Adrenoleukodystrophy: Impaired Oxidation of Very Long Chain Fatty Acids in White Blood Cells, Cultured Skin Fibroblasts, and Amniocytes

Singh, Inderjit; Moser, Ann; Moser, Hugo W.; Kishimoto, Yasuo

doi:10.1203/00006450-198403000-00016

Cited by 220 publications

(96 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This reduction may, however, be sufficient to impair VLCFA catabolism, as reflected by their accumulation in the patient's plasma. A comparable situation is observed in carriers of X-linked adrenoleukodystrophy (46,47). DHAP-AT was moderately decreased without detectable impairment of plasmalogen synthesis in the fibroblasts from this patient.…”

Section: Discussionsupporting

confidence: 52%

Pseudo Infantile Refsum's Disease: Catalase-Deficient Peroxisomal Particles with Partial Deficiency of Plasmalogen Synthesis and Oxidation of Fatty Acids

et al. 1993

View full text Add to dashboard Cite

ABSTRACT. Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum's disease are genetic disorders characterized by the virtual absence of catalasepositive perosisomes and a general impairment of perosisomal functions. Recent studies in these three disorders have provided morphologic evidence of perosisomal "ghosts" of density 1.10 g / c d that contain membrane proteins but lack a majority of the matrix enzyme activities. We report here the biochemical studies in a female infant with clinical features of infantile Refsum's disease whose liver and fibroblasts contained cytosolic catalase but no catalase-positive peroxisomes. Oxidation of phytanic and pipecolic acids was severely impaired, whereas osidation of very-long-chain fatty acids and dihydrosyacetone phosphate acyltransferase activity were only partially decreased. Immunoblot analysis showed that the three peroxisomal &oxidation enzymes (acyl-CoA oxidase, enoyl-CoA hydratasel3-hydrosyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase) were detectable in liver tissues. The 3-ketoacyl-CoA thiolase was of the mature form (41 kD). in contrast with other perosisomal disorders with multipl'i enzyme deficiencies. The majority of these peroxisomal enzvme activities were associated with two subcellular membrane vesicle fractions lacking catalase: one had the density of normal peroxisomes (1.17 g/cm"), the other, yet undescribed, a lower density (1.137 g/cm"). This suggests that perosisomes (density = 1.17 g/cm") and structures with lower density (density = 1.137 g/cm") found in this patient's cultured skin fibroblasts, although lacking catalase, contained functional perosisomal enzymes. This distinguishes this disorder from other disorders of perosisome biogenesis. (Pediatr Res 34: 270-276, 1993) Abbreviations n-ALD, neonatal adrenoleukodystrophy @-ketothiolase or thiolase, 3-ketoacyl-CoA thiolase bifunctional enzyme, enoyl-CoA hydratasel3-hydrosyacylCoA dehydrogenase VLCFA, very-long-chain fatty acid DAB, diaminobenzidine DHAP-AT, dihydroxyacetone phosphate acyltransferase

show abstract

Section: Discussionsupporting

confidence: 52%

Pseudo Infantile Refsum's Disease: Catalase-Deficient Peroxisomal Particles with Partial Deficiency of Plasmalogen Synthesis and Oxidation of Fatty Acids

et al. 1993

View full text Add to dashboard Cite

show abstract

“…Glucocorticoid requirements are similar as for other forms of adrenal insufficiency, ranging from 10 to 40mg glucocorticoid daily, Please return your comments for the attention of the Commissioning Editor at l.tipton@expert-reviews.com VLCFA accumulation, which is suspected to be a crucial factor in the pathogenesis of X-ALD, originates from both diet and endogenous synthesis [73,74]. In patients with X-ALD the ability to degrade VLCFA is impaired [35,74,75]. A pure restriction of VCLFA intake is insufficient to lower VLCFA levels [76].…”

