title: Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study.
abstract: OBJECTIVE
  Acyl-CoA oxidase (ACOX1) deficiency is a rare disorder of peroxisomal very-long chain fatty acid oxidation. No reports detailing attempted treatment, longitudinal imaging, or neuropathology exist. We describe the natural history of clinical symptoms and brain imaging in two siblings with ACOX1 deficiency, including the younger sibling's response to allogeneic unrelated donor hematopoietic stem cell transplantation (HSCT).
  
  
  METHODS
  We conducted retrospective chart review to obtain clinical history, neuro-imaging, and neuropathology data. ACOX1 genotyping were performed to confirm the disease. In vitro fibroblast and neural stem cell fatty acid oxidation assays were also performed.
  
  
  RESULTS
  Both patients experienced a fatal neurodegenerative course, with late-stage cerebellar and cerebral gray matter atrophy. Serial brain magnetic resonance imaging in the younger sibling indicated demyelination began in the medulla and progressed rostrally to include the white matter of the cerebellum, pons, midbrain, and eventually subcortical white matter. The successfully engrafted younger sibling had less brain inflammation, cortical atrophy, and neuronal loss on neuro-imaging and neuropathology compared to the untreated older sister. Fibroblasts and stem cells demonstrated deficient very long chain fatty acid oxidation.
  
  
  CONCLUSIONS
  Although HSCT did not halt the course of ACOX1 deficiency, it reduced the extent of white matter inflammation in the brain. Demyelination continued because of ongoing neuronal loss, which may be due to inability of transplant to prevent progression of gray matter disease, adverse effects of chronic corticosteroid use to control graft-versus-host disease, or intervention occurring beyond a critical point for therapeutic efficacy.
authors.affiliation: Division of Metabolic Disorders, CHOC Children's, 1201 W. La Veta Blvd., Orange, CA, 92868, USA, rawang@choc.org.
authors.forename: Raymond Y
authors.initials: RY
authors.lastname: Wang
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Monuki
authors.forename: James
authors.initials: J
authors.lastname: Powers
authors.forename: Phillip H
authors.initials: PH
authors.lastname: Schwartz
authors.forename: Paul A
authors.initials: PA
authors.lastname: Watkins
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
authors.forename: Ann
authors.initials: A
authors.lastname: Moser
authors.forename: David A
authors.initials: DA
authors.lastname: Shrier
authors.forename: Hans R
authors.initials: HR
authors.lastname: Waterham
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Nugent
authors.forename: Jose E
authors.initials: JE
authors.lastname: Abdenur
mesh_terms: D042962:Acyl-CoA Oxidase / Q000172:deficiency*; D001921:Brain / Q000473:pathology; D020739:Brain Diseases, Metabolic, Inborn / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D002675:Child, Preschool; D017809:Fatal Outcome; D005260:Female; D019416:Head Movements / Q000502:physiology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009123:Muscle Hypotonia / Q000209:etiology; D058953:Neural Stem Cells / Q000637:transplantation; D035781:Siblings; D016896:Treatment Outcome
chemical_list: D042962:Acyl-CoA Oxidase