Adrenoleukodystrophy manifesting as spinocerebellar degeneration.
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X-linked adrenoleukodystrophy (XALD) is an inherited disorder of peroxisomal metabolism. Atypical presentations have been occasionally reported in literature. However, extrapyramidal and cerebellar manifestations are distinctly rare. We report a patient of X-linked adrenoleukodystrophy with cranial and cervical dystonia and neurological presentation resembling spinocerebellar degeneration followed by a brief review of relevant literature. (+info)
A comparative study of straight chain and branched chain fatty acid oxidation in skin fibroblasts from patients with peroxisomal disorders.
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The beta-oxidation of stearic acid and of alpha- and gamma-methyl isoprenoid-derived fatty acids (pristanic and tetramethylheptadecanoic acids, respectively) was investigated in normal skin fibroblasts and in fibroblasts from patients with inherited defects in peroxisomal biogenesis. Stearic acid beta-oxidation by normal fibroblast homogenates was several-fold greater compared to the oxidation of the two branched chain fatty acids. The effect of phosphatidylcholine, alpha-cyclodextrin, and bovine serum albumin on the three activities suggests that different enzymes are involved in the beta-oxidation of straight chain and branched chain fatty acids. Homogenates of fibroblasts from patients with a deficiency in peroxisomes (Zellweger syndrome and infantile Refsum's disease) showed a normal ability to beta-oxidize stearic acid, but the oxidation of pristanic and tetramethylheptadecanoic acid was decreased. Concomitantly, 14CO2 production from the branched chain fatty acids by Zellweger fibroblasts in culture (but not from stearic acid) was greatly diminished. The Zellweger fibroblasts also showed a marked reduction in the amount of water-soluble metabolites from the radiolabeled branched chain fatty acids that are released into the culture medium. The data presented indicate that the oxidation of alpha- and gamma-methyl isoprenoid-derived fatty acids takes place largely in peroxisomes in human skin fibroblasts. (+info)
X-linked adrenoleukodystrophy: clinical, biochemical and pathogenetic aspects.
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X-linked adrenoleukodystrophy (X-ALD) is a clinically heterogeneous disorder ranging from the severe childhood cerebral form to asymptomatic persons. The overall incidence is 1:16,800 including hemizygotes as well as heterozygotes. The principal molecular defect is due to inborn mutations in the ABCD1 gene encoding the adrenoleukodystrophy protein (ALDP), a transporter in the peroxisome membrane. ALDP is involved in the transport of substrates from the cytoplasm into the peroxisomal lumen. ALDP defects lead to characteristic accumulation of saturated very long-chain fatty acids, the diagnostic disease marker. The pathogenesis is unclear. Different molecular mechanisms seem to induce inflammatory demyelination, neurodegeneration and adrenocortical insufficiency involving the primary ABCD1 defect, environmental factors and modifier genes. Important information has been derived from the X-ALD mouse models; species differences however complicate the interpretation of results. So far, bone marrow transplantation is the only effective long-term treatment for childhood cerebral X-ALD, however, only when performed at an early-stage of disease. Urgently needed novel therapeutic strategies are under consideration ranging from dietary approaches to gene therapy. (+info)
Cerebral X-linked adrenoleukodystrophy: follow-up with magnetic resonance imaging.
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OBJECTIVE: To report a case of childhood cerebral X-linked adrenoleukodystrophy (X-ADL), emphasizing the magnetic resonance imaging (MRI) findings at initial evaluation and at the follow-up. CASE REPORT: Five year-old boy, who was asymptomatic, presented with diagnosis of X-ADL for MRI evaluation. The initial brain MRI showed a focal area of enhancement at the splenium of the corpus calosum. One year later, the follow-up MRI showed a progression of the corpus calosus lesion, as well as other lesions in the parietal and occipital lobes. CONCLUSION: The brain MRI follow-up of patients with X-ADL is important to show the progression of the lesions. (+info)
Bile acids and conjugates identified in metabolic disorders by fast atom bombardment and tandem mass spectrometry.
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From a study of the collision-activated fragmentation of bile acids, a qualitative analytical method based on negative ion fast atom bombardment tandem mass spectrometry has been developed. The times for sample preparation and analyses are short. Both free and conjugated bile acids are detected as they occur in biological fluids, without derivatization. For identifying bile acids and conjugates, the method offers better specificity and sensitivity than does the fast atom bombardment mass spectrometric technique alone. Specific scan modes have been developed for the selective detection of taurine conjugates, delta 4-unsaturated taurine conjugates, delta 4-3-keto free acids and their glycine conjugates, free acids and glycine conjugates bearing a hydroxyl group at the C-12 position, sulfates of glycine and taurine conjugates, and a C29 dicarboxylic bile acid, specific for generalized peroxisomal disorders. Applications of this technique demonstrate its potential usefulness, principally in the diagnosis of several peroxisomal disorders. (+info)
Adrenoleukodystrophy: a complex chromosomal rearrangement in the Xq28 red/green-color-pigment gene region indicates two possible gene localizations.
