Cerebral adrenoleukodystrophy (ALD) in only one of monozygotic twins with an identical ALD genotype

Korenke, G. C.; Fuchs, Sigrid; Krasemann, Ernst; Doerr, H. G.; Wilichowski, Ekkehard; Hunneman, D. H.; Hanefeld, F.

doi:10.1002/ana.410400221

Cited by 102 publications

(62 citation statements)

References 13 publications

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“…Others found that severity of the X-ALD phenotype is correlated with expression of an other peroxisomal transporter gene (ABCD4) and of the VLCFA synthase gene BG1 [52]. Recently, we reported that functional polymorphisms of genes and proteins involved in environmental factors may also be involved, as indicated by phenotypic variability in a set of monozygotic twins [55], and the disease may putatively also be triggered by CNS traumas [14].…”

Section: Modifying Factorsmentioning

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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Section: Modifying Factorsmentioning

confidence: 94%

Therapy of X-linked adrenoleukodystrophy

Semmler

Köhler

Jung

et al. 2008

Expert Review of Neurotherapeutics

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“…(n ¼ 18), frame-shift mutations (n ¼ 5), in-frame deletions (n ¼ 2), in-frame insertion (n ¼ 1), nonsense mutation (n ¼ 1), splice site mutation (n ¼ 1). Sixteen of these mutations have been published before (11,21); the remaining 12 mutations comprise nine missense mutations (A141T, Y281H, R389H, G512S, P543L, R554H, Y559H, R617H, R679R), two frame-shift mutations (del 740, del 2132) and one splice site mutation (ins 8 bp 2252). There was no correlation between the loci or kind of mutation and ACTH concentration (Fig.…”

Section: Genetic Examinationsmentioning

confidence: 99%

Variability of endocrinological dysfunction in 55 patients with X-linked adrenoleucodystrophy: clinical, laboratory and genetic findings

Korenke

Roth

Krasemann

et al. 1997

European Journal of Endocrinology

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X-linked adrenoleucodystrophy (ALD) has been shown to be one of the most frequent causes of Addison's disease in men. It is characterized by an impaired peroxisomal b-oxidation of very long chain fatty acids and is associated with mutations of the ALD gene resulting in a defective peroxisomal membrane transport protein. There is a striking variability of endocrinological and neurological symptoms in patients with ALD, with no clearly evident correlation between mutations of the ALD gene and the different neurological phenotypes. No data on endocrinological symptoms and the ALD genotype have been published so far.We report endocrinological, clinical, laboratory and molecular genetic data from 55 patients with ALD from 34 families. Endocrinological symptoms of adrenal insufficiency were observed in 33 patients, 20 of whom showed additional neurological symptoms of cerebral ALD or adrenomyeloneuropathy. Isolated neurological symptoms were seen in 12 patients; in nine patients there were neither endocrinological nor neurological symptoms.Mutations of the ALD gene (n ¼ 28) were detected in 50 patients (including nine sets of brothers) from 32 families. No correlation was found between the ALD gene mutation and endocrinological dysfunction. However, we found that all sets of brothers were concordant for the endocrinological phenotype (cortisol synthesis was reduced in two sets and normal in seven sets), whereas four sets showed a discordant neurological phenotype. As yet unknown hereditary factors other than mutations within the ALD gene may interfere with the endocrinological phenotype more strongly than with the neurological phenotype of ALD.

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“…Both twins carried the same mutation in the X-linked adrenoleukodystrophy (ALD) gene, yet one developed blindness, balance problems, and loss of myelin in the brain, features typical of the progressive and lethal neurological disease, whereas the other remained healthy. The conclusion of the investigators reporting the unusual occurrence was "some nongenetic factors may be important for different adrenoleukodystrophy phenotypes" (Korenke et al 1996). That indeed was a valid conclusion in 1996, given the focus of medical genetics on DNA sequence.…”

Section: Introductionmentioning

confidence: 95%

Epigenetics and Human Disease

Zoghbi

Beaudet

2016

Cold Spring Harb Perspect Biol

212

130

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SUMMARYGenetic causes for human disorders are being discovered at an unprecedented pace. A growing subclass of disease-causing mutations involves changes in the epigenome or in the abundance and activity of proteins that regulate chromatin structure. This article focuses on research that has uncovered human diseases that stem from such epigenetic deregulation. Disease may be caused by direct changes in epigenetic marks, such as DNA methylation, commonly found to affect imprinted gene regulation. Also described are disease-causing genetic mutations in epigenetic modifiers that either affect chromatin in trans or have a cis effect in altering chromatin configuration.

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Cerebral adrenoleukodystrophy (ALD) in only one of monozygotic twins with an identical ALD genotype

Cited by 102 publications

References 13 publications

Therapy of X-linked adrenoleukodystrophy

Therapy of X-linked adrenoleukodystrophy

Variability of endocrinological dysfunction in 55 patients with X-linked adrenoleucodystrophy: clinical, laboratory and genetic findings

Epigenetics and Human Disease

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