Leigh syndrome is a severe inherited brain disease, most often appearing in infancy or early childhood, that progressively damages specific regions of the brain and brainstem. It is considered the most common pediatric presentation of a defined mitochondrial disease, meaning the cells’ energy-producing machinery is broken at a fundamental level.1Journal of Neuropathology & Experimental Neurology. Leigh Syndrome: Neuropathology and Pathogenesis The condition is genetically diverse, with more than 100 different gene defects capable of causing it, and there is currently no cure.
What Happens in the Brain
The hallmark of Leigh syndrome is the development of symmetrical areas of damage in deep brain structures, particularly the basal ganglia and brainstem. Under a microscope, these lesions show a distinctive pattern: overgrowth of certain support cells, tiny blood vessel proliferation, spongy tissue breakdown, and, surprisingly, relative preservation of nerve cells compared to the surrounding tissue.2Journal of Neuropathology & Experimental Neurology. Leigh Syndrome: Neuropathology and Pathogenesis The disease also causes elevated lactic acid in the blood or spinal fluid, a sign that cells are failing to produce energy through normal aerobic pathways and are instead relying on less efficient backup processes.
At its root, the problem is a failure of the mitochondrial energy chain. Every cell in the body depends on mitochondria to convert food into usable energy. When one of the protein complexes in that chain is defective, cells that demand the most energy suffer first. Brain tissue is especially hungry for energy, which is why the nervous system bears the brunt of the damage. Researchers believe that severe energy depletion, lactic acid buildup, and the production of harmful oxygen molecules all contribute to the progressive brain injury seen in these patients.3Oxford Academic. Leigh Syndrome: Neuropathology and Pathogenesis
Symptoms and How the Disease Progresses
Most children with Leigh syndrome appear normal at birth. Symptoms typically emerge in infancy or early childhood and often follow an infection, a period of fasting, or another stress on the body. A large review of published cases found that developmental delay was the most frequent clinical sign, occurring in about 57% of patients. Low muscle tone was the most common motor finding at roughly 42%, followed by breathing problems (34%), seizures (33%), poor feeding (29%), and weakness (27%).4PubMed Central. A meta-analysis and systematic review of Leigh syndrome: clinical manifestations, respiratory chain enzyme complex deficiency, and gene mutations
Once symptoms begin, the disease tends to follow a relentless course. Children who had been meeting developmental milestones start losing skills they previously acquired, both mental and physical. Walking may become unsteady, eye movements can become abnormal, swallowing may grow difficult, and breathing can become irregular or fail entirely.5PubMed Central. Leigh Syndrome: A Comprehensive Review of the Disease and Present and Future Treatments Episodes of rapid decline often alternate with periods of relative stability, but overall the trajectory is downward. Many children with Leigh syndrome die within a few years of symptom onset, frequently from respiratory failure.
Beyond the Brain
Although the neurological damage defines the syndrome, the energy crisis affects other organs too. Numerous reports document cardiomyopathy (an enlarged or weakened heart), kidney tubule dysfunction, gastrointestinal problems, liver disease, and hormonal imbalances in children with Leigh syndrome.6PubMed. Mitochondrial Leigh syndrome: the state of the art Which organs are involved often depends on which gene is mutated, since different gene defects can affect different tissues to varying degrees. A child with one genetic cause might develop heart problems, while another with a different mutation might develop kidney issues instead. This systemic involvement can complicate management considerably, because clinicians need to watch for problems beyond the nervous system.
A Tangle of Genetic Causes
One of the most striking things about Leigh syndrome is its genetic complexity. The same clinical picture can result from defects in any of more than 100 genes, spread across both nuclear DNA and mitochondrial DNA. The condition is described as having both phenotypic and genetic heterogeneity, meaning different genetic defects produce a similar-looking disease, and the same genetic defect can sometimes produce different symptoms in different people.7Europe PMC. The genetics of Leigh syndrome and its implications for clinical practice and risk management
This complexity matters for families. When Leigh syndrome is caused by a nuclear gene mutation, it typically follows standard inheritance patterns: both parents carry one defective copy, and each pregnancy carries a one-in-four chance of producing an affected child. When the mutation sits in mitochondrial DNA, which is inherited exclusively from the mother, the picture gets murkier. A mother may carry a mixture of normal and mutant mitochondrial DNA in her cells, a state called heteroplasmy. The proportion of mutant DNA she passes on is somewhat random, and the severity of disease in her child depends heavily on what fraction of the mitochondria carry the defect. Studies of one commonly affected mitochondrial gene have shown that symptomatic patients carry a significantly higher proportion of mutant mitochondrial DNA than asymptomatic carriers, though there is considerable overlap between the two groups.8PubMed Central. MT-ATP6 mitochondrial disease variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases This makes predicting outcomes for a specific pregnancy very difficult when the family’s mutation is mitochondrial.
