and spinal cord), brain imaging, muscle biopsy, respiratory chain enzyme studies, and genetic testing. To learn more about the various tests run for diagnosing Leigh syndrome, visit GeneReviews and scroll down to the "Testing" section.

Last updated on 05-01-20

Is there genetic testing available for the mitochondrial and nuclear genes known to cause Leigh syndrome?

Although genetic testing is not available for all genes associated with Leigh syndrome, there is genetic testing available for both mitochondrial genes and nuclear genes associated with the condition.

Please see a list of laboratories offering the genetic test for Leigh syndrome by visiting Genetic Testing Registry (GTR), a centralized online resource for information about genetic tests. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Last updated on 05-01-20

What is known about Leigh syndrome diagnosed in adolescence or adulthood?

A very small number of individuals with Leigh syndrome live beyond 10 years of age. Leigh syndrome in adolescents or adults may occur in people who have Leigh syndrome who survive into adulthood, in people with a late onset of symptoms, or in people who experience spontaneous recovery. Adults with Leigh syndrome may have no neurological abnormalities. Rarely, they may have typical features of Leigh syndrome or more generalized mitochondrial disorders.

Last updated on 05-01-20

How might Leigh syndrome be treated?

Treatment of Leigh syndrome is directed toward the specific symptoms present in each person.

Supportive care for Leigh syndrome includes treatment of acidosis, seizures, dystonia, and cardiomyopathy, and attention to nutritional status.

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.

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

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.

Last updated on 05-01-20

Name: United Mitochondrial Disease Foundation 8085 Saltsburg Road, Suite 201
Pittsburgh, PA, 15239 , United States
Phone: +1-412-793-8077 Toll Free: 1-888-317-8633 Fax : +1-412-793-6477 Email: info@umdf.org Url: https://www.umdf.org
Name: MitoAction PO Box 51474
Boston, MA, 02205, United States
Phone: 1-888-MITO-411 (648-6411) for support line Toll Free: 1-888-648-6228 Email: info@mitoaction.org Url: https://www.mitoaction.org/
Name: Alex The Leukodystrophy Charity Alex TLC 45 Peckham High Street
London, SE15 5EB, United Kingdom
Phone: 020 7701 4388 Email: info@alextlc.org Url: https://www.alextlc.org
Name: People Against Leigh Syndrome PALS Lori Martin, Director
Houston, TX,
Phone: 713-863-0485 Email: director@peopleagainstleighs.org Url: http://peopleagainstleighs.org/

Connect with other users with Leigh syndrome on the RareGuru app

Do you have information about a disease, disorder, or syndrome? Want to suggest a symptom?
Please send suggestions to RareGuru!

The RareGuru disease database is regularly updated using data generously provided by GARD, the United States Genetic and Rare Disease Information Center.

People Using the App

Join the RareGuru Community

To connect, share, empower and heal today.

People Using the App