Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy

Abstract

Our study shows that autosomal recessive ACO2 mutations can cause either isolated or syndromic optic neuropathy. This observation identifies ACO2 as the second gene responsible for non-syndromic autosomal recessive optic neuropathies and provides evidence for a genetic overlap between isolated and syndromic forms, giving further support to the view that optic atrophy is a hallmark of defective mitochondrial energy supply.

Functional cellular analyses reveal energy metabolism defect and mitochondrial DNA depletion in a case of mitochondrial aconitase deficiency

“…The resulting defects in ACO2 activity were associated with a relatively severe clinical course that included optic and cerebellar atrophy associated with hearing loss and severe to profound developmental delay (8). Subsequent to that original report (preceding the results on our patient), Metodiev et al described an additional five subjects in three families (two consanguineous) from France and Algeria with other ACO2 pathogenic variants (9). In that cohort, although the core symptoms of ataxia, optic nerve involvement and developmental delay were again noted, the severity of the associated symptoms varied widely.…”

“…In humans, aconitase is expressed as two isoforms – cytosolic (soluble) aconitase (ACO1) and mitochondrial aconitase (ACO2). The mitochondrial isoenzyme ACO2 is encoded by the nuclear gene of the same name ( ACO2) (7), and pathogenic variants in ACO2 have recently been reported to cause infantile cerebellar-retinal degeneration syndrome (OMIM 614559) (8, 9). This syndrome is characterized by diverse neurological symptoms that include ophthalmological abnormalities, truncal hypotonia, muscle atrophy, seizures, and impaired motor and cognitive skills (8).…”

Compound heterozygosity for severe and hypomorphicNDUFS2mutations cause non-syndromic LHON-like optic neuropathy

“…They have been ascribed to biallelic mutations in TMEM126A (OMIM#612988; OPA7 ) , encoding a mitochondrial protein of unknown function, and ACO2 (OMIM#100850; OPA9 ) , encoding the mitochondrial aconitase, and RTN4IP1 (OMIM#610502, OPA10 ),29 encoding the mitochondrial reticulon 4-interacting protein. Interestingly, in addition to non-syndromic optic neuropathies, biallelic ACO2 mutations have been shown to cause syndromic optic neuropathy with encephalopathy and cerebellar atrophy30 31 and SLC25A46 (OMIM#610826) mutations have been reported to cause a wide spectrum of optic atrophy plus phenotypes, including neurodegenerative diseases with cerebellar dysfunction, peripheral neuropathy, progressive myoclonic ataxia and lethal congenital pontocerebellar hypoplasia, and Leigh syndrome with optic atrophy 32–36. These observations support the view that the pleiotropy of nuclear genes involved in optic neuropathy is not restricted to the dominant forms.…”

Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene

“…DOA that presents clinically as an isolated optic neuropathy is caused by mutations in OPA1, mitochondrial dynamin like GTPase (OPA1) (4), OPA3, outer mitochondrial membrane lipid metabolism regulator (OPA3; also associated with cataracts) (5), aconitase 2 (ACO2) (6) and transmembrane protein 126A (TMEM126A) (7) genes, while syndromic DOA forms show greater genetic heterogeneity (8). To date, 224 genes associated with optic atrophy are listed in the Human Phenotype Ontology (HPO) database, the majority presenting with neurological symptoms, such as ataxia, mental retardation and spastic paraplegia (9).…”