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We have characterized a complex chromosomal rearrangement in band Xq28, in an adrenoleukodystrophy patient who also has blue-cone monochromacy. A 130-kb region upstream from the color-vision pigment genes was isolated as yeast artificial chromosome or cosmid clones. Another Xq28 sequence, not included in the above region, was obtained by cloning a deletion breakpoint from the patient. Using probes derived from the cloned sequences, we have shown that the rearrangement affects the color-pigment genes and includes two deletions, most likely separated by a large (greater than 110-kb) inversion. One deletion encompasses part of the pigment gene cluster and 33 kb of upstream sequences and accounts for the patient's blue-cone monochromacy. If this rearrangement also caused ALD, the disease gene would be expected to lie within or close to one of the deletions. However, deletions were not detected in a 50-kb region upstream of the red-color-pigment gene in 81 other ALD patients. Two CpG islands were mapped, at 46 and 115 kb upstream from the pigment genes. (+info)
Photosensitized killing of cultured fibroblasts from patients with peroxisomal disorders due to pyrene fatty acid-mediated ultraviolet damage.
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The influence of pyrene-fatty acids on the resistance of cells to ultraviolet (UV) radiation was investigated in cultured fibroblasts from patients with five types of peroxisomal disorders. All showed reduced survival compared to control. The effect varied with the biochemical defect involved and the chain length of the pyrene fatty acid. Reduced survival was observed in cells deficient in plasmalogens (rhizomelic chondrodysplasia punctata) and in cells deficient in peroxisomal fatty acid oxidation (bifunctional enzyme deficiency), which accumulated pyrene-fatty acids. X-linked adrenoleukodystrophy fibroblasts accumulated pyrene-fatty acids and showed increased UV sensitivity only when exposed to longer-chain pyrene fatty acids. UV radiation resistance was lowest in cells with combined impairment of plasmalogen synthesis and fatty acid oxidation (Zellweger syndrome, neonatal adrenoleukodystrophy), suggesting that UV sensitivity correlates inversely with the ratio of plasmalogens to radical producing substances. Fibroblasts deficient in plasmalogens gained normal UV resistance when their plasmalogen levels were normalized by hexadecylglycerol. UV resistance increased when Zellweger cells were fused with X-linked adrenoleukodystrophy cells, and also when Zellweger cells belonging to different complementation groups were fused. The results provide leads to the pathogenesis of the multiple malformations associated with peroxisomal disorders and a method for the selection of cells in which the metabolic defect has been corrected. (+info)
Live cell FRET microscopy: homo- and heterodimerization of two human peroxisomal ABC transporters, the adrenoleukodystrophy protein (ALDP, ABCD1) and PMP70 (ABCD3).
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The adrenoleukodystrophy protein (ALDP) and the 70-kDa peroxisomal membrane protein (PMP70) are half-ATP-binding cassette (ABC) transporters in the mammalian peroxisome membrane. Mutations in the gene encoding ALDP result in a devastating neurodegenerative disorder, X-linked adrenoleukodystrophy (X-ALD) that is associated with elevated levels of very long chain fatty acids because of impaired peroxisomal beta-oxidation. The interactions of peroxisomal ABC transporters, their role in the peroxisomal membrane, and their functions in disease pathogenesis are poorly understood. Studies on ABC transporters revealed that half-transporters have to dimerize to gain functionality. So far, conflicting observations are described for ALDP. By the use of in vitro methods (yeast two-hybrid and immunoprecipitation assays) on the one hand, it was shown that ALDP can form homodimers as well as heterodimers with PMP70 and ALDR, while on the other hand, it was demonstrated that ALDP and PMP70 exclusively homodimerize. To circumvent the problems of artificial interactions due to biochemical sample preparation in vitro, we investigated protein-protein interaction of ALDP in its physiological environment by FRET microscopy in intact living cells. The statistical relevance of FRET data was determined in two different ways using probability distribution shift analysis and Kolmogorov-Smirnov statistics. We demonstrate in vivo that ALDP and PMP70 form homodimers as well as ALDP/PMP70 heterodimers where ALDP homodimers predominate. Using C-terminal deletion constructs of ALDP, we demonstrate that the last 87 C-terminal amino acids harbor the most important protein domain mediating these interactions, and that the N-terminal transmembrane region of ALDP has an additional stabilization effect on ALDP homodimers. Loss of ALDP homo- or heterodimerization is highly relevant for understanding the disease mechanisms of X-ALD. (+info)