Defects in Respiratory Chain Complexes
The mitochondrial energy chain has five major protein complexes, and Leigh syndrome has been linked to defects in several of them. Complex I deficiency is among the most common causes. Researchers have identified mutations in nuclear genes that encode individual subunits of this complex, such as NDUFS1 and NDUFS8, that cause severe disease in infancy.9JAMA Neurology. Leigh Syndrome Associated With Mitochondrial Complex I Deficiency Due to a Novel Mutation in the NDUFS1 Gene 10The American Journal of Human Genetics. Mutation of a Nuclear-Encoded Subunit of Complex I of the Human Respiratory Chain Associated with Leigh Syndrome Complex IV (also known as cytochrome c oxidase) is another frequent culprit, often through mutations in the SURF1 gene. SURF1 does not encode a piece of the complex itself but rather an assembly factor needed to put the complex together properly. When SURF1 is defective, the amount of functional complex IV drops sharply, and the resulting disease tends to involve the basal ganglia, brainstem, cerebellum, and peripheral nerves.11PubMed Central. Clinical Diagnosis and Treatment of Leigh Syndrome Based on SURF1: Genotype and Phenotype 12PubMed. Expression and functional analysis of SURF1 in Leigh syndrome patients with cytochrome c oxidase deficiency
Pyruvate Dehydrogenase Deficiency
Not all Leigh syndrome is caused by defects in the respiratory chain itself. Pyruvate dehydrogenase complex deficiency is one of the most common causes of brain disease with lactic acid buildup and is a well-recognized trigger of Leigh syndrome.13PubMed. Leigh syndrome: pyruvate dehydrogenase defect. A case with peripheral neuropathy This enzyme complex sits at a metabolic crossroads, converting pyruvate into a form that can enter the energy chain. When it fails, pyruvate backs up and gets shunted into lactic acid instead. In some patients, the deficiency has been traced to a structural abnormality in one of the complex’s components, and adding the missing enzyme in the laboratory restored normal activity in patient cells.14PubMed. Deficiency of pyruvate dehydrogenase complex (PDHC) in Leigh’s disease fibroblasts: an abnormality in lipoamide dehydrogenase affecting PDHC activation This particular cause matters clinically because some forms respond to high-dose thiamine (vitamin B1) supplementation, making it one of the few potentially treatable causes of Leigh syndrome.15PubMed Central. Thiamine Responsive Pyruvate Dehydrogenase Complex Deficiency: A Potentially Treatable Cause of Leigh’s Disease
How Leigh Syndrome Is Diagnosed
Diagnosis generally brings together clinical symptoms, brain imaging, metabolic blood and urine tests, and genetic testing. On brain MRI, the symmetrical bright signals in the basal ganglia or brainstem on certain imaging sequences are considered a defining feature and one of the essential diagnostic criteria.16PubMed Central. Leigh syndrome: MRI findings in two children These findings can appear in the deep gray matter structures and sometimes extend to the thalamus and cerebellum.17Applied Radiology. Leigh Syndrome
Basic metabolic screening plays a critical role in the workup. A combination of lactic acid-to-pyruvate ratios, plasma amino acid profiles, acylcarnitine profiles, and urinary organic acid analysis has been reported to reach a diagnostic rate of up to 80% in experienced centers.18PubMed Central. A Comprehensive Approach to the Diagnosis of Leigh Syndrome Spectrum However, traditional blood markers like lactate and pyruvate are not specific to mitochondrial disease. Newer blood-based markers, particularly fibroblast growth factor 21 and growth differentiation factor 15, appear more promising for identifying mitochondrial energy problems specifically, though they are not yet part of routine clinical practice everywhere.19Portland Press (Essays in Biochemistry). Biomarkers for mitochondrial energy metabolism diseases
Genetic testing has become increasingly central to diagnosis. With so many genes potentially responsible, broad sequencing approaches that analyze large panels of mitochondrial and nuclear genes simultaneously are now the standard. Identifying the specific mutation matters not just for confirming the diagnosis but for predicting how the disease might behave, counseling families about recurrence risk, and determining whether any targeted treatments might apply.
