Very long chain fatty acids adrenoleukodystrophy

Adrenoleukodystrophy is an X-linked dysmyelinative disorder caused by mutations in the ABCD1 gene, which encodes the peroxisomal integral membrane ALD protein, a member of the ATP binding cassette transporter family. These mutations result in impaired clearance of plasma very-long-chain fatty acids. Affected males may present with symmetrical distal axonal polyneuropathy, adrenocortical insufficiency or CNS demyelination, while occasional heterozygous women demonstrate deficits suggestive of multiple sclerosis [56]. Manipulation of dietary fatty acid intake has some minimal therapeutic effect, while bone marrow transplantation has diminished deficits in a few patients. (See in Ch. 41.)... 

Adrenoleukodystrophy X-linked Peroxisomal membrane protein in the ABC transporter family Decreased peroxidation of saturated, very-long-chain fatty acids, causing their accumulation in brain, adrenals and other tissues variable phenotypes with regard to hypomyelination see text 1,26, Ch. 40... 

Kemp S, Valianpour F, Denis S, Ofman R, Sanders RJ, Mooyer P, Barth PG, Wanders RJ (2005) Elongation of very long-chain fatty acids is enhanced in X-linked adrenoleukodystrophy. Mol Genet Metab 84 144-151... 

A second important difference between mitochondrial and peroxisomal fi oxidation in mammals is in the specificity for fatty acyl-CoAs the peroxisomal system is much more active on very-long-chain fatty acids such as hexacosanoic acid (26 0) and on branched-chain fatty acids such as phytanic acid and pristanic acid (see Fig. 17-17). These less-common fatty acids are obtained in the diet from dairy products, the fat of ruminant animals, meat, and fish. Their catabolism in the peroxisome involves several auxiliary enzymes unique to this organelle. The inability to oxidize these compounds is responsible for several serious human diseases. Individuals with Zellweger syndrome are unable to make peroxisomes and therefore lack all the metabolism unique to that organelle. In X-linked adrenoleukodystrophy (XALD), peroxisomes fail to... 

A deficiency of very long-chain fatty acid oxidation in peroxisomes is apparently caused by a defective transporter of the ABC type (Chapter 8).55 The disease, X-linked adrenoleukodystrophy (ALD), has received considerable publicity because of attempts to treat it with "Lorenzo s oil," a mixture of triglycerides of oleic and the C22 monoenoic erucic acid. The hope has... 

X-linked adrenoleukodystrophy (X-ALD) was suspected. Plasma was obtained for the measurement of very long chain fatty acids (VLCFA), which revealed a C26 0 concentration of 1.32 pg/mL, a C24 0/C22 0 ratio of 1.88, and a C26 0/C22 0 ratio of 0.08 (normal is < 0.02), confirming the biochemical diagnosis of X-ALD. Subsequent formal neuropsychological testing was obtained and revealed a performance IQ of 70. Adrenal function was assessed by corticotropin (ACTH) stimulation test and revealed adrenal insufficiency that was treated with replacement therapy with hydrocortisone. 

Kasmussen, M., Maser, A. B., Bone), J-, Khangoora, S-, and Moser, H. W. (1994). Brain, liver, and adipose tissue erucic and very long chain fatty acid levels in adrenoleukodystrophy patients treated with gljTervI tiierucale and trioleate oils (Lorenzo s oiJ),... 

ABCD ABCD 4 Adrenoleukodystrophy (a possible defect in peroxisomal transport or catabohsm of very long-chain fatty acids ABCDl)... 

Brown, F.R., 3d, McAdams, A.J., Cummins, J.W., Konkol, R., Singh, I., Moser, A.B. Moser, H.W. i 9%2) Johns Hopkins Med. J. 151, 34A-351. Cerebro-hepato-renal (Zellweger) syndrome and neonatal adrenoleukodystrophy similarities in phenotype and accumulation of very long chain fatty acids. 

Wanders, R.J., van Roermund, C.W., van Wijland, M.J., Schulgens, RB., van den Bosch, H., Schram, A.W. Tagcr, J.M. (1988) Biochem. Biopl s. Res. Commun. 153, 618 24. Direct demonstration that the deficient oxidation of very long chain fatty acids in X-linked adrenoleukodystrophy is due to an impaired ability of peroxisomes to activate very long chain fatty adds. 

Cartier, N., J. Lopez, P. MouUier, F. Rocchiccioli, M. O. Rolland, P. Jorge, J. Mosser, J. L. Mandel, P. F. Bougneres, O. Danos, ruid et al. 1995. Retroviral-mediated gene transfer corrects very-long-chain fatty acid metabolism in adrenoleukodystrophy fibroblasts. Proc Natl Acad Sci 92 1674-1678. 

Three genetic disorders Zellweger s syndrome, neonatal adrenoleukodystrophy, and childhood adrenoleukodys-trophy) exhibit defective formation of peroxisomes (in Zellweger s syndrome no morphologically detectable peroxisomes are present) or deficiency of one or more constituent enzymes. All three disorders are characterized by a marked accumulation of very long chain, saturated, unbranched fatty acids (tetracosanoic and hexacosanoic acids) in liver and central nervous system tissues, severe neurological symptoms, and early death. 

Synthesis of 22 6n-3 was not impaired in cell lines with X-ALD (Table 2), suggesting that the adrenoleukodystrophy protein (ALDP), a peroxisomal membrane protein that has been hypothesized to transport very-long-chain saturated fatty acids, does not participate in the retroconversion step of 24 6n-3 to 22 6n-3. The biosynthesis of 22 6n-3 was also normal in fibroblasts from patients with Refsum disease, who have a defect in peroxisomal fatty acid a-oxidation, indicating that a-oxidation does not contribute to 22 6n-3 synthesis. 

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