Hamdan Medical Journal 2012; 5:313–326 (http://dx.doi.org/10.7707/hmj.v5i3.212)

REVIEW FOR THE SHEIKH HAMDAN BIN RASHID AL MAKTOUM AWARD FOR MEDICAL SCIENCES

Clinical, biochemical and genetic aspects of peroxisomal disorders – an expanding group of genetic diseases in humans

Ronald JA Wanders

University of Amsterdam, Academic Medical Centre, Department of Clinical Chemistry and Paediatrics, Emma Children’s Hospital, Laboratory Genetic Metabolic Diseases, Amsterdam, the Netherlands

Abstract clitoris hypertrophy, camptodactyly and simian creases. Unaware of this publication Smith, Opitz and (ZS) in its classic form is an autosomal recessive lethal 2 disease characterized by the absence of morphologically recognizable Inhorn in 1965 described ‘a syndrome of multiple . Detailed studies on ZS in the early 1980s have led to developmental defects including polycystic kidneys the discovery of a set of peroxisomal biomarkers in blood which has and intrahepatic biliary dysgenesis in two sibs’, revolutionized our knowledge about peroxisomes and peroxisomal disorders, who presented with a large number of comparable and formed the basis for the discovery of the group of peroxisomal diseases defects including severe hypotonia, high forehead, known at present. Peroxisomal disorders are classi!ed into two distinct shallow supraorbital ridges, camptodactyly, minor groups including the disorders of biogenesis (group 1) and anomalies of the eyes, ears, palate and hands, peroxisome function (group 2). The enzymatic and molecular basis of most and failure to thrive. Two years later, Passarge and peroxisomal disorders has been identi!ed through the years and pre- and McAdams3 described #ve sisters with similar clinical post-natal diagnostic methods have been established. This review describes and pathological features and introduced the term the current state of knowledge with respect to peroxisomes and peroxisomal cerebrohepatorenal syndrome. In 1969, Opitz et disorders with particular emphasis on the clinical biochemical and genetic 4 aspects of these disorders. al. proposed the name Zellweger syndrome. In an editorial comment, McKusick5 suggested that Introduction the two designations proposed by Passarge and 3 4 In 1964 Bowen, Lee, Zellweger and Lindenberg1 McAdam and Opitz et al. be combined, giving rise described a familial syndrome of multiple congenital to the cerebrohepatorenal syndrome of Zellweger. defects in two pairs of siblings (three girls and In practice, the name Zellweger syndrome (ZS) is one boy). Prenatal history and delivery were used most. unremarkable. At birth, hypotonia and a number of congenital anomalies were noted including bilateral In the early 1980s, several patients were presented glaucoma with corneal opacities, bilateral epicanthal to the Department of Paediatrics of the University folds, abnormal ears, a high-arched palate, wide Hospital Amsterdam, the Netherlands, with all the fontanelles, open metopic and lambdoid sutures, signs and symptoms described for ZS. Confronted with the devastating clinical course of ZS in these patients with early death in most of them, it was Correspondence: Professor Ronald JA Wanders, Lab Genetic obvious that prenatal diagnostic methods should Metabolic Diseases, Room F0–226, Academic Medical Centre, become available as soon as possible. In the absence University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the of any such method described in literature, we 313 Netherlands. Email: [email protected] © 2012 The Author(s) 313 Journal Compilation © 2012 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences Hamdan Medical Journal 2012; 5:313–326 (http://dx.doi.org/10.7707/hmj.v5i3.212) REVIEW FOR THE SHEIKH HAMDAN BIN RASHID AL MAKTOUM AWARD FOR MEDICAL SCIENCES

