Chapter 130

## Abstract

Abstract

1. Peroxisomes are subcellular organelles present in virtually every eukaryotic cell catalysing a range of essential metabolic functions mainly related to lipid metabolism. These include: (a) fatty acid β-oxidation; (b) etherphospholipid biosynthesis; (c) fatty acid α-oxidation; (d) isoprenoid biosynthesis; (e) L-pipecolate degradation; (f) glutaryl-CoA metabolism; (g) H2O2-metabolism; and (i) glyoxylate detoxification.

2. Peroxisomes catalyze the β-oxidation of a variety of fatty acids and fatty acid derivatives which can not be handled by mitochondria. The most important substrates for peroxisomal β-oxidation from a patient's point of view are (a) very long chain fatty acids, (b) pristanic acid as derived predominantly from phytanic acid, and (c) di- and trihydroxycholestanoic acid. The latter two compounds are produced from cholesterol in the liver and undergo β-oxidation in the peroxisome to produce the CoA-esters of chenodeoxycholic and cholic acid, respectively. This implies that “bile acid synthesis” represents in fact a degradative mechanism involving β-oxidation rather than a true biosynthetic process.

3. To date, four defined disorders of peroxisomal fatty acid β-oxidation have been identified: (a) acyl-CoA oxidase deficiency (MIM 264470); (b) D-bifunctional protein deficiency (MIM 261515); (c) peroxisomal thiolase deficiency (MIM 261510); and (d) 2-methylacyl-CoA racemase deficiency. Interestingly, the clinical presentation of the first three disorders resembles that of the peroxisome biogenesis disorders (PBDs) in many respects. This is especially true for D-bifunctional protein deficiency since virtually all patients identified sofar (>40) show severe clinical abnormalities including hypotonia, craniofacial dysmorphia, neonatal seizures, hepatomegaly, and developmental delay. Most patients with D-bifunctional protein (D-BP) deficiency die in the first year of life. A remarkable observation is that patients with D-BP deficiency often show disordered neuronal migration.

4. 2-Methylacyl-CoA racemase deficiency is a newly identified disorder of peroxisomal β-oxidation in which only the oxidation of the 2-methyl branched-chain fatty acids pristanic acid and di- and trihydroxycholestanoic acid is impaired. In contrast to patients with acyl-CoA oxidase deficiency or any of the other β-oxidation deficiencies, patients with racemase deficiency do not present early in life, but instead develop a late-onset neuropathy.

5. Diagnosis of a peroxisomal β-oxidation disorder is based on clinical characteristics combined with a series of tests to assess peroxisomal function. Analysis of very long chain fatty acids is a reliable initial screening method. If abnormal, additional tests should be done in plasma (di- and trihydroxycholestanoic, phytanic, and pristanic acid) and erythrocytes (plasmalogens). Flowcharts may be helpful in reaching the correct diagnosis, which always requires detailed studies in fibroblasts, including enzyme analyses, complementation studies, and molecular analyses.

6. Prenatal diagnosis of the various β-oxidation disorders can be done reliably because methods have now been developed that allow analysis in direct chorionic villous material. This obviates the risk associated with culturing chorionic villous cells.

7. A second major function of peroxisomes involves the biosynthesis of ether-linked phospholipids, which differ from the regular diacyl phospholipids in one major aspect, which is the ether-bond at the sn-1 position of the glycerol backbone. The first two enzymatic steps in etherphospholipid synthesis take place in peroxisomes and are catalyzed by dihydroxyacetonephosphate acyltransferase (DHAPAT) and alkyldihydroxyacetonephosphate synthase (alkyl DHAP synthase) Although many functions for etherphospholipids have been suggested, their true physiological function remains elusive.

8. Two isolated defects in etherphospholipid biosynthesis have been described at the level of DHAPAT and alkyl DHAP synthase, respectively. Interestingly, the clinical presentation of patients with DHAPAT- or alkyl DHAP-synthase deficiency resembles that of rhizomelic chondrodysplasia punctata (RCDP) in virtually all aspects, including rhizomelic shortening of the upper extremities, typical facial appearance, congenital contractures, cataract, dwarfism, and severe mental retardation with spasticity.

9. If a patient presents with clinical signs and symptoms of RCDP or a variant form, erythrocyte plasmalogen levels should be determined. Measurement of erythrocyte plasmalogens has proven to be extremely reliable because all patients identified to date with RCDP type 1, 2, or 3 have shown deficient plasmalogens in erythrocytes. Definitive diagnosis in terms of RCDP type 1, 2, or 3 requires detailed enzymatic studies in fibroblasts followed by molecular analysis of the genes encoding PEX7 (PEX7), DHAPAT (GNPAT) or alkyl-DHAP synthase (AGPS), respectively.

10. Prenatal diagnosis of RCDP types 1, 2, and 3 can be done reliably in chorionic villous tissue using a combination of enzymatic and immunologic (blotting) methods and, in selected cases, DNA analysis.

11. The third major function of peroxisomes concerns their role in isoprenoid biosynthesis. There is growing evidence to suggest that the first part of the isoprenoid biosynthetic pathway from acetyl-CoA to farnesylpyrophosphate is peroxisomal. Consequently, mevalonate kinase deficiency is a peroxisomal disorder. Two types of mevalonate kinase deficiency have been described, a severe form dominated by a series of clinical abnormalities in multiple organs and a milder form associated with periodic fever.

12. Peroxisomes also play an indispensable role in glyoxylate detoxification and phytanic acid α-oxidation with hyperoxaluria type 1 and Refsum disease as relevant peroxisomal disorders. These are discussed in other chapters.

13. Finally, peroxisomes are also important for the degradation of L-pipecolate, a degradation product of L-lysine, because L-pipecolate oxidase is a peroxisomal enzyme in man. Several cases of hyperpipecolic acidemia have been described in literature, but a specific enzyme deficiency, for instance at the level of L-pipecolate oxidase, has not been described in any of the patients.

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