ACO2 – Infantile Cerebellar-Retinal Degeneration

ACO2 encodes mitochondrial aconitase 2, a key tricarboxylic acid cycle enzyme. Biallelic ACO2 variants cause infantile cerebellar-retinal degeneration (ICRD; MONDO:0013802), an autosomal recessive neurodegenerative disorder characterized by global developmental delay, cerebellar and optic nerve atrophy, and retinal degeneration.

Clinical validity is definitive: over 20 unrelated probands from at least eight families have been reported with biallelic ACO2 variants consistent with ICRD ([PMID:28463998]; [PMID:25351951]; [PMID:35368710]). Multi-family segregation and recurrent phenotypes across diverse populations, combined with concordant experimental data, meet the highest ClinGen criteria.

Genetic evidence is strong: more than 20 probands carry diverse variant classes, including missense (e.g., c.2303C>A (p.Ala768Asp)), frameshift, and deletions in compound heterozygosity or homozygosity ([PMID:35368710]; [PMID:25351951]). These variants segregate with disease in multiple families, and no benign clustering is observed.

Variant spectrum is broad: missense substitutions predominate, with occasional truncating alleles (e.g., c.2328_2331del (p.Lys776fs)). Variants associated with ICRD are spread across ACO2 without clear domain clustering, and no founder alleles have been identified.

Functional studies provide moderate support: mutant ACO2 fails to complement yeast aco1Δ growth ([PMID:25351951]), patient fibroblasts exhibit <20% aconitase activity reversible by gene rescue ([PMID:26992325]), and Drosophila mAcon1 knock-down mirrors human neurodegeneration ([PMID:40210596]). These data confirm a loss-of-function mechanism.

In summary, biallelic ACO2 loss-of-function variants cause ICRD via TCA cycle disruption in neural tissues. The robust genetic and experimental evidence supports definitive diagnostic utility and guides future therapeutic research.

Key take-home: ACO2 genetic testing is recommended for infants with developmental delay, cerebellar-retinal degeneration, and optic atrophy to enable early diagnosis and intervention.

References

• Journal of medical genetics • 2014 • Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy. PMID:25351951
• PloS one • 2017 • Plasma metabolomics reveals a diagnostic metabolic fingerprint for mitochondrial aconitase (ACO2) deficiency. PMID:28463998
• Molecular genetics and metabolism • 2016 • Functional cellular analyses reveal energy metabolism defect and mitochondrial DNA depletion in a case of mitochondrial aconitase deficiency. PMID:26992325
• Frontiers in genetics • 2022 • Case Report: Infantile Cerebellar-Retinal Degeneration With Compound Heterozygous Variants in ACO2 Gene-Long-Term Follow-Up of a Sibling. PMID:35368710
• Clinical genetics • 2025 • Infantile Cerebellar-Retinal Degeneration Associated With Novel ACO2 Variants: Clinical Features and Insights From a Drosophila Model. PMID:40210596

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