Section: Therapymentioning

confidence: 99%

Therapy of X-linked adrenoleukodystrophy

Semmler

Köhler

Jung

et al. 2008

Expert Review of Neurotherapeutics

View full text Add to dashboard Cite

X-linked adrenoleukodystrophy (X-ALD; OMIM #300100) is caused by defects of the ABCD1 gene on chromosome Xq28, resulting in an impairment of peroxisomal beta-oxidation and the accumulation of saturated very long chain fatty acids (VLCFAs). Primary manifestations occur in the CNS, the adrenal cortex and the testes' Leydig cells. The clinical presentation shows a marked variability which is not explained by the different X-ALD genotypes. Phenotypes range from rapidly progressive cerebral disease with childhood (childhood cerebral ALD [CCALD]) or adulthood (adult cerebral ALD [ACALD]) onset leading to death within a few years, over adult-onset adrenomyeloneuropathy (AMN) with or without focal CNS demyelination, AMN converting into a rapidly progressive, cerebral demyelinating phenotype resembling CCALD, to slow disease progression over decades, or adrenal insufficiency only. Approximately 50% of female heterozygotes develop moderate spastic paresis resembling the AMN phenotype. This review focuses on current experiences with different therapeutic approaches. Lorenzo's oil did not prove to be effective in cerebral inflammatory disease variants, but asymptomatic patients, and speculatively AMN variants without cerebral involvement, as well as female carriers may benefit from early intake of oleic and erucic acids in addition to VLCFA restriction. Hormone-replacement therapy is necessary in all patients with adrenal insufficiency. Hematopoietic stem cell transplantation has been reported to be effective in presymptomatic or early symptomatic CCALD, and may well also be a final therapeutic option in early ACALD patients. Early detection of mutation carriers and timely initiation of therapy is important for the effectiveness of all therapeutic efforts. Gene therapy of endogenous hematopoietic stem cells, pharmacological upregulation of other genes encoding proteins involved in peroxisomal beta-oxidation, reduction of oxidative stress, and possibly lovastatin are candidates for future X-ALD therapies. Future Drugs Ltd: Peer Review PaperPlease return your comments for the attention of the Commissioning Editor at l.tipton@expert-reviews.com Many thanks in advance for your kind assistance. Therapy of X-linked Adrenoleukodystrophy Future Drugs Ltd: Peer Review PaperPlease return your comments for the attention of the Commissioning Editor at l.tipton@expert-reviews.com Many thanks in advance for your kind assistance. et al 1963 [6]. In 1981 the X-ALD locus was mapped to chromosome Xq28 [7], and twelve years later, the X-ALD gene (ABCD1) was identified [8,9]. Today X-ALD has been identified in most countries worldwide and in most ethnic groups. The minimum frequency of hemizygotes in the UnitedStates was determined to be 1:42,000 and the one of hemizygotes plus heterozygotes 1:16,800, suggesting X-ALD as the most common inherited leukodystrophy [10]. X-ALD phenotypesX-ALD is characterized by a highly variable clinical spectrum, from early progressive childhood to mild adulthood disease with only slow symptom progre...

show abstract

“…Although the exact role of ALDP remains elusive, it has been implicated in the transport of VLCFA into peroxisomes (5,6). In patients with X-ALD, the defect in ALDP results in decreased ␤-oxidation of VLCFAs (7). As a result, VLCFAs accumulate in all tissues and plasma (8).…”

mentioning

confidence: 99%

Characterization of the human ω‐oxidation pathway for ω‐hydroxy‐very‐long‐chain fatty acids

Sanders

Ofman

Dacremont³

et al. 2008

FASEB j.

View full text Add to dashboard Cite

Very-long-chain fatty acids (VLCFAs) have long been known to be degraded exclusively in peroxisomes via ␤-oxidation. A defect in peroxisomal ␤-oxidation results in elevated levels of VLCFAs and is associated with the most frequent inherited disorder of the central nervous system white matter, X-linked adrenoleukodystrophy. Recently, we demonstrated that VLCFAs can also undergo -oxidation, which may provide an alternative route for the breakdown of VLCFAs. The -oxidation of VLCFA is initiated by CYP4F2 and CYP4F3B, which produce -hydroxy-VLCFAs. In this article, we characterized the enzymes involved in the formation of very-long-chain dicarboxylic acids from -hydroxy-VLCFAs. We demonstrate that very-longchain dicarboxylic acids are produced via two independent pathways. The first is mediated by an as yet unidentified, microsomal NAD ؉ -dependent alcohol dehydrogenase and fatty aldehyde dehydrogenase, which is encoded by the ALDH3A2 gene and is deficient in patients with Sjögren-Larsson syndrome. The second pathway involves the NADPH-dependent hydroxylation of -hydroxy-VLCFAs by CYP4F2, CYP4F3B, or CYP4F3A. Enzyme kinetic studies show that oxidation of -hydroxy-VLCFAs occurs predominantly via the NAD ؉ -dependent route. Overall, our data demonstrate that in humans all enzymes are present for the complete conversion of VLCFAs to their corresponding very-long-chain dicarboxylic acids.-Sanders, R.-J., Ofman, R., Dacremont, G., Wanders, R. J. A., Kemp, S. Characterization of the human -oxidation pathway for -hydroxy-very-long-chain fatty acids. FASEB J. 22,

show abstract

Adrenoleukodystrophy: Impaired Oxidation of Very Long Chain Fatty Acids in White Blood Cells, Cultured Skin Fibroblasts, and Amniocytes

Cited by 220 publications

References 23 publications

Pseudo Infantile Refsum's Disease: Catalase-Deficient Peroxisomal Particles with Partial Deficiency of Plasmalogen Synthesis and Oxidation of Fatty Acids

Pseudo Infantile Refsum's Disease: Catalase-Deficient Peroxisomal Particles with Partial Deficiency of Plasmalogen Synthesis and Oxidation of Fatty Acids

Therapy of X-linked adrenoleukodystrophy

Characterization of the human ω‐oxidation pathway for ω‐hydroxy‐very‐long‐chain fatty acids

Contact Info

Product

Resources

About