What is Leigh syndrome (Subacute Necrotic Encephalomyelopathy)?

From the Guidelines

Leigh syndrome is a severe neurological disorder characterized by progressive loss of mental and movement abilities, caused by mutations in mitochondrial DNA or nuclear DNA that affect energy production in cells, particularly in the brain, muscles, and nerves. This condition typically appears in infancy or early childhood and often leads to respiratory and heart problems. The clinical presentation of Leigh syndrome can be variable, but it is generally marked by a decline in mental and motor abilities, which can be rapid in some cases [ 1 ]. Treatment for Leigh syndrome is primarily supportive and focuses on managing symptoms, as there is no cure. Medications may include anticonvulsants for seizures, bicarbonate for managing lactic acidosis, and various vitamins and supplements like coenzyme Q10, thiamine, and riboflavin that may help improve mitochondrial function. Some key aspects of Leigh syndrome include:

• Progressive neurological deterioration
• Respiratory failure, which can be precipitated by factors such as general anesthesia [ 1 ]
• Metabolic acidosis with increasing plasma lactate levels
• Limited life expectancy, although some individuals with milder forms may survive into adolescence or adulthood Physical therapy, respiratory support, and nutritional management are also important components of care. The prognosis for Leigh syndrome is generally poor, but early diagnosis and comprehensive management by a multidisciplinary team are essential to provide the best quality of life for affected individuals. In cases where general anesthesia is required, careful consideration and monitoring are necessary due to the risk of metabolic decompensation [ 1 ].

From the Research

Definition and Characteristics of Leigh Syndrome

• Leigh syndrome, also known as subacute necrotizing encephalomyelopathy, is a devastating neurodegenerative disorder characterized by focal, bilaterally symmetric lesions in the basal ganglia, thalamus, and brainstem 2.
• The disease is marked by considerable clinical and genetic heterogeneity, with a wide range of abnormalities, including psychomotor retardation, seizures, nystagmus, ophthalmoparesis, optic atrophy, ataxia, dystonia, and respiratory failure 2, 3.
• Leigh syndrome can also present with peripheral nervous system involvement, non-neurologic abnormalities, and systemic complications such as diabetes, short stature, hypertrichosis, cardiomyopathy, anemia, renal failure, vomiting, or diarrhea 2.

Clinical Manifestations and Age of Onset

• The majority of cases have an onset in early childhood, but adult-onset cases have also been reported 2, 3, 4.
• Symptoms can develop slowly or with rapid progression, often associated with the age of onset, and may include regression of mental and motor skills, disability, and rapid progression to death 3, 5.
• The disease course is characterized by a rapid deterioration of cognitive and motor functions, often resulting in death due to respiratory failure 3, 6.

Genetic Causes and Pathomechanisms

• Leigh syndrome is caused by mutations in over 60 genes, both nuclear and mitochondrial DNA encoded, which affect the activity of the mitochondrial respiratory chain or pyruvate dehydrogenase complex 3, 4.
• The disease encompasses more than 100 separate monogenic disorders associated with enormous clinical and biochemical heterogeneity 4.
• Known genetic causes include defects of subunits and assembly factors of the five oxidative phosphorylation enzymes, disorders of pyruvate metabolism, and vitamin and cofactor transport and metabolism 4.

Diagnosis and Treatment

• Diagnosis is based on clinical, biochemical, and radiological findings, including symmetrical lesions in the basal ganglia or brain stem on MRI, and examinations of fresh muscle tissue or cultured fibroblasts 2, 6.
• There is no cure for affected patients, and treatment options are mostly unsatisfactory, although early treatment might be beneficial for some patients depending on the gene or process affected 3, 6.
• Emerging therapies, including gene-based personalized treatment, may become an important strategy in rare, genetically heterogeneous disorders like Leigh syndrome 3, 4.