Leigh syndrome

Leigh syndrome can be inherited in different ways depending on the location of the responsible gene in each person.^[1]

It is most commonly inherited in an autosomal recessive manner.^[1] 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.^[1]

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.^[1] 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.^[1] 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 can be inherited as either an autosomal recessive trait, an X-linked recessive trait, or as a mutation found within the mitochondrial DNA.^[2]

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.^[2] 

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.^[2] 

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.^[2]

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.^[2]

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

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.