Leigh syndrome is a severe neurological disorder caused by defective energy production in the body’s cells. It typically appears in the first year of life and is characterized by progressive loss of both mental and movement abilities. In most cases, it results in death within two to three years, usually from respiratory failure. A small number of people develop symptoms later in childhood or even adulthood, with a slower course.
How Energy Production Breaks Down
Every cell in your body produces energy through a process that takes place inside mitochondria, tiny structures sometimes called the cell’s power plants. Inside the mitochondria, electrons pass through a chain of five enzyme complexes embedded in the inner membrane. This chain drives the production of ATP, the molecule cells use as fuel for virtually everything they do.
In Leigh syndrome, genetic mutations disrupt one or more steps in this energy-production chain. When the chain breaks down, cells can’t generate enough ATP and become vulnerable to damage, particularly under stress. The brain and muscles, which have the highest energy demands in the body, are hit hardest. The result is progressive destruction of brain tissue in specific, predictable locations.
What Happens in the Brain
The hallmark of Leigh syndrome is a pattern of damage visible on MRI: symmetrical lesions that appear in the basal ganglia (deep brain structures involved in movement control) and the brainstem (which regulates breathing, swallowing, and eye movement). These lesions represent areas of spongy tissue breakdown where cells have died from energy starvation.
The damage tends to follow a pattern over time. In many patients, lesions first appear in the basal ganglia, specifically in structures called the putamen, globus pallidus, caudate nucleus, and thalamus. Months later, the damage spreads to brainstem structures including the substantia nigra, the area surrounding the brain’s central canal, and the medulla. In some patients, brain stem lesions appear first or develop alongside basal ganglia damage. As the disease progresses, the cerebellum, spinal cord, and white matter of the brain can also become involved.
Symptoms and How They Progress
The classic presentation is an infant who develops weak, floppy muscle tone (hypotonia), begins losing developmental milestones they had already reached, and shows signs of basal ganglia or brainstem dysfunction. That brainstem involvement can look like difficulty controlling eye movements, problems with swallowing and breathing, and uncoordinated movements (ataxia). Seizures and vision loss also occur.
The disease often follows a relapsing course, where a child seems stable for weeks or months and then rapidly worsens, frequently triggered by a common illness or fever. Each episode of decline tends to leave the child at a lower baseline than before. The trajectory is a progressive loss of cognitive and motor function, with respiratory failure being the most common cause of death.
Presentations can vary widely. Some children first come to medical attention because of breathing problems like apnea. Others present with progressive leg weakness that develops over years. The age of onset, the speed of decline, and the specific symptoms depend heavily on which gene is mutated and how severely it affects energy production.
Genetics and Inheritance
Leigh syndrome is not caused by a single gene. Defects in at least 16 mitochondrial genes and nearly 100 nuclear genes have been linked to the condition. All of them converge on the same problem: they impair the cell’s ability to produce energy.
This genetic complexity means the syndrome can be inherited in several different ways. Most cases caused by nuclear gene mutations follow an autosomal recessive pattern, meaning a child must inherit a defective copy from both parents. Mitochondrial DNA mutations, which account for roughly 20 to 47 percent of genetically confirmed cases, are inherited exclusively from the mother because mitochondria are passed down through the egg cell. A smaller number of cases are X-linked, meaning the mutated gene sits on the X chromosome. The most common X-linked form involves a gene called PDHA1, which affects a key enzyme complex involved in energy metabolism.
Because mitochondrial DNA mutations follow maternal inheritance, all children of an affected mother will carry the mutation. However, the severity of disease can vary dramatically between siblings depending on how many of their mitochondria carry the defective DNA, a ratio known as heteroplasmy.
How Leigh Syndrome Is Diagnosed
Diagnosis relies on a combination of clinical symptoms, brain imaging, and biochemical testing. The characteristic symmetrical lesions on MRI are often the first strong clue. Specialized MRI techniques can also detect abnormal lactate peaks in brain tissue, which reflect the energy production failure happening at the cellular level.
Blood and cerebrospinal fluid tests typically reveal elevated lactate and pyruvate, two byproducts that accumulate when cells can’t complete normal energy metabolism. A lactate-to-pyruvate ratio above 20 is considered a specific marker for mitochondrial disorders. Lactate levels in cerebrospinal fluid tend to be even more elevated than in blood when the disease is primarily affecting the brain. Additional metabolic workups include plasma amino acid profiles, acylcarnitine profiles, and urinary organic acid analysis.
Genetic testing provides the definitive diagnosis, identifying the specific mutation responsible. Given that nearly 120 different genes can cause Leigh syndrome, broad sequencing panels or whole-exome sequencing are typically needed rather than testing for a single gene.
Treatment and Management
There is no cure for Leigh syndrome, and treatment is largely supportive. The goal is to manage symptoms, maintain nutrition and breathing, control seizures, and try to slow progression where possible.
For a small subset of patients, specific nutritional supplements can make a meaningful difference. Some forms of Leigh syndrome respond to high-dose thiamine (vitamin B1) and biotin (vitamin B7), particularly a condition called biotin-thiamine-responsive basal ganglia disease that can mimic Leigh syndrome closely. In these cases, early and lifelong supplementation can prevent or reverse brain damage. This is one reason accurate genetic diagnosis matters: it can identify the rare treatable forms. Abrupt withdrawal of thiamine in responsive patients has been associated with metabolic crises recurring within 30 days, so treatment cannot be interrupted.
Fever is particularly dangerous because it increases energy demand while simultaneously impairing cellular transport mechanisms, so aggressive temperature control during illness is a critical part of care. Families are typically coached to treat fevers early and seek medical attention quickly during infections.
Experimental Therapies in Development
Several therapeutic approaches are moving toward clinical testing. A gene therapy program using a viral delivery system (AAV9) was initially paused but has since been relaunched with a new therapeutic candidate advancing toward trials. For patients with mutations in the MT-ATP6 gene, one of the most common mitochondrial causes of Leigh syndrome, a multicenter European clinical trial is being planned to test sildenafil, a drug currently used for other conditions. A separate small trial is being prepared for a drug called losmapimod.
On a more experimental front, researchers are developing molecular tools called mitoTALENs that can selectively cut and destroy mutant mitochondrial DNA inside cells, shifting the balance toward healthy copies. These are currently being tested in cell models with promising early results. Much of this work has been driven by patient advocacy organizations, particularly the Leigh Syndrome Foundation, which has played a central role in funding research and identifying drug candidates.