Advertisement

Journal of Inherited Metabolic Disease

, Volume 37, Issue 5, pp 791–799 | Cite as

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

  • Raymond Y. WangEmail author
  • Edwin S. Monuki
  • James Powers
  • Phillip H. Schwartz
  • Paul A. Watkins
  • Yang Shi
  • Ann Moser
  • David A. Shrier
  • Hans R. Waterham
  • Diane J. Nugent
  • Jose E. Abdenur
Original Article

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.

Keywords

Hematopoietic Stem Cell Transplantation Gray Matter Atrophy Very Long Chain Fatty Acid Brainstem Auditory Evoke Response Myelin Pallor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

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.

Supplementary material

10545_2014_9698_Fig4_ESM.jpg (75 kb)
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)

10545_2014_9698_MOESM1_ESM.tif (522 kb)
High resolution image (TIFF 522 kb)
10545_2014_9698_Fig5_ESM.jpg (189 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)

10545_2014_9698_MOESM2_ESM.tif (1 mb)
High resolution image (TIFF 1036 kb)
10545_2014_9698_Fig6_ESM.jpg (196 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)

10545_2014_9698_MOESM3_ESM.tif (125 kb)
High resolution image (TIFF 124 kb)
10545_2014_9698_Fig7_ESM.jpg (79 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)

10545_2014_9698_MOESM4_ESM.tif (346 kb)
High resolution image (TIFF 345 kb)
10545_2014_9698_MOESM5_ESM.docx (24 kb)
ESM 5 (DOCX 23 kb)

