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Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

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.

Interpretation

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.

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Acknowledgments

This study was supported by CHOC Children’s (PHS). We would like to express our gratitude to Nuriel Abdenur for document typesetting and formatting, and to the Commission for Families and Children of Orange County for its support of our clinical work (RYW, JEA).

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Division of Metabolic Disorders, CHOC Children’s, 1201 W. La Veta Blvd., Orange, CA, 92868, USA

    Raymond Y. Wang & Jose E. Abdenur

  2. Department of Pediatrics, University of California-Irvine School of Medicine, Irvine, CA, USA

    Raymond Y. Wang & Jose E. Abdenur

  3. Department of Pathology and Laboratory Medicine, University of California-Irvine School of Medicine, Irvine, CA, USA

    Edwin S. Monuki & Yang Shi

  4. Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

    James Powers

  5. Research Institute, CHOC Children’s, Orange, CA, USA

    Phillip H. Schwartz

  6. Centers for Neuroscience and Translational Research, CHOC Children’s, Orange, CA, USA

    Phillip H. Schwartz

  7. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Paul A. Watkins

  8. Kennedy Krieger Institute, Baltimore, MD, USA

    Paul A. Watkins & Ann Moser

  9. Department of Imaging Sciences, University of Rochester Medical Center, Rochester, NY, USA

    David A. Shrier

  10. Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Hans R. Waterham

  11. Division of Hematology, CHOC Children’s, Orange, CA, USA

    Diane J. Nugent

Authors
  1. Raymond Y. Wang
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  2. Edwin S. Monuki
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  3. James Powers
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  4. Phillip H. Schwartz
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  5. Paul A. Watkins
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  6. Yang Shi
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  7. Ann Moser
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  8. David A. Shrier
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  9. Hans R. Waterham
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  10. Diane J. Nugent
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  11. Jose E. Abdenur
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Corresponding author

Correspondence to Raymond Y. Wang.

Additional information

Communicated by: Piero Rinaldo

Electronic supplementary material

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Supplemental Fig. 1

Microscopic neuropathology of other brain regions (H&E stains). In both patients, severe cerebellar cortical atrophy (a,b) as well as pallor of deep cerebellar white matter (c,d) and cerebral peduncles (asterisks in e,f) are present. Choroid plexus from the right atrium shows severe epithelial loss in patient 1 (g), whereas the choroid plexus from patient 2 (h) appears normal. Arrows designate the substantia nigra. Scale bars: 1 mm (all panels). (JPEG 75 kb)

High resolution image (TIFF 522 kb)

Supplemental Fig. 2

Axial T2-weighted brain MR imaging from patient 2, pre-HSCT at 2.75 years of age (a-c) and 3.75 years post-HSCT at 6.5 years of age (d-f). (a) Demyelination (arrowheads) of cerebellar deep white matter and corticospinal tracts was incipient but progressed (d) to involve the cerebellar peduncles; cerebellar atrophy (asterisk) had also developed. (b,c) There were no visible supra-tentorial abnormalities just prior to transplant, but (e,f) 3.75 years later, there was marked cortical atrophy (asterisk) and non-enhancing demyelination (arrowheads) of the corpus callosum, periventricular, and subcortical white matter. (JPEG 189 kb)

High resolution image (TIFF 1036 kb)

Supplemental Fig. 3

Plasma VLCFA (C26:0 and C26:1) and ratios (C26:C22, C24:22) in patient 2 over his lifetime, demonstrating that all markers remained persistently elevated compared to normal reference range (dotted lines) throughout the post-transplant period despite full donor engraftment. (JPEG 195 kb)

High resolution image (TIFF 124 kb)

Supplemental Fig. 4

Ultrastructural neuropathology. (a,b) The cytoplasm of macrophages contained spiculated inclusions in discrete membrane-bound aggregates that are indistinguishable from inclusions described in other peroxisomal disorders. In patient 2, inclusions were difficult to find, and when found, were present in smaller and less numerous aggregates (arrows in b). (c,d) The spicules consist of paired, parallel fibers. Scale bars: 1 um (b), 200 nm (c,d). (JPEG 79 kb)

High resolution image (TIFF 345 kb)

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Wang, R.Y., Monuki, E.S., Powers, J. et al. Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study. J Inherit Metab Dis 37, 791–799 (2014). https://doi.org/10.1007/s10545-014-9698-3

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  • DOI: https://doi.org/10.1007/s10545-014-9698-3

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