Defects in EARS2 gene may lead to combined oxidative phosphorylation (OXPHOS) deficiency, also known as leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) syndrome, an autosomal recessive neurologic disorder caused by either compound heterozygous or homozygous variants. LTBL is a condition with a well-defined clinical phenotype, characterized by hyperintensities in the deep cerebral white matter, brainstem, and cerebellar white matter along with lactic acidosis due to a defect in mitochondrial respiration.

LTBL has a broad clinical spectrum, ranging from infantile-onset disease (usually after 6 months of age) with relatively mild neurological symptoms followed by spontaneous clinical, biochemical, and radiological improvement, to a more severe phenotype with neonatal/early-infantile onset and rapidly progressive central nervous system disease that stabilizes but does not improve.

Two distinct clinical courses have been described: severe and moderate. The severe form is characterized by early onset, delayed psychomotor development, seizures, hypotonia, and persistently elevated lactate levels, with progressive atrophy of affected brain structures. The mild form usually manifests clinically after 6 months of age with irritability and psychomotor regression, although patients can show clinical and biochemical improvements. The occurrence and extent of recovery most likely depends on the severity of brain damage caused by the first symptomatic episode.