decided to perform a thorough literature search enzymes and – which degrades H2O2 – in which might give a clue for future research aimed a single particle prompted de Duve and coworkers to develop a prenatal laboratory test. One of the to introduce the name ‘peroxisome’. Combined #rst papers we stumbled across, was the – in morphological and biochemical investigations by retrospect – seminal publication by Gold#scher et Baudhuin et al.9 provided unequivocal evidence al.,6 who described the absence of morphologically that microbodies are the morphological equivalent distinguishable peroxisomes in hepatocytes and of peroxisomes. kidney cortex cells of ZS patients. Since at that time virtually nothing was known about peroxisomes, Our literature search in the early 1980s revealed this observation went unnoticed. In fact, much more very little information on mammalian peroxisomes attention was paid to the mitochondrial abnormalities except for two publications. The #rst one was described in the same paper, as is clear from the from Lazarow and de Duve,10 who described the title ‘Peroxisomal and mitochondrial defects in the presence of a fatty acid beta-oxidation system cerebro-hepato-renal syndrome’. Indeed, Gold#scher in peroxisomes. The signi#cance of such a beta- et al.6 documented clear mitochondrial abnormalities oxidation system in mammalian cells next to that characterized by a markedly reduced rate of oxygen in mitochondria, however, was unclear. The other uptake of mitochondria isolated from a brain biopsy paper was by Hajra and coworkers,11 who reported of a ZS patient and a liver biopsy from another ZS that the enzyme dihydroxyacetone phosphate patient with malate (plus glutamate) as substrate acyltransferase (DHAPAT), known to catalyse the #rst but not with ascorbate plus N,N,Ne,Ne-tetramethyl- step in etherphospholipid synthesis, was localized p-phenylenediamine (TMPD) as substrate. These in peroxisomes and not in mitochondria and #ndings led the authors to conclude that ‘the microsomes as thought previously. This important cytochrome portion of the electron transport chain is #nding was soon followed by the discovery that intact but that there is a defect in electron transport the second enzyme involved in etherphospholipid prior to the cytochromes’.6 Based on these results, synthesis, i.e. alkyldihydroxyacetone phosphate ZS was considered to be a mitochondrial disorder. synthase (ADHAPS), was also localized in Subsequent studies by other investigators, however, peroxisomes. These two #ndings prompted us to revealed that the mitochondrial abnormalities at study etherphospholipid in Zellweger the level of the respiratory chain were remarkably patients. In mammals, the main end products of variable among patients, ranging from near-normal etherphospholipid biosynthesis are the plasmalogens to grossly impaired, which argued against ZS as a (1-O-alk-1e-enyl-2-acylphosphoglycerides), which primary mitochondrial disorder. are characterized by the presence of an alpha-, beta-unsaturated ether bond at the sn-1 position Peroxisomes were #rst described as ‘spheric or of the glycerol backbone. Plasmalogen analysis in oval bodies’ present in the cytoplasm of mouse tissues and erythrocytes from Zellweger patients proximal kidney tubules. Rouiller and Bernard7 revealed a marked de#ciency of this special type of identi#ed similar organelles in rat hepatocytes and phospholipids.12 This breakthrough #nding, soon suggested that they were precursors (progenitors) of thereafter, paved the way to the development of mitochondria, rather than distinct cell organelles sui prenatal diagnostic methods.13 generis. The addition of microbodies to the group of biochemically de#ned organelles is closely related Parallel to the work done in Amsterdam, Moser to the development of cell fractionation techniques. and coworkers14 found that the plasma levels of Indeed, the conclusion that catalase, urate oxidase very long-chain fatty acids (VLCFAs) in ZS patients and D-amino acid oxidase are located in a distinct were markedly elevated in contrast to the levels particle di$erent from lysosomes, microsomes and of the long-chain fatty acids, which were normal. mitochondria was reached on the basis of di$erential These results immediately suggested that the and isopycnic-gradient centrifugation studies by de accumulation of VLCFAs had to do with the presence Duve and Baudhuin.8 Importantly, earlier studies by of a beta-oxidation system in peroxisomes and that de Duve and coworkers using the same technique the peroxisomal and mitochondrial beta-oxidation had led to the identi#cation of another subcellular systems might serve di$erent physiological purposes, organelle, the lysosome, for which Christian de Duve catalysing the oxidation of di$erent sets of substrates, received the Nobel Prize in 1974. The concomitant which turned out to be correct, as outlined below. occurrence of hydrogen peroxide-producing

314 © 2012 The Author(s) Journal Compilation © 2012 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences Hamdan Medical Journal 2012; 5:313–326 (http://dx.doi.org/10.7707/hmj.v5i3.212) REVIEW FOR THE SHEIKH HAMDAN BIN RASHID AL MAKTOUM AWARD FOR MEDICAL SCIENCES