Treatment Options Today
There is no cure for Leigh syndrome, and treatment remains largely supportive and often unsatisfactory.20BMJ Journals. A guide to diagnosis and treatment of Leigh syndrome Management typically involves a team of neurologists, metabolic specialists, respiratory therapists, nutritionists, and palliative care providers. The focus is on managing symptoms, preventing metabolic crises, ensuring adequate nutrition, and supporting breathing. Many children eventually need feeding tubes and respiratory support.
Some targeted dietary and metabolic approaches have shown benefit in specific genetic subtypes. Ketogenic diets, which shift the body toward burning fat instead of carbohydrates, have helped control seizures and even improved eye movements and mental development in a handful of patients with particular gene mutations. Restricting certain amino acids has also helped patients whose genetic defect causes buildup of toxic byproducts from amino acid breakdown. But these dietary interventions carry risks, including the potential to worsen metabolic acidosis, and the evidence for them comes entirely from individual case reports and small case series.21PubMed Central. Targeted Therapies for Leigh Syndrome: Systematic Review and Steps Towards a ‘Treatabolome’ – Section: Diets Thiamine supplementation, as noted earlier, represents one of the few situations where a supplement can directly address the underlying biochemical problem, specifically in cases caused by certain pyruvate dehydrogenase defects.
Emerging Therapies and Research
Researchers are pursuing several promising approaches, though none has yet reached routine clinical use. EPI-743, a small molecule designed to protect cells from oxidative damage, showed encouraging results in an open-label study of ten children with genetically confirmed Leigh syndrome. All ten showed reversal of disease progression across multiple standardized scoring systems, with statistically significant improvements in motor function and quality-of-life measures, and no serious drug-related side effects were recorded.22PubMed. EPI-743 reverses the progression of the pediatric mitochondrial disease–genetically defined Leigh Syndrome These results prompted randomized controlled trials.23Biochemical Society Transactions. Emerging therapies for mitochondrial diseases
In mouse models, the drug rapamycin has shown remarkable effects. Mice engineered to lack a key respiratory chain subunit develop brain lesions and neurological symptoms closely resembling Leigh syndrome. When these mice received rapamycin, onset of neurological symptoms was delayed, brain inflammation was reduced, and the characteristic brain lesions were prevented.24PubMed Central. mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome These same mouse models have been invaluable for understanding why specific brain regions are vulnerable. When the gene defect was limited to brain cells only, the mice developed the same progressive deterioration, breathing abnormalities, and death seen in the full-body knockout, confirming that the brain damage alone drives the lethal course of the disease.25PubMed Central. Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndrome
Gene therapy is perhaps the most conceptually appealing approach, since it aims to fix the root cause. For SURF1-related Leigh syndrome, researchers developed a gene replacement strategy using a viral vector injected into the spinal fluid. In mice, a single injection partially but significantly rescued complex IV activity in the liver, brain, and muscle and reduced lactic acid buildup during exercise.26PubMed Central. Adeno-associated viral vector serotype 9-based gene replacement therapy for SURF1-related Leigh syndrome However, further testing revealed that the original vector design caused tissue toxicity in rats, apparently because the protein was being overexpressed. A redesigned version using a weaker gene-driving element achieved similar levels of benefit with minimal toxicity, clearing an important hurdle for eventual human trials.27Molecular Therapy Methods & Clinical Development. Re-engineering SURF1 gene therapy for Leigh syndrome to mitigate overexpression-associated toxicity The catch, of course, is that gene therapy would need to be tailored to each specific gene defect, and with over 100 genes implicated, this approach could help individual genetic subtypes but not the syndrome as a whole.
Can Leigh Syndrome Be Prevented in Families at Risk
For families who already know they carry a Leigh syndrome mutation, several reproductive options exist. When the mutation is in a nuclear gene, preimplantation genetic testing during in vitro fertilization can identify unaffected embryos for transfer. Prenatal diagnosis through chorionic villus sampling or amniocentesis is also an option once the family’s mutation is known.
