ACOX1

Inheritance Pattern: AD

Disease ID:MONDO:0030073

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009919

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0030073

Submitter: ClinGen

The relationship between *ACOX1 *and ACOX1 Upregulation (Mitchell syndrome), a newly described autosomal dominant disorder, was evaluated using the ClinGen Clinical Validity Framework as of October, 2022. *ACOX1 *encodes the first and rate-limiting enzyme of the very-long-chain fatty acid (VLCFA) β-oxidation pathway in peroxisomes and leads to H2O2 production. The disorder is characterized by progressive sensorimotor axonal polyneuropathy and normal very long chain fatty acids (VLCFAs). *ACOX1 *was first reported in relation to autosomal dominant ACOX1 Upregulation (Mitchell syndrome) in 2020 (Chung et al, 2020; PMID: 32169171). Only one missense variant (Asn237Ser) in the heterozygous state has been reported in all individuals with ACOX1 Upregulation (Mitchell syndrome) and most of them are de novo. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Lumping and Splitting Considerations: OMIM entities: Mitchell syndrome (MIM# 618960), Peroxisomal acyl-CoA oxidase deficiency (MIM# 264470). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanisms, inheritance patterns AND phenotypic presentation. Therefore, we have split curations for the disease entities, ACOX1 upregulation and ACOX1 deficiency. Summary of Case Level Data (11 points): Ten probands from seven publications (PMID: 32169171, 35715200, 34570386, 38357503, 37400800, 37846133, 38923841) have been reported with the Asn237Ser variant, and the variant has been proven de novo in five of them. In addition, more individuals with the variant (some confirmed de novo) are expected to be published soon (Hyunglok Chung, personal communication). The overall genetic score with published individuals is 11 points. The mechanism is reported to be gain of function (PMID: 32169171). Summary of experimental data (2.25 points): *ACOX1* was shown to be expressed in glial cells. ACOX1 Upregulation (Mitchell syndrome) is shown to be a result of gain of function and increased generation of ROS. Overexpression in Drosophila and rat Schwann cells prove this mechanism and flies recapitulate the phenotype with loss of axonal and glial cells, inability to fly, walk or feed and death within 2d. Supplementing food with NACA (a potent antioxidant) rescued the lethal phenotype of the variant, and the flies were not only viable, but were able to walk, climb, fly, mate, and reproduce (PMID: 32169171). Expression of the variant in zebrafish showed that swimming distance and velocity of ACOX1 N237S zebrafish larvae were found to be decreased compared to control larvae (PMID: 38357503). In summary, there is definitive evidence to support the relationship between *ACOX1 *and autosomal dominant ACOX1 Upregulation (Mitchell syndrome). This gene-disease pair was originally evaluated by the Peroxisomal Disorders GCEP Dec 29, 2022. It was reevaluated on 11/22/2025. As a result of this reevaluation, the classification changed from Strong to Definitive base on additional publications since the last evaluation (PMID: 38357503, 37400800, 37846133, 38923841).

Inheritance Pattern: AD

Disease ID:MONDO:0030073

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0009919

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0009919

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009919

Submitter: ClinGen

The relationship between ACOX1 and peroxisomal acyl-CoA oxidase deficiency, inherited in the autosomal recessive manner, was evaluated using the ClinGen clinical validity framework as of December 2019 and re-evaluated in October 2022. ACOX1 was first reported in relation to autosomal recessive peroxisomal acyl-CoA oxidase deficiency in 1994 (Fournier et al., PMID: 8040306). Numerous variants have been reported in humans per ClinVar. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of case-level and experimental data: 17.5 points. Variants (nonsense, missense, and frameshift) in this gene have been reported in at least 11 probands in 6 publications (PMID:18536048, PMID: 17458872, PMID: 8040306, PMID: 26965209, PMID: 11815777, PMID: 33234382). The mechanism for disease is expected to be loss of function. This gene-disease association is supported by expression studies, in vitro functional assays, and animal models. In summary, ACOX1 is definitively associated with autosomal recessive peroxisomal acyl-CoA oxidase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. Lumping and Splitting Considerations: OMIM entities: Mitchell syndrome (MIM# 618960), Peroxisomal acyl-CoA oxidase deficiency (MIM# 264470). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanisms, inheritance patterns AND phenotypic presentation. Therefore, we have split curations for the disease entities, ACOX1 deficiency and ACOX1 dysregulation.

Inheritance Pattern: AR

Disease ID:MONDO:0009919

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009919

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009919

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0030073

Submitter: PanelApp Australia