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Biochimica et Biophysica Acta 1763 (2006) 1707–1720 www.elsevier.com/locate/bbamcr

Invited review Peroxisomal disorders: The single peroxisomal enzyme deficiencies ⁎ Ronald J.A. Wanders , Hans R. Waterham

Academic Medical Centre, University of Amsterdam, Netherlands Received 27 July 2006; accepted 18 August 2006 Available online 23 August 2006

Abstract

Peroxisomal disorders are a group of inherited diseases in man in which either peroxisome biogenesis or one or more peroxisomal functions are impaired. The peroxisomal disorders identified to date are usually classified in two groups including: (1) the disorders of peroxisome biogenesis, and (2) the single peroxisomal enzyme deficiencies. This review is focused on the second group of disorders, which currently includes ten different diseases in which the mutant gene affects a protein involved in one of the following peroxisomal functions: (1) ether phospholipid (plasmalogen) biosynthesis; (2) fatty acid beta-oxidation; (3) peroxisomal alpha-oxidation; (4) glyoxylate detoxification, and (5) H2O2 metabolism. © 2006 Elsevier B.V. All rights reserved.

Keywords: Peroxisomes; Alpha-oxidation; Beta-oxidation; Zellweger syndrome; Refsum disease; Adrenoleukodystrophy; Hyperoxaluria; Plasmalogen

1. Introduction features reminiscent of ZS, but no neuronal migration disorder and no progressive white matter disease. The cognitive and The peroxisomal disorders (PDs) are usually subdivided into motor development varies between severe global handicaps and two groups, including: (i) the peroxisome biogenesis disorders moderate learning disabilities with deafness and visual impair- (PBDs); and (ii) the single peroxisomal enzyme (transporter) ment, due to retinopathy. deficiencies (PEDs). RCDP type 1 is clinically quite different from the Zellweger The PBD group comprises Zellweger syndrome (ZS), spectrum disorders (ZSDs) although there are some features neonatal adrenoleukodystrophy (NALD); infantile Refsum shared by RCDP type 1 and the ZSDs including the cranial disease (IRD) and rhizomelic chondrodysplasia punctata facial (broad low nasal bridge, epicanthus, high arched palate, (RCDP) type 1. After the recognition that mutations in the dysplastic external ears, and micrognathia), and ocular same gene can lead to either of the first three disease conditions, abnormalities. Indeed, histopathology of the eyes of ZS and they are nowadays collectively called the Zellweger spectrum RCDP patients showed a number of important common features disorders (ZSDs), that constitute a triad of overlapping disorders including abnormal corneal epithelium and endothelium, with with ZS being the most severe, followed by N-ALD and IRD. mitochondrial proliferation. Furthermore, signs of ganglion Common to all three are liver disease, variable neurodevelop- atrophy and photoreceptor degeneration were found, which mental delay, retinopathy, and perceptive deafness with onset in occurred earlier in ZS as compared to RCDP. These findings led the first months of life. In addition, patients with ZS are severely Kretzer et al. to suggest a common etiological mechanism hypotonic and weak from birth and have distinct facial features, between ZS and RCDP already in 1981 [36]. This suggestion peri-articular calcifications, severe brain dysfunction associated inspired Heymans et al. [31] to study whether RCDP is a with neuronal migration disorders and die before 1 year of age. peroxisomal disorder. RCDP type 1 is not only clinically Patients with N-ALD have hypotonia, seizures, may have different from the ZSDs but also its biochemistry, cell biology, polymicrogyria, have progressive white matter disease, and and genetics are different. Indeed, the ZSDs are now known to usually die in late infancy. Patients with IRD may have external be associated with mutations in a large number of different PEX genes, including PEX 1,2,3,5,6,10,12,13,14,16,19 and 26 [64] ⁎ Corresponding author. [85], whereas mutations in PEX7 are associated with RCDP E-mail address: [email protected] (R.J.A. Wanders). type 1 [4,47], but not with any of the ZSDs.

0167-4889/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.bbamcr.2006.08.010 1708 R.J.A. Wanders, H.R. Waterham / Biochimica et Biophysica Acta 1763 (2006) 1707–1720

Table 1 List of the single peroxisomal enzyme deficiencies Peroxisomal pathway affected Peroxisomal disease Enzyme defect Gene involved (1) Ether phospholipid synthesis • Rhizomelic chondrodysplasia punctata Type 2 (DHAPAT deficiency) DHAPAT GNPAT (2) Peroxisomal beta-oxidation • Rhizomelic chondrodysplasia punctata Type 3 (alkyl-DHAP synthase) ADHAPS AGPS • X-linked adrenoleukodystrophy ALDP ABCD1 • Acyl-CoA oxidase deficiency ACOX1 ACOX1 • D-bifunctional protein deficiency DBP HSD17B4 • 2-MethylacylCoA racemase deficiency AMACR AMACR • Sterol carrier protein X deficiency SCPx SCP2 (3) Peroxisomal alpha-oxidation • Refsum disease (phytanoyl-CoA hydroxylase deficiency) PHYH/PAHX PHYH/PAHX (4) Glyoxylate detoxification • Hyperoxaluria Type 1 AGT AGXT

(5) H2O2-metabolism Acatalasaemia CAT [79] CAT

The second group of peroxisomal disorders includes the also known by their trivial name plasmalogens. Biosynthesis of single peroxisomal enzyme / transporter deficiencies (PEDs), ether phospholipids involves the concerted action of enzymes which can be subdivided into distinct subgroups on the basis of localized in both peroxisomes and the endoplasmic reticulum. the peroxisomal metabolic pathway affected. Table 1 lists the The ether bond, which is characteristic for ether phospholipids, peroxisomal disorders (PBDs) identified so far and their is formed by the peroxisomal enzyme alkyl-DHAP synthase classification into distinct subgroups as used throughout this (encoded by AGPS) which turns the acyl-DHAP, generated review. Until recently, mevalonate kinase deficiency was also from acyl-CoA and dihydroxyacetonephosphate (DHAP) by the believed to be a peroxisomal disorder, but should no longer be peroxisomal enzyme dihydroxyacetonephosphate acyltransfer- considered a peroxisomal disorder because the earlier claim that ase DHAPAT (encoded by GNPAT), into alkyl-DHAP. After mevalonate kinase is a peroxisomal enzyme has now been conversion of alkyl-DHAP into alkyl-G3P either in peroxi- disproven [32]. somes or the endoplasmic reticulum, the final steps of ether In this review we will describe the clinical, biochemical, cell phospholipids synthesis are performed by endoplasmic reticu- biological, and genetic aspects of each of the PEDs and will lum enzymes (see Brites et al. [5] for review). begin by giving a brief update on the function of peroxisomes in human beings and the enzymes and transporters involved. 3.2. Disorders of ether phospholipid biosynthesis

2. Metabolic functions of peroxisomes in humans Two single enzyme deficiencies in the ether phospholipid biosynthetic pathway have been identified so far. These are: (i) Peroxisomes play an indispensable role in human physiology DHAPAT deficiency, and (ii) alkyl-DHAP synthase deficiency. as concluded from the devastating consequences of a defect in the biogenesis of peroxisomes as observed in Zellweger 3.2.1. DHAPAT deficiency (Rhizomelic chondrodysplasia patients. The metabolic functions attributed to peroxisomes punctata type 2) are multiple and include both biosynthetic (ether phospholipid DHAPAT deficiency was first described in 1992 [82] in a biosynthesis, bile acid synthesis, docosahexaenoic acid synth- patient showing all the clinical signs and symptoms of RCDP, esis) and degradative (fatty acid alpha-oxidation, fatty acid beta- including: (i) cranial facial abnormalities at birth, including a oxidation, glyoxylate detoxification, et cetera) pathways. Much high forehead, large fontanels, a low/broad nasal bridge, of the knowledge on the metabolic functions of peroxisomes anteverted nostrils, micrognathia, and a high-arched palate; actually comes from studies on body fluids and tissues from (ii) severe hypotonia; (iii) cataract; (iv) dwarfism; (v) Zellweger patients. The functions of peroxisomes, which are of pronounced rhizomelic shortening, especially of the upper key importance to the group of peroxisomal disorders are: (1) arms, and (vi) striking radiological abnormalities, consistent ether phospholipid biosynthesis; (2) fatty acid beta-oxidation; with RCDP, although there were no stippled calcifications of (3) glyoxylate detoxification, and (4) fatty acid alpha-oxidation. patellae and acetabulum. In order to substantiate the clinical diagnosis RCDP, erythrocyte plasmalogen levels were deter- 3. Ether phospholipid biosynthesis and its disorders mined and found to be fully deficient. The levels of phytanic acid in plasma were normal, however. The significance of this 3.1. Ether phospholipid biosynthesis finding was not immediately clear because phytanic acid is solely derived from exogenous (dietary) sources and may be Ether phospholipids are a special class of phospholipids, completely normal despite a full block in phytanic acid alpha- which differ from the regular diacyl phospholipids in having an oxidation as is the case in RCDP type 1 patients. The same ether-linkage rather than an ester-linkage at the sn-1 position of applies to ZSD patients. Detailed studies in fibroblasts of the the glycerol backbone. Two groups of ether phospholipids can index patient revealed a novel type of RCDP. Indeed, in all be distinguished with either an 1-O-alkyl or an 1-O-alk1-enyl RCDP patients, whose fibroblasts were studied at that time, four linkage. The latter phospholipids (1-O-alk1-enyl-2-acyl phos- abnormalities were found including: (i) a (partial) deficiency of phoglycerides) with an alpha-beta unsaturated ether-bond are DHAPAT; (ii) a marked deficiency of alkyl-DHAP synthase; R.J.A. Wanders, H.R. Waterham / Biochimica et Biophysica Acta 1763 (2006) 1707–1720 1709