When the mutation is in mitochondrial DNA, the situation is more complicated because of heteroplasmy. A mother may carry varying levels of mutant mitochondrial DNA, and the proportion passed to any given egg is unpredictable. Mitochondrial replacement therapy, sometimes called “three-parent IVF,” was developed in part to address this problem. In what may have been a first, this technique was used to prevent the transmission of a Leigh syndrome-causing mitochondrial DNA mutation by replacing the mutation-bearing mitochondria of the mother’s eggs with donated healthy counterparts.28PubMed. Preventing Mitochondrial Disease: A Path Forward Since then, mitochondrial replacement therapy guided by precise maternal genotyping has been successfully applied to allow mothers carrying Leigh syndrome variants to have healthy babies.29PubMed. The Path to Precision Medicine in Leigh Syndrome Spectrum: A Four-Decade Chronicle of Genetic Discovery and Targeted Treatment This technology is not widely available, however, and remains legal in only a few countries.
Adult-Onset Leigh Syndrome
Although Leigh syndrome is overwhelmingly a disease of infants and young children, rare cases in adults have been reported. One documented case involved a 37-year-old woman who developed prolonged gastrointestinal symptoms followed by an acute brainstem crisis with severe metabolic acidosis. Strikingly, she went on to show dramatic clinical and brain-imaging improvement, a course almost unheard of in pediatric cases.30PubMed Central. Adult-onset Leigh’s disease: A rare entity Adult-onset presentations tend to be milder and more variable than childhood forms, possibly because the underlying mutation produces a less severe energy deficit that only becomes symptomatic under significant metabolic stress. Adult cases are easily missed because clinicians do not typically consider a pediatric mitochondrial disease in a grown patient presenting with unexplained brainstem symptoms and acidosis.
Why So Many Genes Produce One Syndrome
A question that puzzles even specialists is why defects in such a wide variety of genes all converge on the same pattern of brain damage. The genes responsible encode subunits of different respiratory chain complexes, assembly factors that help build those complexes, enzymes that feed fuel into the energy chain, and even proteins involved in maintaining mitochondrial DNA itself. What they share is a final common pathway: inadequate cellular energy production. The brain regions most affected, the basal ganglia and brainstem, are among the most metabolically active in the developing nervous system. They sit at a precarious threshold where even a modest drop in energy supply triggers a cascade of lactic acid accumulation, oxidative damage, and ultimately tissue death.
This convergence also explains why the disease is so variable. A mutation that nearly eliminates an enzyme’s function will produce severe disease in early infancy, while one that leaves partial function may not cross the threshold for damage until later childhood, or in rare cases, adulthood. The tissue distribution of gene expression matters too. A gene expressed predominantly in the brain may cause isolated neurological disease, while one active in multiple organs may produce the cardiac, kidney, or liver involvement described earlier. Two children with the same genetic diagnosis can have meaningfully different clinical courses depending on modifier genes, residual enzyme activity, and environmental triggers like infections that temporarily increase energy demand.
The Mouse Models Driving Discovery
Much of what researchers understand about disease mechanisms and potential treatments comes from mouse models, especially those lacking the Ndufs4 gene, which encodes a subunit of respiratory chain complex I. Multiple tissue-specific versions of these mice have been created, allowing scientists to ask precise questions about which cell types drive which symptoms.31PubMed Central. Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention When the gene was deleted only in neurons and brain support cells, the mice developed the same growth failure, progressive loss of coordination, breathing abnormalities, and early death as mice lacking the gene throughout the body.32PubMed Central. Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndrome This confirmed that the neurological damage is the primary driver of death, not failure of other organs.
These models have also been the testing ground for interventions that might never be tried first in children. The rapamycin finding, for instance, was unexpected. Rapamycin is an immune-suppressing drug with no obvious connection to energy metabolism, yet it substantially delayed disease in the mice. The working theory is that rapamycin shifts the cellular metabolism away from pathways that are crippled by the mitochondrial defect, essentially rerouting the cell’s metabolic traffic. Whether this translates to human benefit remains an open question, but it illustrates how animal models can reveal therapeutic angles that would never be predicted from the genetics alone.