From Zellweger syndrome to a set peroxisomal diseases: (1) fatty acid beta-oxidation; (2) of peroxisomal biomarkers in blood etherphospholipid biosynthesis; (3) fatty acid alpha- and the discovery of a whole group of oxidation; and (4) glyoxylate detoxi#cation. These will peroxisomal disorders be discussed only brie%y here. For a detailed review see Wanders and Waterham.15 The availability of two peroxisomal markers including the VLCFAs and plasmalogens, as described above, which could be measured in a simple blood sample Peroxisomal beta-oxidation opened the way to search for additional peroxisomal Peroxisomes oxidize their own set of fatty disorders. This search was greatly helped by acids (FAs) including the VLCFA C26:0, the the subsequent discovery of other peroxisomal branched-chain fatty acid pristanic acid abnormalities including elevated levels of phytanic (2,6,10,14-tetramethylpentadecanoic acid) and di-and acid, pristanic acid, di- and trihydroxycholestanoic trihydroxycholestanoic acid. The last two acids are acid and pipecolic acid in plasma. Importantly, synthesized from cholesterol in the liver and are the #ndings in ZS patients also elicited a renewed converted into cholic acid and chenodeoxycholic acid interest in peroxisomes and inspired biochemists, cell by beta-oxidation (Figure 1). The enzymes involved biologists and geneticists to work on peroxisomes, in peroxisomal beta-oxidation have been identi#ed which has resulted in detailed knowledge about through the years and include two acyl-CoA oxidases, the metabolic role of peroxisomes and how these two bifunctional with enoyl-CoA hydratase organelles are biosynthesized (see reference 15 and 3-hydroxyacyl-CoA dehydrogenase activities for review). All this work has revolutionized our and two thiolases, which are all di$erent from their knowledge about peroxisomes and peroxisomal mitochondrial counterparts. Since peroxisomes lack disorders. First, established diseases which were a citric acid cycle and respiratory chain, full oxidation not known to have any relationship to peroxisomes of fatty acids as #rst handled by peroxisomes requires were identi#ed as peroxisomal disorders (PDs). mitochondria for further processing into CO and H O This is true for infantile Refsum disease (IRD),16 2 2 (Figure 1).29,30 neonatal adrenoleucodystrophy (NALD),17 X-linked adrenoleucodystrophy (X-ALD)18 and rhizomelic chondrodysplasia punctata (RCDP).19 Second, new Etherphospholipid biosynthesis PDs were identi#ed including DHAPAT de#ciency Peroxisomes play an essential role in the synthesis (RCDP type 2),20 alkyl-DHAP synthase de#ciency of etherphospholipids with plasmalogens as main (RCDP type 3),21 acyl-coenzyme A (CoA) oxidase end products in mammals (see Figure 1) since the de#ciency,22 D-bifunctional de#ciency,23,24 #rst part of the biosynthetic pathway formed by the 2-methylacyl-CoA racemase (AMACR) de#ciency25 and two enzymes DHAPAT and ADHAPS occurs solely in sterol carrier protein x (SCPx) de#ciency.26 Another peroxisomes (see Figure 1).31,32 major breakthrough which is of a more recent date is the identi#cation of aberrant phenotypes not previously known to have a peroxisomal origin. In Fatty acid alpha-oxidation this respect, the identi#cation of isolated cerebellar Some FAs, notably those which contain a methyl ataxia in patients with a clear defect in peroxisome group at the 3-position, cannot be beta-oxidized but biogenesis is worth mentioning.27,28 instead require alpha-oxidation #rst to remove the terminal carboxyl group as CO to generate a 2-methyl Our laboratory has played a key role in the 2 FA which can be degraded by beta-oxidation. The identi#cation of most of these disorders, of which structure of the pathway and the enzymes involved 15 have been identi#ed so far (Table 1). All this work have been identi#ed in recent years.33 has led to the identi#cation of thousands of patients worldwide, with our centre as one of the reference centres for the clinical as well as pre- and post-natal Glyoxylate detoxi!cation laboratory diagnosis of PDs. Glyoxylate is a toxic metabolite which has to be degraded rapidly. This occurs in peroxisomes as Metabolic functions of peroxisomes mediated by the peroxisomal enzyme alanine glyoxylate aminotransferase (AGT). In the case of Peroxisomes catalyse a number of essential metabolic a de#ciency of AGT, as in hyperoxaluria type 1, functions, of which four have been directly linked to

© 2012 The Author(s) 315 Journal Compilation © 2012 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences Hamdan Medical Journal 2012; 5:313–326 (http://dx.doi.org/10.7707/hmj.v5i3.212) REVIEW FOR THE SHEIKH HAMDAN BIN RASHID AL MAKTOUM AWARD FOR MEDICAL SCIENCES

TABLE 1 The peroxisomal disorders

Disorder abbreviation MIM number Defective protein Mutant

Disorders of peroxisome biogenesis PBD – group A ZSDs 1. ZS 214 100 PEX1 PEX1 7q21.2 2. NALD 214 110 PEX2 PEX2 8q21.1 3. IRD 202 370 PEX3 PEX3 6q24.2 PEX5 PEX5 12p13.3 PEX6 PEX6 6p21.1 PEX10 PEX10 1p36.32 PEX12 PEX12 17q12 PEX13 PEX13 2p14-p16 PEX14 PEX14 1p36.22 PEX16 PEX16 11p11.2 PEX19 PEX19 1q22 PEX26 PEX26 22q11.21 PBD – group B 4. RCDP-1 215 100 PEX7p PEX7 6q21-q22.2

