Child Neurology: Progressive Cerebellar Atrophy and Retinal Dystrophy - Clues to an Ultra-Rare ACO2-Related Neurometabolic Diagnosis

Pathogenic bi-allelic variants in ACO2, which encodes the enzyme mitochondrial aconitase, are associated with the very rare diagnosis of ACO2-related Infantile Cerebellar Retinal Degeneration (OMIM 614559). We describe the diagnostic odyssey of a 4-year-old female patient with profound global developmental delays, microcephaly, severe hypotonia, retinal dystrophy, seizures, and progressive cerebellar atrophy. Whole exome sequencing (WES) revealed two variants in ACO2; c.2105_2106delAG (p.Gln702ArgfsX9), a likely pathogenic variant, and c.988C>T (p.Pro330Ser) which was classified as a variant of uncertain significance (VUS). While the VUS was confirmed to be maternally inherited, the phase of the other variant could not be confirmed due to lack of a paternal sample. Functional biochemical studies were performed on a research basis to clarify the interpretation of the VUS, which enabled clinical confirmation of the diagnosis of ACO2-related Infantile Cerebellar Retinal Degeneration for our patient.