Ataxia and cerebellar anomalies - childhood onset

Gene: ACO2

Green List (high evidence)

Comment on mode of inheritance: There are numerous patients reported with both mono- and bi-allelic variants in ACO2. Individuals with heterozygous ACO2 variants present with isolated optic atrophy, while those with biallelic variants may present with either syndromic or non-syndromic optic atrophy. Syndromic presentation usually involves cerebellar-retinal degeneration, ataxia, seizures, ID, and developmental delays. Hence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal for Ataxia and cerebellar anomalies - childhood onset.

Created: 8 Oct 2026, 4:56 p.m. | Last Modified: 8 Oct 2026, 4:56 p.m.

Panel Version: 9.41

PMID: 34056600 Charif et al., 2021
Study identified 61 cases harbouring variants in ACO2. 50/61 harboured heterozygous ACO2 variants. 52 individuals had isolated optic atrophy. "27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy (...) with a single case showing hearing loss (P38) and two cases showing a late-onset cerebellar ataxia (P19 and P53)."
However, extraocular features in the dominant cases were not consistent and mostly did not match the AR Infantile cerebellar-retinal degeneration disease entity associated with ACO2 - probably incidental findings.
P19 - somewhat consistent - het for ACO2 p.Gly463Arg and had cerebellar ataxia. Among recessive cases, 1 individual had epilepsy with onset at 22 yrs (comp het for ACO2 c.36+5delG and p.(Gly240Ala)). Another patient presented with kinetic and static cerebellar syndrome with cerebellar atrophy; episode of dysarthria at 45 y - comp het for ACO2 p.(Leu74Val) and p.(Glu464*). No mention of intellectual disability in this cohort.

PMID: 32519519 Blackburn et al., 2020
Report of five patients with biallelic pathogenic variants in ACO2:
Case 1 & 2 - Two sibs with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities.
Case 3 - proband presented with the classic form with cerebellar hypoplasia, ataxia, seizures, moderate‐to‐severe intellectual disability, optic atrophy, and retinitis pigmentosa.
Case 4 - proband demonstrated a spinal muscular atrophy‐like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months.
Case 5 - proband presented with ataxia, severe developmental and motor delays, and seizures; developed severe progressive spastic quadriplegia.
Mostly missense variants; Case 5 had biallelic frameshift variants in ACO2.

PMID: 31106992 Fukada et al., 2019
Report of a Japanese female patient with progressive cerebellar and cerebral atrophy, hypotonia, ataxia, seizure disorder, developmental delay, ophthalmological abnormalities and hearing loss. WES detected comp het missense variants (c.1534G>A, p.Asp512Asn and c.1997G>C, p.Gly666Ala) in ACO2. Parents were healthy and unrelated, confirmed to be het for a variant each.

PMID: 25351951 Metodiev et al., 2014
Study of 5 patients from 3 unrelated families with homozygous or compound heterozygous missense and frameshift mutations in ACO2, with either isolated or syndromic optic neuropathy.

PMID: 22405087 Spiegel et al., 2012
Studied eight individuals from two unrelated families of Arab Muslim origin who presented at 2–6 months of age with truncal hypotonia and athetosis, seizure disorder, profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Six individuals older than 2 years were profoundly intellectually disabled. All patients were homozygous for ACO2 p.Ser112Arg. Method: homozygosity mapping and WES. Ten parents and one of the healthy sibs were confirmed to be heterozygous.

ACO2 is associated with AR Infantile cerebellar-retinal degeneration, OMIM:614559 and AD Optic atrophy 9. OMIM:616289 in OMIM (accesssed 8th Oct 2026).

Created: 8 Oct 2026, 4:41 p.m. | Last Modified: 8 Oct 2026, 4:56 p.m.

Panel Version: 9.41

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Infantile cerebellar-retinal degeneration, OMIM:614559; Optic atrophy 9. OMIM:616289

Publications

• 22405087
• 25351951
• 31106992
• 32519519
• 34056600

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 5 Feb 2023, 5:18 p.m. | Last Modified: 5 Feb 2023, 5:18 p.m.

Panel Version: 3.30

PMID: 34056600 reports 61 cases of genetically unsolved inherited optic neuropathies who were harbouring variants in ACO2, of which 50 carried dominant variants (the remaining 11 cases were biallelic). The authors state that this is the first report of monoallelic pathogenic ACO2 variants resulting in dominant optic atrophy.

Created: 26 May 2022, 1:42 p.m. | Last Modified: 26 May 2022, 1:42 p.m.

Panel Version: 2.295

New paper (34056600) describing ACO2 as a cause of autosomal dominant optic atrophy - update of inheritance needed. Tom Cullup (Great Ormond Street Hospital), 17 Feb 2022

Created: 26 May 2022, 1:42 p.m. | Last Modified: 26 May 2022, 1:42 p.m.

Panel Version: 2.295

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Comment on list classification: New gene added by Zornitza Stark. This gene should be promoted to Green at the next GMS panel update.

Sufficient unrelated cases to ascertain causation (see publications list). Childhood-onset ataxia often reported as a core feature of the disease presentation, particularly in milder cases. Both episodic and classic forms have been described.

Created: 1 Mar 2021, 3:28 p.m. | Last Modified: 1 Mar 2021, 3:28 p.m.

Panel Version: 2.52

Green List (high evidence)

Ataxia is part of the phenotype, particularly in more mildly affected individuals, where it can be the presenting feature.
Sources: Expert list

Created: 12 Sep 2020, 1:23 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Infantile cerebellar-retinal degeneration, MIM#614559

Publications

• 32519519

Variants in this GENE are reported as part of current diagnostic practice