(iii) deficient alpha-oxidation of phytanic acid, and (iv) the normal. Also in the subsequent patient described by de Vet and presence of peroxisomal thiolase I (ACAA1/pTH1) in its 44 colleagues [10] alkyl-DHAP synthase was deficient, but, in kDa precursor form with the 41 kDa mature form completely addition, DHAPATactivity was also low with a residual activity missing [83]. In fibroblasts from this patient, however, only a of about 15%. In order to resolve this peculiar finding, single abnormality was detected, i.e. a full deficiency of complementation studies were performed, which revealed that DHAPAT, which was soon found to be caused by mutations in the two patients did belong to the same genetic complementa- the gene (GNPAT) coding for DHAPAT. Since this first report a tion group representing alkyl-DHAP synthase deficiency. number of additional patients have been reported. Barr and Detailed studies by van den Bosch and co-workers [3] have colleagues [1] reported the second patient with DHAPAT shown that the deficient activity of DHAPAT in the second case deficiency, who also had the severe phenotype. In 1994 Clayton of alkyl-DHAP synthase deficiency is the secondary conse- and co-workers [8] reported on a 21-month-old boy and his 3½- quence of the fact that the alkyl-DHAP synthase protein is year-old sister, who both had isolated DHAPAT deficiency. completely absent in this patient due to a homozygous 128-bp Both siblings had anteverted nerves, normal limbs, hypotonia, deletion which leads to a premature stop. On the other hand, growth and developmental retardation, and feeding difficulties. studies in fibroblasts from the first patient with alkyl-DHAP Eczema was present in a younger patient, whereas a cranial CT- synthase deficiency have shown that the protein is normally scan showed mild cerebral atrophy. The older sister had expressed and correctly localized in peroxisomes as established seizures. The same patients plus an additional sibling in the in fibroblasts from this patient [11]. The protein, however, is same family were later reported by Sztriha and co-workers functionally inactive, due to a 1256G>A mutation, causing the [70,71]. The third patient in the family had a comparable substitution of the amino acid arginine at position 419 by a clinical presentation, again without rhizomelia. A similar, mild histidine [11]. Since DHAPAT is only stable if it forms a case of DHAPAT deficiency was reported first by Moser and co- complex with alkyl-DHAP synthase within the peroxisome, workers [42] and later described in full detail by Elias et al. in these data explain why DHAPAT activity was found to be fully 1998 [15]: the 6½-year-old girl displayed developmental delay, normal in fibroblasts from the first patient described by growth failure and cataract, but no rhizomelia and no cranial Wanders et al. [80], but deficient in patient 2 described by de facial dysmorphism. Vet et al. [10]. Furthermore, these data resolve the puzzling In all patients with established RCDP type 2 the activity of situation in RCDP type 1 in which DHAPAT has long been DHAPAT is severely deficient, which results in a virtually known to be deficient, despite its identification as a typical complete inability to synthesize ether phospholipids, including PTS1 protein. plasmalogens. This is reflected in deficient plasmalogen levels In the few alkyl-DHAP synthase-deficient patients studied so in all tissues investigated including erythrocytes. Importantly, in far, erythrocyte plasmalogens levels were deficient like in all patients studied thus far, erythrocyte plasmalogen levels are RCDP type 1 and type 2 patients. This suggests that erythrocyte clearly deficient, which implies that erythrocyte plasmalogen plasmalogen analysis is an excellent method to resolve whether analysis is a reliable initial biochemical test. Molecular studies a particular patient is affected by one of the peroxisomal forms have led to the identification of different mutations in the gene of RCDP. coding for DHAPAT [50]. 4. Peroxisomal fatty acid beta oxidation and its deficiencies 3.2.2. AlkylDHAP synthase deficiency (rhizomelic chondrodysplasia Type 3) 4.1. Peroxisomal fatty acid beta-oxidation In 1994, the first case of isolated alkyl-DHAP synthase deficiency (RCDP type 3) was described in a patient showing Peroxisomes contain a fatty acid beta-oxidation system all the clinical characteristics of RCDP [80]. Also in this pa- which proceeds via the same principle set of four consecutive tient erythrocyte plasmalogen levels were completely deficient enzymatic reactions as in mitochondria, although the individual whereas plasma phytanic acid levels were normal. Subsequent reactions of the beta-oxidation systems are catalyzed by distinct studies in fibroblasts revealed the complete deficiency of alkyl- enzymes. The peroxisomal and mitochondrial beta-oxidation DHAP synthase with normal values for DHAPAT and phytanic system serve different functions in human cells and catalyze the acid alpha-oxidation and a normally processed peroxisomal beta-oxidation of different fatty acids and fatty acid derivatives. thiolase. In literature only a single patient has been described Indeed, mitochondria catalyze the beta-oxidation of the bulk of since [10] although three additional patients have been FAs derived from the diet, including palmitic (C16:0), oleic identified by dr. H.W. Moser, Baltimore, who all showed (C18:1), linoleic (C18:2) and linolenic (C18:3) acid, whereas classical RCDP with early demise (Dr. H.W. Moser, personal peroxisomes catalyze the beta-oxidation of a different set of communication). The patient described by de Vet et al. [10] was substrates. These include: less affected and is still alive at >10 years, showing mild rhizomelia, generalized contractures, inability to sit or crawl, (1) Very-long-chain fatty acids (VLCFAs), notably hexacosa- cataract, seizures and profound developmental delay. In the noic acid (C26:0): VLCFAs are in part derived from original patient described in Wanders et al. 1994 [80] alkyl- dietary sources but also formed by chain-elongation of DHAP synthase was fully deficient, whereas DHAPAT, long-chain fatty acids. In humans, most of the C26:0 is phytanic acid alpha oxidation, and peroxisomal thiolase were produced by chain elongation. 1710 R.J.A. Wanders, H.R. Waterham / Biochimica et Biophysica Acta 1763 (2006) 1707–1720

(2) Pristanic acid (2,6,10,14-tetramethylpentadecanoic Peroxisomes also contain a different bifunctional protein, acid): pristanic acid cannot be synthesized endogenously which forms and dehydrogenates L-3-hydroxyacyl-CoA esters. in human beings and is solely derived from exogenous Recent evidence suggests that this enzyme is, at least partially, dietary sources either as pristanic acid itself, or via alpha- involved in the peroxisomal oxidation of long-chain dicar- oxidation from its precursor phytanic acid (see Fatty acid boxylic acids [20]. alpha-oxidation). Finally, human peroxisomes contain two peroxisomal (3) Di- and trihydroxycholestanoic acid (DHCA and THCA), thiolases, i.e. pTH1 and pTH2. Human pTH1 is the human which are intermediates in the formation of the primary equivalent of the clofibrate-inducible thiolase identified by bile acids cholic acid and chenodeoxycholic acid from Hashimoto and co-workers [41], whereas pTH2 is identical to cholesterol in the liver. After activation, DHCA and the 58 kDa sterol carrier protein x (SCPx) with both thiolase THCA undergo one cycle of beta-oxidation in peroxi- activity and a sterol carrier protein domain [59]. It is clear now somes to produce the CoA-esters of chenodeoxycholic that pTH2 (SCPx) plays an indispensable role in the oxidation acid and cholic acid, which are subsequently converted of 2-methyl branched-chain fatty acids, whereas pTH1 and into the corresponding taurine or glycine conjugates pTH2 are both involved in C26:0 oxidation. Fig. 2 depicts the within peroxisomes, followed by export from peroxi- involvement of the different enzymes in the oxidation of the somes and final excretion into bile. different FAs and FA-derivatives. (4) Tetracosahexaenoic acid (C24:6ω-3). Peroxisomes play The enzymes described above are necessary and sufficient an important role in the formation of docosahexaenoic for the beta-oxidation of straight-chain fatty acids like C26:0 as acid (C22:6ω-3) [65]. Indeed, recent studies have well as 2-methyl branched-chain fatty acids with the methyl established that the formation of C22:6ω-3 from linolenic group in the (2S)-configuration. However, auxiliary enzymes acid (C18:3ω-3) proceeds via subsequent steps of chain are needed for the beta-oxidation of (2R)-methyl branched- elongation and desaturation, but also involves the chain FAs and unsaturated FAs. Oxidation of (2R)-methyl peroxisomal fatty acid oxidation system, since tetracosa- branched-chain FAs requires the active participation of an hexaenoic acid is beta-oxidized in peroxisomes to enzyme, capable of converting (2R)- into (2S)-branched-chain produce C22:6ω-3 (see [18]). acyl-CoAs. Studies, notably by Schmitz and Conzelmann and (5) Long-chain dicarboxylic acids. Recent studies have co-workers [56–58] have shown that peroxisomes contain 2- shown that at least a long-chain dicarboxylic acid like methylacyl-CoA racemase (AMACR), which is able to convert hexadecadioic acid, which is the dicarboxylic acid of (2R)-methylacyl-CoAs into the corresponding (2S)-methylacyl- palmitic acid, is oxidized exclusively in peroxisomes CoAs and vice versa. The importance of this enzyme for [20]. oxidation of 2-methyl branched-chain fatty acids is stressed by the findings in AMACR-deficient patients in which (2R)- The actual beta-oxidation of all these different FAs in pristanic acid accumulates as well as (25R) di- and trihydrox- peroxisomes involves the participation of a number of different ycholestanoic acid [17,22,23,60]. The accumulation of the latter enzymes including two acyl-CoA oxidases, two multifunc- two species is explained by the fact that the 2-methyl group in tional proteins with enoyl-CoA hydratase and 3-hydroxyacyl- DHCA and THCA, which are produced from cholesterol, has CoA dehydrogenase activities, and two different peroxisomal the (25R)-configuration (see Fig. 2). thiolases. The two acyl-CoA oxidases, called ACOX1 and ACOX2 serve different functions with ACOX1 (straight-chain 4.2. The disorders of peroxisomal beta-oxidation acyl-CoA oxidase) preferentially reacting with the CoA-esters of straight-chain FAs, like C26:0, whereas the second acyl- So far 5 different defects in the peroxisomal beta-oxidation CoA oxidase, i.e. ACOX2 (branched-chain acyl-CoA oxidase) system have been identified, which include: X-linked adreno- catalyses the dehydrogenation of the CoA-esters of 2-methyl leukodystrophy, acyl-CoA oxidase deficiency, D-bifunctional branched-chain FAs, like pristanoyl-CoA and the CoA-esters protein deficiency, sterol carrier protein X (SCPx) deficiency, of the bile acid intermediates DHCA and THCA [78]. The and 2-methylacyl-CoA racemase (AMACR) deficiency. These enoyl-CoA esters of C26:0, pristanic acid, DHCA and THCA diseases will be described below. Biochemical abnormalities, are all handled by a single bifunctional enzyme catalyzing the associated with each of these disorders, are listed in Table 2 (see second (hydration) and third (dehydrogenation) steps of also Fig. 2). peroxisomal beta-oxidation. This enzyme with both enoyl- CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase activ- 4.2.1. X-linked adrenoleukodystrophy ity forms and dehydrogenates D-3-hydroxyacyl-CoA esters The phenotype of X-linked adrenoleukodystrophy (X-ALD) rather than L-3-hydroxyacyl-CoA-esters and is the single varies wildly with at least six phenotypic variants described. enzyme involved in the oxidation of C26:0, pristanic acid as The classification of X-ALD is somewhat arbitrary and based well as DHCA and THCA [12–14,33,34,51,53]. Different on the age of onset and the organs principally involved. X-ALD names have been given to this enzyme, including D- is the most common single peroxisomal disorder with a bifunctional protein (DBP), D-peroxisomal bifunctional minimum incidence of 1:21.000 males in the USA [2] to enzyme (D-PBE), multifunctional enzyme II (MFEII), and 1:15.000 males in France (Aubourg, cited in Kemp et al. (2001)) multifunctional protein 2 (MFP2). [35]. The two most frequent phenotypes are childhood cerebral R.J.A. Wanders, H.R. Waterham / Biochimica et Biophysica Acta 1763 (2006) 1707–1720 1711

