ACOX1 – Peroxisomal Acyl-CoA Oxidase Deficiency

ACOX1 encodes the first and rate-limiting enzyme in peroxisomal β-oxidation of very-long-chain fatty acids, and biallelic pathogenic variants result in peroxisomal acyl-CoA oxidase deficiency, an autosomal recessive leukodystrophy characterized by hypotonia, seizures, developmental delay, failure to thrive, ataxia, pyramidal signs, hypoglycemia, hyponatremia, hyperpigmentation, and adrenal insufficiency (PMID:17458872; PMID:33234382). Neuroimaging demonstrates progressive demyelination and cerebral and cerebellar atrophy, while neuropathology shows neuronal loss and white matter inflammation (PMID:24619150).

Genetic studies have identified 30 probands across >20 unrelated kindreds with autosomal recessive inheritance, confirming the gene–disease relationship. A spectrum of pathogenic variants has been reported, including >20 predicted loss-of-function alleles (nonsense, frameshift, and splice-site) and at least five missense changes demonstrating deleterious effects on protein function (PMID:17458872). An illustrative variant is c.160delC (p.Leu54SerfsTer18) identified in two unrelated siblings (PMID:33234382).

Segregation analyses across multiple families show concordant inheritance of rare biallelic ACOX1 variants in affected sibships and cousins, with at least 6 additional affected relatives demonstrating co-segregation (PMID:8040306; PMID:40326779).

Functional evidence from patient fibroblast and neural stem cell assays reveals markedly reduced β-oxidation activity of C24:0 substrates, enlarged and reduced numbers of peroxisomes, and accumulation of VLCFAs, recapitulating the human biochemical phenotype (PMID:24619150; PMID:33234382). Biochemical characterization of recombinant human ACOX1 isoforms further supports variant pathogenicity by demonstrating altered enzyme activity in vitro (PMID:17603022).

Therapeutic intervention with hematopoietic stem cell transplantation (HSCT) in one sibling attenuated brain inflammation and cortical atrophy but did not prevent disease progression, underscoring the need for early diagnosis and potential enzyme replacement or gene therapy approaches (PMID:24619150).

Together, genetic, segregation, and functional data satisfy the ClinGen criteria for a Definitive gene–disease association, with Strong genetic evidence and Moderate functional corroboration. Key take-home: ACOX1 testing should be integrated into diagnostic workflows for at-risk infants presenting with early neurodegeneration and VLCFA accumulation, guiding timely supportive and experimental therapies.

References

• Human Mutation • 2007 • Clinical, biochemical, and mutational spectrum of peroxisomal acyl-coenzyme A oxidase deficiency. PMID:17458872
• Brain & Development • 2021 • Novel ACOX1 mutations in two siblings with peroxisomal acyl-CoA oxidase deficiency. PMID:33234382
• Journal of Inherited Metabolic Disease • 2014 • Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study. PMID:24619150
• The Journal of Clinical Investigation • 1994 • Large deletion of the peroxisomal acyl-CoA oxidase gene in pseudoneonatal adrenoleukodystrophy. PMID:8040306
• European Journal of Endocrinology • 2025 • Primary adrenal insufficiency caused by pseudo-neonatal adrenoleukodystrophy associated with biallelic ACOX1 mutations. PMID:40326779
• Biochemical and Biophysical Research Communications • 2007 • Biochemical characterization of two functional human liver acyl-CoA oxidase isoforms 1a and 1b encoded by a single gene. PMID:17603022

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