Buhl, E., Garg, S., Monaghan, M., Preston, A., Likeman, M., Dare, J., Evans, J., Taylor, L.S., Berry, I., Urankar, K., Spry, P.G.D., Williams, C., Taylor, R.W., Alston, C.L., Hodge, J.J.L., Majumdar, A. (2025). Infantile Cerebellar-Retinal Degeneration Associated With Novel ACO2 Variants: Clinical Features and Insights From a Drosophila Model.  Clin. Genet. 108(3): 266--278.

FBrf0263061

Research paper

Infantile Cerebellar-Retinal Degeneration (ICRD) is an autosomal recessive neuro-disability associated with hypotonia, seizures, optic atrophy, and retinal degeneration. Recessive variants of the mitochondrial aconitase gene (ACO2) are a known cause of ICRD. Here, we present a paediatric male patient with ICRD, where whole genome sequencing of the family trio revealed segregating heterozygous variants of unknown significance in ACO2. At 4 months, he displayed generalised hypotonia, and by 6 years, visual electrophysiology indicated bilateral optic atrophy. Magnetic Resonance Imaging (MRI) at age seven confirmed optic nerve and cerebellar atrophy, and together with symptoms of developmental delay, align with ICRD. We established a Drosophila animal model to explore the impact of ACO2 loss- and gain-of-function. Manipulating the fly ortholog, mAcon1, through pan-neuronal knock-down or over-expression negatively affected longevity, locomotion, activity, whilst disrupting sleep and circadian rhythms. Mis-expression of mAcon1 in the eye led to impaired visual synaptic transmission and neurodegeneration. These experiments mirrored certain aspects of the human disease, providing a foundation for understanding its biological processes and pathogenic mechanisms, and offering insights into potential targets to screen for future treatments or preventive measures for ACO2-related ICRD.

PMC12319146 (PMC) (EuropePMC)