Table 2 belong to the superfamily of ABC transmembrane transporter Metabolite abnormalities in each of the single peroxisomal beta-oxidation proteins and is called ALDP. ALDP is a so-called half ABC- deficiencies transporter, which must dimerize to generate the functional Peroxisomal disorder Peroxisomal metabolite ABC-transporter. Three additional mammalian peroxisomal VLCFA Pristanic Phytanic DHCA/ half ABC-transporters have been identified, which are closely acid acid THCA related by nucleic acid and protein sequence to ALDP. These are • X-Linked adrenoleukodystrophy ↑ NNN ALDR, PMP70 and PMP69, encoded by ABCD2, ABCD3, and • Acyl-CoA oxidase deficiency ↑(1) NNN ABCD4, respectively. The four transporters may form different • ↑(2) ↑ ↑ ↑(3) D-bifunctional protein deficiency * * heterodimeric combinations in the peroxisomal membrane. • Sterol carrier protein X (SCPx) N ↑* ↑* ↑ deficiency According to Guimaraes et al. [29] ALDP preferentially forms • 2-methylacylCoA racemase N ↑* ↑* ↑ homodimeric combinations. Although definitive experimental (AMACR) deficiency evidence is lacking, ALDP has been claimed to catalyze the Footnote: (1) =plasma VLCFA-levels may not be elevated in all acylCoA oxidase transport of VLCFAs, probably in their coenzyme A ester form, deficient patients (see Rosewich et al. [55]; (2) =plasma VLCFA levels may not across the peroxisomal membrane. This is inferred from ex- always be elevated in all DBP-deficient patients (see Ferdinandusse et al. [19]); periments in the yeast S. cerevisiae, which contains two half *=plasma pristanic acid and phytanic acid are usually elevated but may be ABC-transporters, called Pxa1p and Pxa2p, both showing high deceptively low to even normal as a consequence of the reduced dietary intake of – pristanic acid and/or phytanic acid. N=normal. homology with ALDP [61 63] or [30,69]. The Pxa1p/Pxa2p heterodimer has been shown to transport long-chain acyl-CoA esters across the peroxisomal membrane. This conclusion has ALD (CCALD) and adrenomyeloneuropathy (AMN). Onset of been disputed by McGuiness et al. [39,40], who showed that the CCALD is between 3 and 10 years of age with progressive oxidation of C24:0 is partially deficient in fibroblasts from behavioral, cognitive and neurologic deterioration, often patients with a defect in mitochondrial beta-oxidation at the leading to total disability within 3 years. The cerebral phenotype level of carnitine palmitoyltransferase 1 (CPT1) and very-long- is not only observed in childhood but may also present later in chain acyl-CoA dehydrogenase (VLCAD). Although the extent life in adolescence (adolescence cerebral ALD; ACALD) or of the deficiency was only limited, these results led McGuiness adulthood (adult-cerebral ALD). There is a marked difference et al. [39,40] to conclude that the reduced oxidation of C24:0 in between the cerebral phenotypes on the one hand, and AMN on X-ALD cells is due to mitochondrial abnormalities and that the other, since the cerebral phenotype shows an inflammatory ALDP somehow facilitates the interaction between peroxi- reaction in the cerebral white matter, which resembles, but can somes and mitochondria. Later studies, however, notably by be distinguished from what is observed in multiple sclerosis. In Oezen et al. [49] showed that mitochondria, at least those contrast to CCALD, the inflammatory response is absent or isolated from Abcd1 (−/−) mice, are indistinguishable from mild in AMN, which has a much later age of onset (28+9 wild type mitochondria in all aspects studied, which includes years), and a much slower rate of progression. Finally, it is normal rates of oxidative phosphorylation and normal P/O important to mention that approximately 40 to 50% of women, ratios. heterozygous for X-ALD, develop AMN-like symptoms in Mutation analysis of the ABCD1 gene in X-ALD patients middle age or later. Cerebral involvement and adrenocortical revealed many different, often private mutations. As of April insufficiency are rare, however. For more detailed information 2006 the X-ALD mutation database (http://www.X-ALD.nl/) the reader is referred to the paper by Gärtner and Berger contains 866 mutations of which 526 (21%) are missense elsewhere in this issue. mutations, 196 (23%) are frame shifts, 84 (10%) are nonsense mutations, 32 (4%) are amino acid insertions or deletions, and 4.2.1.1. Biochemistry and molecular basis of X-ALD. The 28 (4%) are large deletions comprising one or more exons. The biochemical hallmark of X-ALD is the accumulation of majority of X-ALD kindreds have a unique mutation. 435 VLCFAs in plasma [43], fibroblasts [44], and other cell types (50%) non-recurrent mutations have been identified. (see [45] for review). Analysis of plasma VLCFAs has proven to be a powerful diagnostic method with very few, if any, false 4.2.2. Acyl-CoA oxidase deficiency negatives. In 15 to 20% of obligate heterozygotes, however, test Acyl-CoA oxidase deficiency was first described by Poll The results are falsely negative, which makes mutation analysis the et al. in 1988 [51] in two siblings, male and female, from a only reliable test for heterozygote identification. Other consanguineous marriage. Both children showed neonatal onset peroxisomal metabolites are normal in plasma from X-ALD hypotonia, delayed motor development, sensory deafness, and patients (see Table 2 and Fig. 2a). The accumulation of VLCFAs retinopathy, with extinguished electroretinograms. There was is due to the impaired oxidation of VLCFAs in peroxisomes. no craniofacial dysmorphia. Although psychomotor develop- Indeed, the rate of C26:0 oxidation in X-ALD fibroblasts is 20 ment was severely delayed both patients showed some progress to 30% of control, compared with a virtually complete in the first 2 years of life after which progressive neurological deficiency in fibroblasts from Zellweger patients lacking regression set in. The cranial CT-scan without contrast peroxisomes. enhancement in the neonatal period was minimally abnormal The X-ALD or ABCD1 gene was identified in 1993, using a in both patients. At 4 years of age a repeated cranial CT-scan positional cloning strategy [46]. The protein turned out to with contrast enhancement was performed in one of the siblings 1712 R.J.A. Wanders, H.R. Waterham / Biochimica et Biophysica Acta 1763 (2006) 1707–1720 showing bilateral enhancing lesions in the centrum semiovale controlled with medication. Most patients do not show cranial and a generally hypodense cerebral white matter. A second facial dysmorphia, although this is not true for all patients. patient was described by Wanders et al. [81]. This patient, when Many of the patients do show some development, followed by examined at the age of 3 years and 10 months, showed regression. Renal and skeletal abnormalities and liver disease generalized hypotonia, failure to thrive, deafness, hepatome- are usually not observed in acyl-CoA oxidase deficiency. The galy, psychomotor retardation, absent reflexes, and frequent average age of death is much later than in patients with D- convulsions. At autopsy, multiple abnormalities were found bifunctional protein deficiency. including atrophy of skeletal muscles, brain stem ganglions, and cerebral nerves. Furthermore, in the brain and adrenals large 4.2.2.1. Biochemistry and molecular basis of acyl-CoA oxidase PAS-positive, sudanophilic astrocytes, and macrophages were deficiency. Since acyl-CoA oxidase-1 is only involved in the found. The liver was fibrotic. Using complementation analysis beta-oxidation of VLCFAs but not in pristanic acid and di- and two further patients were identified by Suzuki et al. in 1994 trihydroxycholestanoic acid (Fig. 1), the only abnormality [37,68]. Both patients showed profound hypotonia, dysmorphic observed in plasma from patients is elevated VLCFAs (Table 2, features, including hypertelorism, epicanthus, long nasal bridge, Fig. 2b). Studies in fibroblasts have shown that the oxidation of low-set ears, and polydactyly in the neonatal period and there C26:0 is markedly deficient with normal pristanic acid beta- was no hepatomegaly or calcific stippling. In the first patients oxidation. Immunofluorescence microscopy analysis of peroxi- there were focal seizures of the left arm at 4 months of age. somes usually reveals enlarged peroxisomes, which are reduced There was head control at 5 months and crawling at 12 months. in number. Molecular analysis has so far been performed in only At 32 months of age this patient could walk without assistance. a few patients [27,55,66]. Since then his motor ability has regressed. At 41 months of age he could not sit, but he did respond to members of the family by 4.2.3. D-bifunctional protein deficiency smiling or crying. The other patient described by Suzuki [68] is D-bifunctional protein deficiency (DBP deficiency) is one of the younger sister of the first patient and clinical manifestations the more recently identified peroxisomal disorders and is now were quite similar. She could control her head at 6 months of known to be relatively frequent among the group of age, crawled at 18 months and walked with support at 22 peroxisomal beta-oxidation deficiencies, second to X-ALD. months, followed by regression. Both patients were alive at four After its first identification by Suzuki et al. [67], and van and 7 years when reported in 1994. Again, using complementa- Grunsven et al. [73] many patients have been identified. The tion analysis, Watkins et al. 1995 [87] identified three additional availability of methods to diagnose DBP-deficiency has led to patients, followed by a more recent report by Kurian et al. [37], detailed studies in previously published patients, affected by an who described a patient with facial dysmorphia, biphasic isolated defect in the peroxisomal beta-oxidation system of neurodevelopmental delay, sensori-neural hearing loss and unknown etiology [6,9,16,38,48,74,77,84]. Furthermore, sev- hepatomegaly bringing the total number of patients to nine. In eral published patients in whom doubt had arisen about the final general, patients with acyl-CoA oxidase deficiency show diagnosis could now be reinvestigated. One of these patients moderate neonatal hypotonia, frequent seizures with the onset was described by Watkins et al. in 1989 [86]. Interestingly, at typically between 2 and 4 months of age but less severe when that time it was believed that this patient had a deficiency of the compared with D-bifunctional protein deficiency and usually other peroxisomal bifunctional enzyme, called L-bifunctional

