Leigh syndrome is not caused by a single gene mutation. It is one of the most genetically complex disorders known, with more than 75 genes identified across both nuclear DNA and mitochondrial DNA. The condition affects roughly 1 in 40,000 people, making it the most common pediatric mitochondrial disease. Despite this genetic diversity, all the mutations share a common result: they cripple the cell’s ability to produce energy.
Why So Many Genes Are Involved
Your cells generate energy through a chain of five protein complexes inside the mitochondria, often called the “powerhouses” of the cell. These complexes work in sequence to convert food into usable fuel. Building and maintaining these complexes requires instructions from dozens of genes, some stored in your regular (nuclear) DNA and others in the small loop of DNA inside the mitochondria themselves. A disabling mutation in any of these genes can starve the brain and muscles of energy, producing the characteristic brain lesions of Leigh syndrome.
Mutations linked to Leigh syndrome have been found in genes affecting all five energy-producing complexes. The two most commonly disrupted are Complex I (the largest complex in the chain, with 38 nuclear-encoded parts) and Complex IV (also called cytochrome c oxidase, which performs the final step before energy is locked into a usable form).
The Most Common Nuclear Gene: SURF1
Among mutations in nuclear DNA, SURF1 is the most frequently identified gene in Leigh syndrome. Located on chromosome 9, SURF1 doesn’t build a piece of Complex IV directly. Instead, it acts as an assembly factor, helping the 13 subunits of Complex IV come together properly. When SURF1 is mutated, Complex IV can’t form or function, and the cell’s energy production drops sharply.
Most children with SURF1 mutations develop typical Leigh syndrome and, unfortunately, face early mortality, often before age ten. About 10% of cases follow a milder, atypical course with longer survival. In one reported case, a patient with two different SURF1 mutations survived to age 18, but this remains the exception. SURF1 mutations are inherited in an autosomal recessive pattern, meaning a child must receive a faulty copy from each parent to develop the disease.
Complex I Gene Mutations
A large family of genes encoding parts of Complex I are also major contributors. Complex I is the entry point for the energy-production chain, and it is built from more subunits than any other complex. The core subunits linked to Leigh syndrome include NDUFS1, NDUFS2, NDUFS3, NDUFS7, NDUFS8, NDUFV1, and NDUFV2. Additional associated subunits, including NDUFS4, NDUFA2, NDUFA9, NDUFA10, NDUFA11, and NDUFA12, have also been identified as causes.
Assembly factors for Complex I matter too. NDUFAF2, NDUFAF5, and NDUFAF6 don’t become part of the finished complex but are essential for putting it together. Mutations in any of these genes reduce the amount of working Complex I, leaving cells unable to process the first step of energy production efficiently. Most of these mutations follow an autosomal recessive inheritance pattern.
The Most Common Mitochondrial Gene: MT-ATP6
Mitochondria carry their own small genome, separate from the DNA in the cell nucleus. Among mitochondrial DNA mutations, MT-ATP6 is the most common cause of Leigh syndrome, responsible for roughly 40% of all mitochondrial DNA-linked cases. This gene encodes a subunit of Complex V, the final complex in the chain that directly synthesizes the cell’s energy currency.
The best-known MT-ATP6 mutations are designated m.8993T>G and m.8993T>C, along with m.9176T>C and m.9185T>C. The severity of disease often correlates with how many copies of the mutated mitochondrial DNA a person carries. Mitochondrial DNA exists in hundreds or thousands of copies per cell, and a higher percentage of mutated copies (called heteroplasmy) generally produces more severe symptoms.
Other mitochondrial genes play smaller roles. MT-TL1 accounts for fewer than 5% of mitochondrial DNA cases, while MT-TK is rare. Genes encoding subunits of Complex I within the mitochondrial genome, including MT-ND3, MT-ND5, and MT-ND6, have also been linked to the syndrome through specific point mutations.
X-Linked Mutations: PDHA1 and NDUFA1
While most Leigh syndrome mutations are autosomal recessive or maternally inherited through mitochondrial DNA, a few follow an X-linked pattern. The most notable is PDHA1, which encodes a key part of the pyruvate dehydrogenase complex. This complex sits upstream of the energy chain itself, converting pyruvate (the end product of sugar breakdown) into the fuel that enters the mitochondrial chain. About 25% of cases of pyruvate dehydrogenase deficiency go on to cause Leigh syndrome.
Because PDHA1 sits on the X chromosome, males are more severely affected. They carry only one copy, so every cell feels the impact of the mutation. Females have two X chromosomes, and random inactivation of one copy in each cell means their symptoms can range from severe to very mild depending on which copy gets silenced in brain and muscle tissue. More than 190 different PDHA1 mutations have been cataloged.
NDUFA1, a Complex I subunit gene, is the other X-linked gene linked to Leigh syndrome, though it is identified far less frequently.
Three Inheritance Patterns
The genetic diversity of Leigh syndrome translates into three distinct ways the condition can be inherited:
- Autosomal recessive: The most common pattern. Both parents carry one faulty copy of a nuclear gene (like SURF1 or the NDUF genes) without symptoms, and each pregnancy carries a 25% chance of producing an affected child.
- Maternal (mitochondrial): Mitochondrial DNA is inherited only from the mother. If she carries a mitochondrial mutation like one in MT-ATP6, all her children may inherit some proportion of mutated copies, but the percentage varies, making the severity unpredictable.
- X-linked: Mutations in PDHA1 or NDUFA1 are passed through the X chromosome. Carrier mothers have a 50% chance of passing the mutation to each child, with sons typically more severely affected.
New Genes Are Still Being Discovered
The list of Leigh syndrome genes continues to grow. In 2024, researchers identified MRPS36 as a new causative gene after studying two brothers with Leigh syndrome who carried identical nonsense mutations. MRPS36 encodes a component of the mitochondrial ribosome, the machinery that translates mitochondrial DNA into working proteins. When this gene is knocked out, the mitochondria can’t build their own components, and the energy chain fails. The brothers presented with involuntary movement symptoms including chorea and dystonia.
As of the most recent counts, more than 75 genes are confirmed causes of Leigh syndrome, and whole exome sequencing has become the standard first-line genetic test in countries where it is available. This broad sequencing approach captures both nuclear and mitochondrial genes simultaneously, which is critical given how many different mutations can produce the same clinical picture.
Why the Specific Mutation Matters
Identifying the exact gene mutation in a given case of Leigh syndrome isn’t just academic. It determines the inheritance pattern, which directly affects family planning decisions and recurrence risk for future pregnancies. It can also influence prognosis: SURF1 mutations, for instance, tend to follow a more predictable and severe course than some Complex I mutations. For mitochondrial DNA mutations like those in MT-ATP6, the percentage of mutated copies can be measured in the mother and used to estimate, though not guarantee, the likelihood of a severely affected child.
The genetic diagnosis also shapes what supportive therapies might help. Some mutations respond to specific vitamin or cofactor supplementation that targets the affected complex, while others do not. Without pinpointing the gene, treatment is entirely empirical.