ACOX1 – Mitchell syndrome

Mitchell syndrome (MITCH) is a rare autosomal dominant neurodegenerative disorder characterized by episodic demyelination, sensorimotor polyneuropathy, hearing loss and variable autonomic and cutaneous symptoms. It is caused by a recurrent gain-of-function variant in the ACOX1 gene, p.Asn237Ser. To date, eight unrelated patients carrying this heterozygous variant have been reported, all presenting with early-onset gait instability, hearing impairment, cutaneous ichthyosis and autonomic features such as abdominal pain, diarrhea, nausea and dysuria ([PMID:37400800], [PMID:38923841]).

Genetic evidence supports autosomal dominant inheritance with de novo occurrence in all cases. A single missense variant, c.710A>G (p.Asn237Ser), recurs as a mutational hotspot across diverse populations. No multi-generational segregation has been observed, but the consistent de novo variant in eight probands meets moderate genetic evidence criteria ([PMID:37400800], [PMID:38923841]).

Functionally, the p.Asn237Ser substitution stabilizes the ACOX1 dimer and dysregulates peroxisomal β-oxidation, leading to excess hydrogen peroxide and oxidative stress. Transient overexpression of human ACOX1 N237S in zebrafish recapitulated motor impairment, activated the integrated stress response, reduced peroxisome density and was rescued by a microglia-targeted dendrimer-N-acetyl-cysteine conjugate ([PMID:38357503]). Drosophila and murine Schwann cell models likewise demonstrated gain-of-function–induced reactive oxygen species and glial loss, reversible by antioxidants ([PMID:32169171]).

Clinically, antioxidant therapies have shown benefit: N-acetylcysteine amide improved symptoms in a Chinese patient ([PMID:37400800]), and monthly intravenous immunoglobulin yielded clinical improvement in a pediatric case ([PMID:38923841]). Topical N-acetylcysteine resolved ichthyosiform lesions in two patients, implicating oxidative stress in skin pathology ([PMID:38923010]).

No conflicting evidence has been reported. The convergence of de novo genetic findings, in vivo models, and patient responses to targeted antioxidant treatment supports a gain-of-function mechanism.

Key take-home: Heterozygous ACOX1 p.Asn237Ser causes Mitchell syndrome via a gain-of-function mechanism, and early genetic diagnosis enables prompt antioxidant or immunomodulatory therapy.

References

• BMC medical genomics • 2023 • A de novo heterozygous variant in ACOX1 gene cause Mitchell syndrome: the first case in China and literature review. PMID:37400800
• American Journal of Medical Genetics Part A • 2024 • ACOX1 gain-of-function variation in a 10-years-old patient responsive to immunomodulating therapy. PMID:38923841
• Frontiers in Pediatrics • 2024 • Generation and characterization of a zebrafish gain-of-function ACOX1 Mitchell disease model. PMID:38357503
• Neuron • 2020 • Loss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms. PMID:32169171
• The Journal of Dermatology • 2025 • Dermatopathological features and successful treatment with topical antioxidant for ichthyosiform lesions in Mitchell syndrome caused by an ACOX1 variant. PMID:38923010

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