Fig. 1. Schematic illustration of the individual transport (ALDP) and enzymatic (AMACR, ACOX1 and 2, DBP, pTH1 and pTH2(SCPx) steps involved in the oxidation of C26:0, pristanic acid and di- and trihydroxycholestanoic acid. R.J.A. Wanders, H.R. Waterham / Biochimica et Biophysica Acta 1763 (2006) 1707–1720 1713

Fig. 2. Schematic illustration of the peroxisomal metabolites which accumulate as result of a deficiency of ALDP (a), acyl-CoA oxidase (b), D-bifunctional protein (c), sterol-carrier protein X (SCPx) (d), and 2-methylacyl-CoA racemase (AMACR) (e). 1714 R.J.A. Wanders, H.R. Waterham / Biochimica et Biophysica Acta 1763 (2006) 1707–1720 protein. A second patient who was reinvestigated was described involved in the beta-oxidation of C26:0, pristanic acid, as well already earlier by Goldfischer et al. in 1986 [28] as pseudo- as di- and trihydroxycholestanoic acid. This implies that, in Zellweger syndrome indicating that the clinical signs and principle, patients with DBP-deficiency would show the symptoms of this patient were similar to those described for accumulation of C26:0, pristanic acid, and di- and trihydrox- classical Zellweger syndrome. This patient was originally ycholestanoic acid in plasma (Fig. 2c). It is now clear, however, believed to have peroxisomal 3-ketoacyl-CoA thiolase defi- that this full set of peroxisomal metabolite abnormalities is not ciency, but upon reinvestigation we found that the true defect in seen in all DBP-deficient patients. Indeed, in 50 of the 53 this patient is again at the level of D-bifunctional protein [24].A patients in whom plasma C26:0 levels and the C26:0/C22:0 number of other patients described in literature with an ratio could be analyzed, definite abnormalities were found. In unknown defect in peroxisomal beta-oxidation, all turned out the remaining three patients a normal profile of VLCFAs was to suffer from DBP deficiency as well [19]. found whereas phytanic acid and pristanic acid levels were also D-bifunctional protein is a protein with two catalytic normal as well as the bile acid intermediates THCA and DHCA. activities including a 2-enoyl-CoA hydratase unit and a (3R)- In contrast, a clearly abnormal VLCFA profile was observed in hydroxyacyl-CoA dehydrogenase unit. As a consequence three fibroblasts from these three patients, which points to a different types of DBP deficiency can be distinguished discrepancy between results in plasma as compared to depending on which activity is deficient: (i) type 1 deficient fibroblasts. In the 50 patients with abnormal plasma VLCFAs, patients have a deficiency of both the hydratase and phytanic and pristanic acid levels varied considerably, which dehydrogenase activities of DBP (in fibroblasts of virtually all follows logically from the fact that both compounds originate type 1 deficient patients no DBP protein can be detected by from dietary sources only. As first reported by van Grunsven immunoblotting and upon immunofluorescence using an anti- et al. [72] DPB-deficient patients may show no accumulation body raised against DBP); (ii) type 2 deficient patients, have an of THCA and DHCA. In the large cohort study by isolated deficiency of the hydratase unit; and (iii) type 3 Ferdinandusse et al. [19] 12 patients (26%) had no accumula- deficient patients, have an isolated deficiency of the dehydro- tion of THCA and DHCA. Docosahexaenoic acid (DHA) and genase unit. This classification can be made on the basis of arachidonic acid (AA) were determined in only a small enzyme activity measurements in combination with mutation number of patients. In 43% reduced levels of DHA and AA analysis. were found in plasma whereas in erythrocytes only a single Recently, we reported the clinical, biochemical, and genetic patient had a marginally decreased DHA level. Plasmalogens characteristics of a large cohort of DBP-deficient patients. in erythrocytes were normal in all DBP-deficient patients Enzyme activity measurements in combination with molecular studied. Interestingly, biochemical analysis showed that there data revealed that 27% of the patients were DBP type 1 is a good correlation between several biochemical parameters deficient, 28% type 2 deficient, and 45% type 3 deficient. No and the survival of DBP-deficient patients with C26:0 beta- evident differences were found between the clinical signs and oxidation in cultured skin fibroblast being the best predictive symptoms of patients affected by type 1, 2 or 3 deficiency. marker in terms of life expectancy. The fact that three patients Virtually all patients presented with neonatal hypotonia (98%), were identified without any biochemical abnormalities in and seizures (93%) within the first months of life. 19 patients plasma indicates that D-bifunctional protein deficiency cannot (15%) were reported to have had infantile spasms at any time. be excluded on the basis of measurement of peroxisomal Failure to thrive was observed in 43% of the patients. Visual parameters in plasma only. Molecular analysis of the system failure, including nistagmus, strabismus or failure to HSD17B4 gene has revealed a large number of often private fixate objects at 2 months was reported in 45% of patients. mutations with only one mutation being more frequent [25,73]. Almost none of the patients acquired any psychomotor development. External dysmorphia was present in 68% of 4.2.4. Sterol carrier protein X (SCPx) deficiency patients and resembled that of patients with Zellweger Sterol carrier protein X (SCPx) deficiency has so far been syndrome. Frequently described abnormalities were: high described in a single patient who was only studied in detail at 44 forehead, high arched palate and large fontanel, long philtrum, years of age, following a 20-year history of dystonic head epicanthal folds, hypertelorism, microcephaly, shallow supra- tremor and spasmodic torticollis. At 29 years of age, orbital ridges, retrognatia, and low set ears. Kaplan–Meier hypergonadotrophic hypogonadism and azoospermia were survival analysis revealed that all type 1 deficient patients died diagnosed. Cranial MRI revealed a number of abnormalities within the first 14 months of life (mean age of death: 6.9 including bilateral hyper intense signals in the thalamus, months), whereas the mean age of death for type 2 and type 3 butterfly-like lesions in the ponds, as well as lesions in the deficiency was 10.7 months and 17.6 months. The major cause occipital region without gadolinium enhancement. Neurological of death was pneumonia for almost all patients. Only five of the examination revealed hyposmia, pathological saccadic eye patients showed prolonged survival (>5 years), one of whom movements, and a slight hypoacusis. Ophthalmological inves- was a type 2 patient and the other 4 type 3 patients. tigations revealed no abnormalities. Nerve conduction studies of the lower extremities showed a predominantly motor and 4.2.3.1. Biochemistry and molecular basis of slight sensory neuropathy with conduction blocks in the tibial DBP-deficiency. D-bifunctional protein holds a central posi- nerves, reduced motor action potentials in the left peroneal tion in the peroxisomal fatty acid beta-oxidation pathway and is nerve, and reduced amplitude of the left sural nerve. R.J.A. Wanders, H.R. Waterham / Biochimica et Biophysica Acta 1763 (2006) 1707–1720 1715

The combination of adult-onset sensory motor neuropathy stage liver disease. Studies in the recipient revealed marked and the grey and white matter abnormalities observed upon elevation of both (25R)-THCA and (25R)-DHCA in urine MRI, raised the possibility of AMACR deficiency despite the indicating that the sibling, whose liver was transplanted, had also absence of retinitis pigmentosa, which is a frequent finding both been affected by AMACR deficiency. This finding prompted in AMACR deficiency as well as in Refsum disease. Detailed institution of a therapy involving ursodeoxycholic acid. The laboratory investigations revealed slightly abnormal di- and recipient has remained in good health 8 years after transplanta- trihydroxycholestanoic acid levels, whereas pristanic acid was tion while still receiving ursodeoxycholic acid, at least when clearly elevated (>10-fold the upper limit of normal). Plasma reported in 2003 [60]. Interestingly, the patients described by VLCFAs were completely normal. Taken together, these Setchell et al. [60] were homozygous for the same mutation as abnormalities clearly pointed to a defect in the peroxisomal described by Ferdinandusse et al. [17] in the two patients with metabolism of 2-methyl branched-chain fatty acids. adult-onset sensory motor neuropathy. The mutation which changes a serine at position 52 by a proline leads to a complete 4.2.4.1. Biochemistry and molecular basis of SCPx loss of enzyme activity as established by expression studies in E. deficiency. Studies in fibroblasts from the index patient coli [17]. Clarke et al. [7] have described an additional patient revealed normal oxidation of C26:0 whereas the beta-oxidation with tremor, retinitis pigmentosa, and deep white matter MRI of pristanic acid was markedly deficient with residual activity changes, who subsequently developed encephalopathy with left amounting to <10% of mean control. These results pointed to hemiparesis and an unchanged MRI. Taken together, these data either branched-chain acyl-CoA oxidase, 2-methylacyl-CoA suggest that AMACR deficiency can have two wildly different racemase, or sterol carrier protein X (SCPx) as deficient enzyme phenotypic presentations, one characterized by early onset liver (see Fig. 1). Subsequent enzyme activity measurement showed failure, which may resolve, but may also lead to early death, as normal activities of branched acyl-CoA oxidase as well as 2- described by Setchell et al. [60], whereas the other presentation methyl acyl-CoA racemase. In contrast, the activity of SCPx is dominated by a late onset sensory neuropathy plus additional was fully deficient. Immunoblot analysis showed the absence of features. both the full-length 58-kDa SCPx as well as the 46-kDa thiolase domain of SCPx in fibroblasts of the patient. In contrast, the 13- 4.2.5.1. Biochemistry and molecular basis of racemase kDa SCP2 protein was normally present. Molecular analysis deficiency. AMACR plays a crucial role in the degradation of revealed a homozygous 1-nucleotide insertion, 545_546insA FAs with a methyl group in the (2R)-configuration such as (2R)- leading to a frame shift and premature stop codon (I184fsX7) pristanic acid, (25R)-THCA, and (25R)-DHCA (Fig. 1). In all [21]. patients with AMACR deficiency reported so far, pristanic acid, As shown in Fig. 2d pristanic acid and the bile acid THCA and DHCA have been found to accumulate, which intermediates di- and trihydroxycholestanoic acid are the follows logically from the role of AMACR in the oxidation of expected peroxisomal metabolites to accumulate in SCPx pristanic acid as well as di- and trihydroxycholestanoic acid, but deficiency. not C26:0 (see Fig. 2e). It has been established that racemase- deficient patients accumulate exclusively the (25R)-isomer of 4.2.5. 2-Methyl-acylCoA racemase (AMACR) deficiency free and taurine-conjugated DHCA and THCA, whereas in AMACR deficiency was first described in 2000 by patients with cholestatic liver disease for instance, both (25R)- Ferdinanusse et al. [17] in three patients, two of whom suffered and (25S)-isomers accumulate [22,60]. from adult-onset sensory motor neuropathy. One patient also had Interestingly, AMACR is a protein equipped with both a pigmentary retinopathy, reminiscent of Refsum disease, as well mitochondrial and peroxisomal targeting signal, which explains as epilepsy, migraine and depression, whereas the second patient its presence in both mitochondria and peroxisomes. Mitochon- had pyramidal signs. The third patient was a child without drial AMACR plays a similar crucial role in the degradation of neuropathy but it should be noted that this child also had (2R)-FAs just like peroxisomal AMACR. One of the (2R)-FAs, Niemann–Pick type C. Interestingly, Setchell et al. [60] reported the oxidation of which is dependent on mitochondrial AMACR two siblings with racemase deficiency but a completely different activity, is (2R,6R)-dimethylheptanoic acid, which is produced phenotype. Both patients displayed fulminant liver disease, from pristanic acid by beta-oxidation. Pristanic acid is a mixture starting at early age. The index patient presented at 2 weeks of of two diastereomers including (2R,6R,10R) and (2S,6R,10R) age with coagulopathy, vitamin D and E deficiency and mild pristanic acid. Oxidation of the (2R-) but not the (2S)-form is cholestasis. Plasma analysis revealed elevated levels of the bile- deficient in case of AMACR deficiency. Hence, one would acid intermediates di- and trihydroxycholestanoic acid (DHCA expect accumulation of (2R,6R)-dimethylheptanoic acid in and THCA). Furthermore, plasma VLCFAs, phytanic acid, and patients with racemase deficiency. However, no specific fatty red blood cell plasmalogens were all normal, whereas pristanic acid abnormalities resulting for the deficiency of mitochondrial acid was markedly elevated (10-fold). These data suggested AMACR in AMACR deficient patients have been documented AMACR deficiency, which was confirmed in fibroblasts [75]. in literature. Remarkably, a previous child in the family had died earlier at 5.5 Mutation analysis has been performed in all patients reported months of age from an intracranial bleed secondary to vitamin K so far. Remarkably, four of the patients were homozygous for a deficiency and his liver was harvested for orthotopic transplan- point mutation (154T>C), which leads to a single amino acid tation (OLT) and placed into a 28-month-old child with end- substitution (S52P). 1716 R.J.A. Wanders, H.R. Waterham / Biochimica et Biophysica Acta 1763 (2006) 1707–1720

