Child Neurology: Neurodegenerative Encephalomyelopathy Associated With ACOX1 Gain-of-Function Variation Partially Responsive to Immunotherapy

Abstract

Acyl-CoA Oxidase 1 (ACOX1) is a peroxisomal enzyme involved in beta-oxidation of very long chain fatty acids. Although loss of function of ACOX-1 had been previously described, gain-of-function mutation of ACOX-1 gene has only been recently identified, with a paucity of known cases. Gain of function mutation results in over production of reactive oxygen species, resulting in progressive neurodegeneration with discrete relapses.We report a 19-year-old-female with a 5-year history of longitudinally extensive posterior predominant myelopathy, bilateral corneal scars, and white matter lesions presented with first time seizure, progressive sensorineural hearing loss, icthiosyform rash, and cauda equina syndrome. Extensive work-up was unrevealing. The patient had no response to high dose steroids but stabilization and improvement with return to baseline over six months with IVIg and low dose mycophenolate mofetil. WES performed 4 years prior was non-diagnostic, but subsequent reanalysis revealed a heterozygous mutation in the ACOX1 gene (NM_004035.6: c.710A>G, p.Asn237Ser), now considered to be pathogenic.This case reports a rare condition and highlights the importance of reanalysis of previously non-diagnostic genome/exome sequencing data. Further, the patient’s clinical stability for over one year on immunotherapy raises the possibility of disease modification in an otherwise universally fatal condition.

Generation and characterization of a zebrafish gain-of-function ACOX1 Mitchell disease model

“…Interestingly, patients with Mitchell syndrome may present with a skin rash or ichthyosis similar to that observed in other conditions with impaired VLCFA production, such as ELOVL1 deficiency. However, in contrast to ELOVL1 deficiency, skin biopsies showed no evidence of lipid inclusions ( 9 , 22 ).…”

“…The ACOX1 (c.710A>G; p.N237S) gain-of-function mutation (OMIM # 609751.0008) was identified as a putative de novo variant causing Mitchell syndrome (OMIM # 618960), an autosomal dominant, progressive degenerative process involving sensorineural hearing loss, polyneuropathy, cognitive decline, and seizures ( 5 ). As of May 2023, 20 cases have been reported globally by the Mitchell and Friends Foundation and 4 case reports have been published ( 8 , 9 ). The N237S substitution has been shown to produce a stabilized active ACOX1 dimer, resulting in dysregulated enzymatic activity, increased oxidative stress, and glial damage ( 5 ).…”

ACOX1 Gain-of-Function Variant in Two German Pediatric Patients, in One Case Mimicking Autoimmune Inflammatory Disease

“…Pathophysiologically, the N237S variant increases levels of reactive oxygen species in glia cells, 2 and N-acetylcysteine amide (NACA) was shown to be beneficial in drosophila. However, this substance is not approved for therapy in humans, and NAC, which was used instead in few patients, [2][3][4] does not cross the blood-brain barrier. Our two patients received the diagnosis either shortly before or even years after death, so that a therapeutic trial with NAC was not possible; however, the few patients given this substance so far did not show substantial benefit.…”

“…Only five patients with Mitchell syndrome have been described worldwide. [2][3][4] We add here two additional German patients who were identified through trio ES shortly after publication of the first three cases and re-evaluation of exome data originally analyzed 13 years earlier, respectively. This latter case clearly indicates the importance of reevaluation of next-generation sequencing data, as the analysis pipelines always depend on current knowledge about disease-associated genes and modes of inheritance.…”

“…2 The disease was fatal for the first patient at the age of 19 years, the second was alive, but comatose at 15 years, and the third was 9 years of age and alive at the time of publication. Subsequently, two additional patients were described, one of which was still alive at 20 years, 3 while the other died at 9 years of age. 4 This novel disorder was named Mitchell disease after the first identified patient.…”