Disorders of peroxisome function Fatty acid beta-oxidation 5. X-ALD 300 100 ALDP ABCD1 Xq28 6. ACOX de!ciency 264 470 ACOX1 ACOX1 17q25.1 7. DBP de!ciency 261 515 DBP/MFP2/MFEII HSD17B4 5q2 8. SCPx de!ciency - SCPx SCP2 1p32 9. AMACR de!ciency 604 489 AMACR AMACR 5p13.2-q11.1 Etherphospholipid biosynthesis 10. RCDP-2 222 765 DHAPAT GNPAT 1q42.1–42.3 11. RCDP-3 600 121 ADHAPS AGPS 2q33 Fatty acid alpha-oxidation 12. ARD/CRD 266 500 PHYH/PAHX PHYH/PAHX 10p15-p14 Glyoxylate metabolism 13. PH-1 259 900 AGT AGXT 2q37.3 Bile acid synthesis (conjugation) 14. BAAT de!ciency 607 748 BAAT BAAT 9q31.1

H2O2 metabolism 15. Acatalasaemia 115 500 Catalase CAT 11p13

ABCD1, adenosine triphosphate (ATP)-binding cassette, subfamily D (ALD), member 1; ACOX, acyl-CoA oxidase; ADHAPS, alkyldihydroxyacetone phosphate synthase; AGPS, alkylglycerone phosphate synthase; AGT, alanine glyoxylate aminotransferase; AGXT, alanine glyoxylate aminotransferase; AMACR, alpha-methylacyl-CoA racemase; ARD, adult Refsum disease; BAAT, bile acid-CoA, amino acid N-acyltransferase; CRD, classic Refsum disease; DBP, D-bifunctional protein; GNPAT, glyceronephosphate O-acyltransferase; HSD17B4, hydroxysteroid (17-beta) dehydrogenase 4; IRD, infantile Refsum disease; MIM, Mendelian Inheritance in Man; NALD, neonatal adrenoleucodystrophy; PBD, peroxisome biogenesis disorder; PEX, peroxisomal biogenesis factor; RCDP-1, rhizomelic chondrodysplasia punctata type 1; RCDP-2, rhizomelic chondrodysplasia puncatata type 2; RCDP-3, rhizomelic chondrodysplasia puncatata type 3; SCPx, sterol carrier protein X; PH-1, hyperoxaluria type 1; X-ALD, X-linked adrenoleucodystrophy; ZSD, Zellweger spectrum disorder.

316 © 2012 The Author(s) Journal Compilation © 2012 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences Hamdan Medical Journal 2012; 5:313–326 (http://dx.doi.org/10.7707/hmj.v5i3.212) REVIEW FOR THE SHEIKH HAMDAN BIN RASHID AL MAKTOUM AWARD FOR MEDICAL SCIENCES

A B C D E

Phytanic acid Pristanic acid VLCFA DHCA THCA Acyl-CoA +DHAP +long-chain alcohol CoASH CoASH CoASH CoASH

Phytanoyl-CoA Pristanoyl-CoA VLCF-CoA DHC-CoA THC-CoA

DHAPAT+ -oxidation ß-oxidation ß-oxidation ß-oxidation Alkyl-DHAP (1 cycle) (3 cycles) (? cycles) (1 cycle) synthase

CoASH CO2 Acetyl-CoA Acetyl-CoA Chenodeoxy- choloyl-CoA FA

Pristanoyl-CoA Propionyl-CoA Medium-chain- Choloyl-CoA Alkyl-DHAP Acyl-CoA 4,8-DMN-CoA Glycine/ Taurine PEROXISOME Glyco/Tauro Glyco/Tauro ER chenodeoxy cholic acid Transport to Transport to cholic acid mitochondria mitochondria + further oxidation + further oxidation Etherphospholipids

