Submission Details

The relationship between *ACOX1 *and ACOX1 Dysregulation (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 Dysregulation (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 Dysregulation (Mitchell syndrome) and most of them are de novo. Evidence supporting this gene-disease relationship includes case-level data and experimental data.

Summary of Case Level Data (5.5 points): Five probands from three publications (PMID: 32169171, 35715200, 34570386, ) have been reported with the Asn237Ser variant, and the variant has been proven de novo in three of them. In addition, at least ten more individuals with the variant (confirmed de novo in seven) are being followed by Chung et al and are soon to be published (Hyunglok Chung, personal communication). The overall genetic score with published individuals is 5.5 points; however, considering additional unpublished probands with the de novo variant, the score would be >12 points.

The mechanism is reported to be gain of function (PMID: 32169171).

Summary of experimental data (2 points): *ACOX1 *was shown to be expressed in glial cells. ACOX1 Dysregulation (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).

In summary, there is strong evidence to support the relationship between *ACOX1 *and autosomal dominant ACOX1 Dysregulation (Mitchell syndrome). Three years must elapse from the first proposal of the association to reach a definitive classification without any valid contradictory evidence. We will re-evaluate this gene-disease relationship at that time to determine if an upgraded classification of definitive is warranted.

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 dysregulation and ACOX1 deficiency.