5. Peroxisomal alpha-oxidation and its disorders to 100 mg. Restriction of common phytanic acid containing foods, such as butter, cheeses, lamb, beef and certain fish, helps 5.1. Fatty acid alpha-oxidation to lower plasma phytanic acid levels, which may stop the progression of the peripheral neuropathy with improved muscle Fatty acids with a methyl group at the 3-position cannot be strength and regression of ichthyosis and correction of non- beta-oxidized because the 3-methyl group simply blocks beta- specific abnormalities of electrocardiogram. oxidation. Fortunately, there are other mechanisms by which such FAs can be degraded including alpha- and omega- 5.2.2. Biochemistry and molecular basis of Refsum disease oxidation. Alpha-oxidation involves the oxidative decarbox- Plasma phytanic acid is generally considered to be an ylation of 3-methyl FAs to produce 2-methyl FAs, which can be excellent marker for Refsum disease since all Refsum disease degraded by beta-oxidation. In higher eukaryotes, including patients have so far been found to have markedly elevated humans, peroxisomes are the sole site of alpha-oxidation. The plasma phytanic acid levels, even if they are on therapy. enzymatic machinery required for FA alpha-oxidation, has been Although this may be true for patients with classical Refsum resolved in recent years and requires the concerted action of 3 disease caused by mutations in the phytanoyl-CoA hydroxylase enzymes including: (1) phytanoyl-CoA hydroxylase; (2) 2- gene, the situation may be different in those patients in which hydroxyphytanoyl-CoA lyase, and (3) pristanal-dehydrogenase PEX7 is mutated. Indeed, in these patients plasma phytanic as described in detail elsewhere in this volume. The actual acid levels are generally much lower, and recent studies by Horn decarboxylation is catalyzed by the enzyme 2-hydroxy et al. (manuscript submitted for publication) have shown that phytanoyl-CoA lyase, which splits 2-hydroxyphytanoyl-CoA, levels can actually be completely normal. If plasma phytanic the product of the first enzyme of the pathway, i.e. phytanoyl- acid levels are elevated additional studies, preferably in CoA hydroxylase, into formyl-CoA and pristanal. Subse- fibroblasts, should be done to pinpoint the underlying defect. quently, pristanal is oxidized into pristanic acid via a In all Refsum disease patients studied to date whether mutated peroxisomal aldehyde dehydrogenase, which has not been in PAHX or PEX7, discrimination between the two forms of identified yet. Pristanic acid, which now has its first methyl- Refsum disease can be made by performing detailed studies in group at the 2-position, can then be degraded by beta- fibroblasts, especially by analyzing other PTS2 proteins, like oxidation. The first two enzymes, including phytanoyl-CoA peroxisomal thiolase and alkyl-DHAP synthase, using immu- hydroxylase and 2-hydroxyphytanoyl-CoA lyase have been noblot analysis, enzyme activity measurements, and immuno- identified in different species. Human phytanoyl-CoA hydro- fluorescence microscopy analysis, followed by molecular xylase is a typical PTS2 protein which explains why it is not analysis of the two different genes [79]. only deficient in Refsum disease but also in rhizomelic chondrodysplasia punctata type 1 (RCDP type 1), which is 6. Glyoxylate detoxification and its disorders caused by mutations in the PEX7 gene encoding the PTS2 receptor. Human 2-hydroxyphytanoyl-CoA lyase is a typical 6.1. Glyoxylate detoxification PTS1 protein [26]. In humans, peroxisomes play a crucial role in the 5.2. The disorders of fatty acid alpha-oxidation detoxification of glyoxylate as exemplified by the devastating consequences of a deficiency of the peroxisomal enzyme 5.2.1. Refsum disease alanine glyoxylate aminotransferase (AGT) in hyperoxaluria Refsum disease usually presents in late childhood with type 1. AGT catalyses the transamination of glyoxylate to progressive deterioration of night vision, the occurrence of a glycine with alanine as the preferred amino group donor. It is progressive retinitis pigmentosa, and anosmia, later in life not exactly known from which precursors glyoxylate is formed. followed by deafness, ataxia, polyneuropathy, ichthyosis and If glyoxylate is not immediately detoxified by AGT, either due cardiac arrhythmias. Short metacarpals and metatarsals are also to its deficient activity in peroxisomes or its mislocalization to found in some 30% of Refsum disease patients. Furthermore, mitochondria as described below, glyoxylate will accumulate in psychiatric disturbances have been reported in a subset of peroxisomes and will either be reduced to glycolate or oxidized patients. It is quite clear now that only few patients develop the to oxalate. Glycolate is water soluble and can be excreted via the full spectrum of clinical signs and symptoms originally defined urine. This is not true, however, for oxalate, which precipitates by Refsum [54]. Indeed, a study of 16 Refsum disease patients as calcium oxalate. Deposition of calcium oxalate within the with full clinical information for a period for up to 60 years kidney parenchymatous tissue (nephrocalcinosis) or the renal revealed that all 16 patients developed retinitis pigmentosa, 15 pelvis/urinary tract (urolithiasis) continues until eventually out of 16 developed anosmia, whereas neuropathy, deafness and renal function is impaired causing subsequent sequelae, like ataxia was only found in 11, 10 and 8 patients, respectively [88]. uremia and systemic oxalosis. The failure to clear oxalate from Finally, ichthyosis was only present in 4 of the 16 patients the body leads to its further deposition in almost all areas of the studied. Refsum disease is one of the few peroxisomal disorders body, affecting multiple tissues in addition to the kidneys and for which a therapy has been developed which is based on the urinary tract, including: (a) the myocardium with heart block, dietary restriction of phytanic acid. The average human daily myocarditis, and cardioembolic stroke; (b) the nerves (periph- diet intake of phytanic acid in western countries amounts to 50 eral neuropathy); (c) bone (bone pain, multiple fractures, R.J.A. Wanders, H.R. Waterham / Biochimica et Biophysica Acta 1763 (2006) 1707–1720 1717 osteosclerosis; (d) the eyes (retinopathy, optic atrophy); (e) bone towards: (a) decreasing the production of oxalate by inhibiting marrow, and (f) other organs. oxalate synthesis, and (b) increasing the solubility of oxalate at a given urinary concentration of oxalate. Most of the efforts have 6.1.1. Primary hyperoxaluria type 1 concentrated on ways to increase the solubility of calcium Primary hyperoxaluria type 1 (PH1) is clinically variable oxalate with high fluid intake and alkalinization of the urine as both in symptoms and timing. In most patients, first symptoms the main stays. Indeed, excessive volume is necessary to help start before 5 years of age. There is an enormous spread, excrete the enormous amounts of endogenously reproduced however, in the ages at which the disease becomes apparent, oxalate. Haemodialysis can remove large quantities of oxalate which can be as early as the first year of life or even beyond the and its precursors. Importantly, a substantial percentage of PH1 5th decade. In its severe neonatal presentation PH1 is patients respond to pyridoxin. Indeed, pyridoxin at the usual characterized by rapidly progressive oxalosis, renal failure daily dose of 1000 mg/m2 body surface area can bring about a and early death. substantial reduction in the production and excretion of oxalate, The most common method of diagnosing PH1 is by except in patients with a pyridoxin-resistant form of the disease. measuring urinary oxalate excretion. Markedly elevated urinary The efficacy of pyridoxin is probably directly related to the oxalate levels are usually indicative for either PH1 or a second extent to which AGT is deficient. Indeed, if there is some type of hyperoxaluria, PH2, which is due to a deficiency of residual activity, high levels of pyridoxal phosphate, which is the glyoxylate reductase. For differential diagnosis, urinary glyco- obligatory cofactor in the AGT enzyme reaction, may allow late and L-glycerate must be measured. It should be noted that a residual enzyme activity operate optimally. In this way, flux significant number of PH1 patients (up to 25%) with proven through AGT may be stimulated substantially, leading to a AGT deficiency have hyperoxaluria but no hyperglycolic reduced production of oxalate. Recent studies have shown a aciduria. At the other extreme, some PH1 patients have extreme clear association between homozygosity for the two mistarget- hyperglycolic aciduria with only mildly elevated oxalate ing mutations Gly170Arg and Phe152Ile, and pyridoxin excretion. In addition, isolated hyperglycolic aciduria and responsiveness, the reason being that pyridoxin is able to concomitant hyperoxaluria and hyperglycolic aciduria have interfere with the mistargeting of AGT to the mitochondria been found in patients with normal AGT levels. thereby increasing the residual activity in peroxisomes from 5 to Definitive diagnosis of PH1 and PH2 requires enzymatic 10%. In our experience, all patients homozygous for the studies and subsequent molecular analysis. Enzymatic diag- Gly170Arg substitution with a preserved renal function at the nosis of PH2 is straightforward, since the enzyme glyoxylate timeofdiagnosis,wereabletopreserverenalfunction reductase can be measured reliably in lymphocytes. Enzymatic throughout the follow-up period when treated with pyridoxin, diagnosis of PH1 is much less straightforward for two reasons. high fluid intake, and potassium citrate [76]. In case of pyridoxin Firstly, in contrast to glyoxylate reductase, AGT is only insensitivity combined liver / kidney transplantation is expressed in liver, which requires a percutaneous liver needle warranted. biopsy. Secondly, and more importantly, although AGT can be measured reliably in minimal amounts of liver material, the Acknowledgements results of AGT enzyme testing are not unequivocal. The reason is that AGT activity may be quite normal as measured in a The work was financially supported by grants from the: human liver homogenate, but may be inactive under in vivo European Union (grant LSHM CT2004 502987, entitled X- conditions because of its mislocalization to the mitochondrion. linked adrenoleukodystrophy (X-ALD) Pathogenesis; animal This astonishing phenotype of an enzyme being functionally models and therapy), and European Union (grant LSHG-CT- inactive because of its localization in the wrong compartment 2004-512018, entitled Peroxisomes in health and disease); obviously complicates the results of the AGT enzyme assay. European Leukodystrophy Association (ELA), (project entitled Since this peroxisome-to-mitochondrion-mistargeting pheno- Elongation of very long-chain fatty acids in X-Linked type is quite frequent, there is a strong case for direct molecular adrenoleukodystrophy: an option for a therapy?), and also by analysis of the AGXT gene as we do in our own centre, since the two grants of the Princes Beatrix Funds (project number underlying cause for the mistargeting of AGT to the MAR02-116, entitled X-linked adrenoleukodystrophy and the mitochondrion has been established now. Indeed, a Gly170Arg search for new treatment strategies, and project number substitution on the background of the minor AGXT allele MAR03-216, entitled Identification of the underlying defect in (frequency in the normal population : 4%) leads to mistargeting patients suffering from an unknown defect in peroxisomal beta- of 90% of AGT to the mitochondrion. The same is true for the oxidation with particular emphasis on auxiliary enzymes and Phe152Ile mutation. In addition to these two mutations more transporters involved in beta-oxidation). than 50 additional mutations in the AGXT gene have been identified which, in general, render the enzyme inactive without References changing its subcellular localization. [1] D.G. Barr, J.M. Kirk, M. al Howasi, R.J.A. Wanders, R.B.H. Schutgens, Rhizomelic chondrodysplasia punctata with isolated DHAP-AT defi- 6.1.2. Treatment ciency, Arch. Dis. Child. 68 (1993) 415. PH1 is one of the few peroxisomal diseases for which some [2] L. Bezman, A.B. Moser, G.V. Raymond, P. Rinaldo, P.A. Watkins, K.D. therapeutic options are available. Treatment of PH1 is directed Smith, N.E. Kass, H.W. Moser, Adrenoleukodystrophy: incidence, new 1718 R.J.A. Wanders, H.R. Waterham / Biochimica et Biophysica Acta 1763 (2006) 1707–1720

