What Gene Mutation Is Involved In Leigh Syndrome?

Leigh syndrome is not caused by one gene mutation. It is a group of inherited mitochondrial disorders, and more than 75 different genes have been linked to it. The most common mutations affect nuclear DNA — particularly the SURF1 gene — while others occur in mitochondrial DNA, most often in the MT-ATP6 gene.

That distinction matters. Leigh syndrome is defined by its clinical and brain-imaging features, not by a single genetic cause. Two children with the same diagnosis may carry mutations in completely different genes, inherited in different ways, with different implications for the rest of the family.

What Gene Mutation Is Involved In Leigh Syndrome?

There is no single answer, because Leigh syndrome is genetically heterogeneous. Researchers have identified disease-causing mutations in more than 75 genes, and the list continues to grow as genetic testing improves.

The genes fall into two broad groups based on where they sit in the cell.

• Nuclear DNA genes. These are inherited from both parents. The most frequently implicated is SURF1, which accounts for a substantial share of Leigh syndrome cases in which a genetic cause is found. Other commonly involved nuclear genes include those encoding subunits of the pyruvate dehydrogenase complex, Complex I and Complex II of the mitochondrial respiratory chain, and several assembly factors.
• Mitochondrial DNA genes. These are inherited only from the mother. The most commonly implicated is MT-ATP6, along with other mitochondrial genes that encode parts of the respiratory chain.

Estimates of how common each gene is vary widely by population and by how cases are identified. SURF1 mutations are especially common in some European cohorts. MT-ATP6 mutations appear more often in others. No single global figure applies to everyone.

How Do These Mutations Cause Leigh Syndrome?

Nearly all of the genes linked to Leigh syndrome share one job: they help mitochondria produce energy. When those genes are mutated, the machinery that converts food into usable cellular energy breaks down.

The result is a specific pattern of damage. Cells with the highest energy demands are hit hardest. That means the brain, the brainstem, the basal ganglia, and the muscles. This is why Leigh syndrome produces neurological symptoms and why brain imaging shows characteristic changes in those regions.

The underlying problem is almost always a defect in oxidative phosphorylation, the process by which mitochondria generate ATP, the cell’s energy currency. Different genes disrupt this process at different points, but the downstream effect converges on energy failure and, in many cases, cell death.

One detail worth understanding: the severity and timing of symptoms depend heavily on which gene is affected and how much of the mitochondrial energy system is impaired. Two children with the same clinical diagnosis can have very different courses.

Is Leigh Syndrome Inherited From the Mother or Both Parents?

It depends entirely on which gene carries the mutation. This is one of the most important things for families to understand, because it affects genetic counseling for everyone in the family.

• Nuclear DNA mutations are inherited in patterns that typically involve both parents. Some are autosomal recessive, meaning each parent carries one copy of the mutation and neither is affected. Others follow different patterns depending on the gene.
• Mitochondrial DNA mutations are inherited only from the mother. Fathers do not pass mitochondrial DNA to their children.

There is an added layer of complexity with mitochondrial DNA. A single cell contains many copies of mitochondrial DNA, and not all of them carry the mutation. This mixture is called heteroplasmy. The proportion of mutated mitochondrial DNA a child inherits affects how severe the disease is and whether symptoms appear at all.

This is why two siblings can inherit the same mitochondrial mutation from their mother and have very different outcomes. It also means a mother who carries a mitochondrial mutation may be completely unaffected.

What Are the Symptoms and When Do They Appear?

Leigh syndrome most often begins in infancy or early childhood, though later-onset forms exist. Symptoms reflect the regions of the brain and nervous system that are affected.

Early signs commonly include:

• Loss of previously acquired motor skills, such as sitting or walking
• Poor muscle tone, or on the other hand, muscle stiffness
• Difficulty feeding and poor weight gain
• Developmental delay or regression
• Fatigue and weakness

As the disease progresses, more serious neurological symptoms can appear. These may include problems with eye movement, breathing difficulties, seizures, and impaired swallowing. Breathing problems are particularly concerning because they can stem from brainstem involvement.

Symptoms often come in episodes. A minor illness, infection, or metabolic stress can trigger a sudden worsening, followed by partial recovery. This pattern of stepwise decline is a hallmark of many mitochondrial disorders.

The age of onset and the rate of progression vary widely depending on the specific gene involved and the degree of energy failure.

How Is Leigh Syndrome Diagnosed?

Diagnosis rests on a combination of clinical signs, brain imaging, and genetic testing. No single test confirms it alone.

Brain MRI is central. It typically shows symmetric lesions in the basal ganglia and brainstem — a pattern that is characteristic of Leigh syndrome, though not entirely unique to it. Blood and cerebrospinal fluid tests often show elevated lactate, which points to impaired energy metabolism.

Genetic testing confirms the diagnosis and identifies the specific gene involved. This step matters because it shapes genetic counseling and, in some cases, informs treatment decisions. Testing may involve a targeted panel, whole exome sequencing, or whole genome sequencing, depending on the clinical situation.

Because so many genes can be involved, a negative result on a limited panel does not rule out Leigh syndrome. Broader testing may be needed.

Is There a Treatment or Cure for Leigh Syndrome?

There is no cure for Leigh syndrome. No treatment currently reverses the underlying genetic defect or restores normal mitochondrial function.

Management focuses on supporting the patient and slowing complications. This typically involves a team of specialists, including neurologists, metabolic specialists, dietitians, and therapists. Common approaches include:

• Nutritional support, sometimes with specific dietary adjustments depending on the gene involved
• Physical, occupational, and speech therapy
• Medications to manage seizures, movement problems, or other symptoms
• Careful monitoring and treatment of infections, which can trigger severe episodes

Some clinicians use vitamin or cofactor supplements such as thiamine, riboflavin, or coenzyme Q10, particularly when the specific gene defect suggests a potential benefit. The evidence for these supplements is limited, and their effectiveness varies by gene. They are generally used as supportive measures rather than proven treatments.

Certain gene-specific approaches exist. For example, in cases involving pyruvate dehydrogenase complex deficiency, a ketogenic diet may be recommended because it bypasses the defective enzyme pathway. This is a targeted strategy, not a general treatment for all Leigh syndrome.

Research into gene therapy and other targeted treatments is ongoing, but no such therapy is currently approved for clinical use.

What Is the Outlook for Someone With Leigh Syndrome?

The prognosis is generally serious. Leigh syndrome is a progressive disorder, and many affected children do not survive into adulthood. However, the range is wide, and some people with milder forms live longer.

Outcomes depend on several factors: which gene is mutated, the age at which symptoms begin, how quickly the disease progresses, and how well complications are managed. Later-onset forms and certain gene variants tend to have a slower course.

Because the range is so broad, no single life expectancy figure applies to everyone. Families should discuss prognosis with their care team, who can provide guidance based on the specific genetic findings.