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

Raymond Y. Wang, 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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)791-799
Number of pages9
JournalJournal of Inherited Metabolic Disease
Volume37
Issue number5
DOIs
StatePublished - Sep 1 2014
Externally publishedYes

Fingerprint

Acyl-CoA Oxidase
Hematopoietic Stem Cell Transplantation
Siblings
Fatty Acids
White Matter
Demyelinating Diseases
Encephalitis
Atrophy
Fibroblasts
Gray Matter
Peroxisomal Disorders
Unrelated Donors
Neural Stem Cells
Pons
Graft vs Host Disease
Mesencephalon
Neuroimaging
Cerebellum
Adrenal Cortex Hormones
Stem Cells

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency : a sibling comparison study. / Wang, Raymond Y.; Monuki, Edwin S.; Powers, James; Schwartz, Phillip H.; Watkins, Paul A.; Shi, Yang; Moser, Ann; Shrier, David A.; Waterham, Hans R.; Nugent, Diane J.; Abdenur, Jose E.

In: Journal of Inherited Metabolic Disease, Vol. 37, No. 5, 01.09.2014, p. 791-799.

Research output: Contribution to journalArticle

Wang, RY, Monuki, ES, Powers, J, Schwartz, PH, Watkins, PA, Shi, Y, Moser, A, Shrier, DA, Waterham, HR, Nugent, DJ & Abdenur, JE 2014, 'Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study' Journal of Inherited Metabolic Disease, vol 37, no. 5, pp. 791-799. DOI: 10.1007/s10545-014-9698-3

Wang, Raymond Y.; Monuki, Edwin S.; Powers, James; Schwartz, Phillip H.; Watkins, Paul A.; Shi, Yang; Moser, Ann; Shrier, David A.; Waterham, Hans R.; Nugent, Diane J.; Abdenur, Jose E. / Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency : a sibling comparison study.

In: Journal of Inherited Metabolic Disease, Vol. 37, No. 5, 01.09.2014, p. 791-799.

Research output: Contribution to journalArticle

@article{2d61b0e14eb843c5bc1a59ea3fdd9d67,
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.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.",
author = "Wang, {Raymond Y.} and Monuki, {Edwin S.} and James Powers and Schwartz, {Phillip H.} and Watkins, {Paul A.} and Yang Shi and Ann Moser and Shrier, {David A.} and Waterham, {Hans R.} and Nugent, {Diane J.} and Abdenur, {Jose E.}",
year = "2014",
month = "9",
doi = "10.1007/s10545-014-9698-3",
volume = "37",
pages = "791--799",
journal = "Journal of Inherited Metabolic Disease",
issn = "0141-8955",
publisher = "Springer Netherlands",
number = "5",

}

TY - JOUR

T1 - Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency

T2 - Journal of Inherited Metabolic Disease

AU - Wang,Raymond Y.

AU - Monuki,Edwin S.

AU - Powers,James

AU - Schwartz,Phillip H.

AU - Watkins,Paul A.

AU - Shi,Yang

AU - Moser,Ann

AU - Shrier,David A.

AU - Waterham,Hans R.

AU - Nugent,Diane J.

AU - Abdenur,Jose E.

PY - 2014/9/1

Y1 - 2014/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84991017534&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84991017534&partnerID=8YFLogxK

U2 - 10.1007/s10545-014-9698-3

DO - 10.1007/s10545-014-9698-3

M3 - Article

VL - 37

SP - 791

EP - 799

JO - Journal of Inherited Metabolic Disease

JF - Journal of Inherited Metabolic Disease

SN - 0141-8955

IS - 5

ER -