mutation rate, and results of extended family screening, Ann. Neurol. 49 [18] S. Ferdinandusse, S. Denis, P.A. Mooijer, Z. Zhang, J.K. Reddy, A.A. (2001) 512. Spector, R.J.A. Wanders, Identification of the peroxisomal beta-oxidation [3] J. Biermann, W.W. Just, R.J.A. Wanders, H. van den Bosch, Alkyl- enzymes involved in the biosynthesis of docosahexaenoic acid, J. Lipid dihydroxyacetone phosphate synthase and dihydroxyacetone phosphate Res. 42 (2001) 1987. acyltransferase form a protein complex in peroxisomes, Eur. J. Biochem. [19] S. Ferdinandusse, S. Denis, P.A. Mooyer, C. Dekker, M. Duran, R.J. 261 (1999) 492. Soorani-Lunsing, E. Boltshauser, A. Macaya, J. Gartner, C.B. Majoie, P.G. [4] N. Braverman, L. Chen, P. Lin, C. Obie, G. Steel, P. Douglas, P.K. Barth, R.J. Wanders, B.T. Poll-The, Clinical and biochemical spectrum of Chakraborty, J.T. Clarke, A. Boneh, A. Moser, H. Moser, D. Valle, D-bifunctional protein deficiency, Ann. Neurol. 59 (2006) 92. Mutation analysis of PEX7 in 60 probands with rhizomelic chondrodys- [20] S. Ferdinandusse, S. Denis, C.W.T. van Roermund, R.J.A. Wanders, G. plasia punctata and functional correlations of genotype with phenotype, Dacremont, Identification of the peroxisomal {beta}-oxidation enzymes Hum. Mutat. 20 (2002) 284. involved in the degradation of long-chain dicarboxylic acids, J. Lipid Res. [5] P. Brites, H.R. Waterham, R.J.A. Wanders, Functions and biosynthesis of 45 (2004) 1104. plasmalogens in health and disease, Biochim. Biophys. Acta 1636 (2004) [21] S. Ferdinandusse, P. Kostopoulos, S. Denis, H. Rusch, H. Overmars, U. 219. Dillmann, W. Reith, D. Haas, R.J.A. Wanders, M. Duran, M. Marziniak, [6] E. Christensen, S.A. Pedersen, H. Leth, C. Jakobs, R.B.H. Schutgens, Mutations in the gene encoding peroxisomal sterol carrier protein X R.J.A. Wanders, A new peroxisomal beta-oxidation disorder in twin (SCPx) cauise leukencephalopathy with dystonia and motor neuropathy, J. neonates: defective oxidation of both cerotic and pristanic acids, J. Inherited Lipid Res. 45 (2004) 1104. Metab. Dis. 20 (1997) 658. [22] S. Ferdinandusse, H. Overmars, S. Denis, H.R. Waterham, R.J.A. [7] C.E. Clarke, S. Alger, M.A. Preece, M.A. Burdon, S. Chavda, S. Denis, S. Wanders, P. Vreken, Plasma analysis of di- and trihydroxycholestanoic Ferdinandusse, R.J.A. Wanders, Tremor and deep white matter changes in acid diastereoisomers in peroxisomal alpha-methylacyl-CoA racemase alpha-methylacyl-CoA racemase deficiency, Neurology 63 (2004) 188. deficiency, J. Lipid Res. 42 (2001) 137. [8] P.T. Clayton, S. Eckhardt, J. Wilson, C.M. Hall, Y. Yousuf, R.J.A. [23] S. Ferdinandusse, H. Rusch, A.E. van Lint, G. Dacremont, R.J.A. Wanders, R.B.H. Schutgens, Isolated dihydroxyacetonephosphate acyl- Wanders, P. Vreken, Stereochemistry of the peroxisomal branched-chain transferase deficiency presenting with developmental delay, J. Inherited fatty acid alpha- and beta-oxidation systems in patients suffering from Metab. Dis. 17 (1994) 533. different peroxisomal disorders. J. Lipid Res. 43 (2002) 438. [9] P.T. Clayton, B.D. Lake, M. Hjelm, J.B. Stephenson, G.T. Besley, R.J.A. [24] S. Ferdinandusse, E.G. van Grunsven, W. Oostheim, S. Denis, E.M. Wanders, A.W. Schram, J.M. Tager, R.B.H. Schutgens, A.M. Lawson, Bile Hogenhout, L. IJlst, C.W. van Roermund, H.R. Waterham, S. Goldfischer, acid analyses in “pseudo-Zellweger” syndrome: clues to the defect in R.J.A. Wanders, Reinvestigation of Peroxisomal 3-Ketoacyl-CoAThiolase peroxisomal beta-oxidation, J. Inherited Metab. Dis. 11 (Suppl. 2) (1988) Deficiency: Identification of the True Defect at the Level of D-Bifunctional 165. Protein, Am. J. Hum. Genet. 70 (2002) 1589. [10] E.C. de Vet, L. IJlst, W. Oostheim, C. Dekker, H.W. Moser, H. van den [25] S. Ferdinandusse, M.S. Ylianttila, J. Gloerich, M.K. Koski, W. Oostheim, Bosch, R.J.A. Wanders, Ether lipid biosynthesis. Alkyl-dihydroxyaceto- H.R. Waterham, J.K. Hiltunen, R.J.A. Wanders, T. Glumoff, Mutational nephosphate synthase protein deficiency leads to reduced dihydroxy- spectrum of D-bifunctional protein deficiency and structure based acetonephosphate acyltransferase activities, J. Lipid Res. 40 (1999) genotype-phenotype analysis, Am. J. Hum. Genet. 78 (2006) 112. 1998. [26] V. Foulon, V.D. Antonenkov, K. Croes, E. Waelkens, G.P. Mannaerts, P.P. [11] E.C. de Vet, L. IJlst, W. Oostheim, R.J.A. Wanders, H. van den Bosch, Van Veldhoven, M. Casteels, Purification, molecular cloning, and Alkyl-dihydroxyacetonephosphate synthase: fate in peroxisome biogen- expression of 2-hydroxyphytanoyl-CoA lyase, a peroxisomal thiamine esis disorders and identification of the point mutation underlying a single pyrophosphate-dependent enzyme that catalyzes the carbon-carbon bond enzyme deficiency, J. Biol. Chem. 273 (1998) 10296. cleavage during alpha-oxidation of 3-methyl-branched fatty acids, Proc. [12] M. Dieuaide-Noubhani, S. Asselberghs, G.P. Mannaerts, P.P. Van Natl. Acad. Sci. U. S. A. 96 (1999) 10039. Veldhoven, Evidence that multifunctional protein 2, and not multi- [27] B. Fournier, J.M. Saudubray, B. Benichou, S. Lyonnet, A. Munnich, H. functional protein 1, is involved in the peroxisomal beta-oxidation of Clevers, B.T. Poll-The, Large deletion of the peroxisomal acyl-CoA pristanic acid, Biochem. J. 325 (1997) 367. oxidase gene in pseudoneonatal adrenoleukodystrophy, J. Clin. Invest. 94 [13] M. Dieuaide-Noubhani, D. Novikov, E. Baumgart, J.C. Vanhooren, M. (1994) 526. Fransen, M. Goethals, J. Vandekerckhove, P.P. Van Veldhoven, G.P. [28] S. Goldfischer, J. Collins, I. Rapin, P. Neumann, W. Neglia, A.J. Spiro, T. Mannaerts, Further characterization of the peroxisomal 3-hydroxyacyl- Ishii, F. Roels, J. Vamecq, F. Van Hoof, Pseudo-Zellweger syndrome: CoA dehydrogenases from rat liver. Relationship between the different deficiencies in several peroxisomal oxidative activities, J. Pediatr. 108 dehydrogenases and evidence that fatty acids and the C27 bile acids di- and (1986) 25. tri-hydroxycoprostanic acids are metabolized by separate multifunctional [29] C.P. Guimaraes, P. Domingues, P. Aubourg, F. Fouquet, A. Pujol, G. proteins, Eur. J. Biochem. 240 (1996) 660. Jimenez-Sanchez, C. Sa-Miranda, J.E. Azevedo, Mouse liver PMP70 and [14] M. Dieuaide-Noubhani, D. Novikov, J. Vandekerckhove, P.P. Veldhoven, ALDP: homomeric interactions prevail in vivo, Biochim. Biophys. Acta G.P. Mannaerts, Identification and characterization of the 2-enoyl-CoA 1689 (2004) 235. hydratases involved in peroxisomal beta-oxidation in rat liver, Biochem. J. [30] E.H. Hettema, C.W.T. van Roermund, B. Distel, M. van den Berg, C. 321 (1997) 253. Vilela, C. Rodrigues-Pousada, R.J.A. Wanders, H.F. Tabak, The ABC [15] E.R. Elias, M. Mobassaleh, A.K. Hajra, A.B. Moser, Developmental delay transporter proteins Pat1 and Pat2 are required for import of long-chain and growth failure caused by a peroxisomal disorder, dihydroxyacetone- fatty acids into peroxisomes of Saccharomyces cerevisiae, EMBO J. 15 phosphate acyltransferase (DHAP-AT) deficiency, Am. J. Med. Genet. 80 (1996) 3813. (1998) 223. [31] H.S.A. Heymans, J.W. Oorthuys, G. Nelck, R.J.A. Wanders, R.B.H. [16] M. Espeel, F. Roels, L. Van Maldergem, D. De Craemer, G. Dacremont, Schutgens, Rhizomelic chondrodysplasia punctata: another peroxisomal R.J.A. Wanders, T. Hashimoto, Peroxisomal localization of the immunor- disorder, N. Engl. J. Med. 313 (1985) 187. eactive beta-oxidation enzymes in a neonate with a beta-oxidation defect. [32] S. Hogenboom, J.J.M. Tuyp, M. Espeel, J. Koster, R.J.A. Wanders, H.R. Pathological observations in liver, adrenal cortex and kidney, Virchows Waterham, Mevalonate kinase is a cytosolic enzyme in humans, J. Cell Sci. Arch. A: Pathol. Anat. Histopathol. 419 (1991) 301. 117 (2004) 631. [17] S. Ferdinandusse, S. Denis, P.T. Clayton, A. Graham, J.E. Rees, J.T. Allen, [33] L.L. Jiang, T. Kurosawa, M. Sato, Y. Suzuki, T. Hashimoto, Physiological B.N. Mclean, A.Y. Brown, P. Vreken, H.R. Waterham, R.J.A. Wanders, role of D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA dehydrogenase bifunctional protein, J. Biochem. (Tokyo) 121 (1997) racemase cause adult-onset sensory motor neuropathy, Nat. Genet. 24 506. (2000) 188. [34] L.L. Jiang, S. Miyazawa, T. Hashimoto, Purification and properties of rat R.J.A. Wanders, H.R. Waterham / Biochimica et Biophysica Acta 1763 (2006) 1707–1720 1719