Bile CO2 + H2O CO2 + H2O

FIGURE 1 Schematic diagram depicting the main functions of peroxisomes (see text for details). glyoxylate accumulates and gives rise to glycolate uptake of the peroxisomal matrix proteins via two and oxalate, which precipitates as calcium oxalate di$erent cycling receptors, i.e. peroxisomal biogenesis with devastating consequences, as observed in factor 7 (PEX7) and peroxisomal biogenesis factor 5 hyperoxaluria patients.34 (PEX5), which recognize distinct groups of proteins containing either a peroxisomal targeting signal 2 (PTS2; in the case of PEX7) or peroxisomal targeting Peroxisome biogenesis signal 1 (PTS1; in the case of PEX5) sequence as In recent years much has been learned about targeting signal. It was originally thought that the biogenesis of peroxisomes and many of the peroxisomes are autonomous organelles like key players in peroxisome biogenesis have been mitochondria, which means that they cannot form de identi#ed, which has paved the way to the discovery novo but only from pre-existing organelles, but this is of the molecular basis of most of the peroxisome no longer true for peroxisomes (Figure 2). Resolution biogenesis disorders. The biogenesis of peroxisomes of the principal features of peroxisome biogenesis resembles that of mitochondria in several respects, and the identi#cation of the involved, called although there are di$erences as well. A common PEX genes, has allowed the identi#cation of the feature of the biogenesis of peroxisomes and molecular defect in virtually all patients with a defect mitochondria is that both organelles acquire their in peroxisome biogenesis, as recently described by us proteins through the speci#c uptake of proteins in > 600 patients.35 from the cytosol by virtue of speci#c receptors recognizing certain target sequences in the di$erent Peroxisomes start their life in the endoplasmic proteins ultimately destined for the peroxisome reticulum, but may also form from pre-existing or mitochondrion, respectively. In the case of peroxisomes. The peroxisomal biogenesis peroxisomes, peroxisomal membrane proteins (PMPs) factor 3 (PEX3) is essential for this initial phase of are imported #rst, with peroxisomal biogenesis peroxisome biogenesis in which a pre-peroxisome factor 19 (PEX19) as cycling receptor, followed by the is generated. The peroxin peroxisomal biogenesis

© 2012 The Author(s) 317 Journal Compilation © 2012 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences Hamdan Medical Journal 2012; 5:313–326 (http://dx.doi.org/10.7707/hmj.v5i3.212) REVIEW FOR THE SHEIKH HAMDAN BIN RASHID AL MAKTOUM AWARD FOR MEDICAL SCIENCES

Examples : - Acyl-CoA oxidase 1 and 2

- L-and D-Bifunctional protein PTS1-proteins ( , , etc) - Peroxisomal 2 (SCPx) - DHAPAT - Alanine glyoxylate transferase PEX5 - 2-Hydroxyphytanoyl-CoA lyase - Etc. PEX16 ( ) PEX5

ER

fission PEX19 PEX7

PEX3 ( ) PEX19 PEX7 PTS2-proteins ( , ,etc)

Examples : – Phytanoyl-CoA hydroxylase PMPs ( , , ,etc) – Alkyl DHAP synthase – Peroxisomal thiolase 1

FIGURE 2 Biogenesis of peroxisomes in humans. factor 16 (PEX16) also plays a role – albeit unresolved and the disorders of peroxisome function in yet – in this initial phase of peroxisome biogenesis. subgroup 2 (see Table 1). Subsequently, the PMPs are inserted into this pre- peroxisomal vesicle with a key role for the cytosolic Peroxisome biogenesis disorders cycling receptor, PEX19. The next phase is the import of matrix proteins mediated by PEX5 for PTS1 proteins The PBD group is also subclassi#ed into two groups, and PEX7 for PTS2 proteins. Next, peroxisomes A and B. In group A disorders, both the PTS1 and PTS2 undergo proliferation and division. The division of pathways of peroxisome biogenesis are impaired peroxisomes involves three distinct sequential steps: (group A), whereas in the disorders of group B elongation of peroxisomes, membrane constriction only the PTS2 pathway is de#cient (group B). This and, #nally, #ssion of peroxisomes. The proteins subclassi#cation is important because the PBDs dynamine-like protein 1 (DLP1), mammalian #ssion 1 involved are clinically very di$erent and also require (hFIS1) and mammalian mitochondrial #ssion factor di$erent laboratory methods for identi#cation. (M$) are involved in this process. Remarkably, the last three proteins play a role not only in the #ssion of Zellweger spectrum disorders peroxisomes but also in the #ssion of mitochondria. With respect to the elongation of peroxisomes, Peroxisome biogenesis disorders group A di$erent PEX11 proteins are involved. comprises three di$erent disorders: ZS, neonatal adrenoleucodystrophy (NALD) and IRD. Since the identi#cation of phenotypes in between ZS and IRD The peroxisomal disorders and ZS and NALD, the name Zellweger spectrum The group of peroxisomal disorders is generally disorders (ZSDs) has been introduced. Clinical signs subdivided into two distinct groups with the and symptoms of ZSD patients vary markedly, disorders of peroxisome biogenesis in subgroup 1 ranging from the full constellation of abnormalities seen in ZS patients (craniofacial, neurological,

