Adrenoleukodystrophy

As might be predicted from these similarities between PNS and CNS, many disease entities can affect both these tissues. It should be noted, however, that the clinical expression of such diseases is variable and is sometimes restricted to the PNS. For example, patients with thiamine deficiency may display symmetrical distal sensorimotor polyneuropathy without accompanying CNS degeneration. Untreated infection with human immunodeficiency virus (HIV) may cause early polyneuropathy, with dementia appearing months or years later. Similarly, patients with sulfatidase deficiency or adrenoleukodystrophy may present initially with polyneuropathy, while their CNS dysfunction remains clinically undetectable. 

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.)... 

Kemp, S., Pujol, A., Waterham, H. R. et al. ABCD1 mutations and the X-linked adrenoleukodystrophy muation database role in diagnosis and clinical correlations. Hum. Mutat. 18 499-515,2001. 

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... 

IRD, infantile Refsum s disease NALD, neonatal adrenoleukodystrophy ZS, Zellweger s syndrome. 

ALDP, DHAP, dihydroxyacetone phosphate DHAPAT, dihydroxyacetone phosphate acyltransferase NALD, neonatal adrenoleukodystrophy RCDP, rhizomelic chondrodysplasia punctata X-ALD, X-linked adrenoleukodystrophy ZS, Zellweger s syndrome. 

Globoid leukodystrophy Metachromatic leukodystrophy X-linked adrenoleukodystrophy Refsum s disease Cystinosis... 

Krivit, W., Peters, C. and Shapiro, E. G. Bone marrow transplantation as effective treatment of central nervous system disease in globoid cell leukodystrophy, metachro-matic leukodystrophy, adrenoleukodystrophy, mannosidosis, fucosidosis, aspartylglucosaminuria, Hurler, Maroteaux-Lamy, and Sly syndromes, and Gaucher disease type III. Curr. Opin. Neurol. 12 167-176,1999. 

Peters, C., Charnas, L. R., Tan, Y. et al. Cerebral X-linked adrenoleukodystrophy The international hematopoietic cell transplantation experience from 1982 to 1999. Blood 104 881-888,2004. 

ALD adrenoleukodystrophy CaMK Ca2+-calmodulin-dependent protein kinase cyclic adenosine 3, 5 -monophosphate... 

X-IInked adrenoleukodystrophy (X-ALD) is a progressive, inherited neurologic disorder arising from a defect in peroxisomal VLCFA oxidation. 

Deficiency can lead to cancer and immune system dysfunction Stabilizes proteins used in the immune system Promotes membrane binding that is essential for proper protein localization or biological function May hinder progression of adrenoleukodystrophy Reduces low-density lipoprotein in the blood Reduces platelet stickiness and protects against coronary heart disease... 

Crowther, M. A., Barr, R. D., Kelton, J., Whelan, D., and Greenwald, M. (1995). Profound thrombocytopenia complicating dietary erucic acid therapy for adrenoleukodystrophy. Am. ]. Hematol. 48(2), 132-133. 

Rizzo, W. B., Watkins, P. A., Phillips, M. W., Cranin, D., Campbell, B., and Avigan, J. (1986). Adrenoleukodystrophy Oleic acid lowers fibroblast saturated C22-26 fatty acids. Neurology 36,357-361. 

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... 

There are many other neurodegenerative diseases, some with a high incidence, and others rare. They include Parkinson disease (p. 1790), Huntington disease (Table 26-4), spinal muscular atrophy (SMA a leading hereditary cause of infant mortality),1162a b amyotrophic lateral sclerosis (ALS), prion diseases (Box 29-E), ataxias, and other diseases caused by triple-repeat DNA sequences (Table 26-4) and X-linked adrenoleukodystrophy (ALD p. 945).1163 In the last, membrane function is disrupted. Although these diseases arise from a variety of causes many of them have in common amyloidosis, the deposition of insoluble proteins in or around neurons.11633... 

Kickler TS, Zinkham WH, Moser A, Shankroff J, Borel J, Moser H. Effect of erucic acid on platelets in patients with adrenoleukodystrophy. Biochem Mol Med 1996 57(2) 125-33. 

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. 

Figure 13-1. MRI of brain in a patient with X-Iinked adrenoleukodystrophy. Brain magnetic resonance image obtained shortly after diagnosis shows diffuse abnormal signal in the white matter of the posterior hemisphere extending anteriorly.

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