Haematopoietic stem cell transplantation in 12 patients with cerebral X-linked adrenoleukodystrophy

Baumann, Matthias; Korenke, Christoph; Weddige-Diedrichs, Almuth; Wilichowski, Ekkehard; Hunneman, D. H.; Wilken, Bernd; Brockmann, Knut; Klingebiel, Thomas; Niethammer, D.; Kühl, Jörn Sven; Ebell, Wolfram; Hanefeld, F.

doi:10.1007/s00431-002-1097-3

Cited by 40 publications

(37 citation statements)

References 25 publications

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“…Also, this disorder generally results in permanent neurologic deficits if multifocal findings are present on DWI, although degrees of clinical and imaging reversibility have been reported in a few instances [15,16,19]. Our three patients with acute symptoms who were later found to have leukodystrophies were excluded from analysis because these are also not typically considered toxic causes of leukoencephalopathy but rather congenital genetic disorders; an acute presentation and a severe lesion extent herald a tendency not to normalize on followup MRI as well as a poor clinical prognosis [51,52]. Regardless of whether these entities have some reversible component, this study showed that HIE and congenital causes can be discerned from the causes of toxic leukoencephalopathy by comparing the distribution of abnormalities on DWI with the distribution on FLAIR (Figs.…”

Section: Mckinney Et Almentioning

confidence: 99%

Acute Toxic Leukoencephalopathy: Potential for Reversibility Clinically and on MRI With Diffusion-Weighted and FLAIR Imaging

McKinney

Kieffer

Paylor

et al. 2009

American Journal of Roentgenology

154

168

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Acute toxic leukoencephalopathy with reduced diffusion may be clinically reversible and radiologically reversible on DWI, and may also be reversible, but to a lesser degree, on FLAIR MRI. None of the imaging markers measured in this study appears to correlate with clinical outcome, which underscores the necessity for prompt recognition of this entity. Alerting the clinician to this potentially reversible syndrome can facilitate treatment and removal of the offending agent in the early stages.

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Section: Mckinney Et Almentioning

confidence: 99%

Acute Toxic Leukoencephalopathy: Potential for Reversibility Clinically and on MRI With Diffusion-Weighted and FLAIR Imaging

McKinney

Kieffer

Paylor

et al. 2009

American Journal of Roentgenology

154

168

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“…However, both children had a subtype of Farber disease with involvement of the central nervous system and died because of a deterioration of their neurological status. So, as is also the case in other lysosomal storage disorders with severe CNS disease [23], hematopoietic stem cell transplantation does not seem to provide a benefit for these children, as it is not able to abolish or even reduce the neurotoxic effects of excessive ceramide accumulation in the brain. However, as HSCT can provide a healthy immune system and thus correct the abnormal inflammatory response and symptoms of disease, there could be an option for hematopoietic stem cell transplantation in those children with a predominance of the inflammatory component of the disorder.…”

Section: Part Iii: Therapeutic Approaches To Farber Disease Patients mentioning

confidence: 99%

Farber disease: clinical presentation, pathogenesis and a new approach to treatment

et al. 2007

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Background: Farber Disease is an autosomal-recessively inherited, lysosomal storage disorder caused by acid ceramidase deficiency and associated with distinct clinical phenotypes. Children with significant neurological involvement usually die early in infancy, whereas patients without or only mild neurological findings suffer from progressive joint deformation and contractures, subcutaneous nodules, inflammatory, periarticular granulomas, a hoarse voice and finally respiratory insufficiency caused by granuloma formation in the respiratory tract and interstitial pneumonitis leading to death in the third or fourth decade of live. As the inflammatory component of this disorder is caused by some kind of leukocyte dysregulation, allogeneic hematopoietic stem cell transplantation can restore a healthy immune system and thus may provide a curative option in Farber Disease patients without neurological involvement. Previous stem cell transplantations in two children with severe neurological involvement had resulted in a disappointing outcome, as both patients died of progressive deterioration of their neurological status. As a consequence, stem cell transplantation does not appear to be able to abolish or even reduce the neurotoxic effects of the abundant ceramide storage in the brain.

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“…The first report about a favorable effect of HCT in a CCALD patient was published in 1990 [95] and several subsequent reports in small patients series showed positive results [96][97][98][99][100]. Follow-up studies demonstrated that the beneficial effect is maintained for 5-10 years [101,102]. The most comprehensive study by Peters et al included 94…”

Section: Therapymentioning

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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Haematopoietic stem cell transplantation in 12 patients with cerebral X-linked adrenoleukodystrophy

Cited by 40 publications

References 25 publications

Acute Toxic Leukoencephalopathy: Potential for Reversibility Clinically and on MRI With Diffusion-Weighted and FLAIR Imaging

Acute Toxic Leukoencephalopathy: Potential for Reversibility Clinically and on MRI With Diffusion-Weighted and FLAIR Imaging

Farber disease: clinical presentation, pathogenesis and a new approach to treatment

Therapy of X-linked adrenoleukodystrophy

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