D-3-hydroxyacyl-CoA dehydratase: D-3-hydroxyacyl-CoA dehydratase/ with enlarged peroxisomes and a specific deficiency of acyl-CoA D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein, J. Biochem. oxidase (pseudo-neonatal adrenoleukodystrophy), Am. J. Hum. Genet. (Tokyo) 120 (1996) 633. 42 (1988) 422. [35] S. Kemp, A. Pujol, H.R. Waterham, B.M. van Geel, C.D. Boehm, G.V. [52] Y.M. Qin, A.M. Haapalainen, D. Conry, D.A. Cuebas, J.K. Hiltunen, D.K. Raymond, G.R. Cutting, R.J.A. Wanders, H.W. Moser, ABCD1 mutations Novikov, Recombinant 2-enoyl-CoA hydratase derived from rat perox- and the X-linked adrenoleukodystrophy mutation database: role in isomal multifunctional enzyme 2: role of the hydratase reaction in bile acid diagnosis and clinical correlations, Hum. Mutat. 18 (2001) 499. synthesis, Biochem. J. 328 (1997) 377. [36] F.L. Kretzer, H.M. Hittner, R. Mehta, Ocular manifestations of Conradi [53] Y.M. Qin, M.H. Poutanen, H.M. Helander, A.P. Kvist, K.M. Siivari, W. and Zellweger syndromes, Metab. Pediatr. Ophthalmol. 5 (1981) 1. Schmitz, E. Conzelmann, U. Hellman, J.K. Hiltunen, Peroxisomal [37] M.A. Kurian, S. Ryan, G.T.N. Besley, R.J.A. Wanders, M.D. King, multifunctional enzyme of beta-oxidation metabolizing D-3-hydroxya- Straight-chain acyl-CoA oxidase deficiency presenting with dysmorphia, cyl-CoA esters in rat liver: molecular cloning, expression and character- neurodevelopmental autistic-type regression and a selective pattern of ization, Biochem. J. 321 (1997) 21. leukodystrophy, J. Inherited Metab. Dis. 27 (2004) 105. [54] S. Refsum, Heredopathia atactica polyneuritiformis, Acta Psychiatr. [38] H. Mandel, M. Berant, A. Aizin, R. Gershony, S. Hemmli, R.B.H. Scand., Suppl. 38 (1946) 1. Schutgens, R.J.A. Wanders, Zellweger-like phenotype in two siblings: a [55] H. Rosewich, H.R. Waterham, R.J.A. Wanders, S. Ferdinandusse, M. defect in peroxisomal beta-oxidation with elevated very long-chain fatty Henneke, D. Hunneman, J. Gartner, Pitfall in metabolic screening in a acids but normal bile acids, J. Inherited Metab. Dis. 15 (1992) 381. patient with fatal peroxisomal beta-oxidation defect, Neuropediatrics 37 [39] M.C. McGuinness, J.F. Lu, H.P. Zhang, G.X. Dong, A.K. Heinzer, P.A. (2006) 95. Watkins, J. Powers, K.D. Smith, Role of ALDP (ABCD1) and [56] W. Schmitz, C. Albers, R. Fingerhut, E. Conzelmann, Purification and mitochondria in X-linked adrenoleukodystrophy, Mol. Cell. Biol. 23 characterization of an alpha-methylacyl-CoA racemase from human liver, (2003) 744. Eur. J. Biochem. 231 (1995) 815. [40] M.C. McGuinness, H.P. Zhang, K.D. Smith, Evaluation of pharmacolo- [57] W. Schmitz, E. Conzelmann, Stereochemistry of peroxisomal and gical induction of fatty acid beta-oxidation in X-linked adrenoleukody- mitochondrial beta-oxidation of alpha-methylacyl-CoAs, Eur. J. Biochem. strophy, Mol. Genet. Metab. 74 (2001) 256. 244 (1997) 434. [41] S. Miyazawa, T. Osumi, T. Hashimoto, The presence of a new 3-oxoacyl- [58] W. Schmitz, H.M. Helander, J.K. Hiltunen, E. Conzelmann, Molecular CoA thiolase in rat liver peroxisomes, Eur. J. Biochem. 103 (1980) 589. cloning of cDNA species for rat and mouse liver alpha- methylacyl-CoA [42] A.B. Moser, M. Rasmussen, S. Naidu, P.A. Watkins, M. McGuinness, A.K. racemases, Biochem. J. 326 (1997) 883. Hajra, G. Chen, G. Raymond, A. Liu, D. Gordon, K. Garnaas, D.S. Walton, [59] U. Seedorf, P. Brysch, T. Engel, K. Schrage, G. Assmann, Sterol carrier O.H. Skjeldal, M.A. Guggenheim, L.G. Jackson, E.R. Elias, H.W. Moser, protein X is peroxisomal 3-oxoacyl coenzyme A thiolase with intrinsic Phenotype of patients with peroxisomal disorders subdivided into sixteen sterol carrier and lipid transfer activity, J. Biol. Chem. 269 (1994) complementation groups, J. Pediatr. 127 (1995) 13. 21277. [43] H.W. Moser, A.B. Moser, K.K. Frayer, W. Chen, J.D. Schulman, B.P. [60] K.D. Setchell, J.E. Heubi, K.E. Bove, N.C. O'Connell, T. Brewsaugh, S.J. O'Neill, Y. Kishimoto, Adrenoleukodystrophy: increased plasma content Steinberg, A. Moser, R.H. Squires Jr., Liver disease caused by failure to of saturated very long chain fatty acids, Neurology 31 (1981) 1241. racemize trihydroxycholestanoic acid: gene mutation and effect of bile acid [44] H.W. Moser, A.B. Moser, N. Kawamura, J. Murphy, K. Suzuki, H. therapy, Gastroenterology 124 (2003) 217. Schaumburg, Y. Kishimoto, Adrenoleukodystrophy: elevated C26 fatty [61] N. Shani, A. Sapag, D. Valle, Characterization and analysis of conserved acid in cultured skin fibroblasts, Ann. Neurol. 7 (1980) 542. motifs in a peroxisomal ATP-binding cassette transporter, J. Biol. Chem. [45] H.W. Moser, K.D. Smith, P.A. Watkins, J. Powers, A.B. Moser, X-Linked 271 (1996) 8725. Adrenoleukodystrophy, in: C.R. Scriver, A.L. Beaudet, W.S. Sly, D. Valle [62] N. Shani, D. Valle, A Saccharomyces cerevisiae homolog of the human (Eds.), The Metabolic and Molecular Bases of Inherited Disease, Mc adrenoleukodystrophy transporter is a heterodimer of two half ATP- Graw-Hill, New York, 2001, pp. 3257–3301. binding cassette transporters, Proc. Natl. Acad. Sci. U. S. A. 93 (1996) [46] J. Mosser, A.M. Douar, C.O. Sarde, P. Kioschis, R. Feil, H. Moser, A.M. 11901. Poustka, J.L. Mandel, P. Aubourg, Putative X-linked adrenoleukodystro- [63] N. Shani, P.A. Watkins, D. Valle, PXA1, a possible Saccharomyces phy gene shares unexpected homology with ABC transporters, Nature 361 cerevisiae ortholog of the human adrenoleukodystrophy gene, Proc. Natl. (1993) 726. Acad. Sci. U. S. A. 92 (1995) 6012. [47] A.M. Motley, P. Brites, L. Gerez, E.M. Hogenhout, J. Haasjes, R. Benne, [64] N. Shimozawa, T. Tsukamoto, T. Nagase, Y. Takemoto, N. Koyama, Y. H.F. Tabak, R.J.A. Wanders, H.R. Waterham, Mutational spectrum in the Suzuki, M. Komori, T. Osumi, G. Jeannette, R.J.A. Wanders, N. Kondo, PEX7 gene and functional analysis of mutant alleles in 78 patients with Identification of a new complementation group of the peroxisome rhizomelic chondrodysplasia punctata type 1, Am. J. Hum. Genet. 70 biogenesis disorders and PEX14 as the mutated gene, Hum. Mutat. 23 (2002) 612. (2004) 552. [48] S. Naidu, G. Hoefler, P.A. Watkins, W.W. Chen, A.B. Moser, S. Hoefler, [65] H. Sprecher, D.L. Luthria, B.S. Mohammed, S.P. Baykousheva, N.E. Rance, J.M. Powers, M. Beard, W.R. Green, et al., Neonatal Reevaluation of the pathways for the biosynthesis of polyunsaturated seizures and retardation in a girl with biochemical features of X-linked fatty acids. J. Lipid Res. 36 (1995) 2471. adrenoleukodystrophy: a possible new peroxisomal disease entity, [66] Y. Suzuki, M. Iai, A. Kamei, Y. Tanabe, S. Chida, S. Yamaguchi, Z. Zhang, Neurology 38 (1988) 1100. Y. Takemoto, N. Shimozawa, N. Kondo, Peroxisomal acyl CoA oxidase [49] I. Oezen, W. Rossmanith, S. Forss-Petter, S. Kemp, T. Voigtlander, K. deficiency, J. Pediatr. 140 (2002) 128. Moser-Thier, R.J.A. Wanders, R.E. Bittner, J. Berger, Accumulation of [67] Y. Suzuki, L.L. Jiang, M. Souri, S. Miyazawa, S. Fukuda, Z. Zhang, M. very long-chain fatty acids does not affect mitochondrial function in Une, N. Shimozawa, N. Kondo, T. Orii, T. Hashimoto, D-3-hydroxyacyl- adrenoleukodystrophy protein deficiency, Hum. Mol. Genet. 14 (2005) CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase bifunctional pro- 1127. tein deficiency: a newly identified peroxisomal disorder, Am. J. Hum. [50] R. Ofman, E.H. Hettema, E.M. Hogenhout, U. Caruso, A.O. Muijsers, R.J. Genet. 61 (1997) 1153. A. Wanders, Acyl-CoA-dihydroxyacetonephosphate acyltransferase— [68] Y. Suzuki, N. Shimozawa, S. Yajima, S. Tomatsu, N. Kondo, Y. Nakada, S. cloning of the human cDNA and resolution of the molecular basis in Akaboshi, M. Lai, Y. Tanabe, T. Hashimoto, R.J.A. Wanders, R.B.H. rhizomelic chondrodysplasia punctata type 2, Hum. Mol. Genet. 7 (1998) Schutgens, H.W. Moser, T. Orii, Novel subtype of peroxisomal acyl-CoA 847. oxidase deficiency and bifunctional enzyme deficiency with detectable [51] B.T. Poll-The, F. Roels, H. Ogier, J. Scotto, J. Vamecq, R.B.H. enzyme protein: identification by means of complementation analysis, Am. Schutgens, R.J.A. Wanders, C.W.T. van Roermund, M.J. van Wijland, J. Hum. Genet. 54 (1994) 36. A.W. Schram, J.M. Tager, J.M. Saudubray, A new peroxisomal disorder [69] E.E. Swartzman, M.N. Viswanathan, J. Thorner, The PAL1 gene product is 1720 R.J.A. Wanders, H.R. Waterham / Biochimica et Biophysica Acta 1763 (2006) 1707–1720

