Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study

Mahmood, Asif; Raymond, Gerald V.; Dubey, Prachi; Peters, Charles; Moser, Hugo W.

doi:10.1016/s1474-4422(07)70177-1

Cited by 158 publications

(163 citation statements)

References 22 publications

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“…Rapid diagnosis in a white matter disease decreases patient and family anxiety and allows the rapid institution of appropriate therapy, if available. 39 The imaging protocol in patients with a suspected leukoencephalopathy should be sufficient to answer the above four items. The minimum imaging protocol includes T1W, T2W, and FLAIR images of the brain.…”

Section: Discussionmentioning

confidence: 99%

Invited Article: An MRI-based approach to the diagnosis of white matter disorders

Schiffmann¹,

Knaap²

2009

Neurology

475

424

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Background:There are many different white matter disorders, both inherited and acquired, and consequently the diagnostic process is difficult. Establishing a specific diagnosis is often delayed at great emotional and financial costs. The pattern of brain structures involved, as visualized by MRI, has proven to often have a high diagnostic specificity. Methods:We developed a comprehensive practical algorithm that relies mainly on the characteristics of brain MRI. Results:The initial decision point defines a hypomyelination pattern, in which the cerebral white matter is hyperintense (normal), isointense, or slightly hypointense relative to the cortex on T1-weighted images, vs other pathologies with more prominent hypointensity of the cerebral white matter on T1-weighted images. In all types of pathology, the affected white matter is hyperintense on T2-weighted images, but, as a rule, the T2 hyperintensity is less marked in hypomyelination than in other pathologies. Some hypomyelinating disorders are typically associated with peripheral nerve involvement, while others are not. Lesions in patients with pathologies other than hypomyelination can be either confluent or isolated and multifocal. Among the diseases with confluent lesions, the distribution of the abnormalities is of high diagnostic value. Additional MRI features, such as white matter rarefaction, the presence of cysts, contrast enhancement, and the presence of calcifications, further narrow the diagnostic possibilities. White matter disorders or leukoencephalopathies comprise all disorders that exclusively or predominantly affect the white matter of the brain. Leukodystrophies are genetically determined leukoencephalopathies. There are many different leukoencephalopathies, which can occur at all ages, be progressive or static, and be genetic or acquired. Conclusion:1,2 The diagnostic workup is complicated. Many tests are performed, at high financial and emotional costs and often with disappointing results. 3MRI has proven to be pivotal in the diagnostic workup of patients with leukoencephalopathies.2 First, the presence of white matter abnormalities is usually established with MRI. CT may show white matter hypodensity, but it is much less sensitive than MRI and gives no details. Secondly, it has been shown repeatedly that individual leukoencephalopathies present themselves with distinct patterns of MRI abnormalities, which are homogeneous among patients with the same disorder and different in patients with different disorders, indicating the high diagnostic value of MRI patterns.

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Section: Discussionmentioning

confidence: 99%

Invited Article: An MRI-based approach to the diagnosis of white matter disorders

Schiffmann¹,

Knaap²

2009

Neurology

475

424

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“…Comparison with a historical series of 283 CCALD patients without HCT therapy excluded the possibility that the favorable prognosis of not or mildly affected CCALD patients after HCT is attributable to a distinct phenotype category with a better prognosis even without HCT therapy. In addition, a significant difference in 5 years survival (95% in HCT versus 57% without HCT) and in the degree of disease progression (53% neurologically stable patients after HCT versus 6% stable patients without HCT) was found [103].…”

Section: Therapymentioning

confidence: 94%

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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“…Regardless of triggering agent, the small and intermediate conductance potassium channels, SK3 and IK1, are key components of EDHF-mediated relaxation. 4,5 Cheng et al performed ex vivo studies of small mesenteric arterioles (150-200 m in diameter) derived from control mice, or transgenic mice with severe HHcy, to characterize vascular relaxation in response to a battery of agonists and inhibitors, and also to provide material for biochemical and immunohistologic studies. The central finding is that EDHF-mediated relaxation is compromised in the mice with severe HHcy; interestingly, despite robust increases in arterial SK3 and IK1 expression, the net function of these channels is significantly impaired in the setting of severe HHcy.…”

Section: Channeling the Homocysteine Chapel -------------------------mentioning

confidence: 99%

“…Loss of Krit1, a rap1 effector, leads to cerebral cavernous malformation, which is associated with uncompensated rhoA activation. [4][5][6] Conversely, hemangiomas are associated with elevated rac1/reactive oxygen signaling (see figure 9 ). 7,8 The lessons from the study by Lakshmikanthan et al suggest that rap1 signaling is required for normal vasculature, and that a careful balance of rap1 signaling results in tonic VEGFR2 activation, which allows normal vessels to respond rapidly to an angiogenic stimulus.…”

Section: Beating the Rap In Angiogenesis ----------------------------mentioning

confidence: 99%

Channeling the homocysteine chapel

Sibinga

2011

Blood

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Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study

Cited by 158 publications

References 22 publications

Invited Article: An MRI-based approach to the diagnosis of white matter disorders

Invited Article: An MRI-based approach to the diagnosis of white matter disorders

Therapy of X-linked adrenoleukodystrophy

Channeling the homocysteine chapel

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