Leigh syndrome

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.^[1] A child always shares the same mtDNA with his/her maternal siblings and mother.^[2]
• 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.^[3][4] 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.^[2]

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.

Leigh syndrome can be inherited in different ways depending on the location of the responsible gene in each person.^[5]

It is most commonly inherited in an autosomal recessive manner.^[5] 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.^[5]

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.^[5] 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.^[5] 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.

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.