Peroxisomal disorder

Patients with abetalipoproteinaemia, a rare inborn disorder of lipoprotein metabolism, are totally deficient in vitamin E fiom birth and, if untreated, invariably develop a characteristic pigmentary retinopathy similar to that seen in retinitis pigmentosa and peroxisomal disorders. The same retinopathy has been observed in other patients with severe and chronic vitamin E deficiency. A essive vitamin E replacement therapy in all these patients has been shown either to prevent, to halt the progression of, or in some cases, to improve the characteristic visual abnormalities (Muller and Lloyd, 1982). 

Refsum s disease is an autosomal recessive peroxisomal disorder characterized by accumulation of phytanic acid and other 3-alkyl-branched fatty acids [55]. Patients develop hypertrophic demyelinative polyneuropathy, retinitis pigmentosa, ichthyosis and deafness. The disorder can be successfully treated by institution of a diet poor in phytanic acid, in conjunction with plasmapheresis to remove circulating phytanic acid. 

Other leukodystrophies are associated with the lysosomal and peroxisomal disorders in which specific lipids or other substances accumulate due to a deficiency in a catabolic enzyme - for example Krabbe s disease, meta-chromatic leukodystrophy (MLD) and adrenoleuko-dystrophy (ALD) [1,2]. (These are discussed in detail in Ch. 40.) Similarly, disorders of amino acid metabolism can lead to hypomyelination - for example phenylketonuria and Canavan s disease (spongy degeneration) [1, 2, 25] (Ch. 40). The composition of myelin in the genetically... 

TABLE 41-7 Therapies of lysosomal and peroxisomal disorders that have shown success in clinical trials... 

The diagnosis of lysosomal disorders is usually based on enzymatic assays in white blood cells or cultured skin fibroblasts [ 1 ]. Molecular studies required for identification of carriers. Initial diagnosis of peroxisomal disorders... 

Kallijaevi, J., a. E. Lehesjoki, and M. Lipsanen-Nyman, Mulibrey nanism - a novel peroxisomal disorder. Adv Exp Med Biol, 2003, 544, 31-7. 

Pettus BJ, Baes M, Busman M, Hannun YA, Van Veldhoven PP. 2004. Mass spectrometric analysis of ceramide perturbations in brain and fibroblasts of mice and human patients with peroxisomal disorders. Rapid Commun Mass Spectrom 18 1569. 

Wanders RJA (1999) Peroxisomal disorders clinical, biochemical and molecular aspects. Neurochem Res 24 565-580... 

Martinez M (1990) Severe deficiency of docosahexaenoic acid in peroxisomal disorders a defect of delta 4 desaturation Neurology 40 1292-1298... 

Table 3.4.1 Levels of very-long-chain fatty acids (VLCFA), pristanic acid and phytanic acid in the different peroxisomal disorders. AMACR 2-methyl acyl-CoA racemase, N normal, RCDP rhizomelic chondrodysplasia punctata, SCP-x sterol carrier protein, ZSDs Zellweger spectrum disorders,...

Peroxisomal disorders (Zellweger syndrome, Refsum s disease, neonatal adre-noleukodystrophy) are characterised by defective peroxisome biogenesis, or, being present, peroxisomes lacking / -oxidative enzymes. In the BA biosynthetic pathway, dihydroxycoprostanic acid (DHCA) and trihydroxycoprostanic acid (THCA) are /1-oxidised in peroxisomes to produce CA and CDCA, respectively, whereas peroxisomal disorders cause a defective oxidation of the BA precursor side chain, which leads to an accumulation of C27 bile acids, notably 3 ,7 -dihydroxy-5/3-cholesta-noic acid (DHCA) and 3a,7a,12a-trihydroxy-5/l-cholestanoic acid (THCA), in the plasma and urine of affected patients. 

L-Pipecolic acid is a marker for peroxisomal disorders. Three EPMEs were used for the enantioanalysis of L-pipecolic acid [42]. These electrodes are based on carbon paste impregnated with different... 

Farooqui A. A., Ong W. Y., and Horrocks L. A. (2003a). Plasmalogens, docosahexaenoic acid, and neurological disorders. In Roels F., Baes M., and de Bies S. (eds.), Peroxisomal Disorders and Regulation of Genes. Kluwer Academic/Plenum Publishers, London, pp. 335-354. 

Peroxisomal disorders Increased Decreased Beneficial (Martinez et al., 2000)... 

Martinez M., Vazquez E., Garcia-Silva M. T., Manzanares J., Bertran J. M., Castello F., and Mougan I. (2000). Therapeutic effects of docosahexaenoic acid ethyl ester in patients with generalized peroxisomal disorders. Am. J. Clin. Nutr. 71 376S-385S. 

The elevation of VLCFA can be detected in most body tissues and fluids and forms the basis for a diagnostic assay for the identification of affected individuals.The most frequently used test is the measurement of VLCFA in plasma which has been shown to be very sensitive. Although VLCFA are increased in some of the other peroxisomal disorders, including Zellweger syndrome, infantile Refsum disease, and neonatal ALD, the clinical presentations of these disorders are very different from X-ALD, and the discrimination of... 

Mass spectrometry has become an indispensable method for the analysis of bile acids by virtue of its power to identify, assign structure and quantify free or conjugated bile acids, either pure or in mixtures. It is useful not only to study the metabolism of bile acids but also for the detection and diagnosis of metabolic diseases. Indeed, numerous metabolic diseases resulting from an alteration of the conversion of cholesterol to bile acids have been described, including peroxisomal disorders resulting in a block of (3-oxidation of the lateral chain and other enzyme deficiencies interfering with the biochemistry of the side chain or the steroid nucleus. 

Peroxisomal disorders of bile acid synthesis, both in the side-chain decomposition process and at the steroid ring, can cause atrophy of the small bile ducts. This gives rise to Zellweger s syndrome with asyndromic bile-duct hypoplasia. (513) (s. pp 234, 603) (s. tabs. 13.3, 13.4)... 

Moser, H., attd Moser, A. (1996). V ry-long-chain fatty acids in diagnosis, pathogenesis, and therapy of peroxisomal disorders. Lipids 31, Si41-Si45. 

D.W. Johnson, M.-U. Trinh, T. Oe, Measurement of plasma pristanic, phytanic and very long chain fatty acids by LC-ESI-MS-MS for the diagnosis of peroxisomal disorders, J. Chromatogr. B, 798 (2003) 159. 

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