318 © 2012 The Author(s) Journal Compilation © 2012 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences Hamdan Medical Journal 2012; 5:313–326 (http://dx.doi.org/10.7707/hmj.v5i3.212) REVIEW FOR THE SHEIKH HAMDAN BIN RASHID AL MAKTOUM AWARD FOR MEDICAL SCIENCES skeletal, ocular and hepatological) to the milder Table 2 shows that about two-thirds of our cohort presentations observed in NALD and especially IRD of ZSD patients carry mutations in PEX1, whereas patients. Because of this diversity in clinical signs mutations in any of the other PEX genes are far and symptoms we advocate performing peroxisomal less frequent. biomarker pro#ling in blood samples of any patient with a (variable) combination of neurodevelopmental Treatment delay, retinopathy, perceptive deafness, plus or minus liver disease. In the meantime, however, new milder As a result of the multiplicity and severity of phenotypes have been identi#ed, including isolated de#cits, only supportive and symptomatic care cerebellar ataxia, lacking these features.27,28 is recommended for patients with classic ZS. For patients with the somewhat milder variants, considerable success has been achieved with Laboratory diagnosis multidisciplinary early intervention including physical The laboratory diagnosis of patients suspected to and occupational therapy, hearing aids, alternative su$er from a ZSD starts with the analysis of known communication, nutrition and support for the peroxisomal biomarkers with VLCFA analysis as a parents. Although most patients continue to function #rst-line test. If abnormal, the other parameters in the profoundly or severally retarded range, some should be tested, followed by detailed studies make signi#cant gains in self-help skills, and several in #broblasts, which includes complementation are now in a stable condition in their teens or even analysis. Already in 198736 we established that ZS early 20s. In the past, several strategies have been is a genetically heterogeneous disease through tried to correct the biochemical abnormalities: (1) oral identi#cation of four complementation groups. In administration of cholic acid and chenodeoxycholic subsequent years, additional complementation acid; (2) administration of the ethyl ester of groups have been identi#ed and now total 12 distinct docosahexaenoic acid; and (3) the oral administration groups.37 The underlying gene defect in each of these of batyl alcohol in order to restore plasmalogen levels. complementation groups has been determined, Unfortunately, reports remain anecdotal and no as shown in Table 2. We recently published our #rm conclusions can be drawn at present about the combined results of complementation analysis e"cacy of any of the three strategies. followed by molecular analysis of the relevant PEX gene in > 600 ZSD patients (Table 2). Inspection of Rhizomelic chondrodysplasia punctata

TABLE 2 Frequency distribution of PEX gene defects Peroxisome biogenesis disorders group B contains among 613 patients diagnosed with a ZSD only a single representative, i.e. RCDP. RCDP is clinically characterized by a disproportionately short Number of patient stature primarily a$ecting the proximal parts of the PEX gene cell lines analysed Frequency (%) extremities, typical facial appearance, congenital PEX1 358 58 contractures, characteristic ocular involvement and PEX2 23 4 severe mental and growth retardation. Radiological PEX3 3 < 1 studies usually reveal shortening, metaphyseal PEX5 13 2 cupping and disturbed ossi#cation of humeri and/ PEX6 97 16 or femora, together with epiphyseal and extra- PEX10 19 3 epiphyseal calci#cations. The gene defective in RCDP type 1 is the PEX7 gene, which codes for PEX7, which PEX12 54 9 is the cycling receptor involved in the recognition of PEX13 10 1 PTS2 proteins in the cytosol followed by the delivery PEX14 3 < 1 to the peroxisome and uptake into the peroxisome PEX16 8 1 (see Figure 2). Typical PTS2 proteins are ADHAPS, PEX19 4 < 1 involved in etherphospholipid biosynthesis, and PEX26 21 3 phytanoyl-CoA hydroxylase (PHYH/PHAX), involved in fatty acid alpha oxidation, which explains why RCDP Data extracted from Ebberink MS, Mooijer PA, Gootjes J, et al. Genetic classi!cation and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum patients have low plasmalogen levels in erythrocytes disorder. Hum Mutat 2011; 32, 59–69. http://dx.doi.org/10.1002/humu.21388 and high plasma phytanic acid levels.

© 2012 The Author(s) 319 Journal Compilation © 2012 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences Hamdan Medical Journal 2012; 5:313–326 (http://dx.doi.org/10.7707/hmj.v5i3.212) REVIEW FOR THE SHEIKH HAMDAN BIN RASHID AL MAKTOUM AWARD FOR MEDICAL SCIENCES

