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Recessive variants of the mitochondrial aconitase gene (\n                    <jats:italic>ACO2<\/jats:italic>\n                    ) 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\n                    <jats:italic>ACO2<\/jats:italic>\n                    . At 4\u2009months, he displayed generalised hypotonia, and by 6\u2009years, 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\n                    <jats:italic>Drosophila<\/jats:italic>\n                    animal model to explore the impact of\n                    <jats:italic>ACO2<\/jats:italic>\n                    loss\u2010 and gain\u2010of\u2010function. Manipulating the fly ortholog,\n                    <jats:italic>mAcon1<\/jats:italic>\n                    , through pan\u2010neuronal knock\u2010down or over\u2010expression negatively affected longevity, locomotion, activity, whilst disrupting sleep and circadian rhythms. Mis\u2010expression of\n                    <jats:italic>mAcon1<\/jats:italic>\n                    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\n                    <jats:italic>ACO2<\/jats:italic>\n                    \u2010related ICRD.\n                  <\/jats:p>","DOI":"10.1111\/cge.14745","type":"journal-article","created":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T22:19:15Z","timestamp":1744323555000},"page":"266-278","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Infantile Cerebellar\u2010Retinal Degeneration Associated With Novel\n                    <i>ACO2<\/i>\n                    Variants: Clinical Features and Insights From a\n                    <i>Drosophila<\/i>\n                    Model"],"prefix":"10.1111","volume":"108","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1274-5870","authenticated-orcid":false,"given":"Edgar","family":"Buhl","sequence":"first","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience University of Bristol  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7297-5494","authenticated-orcid":false,"given":"Suchika","family":"Garg","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology University Hospitals Bristol NHS Foundation Trust  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1114-8495","authenticated-orcid":false,"given":"Marie","family":"Monaghan","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology University Hospitals Bristol NHS Foundation Trust  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9723-8305","authenticated-orcid":false,"given":"Amy","family":"Preston","sequence":"additional","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience University of Bristol  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcus","family":"Likeman","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neuroradiology University Hospitals Bristol NHS Foundation Trust  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julianne","family":"Dare","sequence":"additional","affiliation":[{"name":"Department of Community Paediatrics, Community Children's Health Partnership Kingswood Locality Hub  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie","family":"Evans","sequence":"additional","affiliation":[{"name":"Bristol Genetics Laboratory North Bristol NHS Trust  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucie S.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences Newcastle University  Newcastle Upon Tyne UK"},{"name":"NHS Highly Specialised Service for Rare Mitochondrial Disorders Newcastle Upon Tyne Hospitals NHS Foundation Trust  Newcastle Upon Tyne UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian","family":"Berry","sequence":"additional","affiliation":[{"name":"Bristol Genetics Laboratory North Bristol NHS Trust  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn","family":"Urankar","sequence":"additional","affiliation":[{"name":"Department of Neuropathology North Bristol Hospital NHS Foundation Trust  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul G. D.","family":"Spry","sequence":"additional","affiliation":[{"name":"Department of Paediatric Ophthalmology University Hospitals Bristol NHS Foundation Trust  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cathy","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Paediatric Ophthalmology University Hospitals Bristol NHS Foundation Trust  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7768-8873","authenticated-orcid":false,"given":"Robert W.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences Newcastle University  Newcastle Upon Tyne UK"},{"name":"NHS Highly Specialised Service for Rare Mitochondrial Disorders Newcastle Upon Tyne Hospitals NHS Foundation Trust  Newcastle Upon Tyne UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2095-5464","authenticated-orcid":false,"given":"Charlotte L.","family":"Alston","sequence":"additional","affiliation":[{"name":"Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences Newcastle University  Newcastle Upon Tyne UK"},{"name":"NHS Highly Specialised Service for Rare Mitochondrial Disorders Newcastle Upon Tyne Hospitals NHS Foundation Trust  Newcastle Upon Tyne UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4741-2363","authenticated-orcid":false,"given":"James J. 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