References

  1. Adzhubei IA, Schmidt S, Peshkin L et al (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249PubMedCentralPubMedCrossRefGoogle Scholar
  2. Aubourg P, Blanche S, Jambaqué I et al (1990) Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J Med 322:1860–1866PubMedCrossRefGoogle Scholar
  3. Berciano J (1982) Olivopontocerebellar atrophy. A review of 117 cases. J Neurol Sci 53:253–272PubMedCrossRefGoogle Scholar
  4. Brownell B, Oppenheimer D, Hughes J (1970) The central nervous system in motor neurone disease. J Neurol Neurosurg Psychiatry 33:338–357PubMedCentralPubMedCrossRefGoogle Scholar
  5. Carrozzo R, Bellini C, Lucioli S et al (2008) Peroxisomal acyl-CoA-oxidase deficiency: two new cases. Am J Med Genet A 146A:1676–1681PubMedCrossRefGoogle Scholar
  6. El Hajj HI, Vluggens A, Andreoletti P et al (2012) The inflammatory response in acyl-CoA oxidase 1 deficiency (pseudoneonatal adrenoleukodystrophy). Endocrinology 153:2568–2575PubMedCentralPubMedCrossRefGoogle Scholar
  7. Farioli-Vecchioli S, Moreno S, Cerù MP (2001) Immunocytochemical localization of acyl-CoA oxidase in the rat central nervous system. J Neurocytol 30:21–33PubMedCrossRefGoogle Scholar
  8. Ferdinandusse S, Denis S, Hogenhout EM et al (2007) Clinical, biochemical, and mutational spectrum of peroxisomal acyl-coenzyme A oxidase deficiency. Hum Mutat 28:904–912PubMedCrossRefGoogle Scholar
  9. Ferdinandusse S, Barker S, Lachlan K et al (2010) Adult peroxisomal acyl-coenzyme A oxidase deficiency with cerebellar and brainstem atrophy. J Neurol Neurosurg Psychiatry 81:310–312PubMedCrossRefGoogle Scholar
  10. Fouquet F, Zhou JM, Ralston E et al (1997) Expression of the adrenoleukodystrophy protein in the human and mouse central nervous system. Neurobiol Dis 3:271–285PubMedCrossRefGoogle Scholar
  11. Ghatak NR, Nochlin D, Peris M, Myer EC (1981) Morphology and distribution of cytoplasmic inclusions in adrenoleukodystrophy. J Neurol Sci 50:391–398PubMedCrossRefGoogle Scholar
  12. Hein S, Schönfeld P, Kahlert S, Reiser G (2008) Toxic effects of X-linked adrenoleukodystrophy-associated, very long chain fatty acids on glial cells and neurons from rat hippocampus in culture. Hum Mol Genet 17:1750–1761PubMedCrossRefGoogle Scholar
  13. Iwata NK, Kwan JY, Danielian LE et al (2011) White matter alterations differ in primary lateral sclerosis and amyotrophic lateral sclerosis. Brain 134:2642–2655PubMedCentralPubMedCrossRefGoogle Scholar
  14. Jia Z, Moulson CL, Pei Z et al (2007) FATP4 is the principal very long-chain fatty acyl-CoA synthetase in skin fibroblasts. J Biol Chem 282:20573–20583PubMedCrossRefGoogle Scholar
  15. Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 5:1073–1081CrossRefGoogle Scholar
  16. Kurian MA, Ryan S, Besley GT et al (2004) Straight-chain acyl-CoA oxidase deficiency presenting with dysmorphia, neurodevelopmental autistic-type regression and a selective pattern of leukodystrophy. J Inherit Metab Dis 27:105–108PubMedCrossRefGoogle Scholar
  17. Loes DJ, Hite S, Moser H et al (1994) Adrenoleukodystrophy: a scoring method for brain MR observations. Am J Neuroradiol 15:1761–1766PubMedGoogle Scholar
  18. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  19. Miller WP, Rothman SM, Nascene D et al (2011) Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood 118:1971–1978PubMedCrossRefGoogle Scholar
  20. Padovan CS, Yousry TA, Schleuning M et al (1998) Neurological and neuroradiological findings in long-term survivors of allogeneic bone marrow transplantation. Ann Neurol 43:627–633PubMedCrossRefGoogle Scholar
  21. Peters C, Charnas LR, Tan Y et al (2004) Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Blood 104:881–888PubMedCrossRefGoogle Scholar
  22. Poll-The BT, Roels F, Ogier H et al (1988) A new peroxisomal disorder with enlarged peroxisomes and a specific deficiency of acyl-CoA oxidase (pseudo-neonatal adrenoleukodystrophy). Am J Hum Genet 42:422–434PubMedCentralPubMedGoogle Scholar
  23. Powers JM, Moser HW (1998) Peroxisomal disorders: genotype, phenotype, major neuropathologic lesions, and pathogenesis. Brain Pathol 8:101–120PubMedCrossRefGoogle Scholar
  24. Powers JM, Moser HW, Moser AB, Schaumburg HH (1982) Fetal adrenoleukodystrophy: the significance of pathologic lesions in adrenal gland and testis. Hum Pathol 13:1013–1019PubMedCrossRefGoogle Scholar
  25. Rosewich H, Waterham HR, Wanders RJ et al (2006) Pitfall in metabolic screening in a patient with fatal peroxisomal beta-oxidation defect. Neuropediatrics 37:95–98PubMedCrossRefGoogle Scholar
  26. Schaumberg HH, Powers JM, Raine CS et al (1975) Adrenoleukodystrophy. A clinical and pathological study of 17 cases. Arch Neurol 32:577–591CrossRefGoogle Scholar
  27. Schwartz PH, Bryant PJ, Fuja TJ et al (2003) Isolation and characterization of neural progenitor cells from post-mortem human cortex. J Neurosci Res 74:838–851PubMedCrossRefGoogle Scholar
  28. Shapiro E, Krivit W, Lockman L et al (2000) Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy. Lancet 356:713–718PubMedCrossRefGoogle Scholar
  29. Suzuki Y, Shimozawa N, Yajima S et al (1994) Novel subtype of peroxisomal acyl-CoA oxidase deficiency and bifunctional enzyme deficiency with detectable enzyme protein: identification by means of complementation analysis. Am J Hum Genet 54:36–43PubMedCentralPubMedCrossRefGoogle Scholar
  30. Suzuki Y, Iai M, Kamei A et al (2002) Peroxisomal acyl CoA oxidase deficiency. J Pediatr 140:128–130PubMedCrossRefGoogle Scholar
  31. Terao S, Sobue G, Yasuda T et al (1995) Magnetic resonance imaging of the corticospinal tracts in amyotrophic lateral sclerosis. J Neurol Sci 133:66–72PubMedCrossRefGoogle Scholar
  32. van der Knaap MS, Wassmer E, Wolf NI et al (2012) MRI as diagnostic tool in early-onset peroxisomal disorders. Neurology 78:1304–1308PubMedCrossRefGoogle Scholar
  33. Wanders RJ, Schelen A, Feller N et al (1990) First prenatal diagnosis of acyl-CoA oxidase deficiency. J Inherit Metab Dis 13:371–374PubMedCrossRefGoogle Scholar
  34. Watkins PA, McGuinness MC, Raymond GV et al (1995) Distinction between peroxisomal bifunctional enzyme and acyl-CoA oxidase deficiencies. Ann Neurol 38:472–477PubMedCrossRefGoogle Scholar
  35. Zivadinov R (2005) Steroids and brain atrophy in multiple sclerosis. J Neurol Sci 233:73–81PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Raymond Y. Wang
    • 1
    • 2
    Email author
  • Edwin S. Monuki
    • 3
  • James Powers
    • 4
  • Phillip H. Schwartz
    • 5
    • 6
  • Paul A. Watkins
    • 7
    • 8
  • Yang Shi
    • 3
  • Ann Moser
    • 8
  • David A. Shrier
    • 9
  • Hans R. Waterham
    • 10
  • Diane J. Nugent
    • 11
  • Jose E. Abdenur
    • 1
    • 2
  1. 1.Division of Metabolic DisordersCHOC Children’sOrangeUSA
  2. 2.Department of PediatricsUniversity of California-Irvine School of MedicineIrvineUSA
  3. 3.Department of Pathology and Laboratory MedicineUniversity of California-Irvine School of MedicineIrvineUSA
  4. 4.Department of Pathology and Laboratory MedicineUniversity of Rochester School of Medicine and DentistryRochesterUSA
  5. 5.Research InstituteCHOC Children’sOrangeUSA
  6. 6.Centers for Neuroscience and Translational ResearchCHOC Children’sOrangeUSA
  7. 7.Department of NeurologyJohns Hopkins School of MedicineBaltimoreUSA
  8. 8.Kennedy Krieger InstituteBaltimoreUSA
  9. 9.Department of Imaging SciencesUniversity of Rochester Medical CenterRochesterUSA
  10. 10.Laboratory Genetic Metabolic Diseases, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
  11. 11.Division of HematologyCHOC Children’sOrangeUSA

Personalised recommendations