Adrenoleukodystrophy: Incidence, new mutation rate, and results of extended family screening

Bezman, Lena; Moser, Ann B.; Raymond, Gerald V.; Rinaldo, Piero; Watkins, Paul A.; Smith, Kirby D.; Kass, Nancy E.; Moser, Hugo W.

doi:10.1002/ana.101

Cited by 296 publications

(143 citation statements)

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“…States 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].…”

Section: Introductionmentioning

confidence: 99%

Therapy of X-linked adrenoleukodystrophy

Semmler

Köhler

Jung

et al. 2008

Expert Review of Neurotherapeutics

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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...

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“…States 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].…”

Section: Introductionmentioning

confidence: 99%

Therapy of X-linked adrenoleukodystrophy

Semmler

Köhler

Jung

et al. 2008

Expert Review of Neurotherapeutics

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“…10,11 The incidence in males is estimated to be 1:21,000, and 1:14,000 in females. 12 All ethnic groups are affected without apparent predilection for any one group. More than 500 different mutations in the ABCD1 gene have been described in X-ALD patients, 13 and are updated in the website http://www.x-ald.nl).…”

Section: Introductionmentioning

confidence: 99%

Therapy of X-linked adrenoleukodystrophy

Moser

2006

NeuroRX

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Summary: Current therapies for X-linked adrenoleukodystrophy (X-ALD) include replacement therapy with adrenal steroids, which is mandatory for all patients with impaired adrenal function but does not alter neurological progression significantly; dietary therapy with "Lorenzo's Oil," which appears to have a preventive effect in asymptomatic boys whose brain MRI is normal; and hematopoietic stem cell transplantation in patients in the early stage of the cerebral inflammatory phenotype. Application of these interventions requires careful assessment of the patients' phenotype, which often changes over time. Family screening provides important opportunities for disease prevention.

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“…X-linked adrenoleukodystrophy (X-ALD; OMIM 300100) is the most common inherited peroxisomal disorder with an incidence of ϳ1 in 17,000 (1). It is a progressive neurodegenerative disease that affects cerebral white matter, spinal cord, peripheral nerves, adrenal cortex, and testis (2).…”

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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.

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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,

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Adrenoleukodystrophy: Incidence, new mutation rate, and results of extended family screening

Cited by 296 publications

References 18 publications

Therapy of X-linked adrenoleukodystrophy

Therapy of X-linked adrenoleukodystrophy

Therapy of X-linked adrenoleukodystrophy

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

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