Likely inborn error of metabolism

Gene: ACOX2

Green List (high evidence)

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

Created: 12 Mar 2026, 10:16 a.m. | Last Modified: 12 Mar 2026, 10:16 a.m.

Panel Version: 8.94

Green List (high evidence)

Comment on list classification: There are at least 7 unrelated individuals with biallelic variants in ACOX2, presenting with persistent elevation of transaminase levels and C27 intermediate bile acids. 2 patients had liver fibrosis and developmental delay. The association is supported by a mouse model, where Acox2 knockout resulted in elevated hepatic transaminases, liver fibrosis and hepatic inflammation.
Based on the available evidence, this gene should be rated Green for Likely inborn error of metabolism.

Created: 15 Oct 2025, 3:28 p.m. | Last Modified: 15 Oct 2025, 3:29 p.m.

Panel Version: 8.62

PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal. This variants seems to be associated with a mild phenotype.

PMID: 29287774 Ferdinandusse et al., 2018
Report of a girl of Pakistani origin, consanguineous parents. Homozygous for a 4-nucleotide deletion in ACOX2: c.461-464delTCTG (p.Thr154Serfs*25). Presented at birth with thoracolumbar scoliosis, arthrogryposis, neuropathy and myopathy. Patient died at around 6 months, after intensive support was withdrawn. Disproportionate increase of the peroxisomal C27-bile acid intermediates was observed. Absence of ACOX2 protein in patient's fibroblast homogenate was shown by immunoblot. Seq method: panel 26 peroxisomal genes - other variants likely contributed to the severity of the phenotype in this patient.

PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.
Case 3: 15yo male, Spanish; presented with abdominal distension, steatorrhea, and hypertransaminasemia with childhood onset; liver biopsy showed slight fibrosis. Compound het for c.673C>T, p.(Arg225Trp) and c.456_459del, p.(Thr154Serfs*25). Het parents unaffected.
Case 4: 7yo boy; presented with congenital heart disease (mild mitral stenosis, and moderate‐severe aortic insufficiency) with slight developmental delay and oscillating hypertransaminasemia. Compound het: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). Elevated C27‐BA proportion, treated with UDCA.

Zhang Y, et al., 2021, PMID: 33340570: ACOX2 KO mice had elevated hepatic transaminases, liver fibrosis and hepatic inflammation.

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).

Created: 15 Oct 2025, 1:48 p.m. | Last Modified: 15 Oct 2025, 3:26 p.m.

Panel Version: 8.62

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Bile acid synthesis defect, congenital, 6, OMIM:617308

Publications

• 27647924
• 27884763
• 29287774
• 33340570
• 35395098