General description

Leigh syndrome, also known as subacute necrotizing encephalopathy, is a rare genetic disorder characterized by the progressive degeneration of the central nervous system, including the brain, spinal cord, and optic nerves. Symptoms typically begin between three months and two years of age but may appear later. Common initial signs include developmental regression, hypotonia, loss of motor skills, irritability, vomiting, and seizures. The disease can progress to generalized weakness, lactic acidosis, and respiratory or kidney dysfunction. Acute exacerbations are often triggered by stressors such as infections, fever, dehydration, anesthesia, or surgery.

Leigh syndrome results from defects in mitochondrial energy production, affecting enzymes in the mitochondrial respiratory chain complexes or the pyruvate dehydrogenase complex. The condition can be inherited through various patterns, most commonly autosomal recessive, maternal (mtDNA), or X-linked recessive, and has been linked to over 95 genes in both nuclear DNA (nDNA) and mtDNA.

The disorder can be classified based on genetic origin into nDNA-associated and mtDNA-associated forms. In nDNA-associated cases, complex I deficiency, often caused by mutations in the NDUFS4 gene, is the most frequent issue. Other less common defects involve complex II and III deficiencies (e.g., SDHA, SDHB, UQCRQ mutations) and ubiquinone deficiencies (e.g., COQ9 mutations). Complex IV defects account for about 15% of cases, with SURF1 mutations being the most common, associated with longer survival.

For mtDNA-associated Leigh syndrome, mutations in complex I subunits (ND1-ND6), complex IV (CO3), and complex V (ATP6, ATP8) are prevalent. Mutations in the ATP6 gene account for around 10% of these cases.

Radiographic features

Leigh syndrome is characterized by bilateral lesions in the brainstem or basal ganglia, with MRI typically showing symmetric T2-weighted/FLAIR hyperintensity in areas such as the thalamus, brainstem tegmentum (especially the periaqueductal gray matter), basal ganglia, subthalamic nucleus, dentate nucleus, and inferior olivary nucleus. Less frequently, lesions may also appear in the white matter, cortex, cerebellum, and spinal cord. In cases associated with SURF1 mutations, imaging often spares the basal ganglia, but involves the brainstem more extensively, particularly affecting areas like the subthalamic nucleus, periaqueductal gray matter, central tegmental tract, dentate nucleus, and inferior olivary nucleus.

Magnetic resonance spectroscopy (MRS) may show elevated lactate levels in the basal ganglia, reflecting respiratory chain dysfunction and anaerobic metabolism, consistent with increased serum and cerebrospinal fluid lactate levels.