ObjectivesTo report the first Mexican case with two novelAARS2mutations causing primary ovarian failure, uterusinfantilis, and early-onset dementia secondary to leukoencephalopathy.MethodsDetailed clinical, clinimetric, neuroimaging features, muscle biopsy with biochemical assays of the main oxidative phosphorylation complexes activities, and molecular studies were performed on samples from a Mexican female.ResultsWe present a 41-year-old female patient with learning difficulties since childhood and primary amenorrhea who developed severe cognitive, motor, and behavioral impairment in early adulthood. Neuroimaging studies revealed frontal leukoencephalopathy with hypometabolism at the fronto-cerebellar cortex and caudate nucleus. Uterusinfantiliswas detected on ultrasound study. Clinical exome sequencing identified two novel variants, NM_020745:c.2864G>A (p.W955*) and NM_020745:c.1036C>A (p.P346T, p.P346Wfs*18), inAARS2. Histopathological and biochemical studies on muscle biopsy revealed mitochondrial disorder with cytochrome C oxidase (COX) deficiency.ConclusionsSeveral adult-onset cases of leukoencephalopathy and ovarian failure associated withAARS2variants have been reported. To our best knowledge, none of them showed uterusinfantilis. Here we enlarge the genetic and phenotypic spectrum ofAARS2-related dementia with leukoencephalopathy and ovarian failure and contribute with detailed clinical, clinometric, neuroimaging, and molecular studies to disease and novel molecular variants characterization.