Laboratory diagnosis cerebral phenotype is not only observed in childhood, but may also present later in life in adolescence If a patient is suspected of su$ering from RCDP, (adolescent cerebral ALD; ACALD) or adulthood (adult plasmalogen analysis is the #rst-line test to be cerebral ALD). There is a marked di$erence between performed since in virtually all patients, at least in the cerebral phenotypes, on the one hand, and AMN, our hands, plasmalogens in erythrocytes are grossly on the other, since the cerebral phenotypes show an de#cient. Analysis of phytanic acid is also helpful, in%ammatory reaction in the cerebral white matter although it should be remembered that phytanic acid which resembles, but can be distinguished from, levels may vary from normal to markedly elevated what is observed in multiple sclerosis. In contrast as phytanic acid is derived from dietary sources only. with CCALD, the in%ammatory response is absent or Subsequently, studies in #broblasts are warranted mild in AMN, which has a much later age of onset to discriminate between RCDP type 1, 2 and 3 (see (28 ± 9 years) and a much lower rate of progression. below) followed by analysis of the relevant genes, It is important to mention that approximately including PEX7, GNPAT or AGPS (see Table 1). 40–50% of women heterozygous for X-ALD develop AMN-like symptoms in middle age or later. Cerebral Treatment involvement and adrenocortical insu"ciency, however, are rare. No realistic options for therapy have been documented in literature so far. Laboratory diagnosis Disorders of peroxisome function Plasma VLCFA analysis is the #rst line of testing in patients suspected of su$ering from one of the The disorders of peroxisome function can best be X-ALD phenotypes and has been proven to be an subclassi#ed according to the metabolic function exceptionally robust biomarker for X-ALD, especially which is actually lost. This includes peroxisomal fatty when the algorithm developed by Moser et al.38 is acid beta-oxidation, etherphospholipid synthesis, used. If abnormal, molecular analysis of the adenosine fatty acid alpha-oxidation, glyoxylate metabolism, bile triphosphate (ATP)-binding cassette, subfamily acid conjugation and H O metabolism. 2 2 D (ALD), member 1 (ABCD1) gene is warranted, which has so far revealed > 600 di$erent mutations The disorders of peroxisome fatty acid (see: http://www.x-ald.nl). beta-oxidation At present, #ve di$erent disorders of peroxisomal Treatment beta-oxidation can be distinguished: (1) X-linked It is crucially important to provide adrenal adrenoleucodystrophy; (2) acyl-CoA oxidase hormone therapy for every ALD patient with de#ciency; (3) D-bifunctional protein de#ciency; adrenocortical insu"ciency. Almost all a$ected boys (4) SCPx de#ciency; and (5) alpha-methylacyl-CoA and 60% of men with AMN have impaired adrenal racemase (AMACR) de#ciency. reserve.39 Consequently, all patients diagnosed should undergo an adrenocorticotropic hormone (ACTH) X-linked adrenoleucodystrophy stimulation test. X-linked adrenoleucodystrophy has a widely variable Allogeneic haematopoietic stem cell transplantation phenotypic presentation with at least six di$erent (HCT) is the only treatment that can arrest or phenotypic variants described. The classi#cation of even reverse cerebral demyelination provided the X-ALD is somewhat arbitrary and based on the age procedure is performed at an early stage of the at onset and the organs principally involved. X-ALD is disease and this point is absolutely crucial (see the most common single with reference 40 for the latest information). Although a minimum incidence of 1 : 21 000 males in the USA38 more than 200 X-ALD patients have now been to 1 : 15 000 males in France. The two most frequent transplanted successfully41 and 20 years’ follow-up of phenotypes are childhood cerebral ALD (CCALD) and treated patients has con#rmed the bene#cial e$ect adrenomyeloneuropathy (AMN). Onset of CCALD of allogeneic HCT in X-ALD de#nitively, the procedure is between 3 and 10 years of age, with progressive remains associated with serious limitations. Therefore, behavioural, cognitive and neurological deterioration, human stem cell (HSC) gene therapy will certainly be often leading to total disability within 3 years. The an alternative to allogeneic HCT in the near future.

320 © 2012 The Author(s) Journal Compilation © 2012 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences Hamdan Medical Journal 2012; 5:313–326 (http://dx.doi.org/10.7707/hmj.v5i3.212) REVIEW FOR THE SHEIKH HAMDAN BIN RASHID AL MAKTOUM AWARD FOR MEDICAL SCIENCES