a peroxisomal ATP-binding cassette transporter in the yeast Saccharo- chain fatty acids and of the bile acid intermediates di- and myces cerevisiae, J. Cell Biol. 132 (1996) 549. trihydroxycoprostanic acids are oxidized by one single peroxisomal [70] L. Sztriha, L.I. Al Gazali, R.J.A. Wanders, R. Ofman, M. Nork, G.G. branched chain acyl-CoA oxidase in human liver and kidney, J. Biol. Lestringant, Abnormal myelin formation in rhizomelic chondrodysplasia Chem. 268 (1993) 10335. punctata type 2 (DHAPAT-deficiency), Dev. Med. Child Neurol. 42 (2000) [79] R.J.A. Wanders, Metabolic and molecular basis of peroxisomal disorders: 492. A review, Am. J. Med. Genet. 126A (2004) 355. [71] L.S. Sztriha, M.P. Nork,Y.M.Abdulrazzaq,L.I.al-Gazali,D.B. [80] R.J.A. Wanders, C. Dekker, V.A. Horvath, R.B.H. Schutgens, J.M. Tager, Bakalinova, Abnormal myelination in peroxisomal isolated dihydroxya- P. Van Laer, D. Lecoutere, Human alkyldihydroxyacetonephosphate cetonephosphate acyltransferase deficiency, Pediatr. Neurol. 16 (1997) synthase deficiency: a new peroxisomal disorder, J. Inherited Metab. 232. Dis. 17 (1994) 315. [72] E.G. van Grunsven, P.A.W. Mooijer, P. Aubourg, R.J.A. Wanders, Enoyl- [81] R.J.A. Wanders, A. Schelen, N. Feller, R.B.H. Schutgens, F. Stellaard, C. CoA hydratase deficiency: identification of an new type of D-bifunctional Jakobs, B. Mitulla, G. Seidlitz, First prenatal diagnosis of acyl-CoA protein deficiency, Hum. Mol. Genet. 8 (1999) 1509. oxidase deficiency, J. Inherited Metab. Dis. 13 (1990) 371. [73] E.G. van Grunsven, E. van Berkel, L. IJlst, P. Vreken, J.B. de Klerk, J. [82] R.J.A. Wanders, H. Schumacher, J. Heikoop, R.B.H. Schutgens, J.M. Adamski, H. Lemonde, P.T. Clayton, D.A. Cuebas, R.J.A. Wanders, Tager, Human dihydroxyacetonephosphate acyltransferase deficiency: a Peroxisomal D-hydroxyacyl-CoA dehydrogenase deficiency: resolution of new peroxisomal disorder, J. Inherited Metab. Dis. 15 (1992) 389. the enzyme defect and its molecular basis in bifunctional protein [83] R.J.A. Wanders, R.B.H. Schutgens, P.G. Barth, Peroxisomal disorders: a deficiency, Proc. Natl. Acad. Sci. U. S. A. 95 (1998) 2128. review. J. Neuropathol. Exp. Neurol. 54 (1995) 726. [74] L. Van Maldergem, M. Espeel, R.J.A. Wanders, F. Roels, P. Gerard, E. [84] R.J.A. Wanders, C.W.T. van Roermund, A. Schelen, R.B.H. Schutgens, Scalais, G.P. Mannaerts, M. Casteels, Y. Gillerot, Neonatal seizures and J.M. Tager, J.B. Stephenson, P.T. Clayton, A bifunctional protein with severe hypotonia in a male infant suffering from a defect in peroxisomal deficient enzymic activity: identification of a new peroxisomal disorder beta-oxidation, Neuromuscul. Disord. 2 (1992) 217. using novel methods to measure the peroxisomal beta-oxidation enzyme [75] P.P. Van Veldhoven, E. Meyhi, R.H. Squires, M. Fransen, B. Fournier, V. activities, J. Inherited Metab. Dis. 13 (1990) 375. Brys, M.J. Bennett, G.P. Mannaerts, Fibroblast studies documenting a case [85] R.J.A. Wanders, H.R. Waterham, Peroxisomal disorders I: biochemistry of peroxisomal 2-methylacyl-CoA racemase deficiency: possible link and genetics of peroxisome biogenesis disorders, Clin. Genet. 67 (2005) between racemase deficiency and malabsorption and vitamin K deficiency, 107. Eur. J. Clin. Invest. 31 (2001) 714. [86] P.A. Watkins, W.W. Chen, C.J. Harris, G. Hoefler, S. Hoefler, D.C. Blake Jr., [76] C.S. van Woerden, J.W. Groothoff, F.A. Wijburg, C. Annink, R.J.A. A. Balfe, R.I. Kelley, A.B. Moser, M.E. Beard, Peroxisomal bifunctional Wanders, H.R. Waterham, Clinical implications of mutation analysis in enzyme deficiency, J. Clin. Invest. 83 (1989) 771. primary hyperoxaluria type 1, Kidney Int. 66 (2004) 746. [87] P.A. Watkins, M.C. McGuinness, G.V. Raymond, B.A. Hicks, J.M. Sisk, [77] C. Vanhole, F. de Zegher, P. Casaer, H. Devlieger, R.J.A. Wanders, G. A.B. Moser, H.W. Moser, Distinction between peroxisomal bifunctional Vanhove, J. Jaeken, A new peroxisomal disorder with fetal and neonatal enzyme and acyl-CoA oxidase deficiencies, Ann. Neurol. 38 (1995) adrenal insufficiency, Arch. Dis. Child., Fetal Neonatal Ed. 71 (1994) 472. F55. [88] A.S. Wierzbicki, M.D. Lloyd, C.J. Schofield, M.D. Feher, F.B. Gibberd, [78] G.F. Vanhove, P.P. Van Veldhoven, M. Fransen, S. Denis, H.J. Eyssen, Refsum's disease: a peroxisomal disorder affecting phytanic acid alpha- R.J.A. Wanders, G.P. Mannaerts, The CoA esters of 2-methyl-branched oxidation, J. Neurochem. 80 (2002) 727.