Leigh’s disease, also known as Leigh syndrome, is a rare and severe genetic neurometabolic disorder. It causes progressive damage to the central nervous system, which includes the brain, spinal cord, and optic nerves. This condition typically affects infants and young children, leading to a decline in their neurological functions, impacting how the body controls movement, breathing, and other functions.
Understanding Leigh’s Disease
Leigh’s disease is a type of mitochondrial disease, involving a malfunction of mitochondria, the “powerhouses” within cells responsible for generating energy. These cellular structures convert food energy into adenosine triphosphate (ATP), the primary energy currency cells use. When mitochondria do not function properly, cells experience an energy deficit, leading to damage or death. Tissues requiring high energy, such as the brain, muscles, and heart, are especially vulnerable.
Leigh’s disease is caused by inherited mutations in either mitochondrial DNA (mtDNA) or nuclear DNA. Most cases involve mutations in nuclear DNA, though about 10-20% are linked to mtDNA. These genetic changes disrupt oxidative phosphorylation, the process by which mitochondria use oxygen to convert food energy into a usable form. Over 110 different genes have been associated with Leigh’s disease, with many involved in mitochondrial energy production. For instance, mutations in the MT-ATP6 gene can block ATP generation, while other gene variants can reduce the activity of protein complexes in the mitochondrial respiratory chain, impairing energy production.
Signs, Symptoms, and Progression
Leigh’s disease often manifests in infancy or early childhood (three months to two years of age), though rare cases can appear in adolescence or adulthood. Infants may initially appear healthy and reach some developmental milestones before experiencing a regression, losing acquired motor and mental abilities. Initial symptoms often include feeding difficulties like vomiting, diarrhea, and trouble swallowing, leading to poor growth and weight gain.
As the disease progresses, neurological symptoms emerge. Affected individuals may develop weak muscle tone (hypotonia), involuntary muscle contractions (dystonia), and problems with movement and balance (ataxia). Other common neurological signs include seizures, rapid, involuntary eye movements (nystagmus), and degeneration of the optic nerves, potentially leading to vision loss. Breathing difficulties are common and can worsen, often leading to acute respiratory failure and death.
Some individuals may also develop hypertrophic cardiomyopathy (thickening of the heart muscle) or elevated lactate levels in blood, urine, or cerebrospinal fluid. Progression varies; early-onset cases are more severe, often resulting in death by age three due to respiratory complications. Later-onset individuals may experience slower progression and live into their mid-teens or early twenties.
Diagnosis and Care Approaches
Diagnosing Leigh’s disease involves a combination of clinical evaluation, neuroimaging, metabolic testing, and genetic analysis. Clinical assessment identifies characteristic neurological symptoms and developmental regression. Neuroimaging, particularly magnetic resonance imaging (MRI) of the brain, reveals specific symmetrical lesions in areas like the basal ganglia, brainstem, thalamus, and cerebellum. These distinctive lesions are a hallmark of the condition.
Metabolic testing detects abnormalities like elevated lactate levels in blood or cerebrospinal fluid, suggesting impaired mitochondrial metabolism. Genetic testing is the definitive method for confirming diagnosis, identifying mutations in nuclear or mitochondrial DNA. Various genetic testing methods pinpoint specific changes.
There is no cure for Leigh’s disease; treatments focus on managing symptoms and providing supportive care. Management aims to improve quality of life and includes medications for seizures, nutritional support for feeding difficulties and growth, and physical therapy to maintain motor skills and muscle function. Research explores potential new therapies, such as gene therapy to replace or repair faulty mitochondrial DNA. This includes investigating gene editing technologies like CRISPR-Cas9, with promising preclinical results.