Two X-ALD patients have recently been successfully acquired any psychomotor developments and the few treated using this strategy.42 patients who did showed progressive loss of motor achievements subsequently. External dysmorphia was a frequent #nding (58%) and resembled that of Acyl-CoA oxidase de!ciency patients with ZS as characterized by high forehead, All patients identi#ed so far had psychomotor high-arched palate, large fontanelles, long philtrum, retardation, but did acquire limited skills, including epicanthal folds, hypertelorism, macrocephaly, the ability to sit and stand up unsupported, with shallow supraorbital ridges, retrognathia and voluntary control of hand function and limited low-set ears. speech. In most patients (83%), however, there was loss of motor achievements with a mean age at D-Bifunctional protein de#ciency is subdivided regression of 28 months. Brain imaging [magnetic into three di$erent types depending on whether resonance (MRI) and/or computerized tomography it is the complete DBP which is missing (type I) or (CT)] revealed cerebral and/or cerebellar white-matter only the hydratase (type II) or 3-hydroxyacyl-CoA abnormalities in all patients investigated (12 out dehydrogenase component (type III) which is of 12). Three of these patients showed neocortical de#cient. Most patients die before 2 years of age. dysplasia. Other abnormalities include hypotonia (97%), seizures (91%), visual system failure (78%), Laboratory diagnosis impaired hearing (77%), facial dysmorphia (50%), hepatomegaly (50%) and failure to thrive (37%). The de#cient activity of DBP leads to a number of Interestingly, two adult patients with acyl-CoA biochemical abnormalities including elevated plasma oxidase de#ciency have recently been described.43 levels of VLCFAs, phytanic acid, pristanic acid and the bile acid intermediates di- and trihydroxycholestanoic acid, although not in all patients. First-line testing Laboratory diagnosis should include VLCFA analysis, which is abnormal in Elevated plasma VLCFA levels have been found in all virtually all patients. Subsequent detailed studies in patients described in literature with proven acyl-CoA #broblasts need to be done to determine whether or oxidase de#ciency except for one. Indeed, Rosewich not there is a full de#ciency of DBP or a defect in one et al.44 described a true case of acyl-CoA oxidase of the two components of DBP only. Finally, molecular de#ciency with normal plasma VLCFAs. Acyl-CoA analysis has to be done to pinpoint the molecular oxidase de#ciency in this patient was suspected defect, which has revealed a multitude of often based on the characteristic MRI #ndings. The private mutations with only one frequent mutation in molecular basis of acyl-CoA oxidase de#ciency has the hydroxysteroid (17-G) dehydrogenase 4 (HSD17B4) been worked out and has revealed marked genetic gene (c.46G q A; allele frequency 24%). heterogeneity with often private mutations.45 Treatment Treatment No realistic therapeutic measures for DBP de#ciency No treatment options have been described for acyl- have been described. CoA oxidase de#ciency. Peroxisomal sterol carrier protein X de!ciency D-Bifunctional protein de!ciency This defect has only been described in a single patient D-Bifunctional protein de#ciency was #rst described so far. The patient involved is a 45-year-old white independently by Suzuki et al.23 and our own man with a 28-year history of dystonic head tremor group.24 In 2006, we reported on the clinical and and spasmodic torticollis. He had noticed a starter biochemical spectrum of DBP de#ciency in 126 for the #rst time at 7 years of age. At 17 years of age patients. The clinical presentation of DBP de#ciency he developed spasmodic torticollis to the left side is dominated by neonatal hypotonia (98%) and with dystonic head tremor in stressful situations. seizures (93%) within the #rst months of life. Failure On check-up at 29 years of age, brain MRI showed to thrive was observed in 43% of the patients. Visual bilateral hyperintense signals in the thalamus, system failure, including nystagmus, strabismus butter%y-like lesions in the pons and some lesions and/or failure to #xate objects at 2 months, was in the occipital region. Neurological examination also frequent (54%). Almost none of the patients revealed hyposmia, pathological saccadic eye

© 2012 The Author(s) 321 Journal Compilation © 2012 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences Hamdan Medical Journal 2012; 5:313–326 (http://dx.doi.org/10.7707/hmj.v5i3.212) REVIEW FOR THE SHEIKH HAMDAN BIN RASHID AL MAKTOUM AWARD FOR MEDICAL SCIENCES movements and a slight hyperacusis. There were signs Disorders of etherphospholipid of slight cerebellar ataxia with a left-sided intention biosynthesis tremor, balance and gait impairment, and a slight left-sided rebound phenomenon. Rhizomelic chondrodysplasia punctata type 2 and type 3 Laboratory diagnosis In 1992,20 we reported a patient with all the signs and symptoms described for RCDP, but with a di$erent Analysis of the peroxisome metabolites in plasma biochemical pro#le both in blood as well as in of the patient revealed no abnormalities except for #broblasts. The #nding that erythrocyte plasmalogen trace amounts of the bile acid intermediates 3F, levels were fully de#cient while plasma phytanic acid 7F-dihydroxy-5G-cholestanoic acid (DHCA) and 3F, was normal suggested that we were dealing with a 7F, 12F-trihydroxy-5G-cholestanoic acid (THCA). di$erent peroxisomal form of RCDP. Detailed studies Interestingly, more marked abnormalities were found in #broblasts followed up by molecular studies a few in the patient’s urine including large amounts of bile years later revealed that DHAPAT de#ciency in this alcohols (see Ferdinandusse et al.26 for further details). patient was due to mutations in the encoding gene GNPAT.48,49 Two years later, we identi#ed another Treatment peroxisomal form of RCDP, again in a patient with all the signs and symptoms of RCDP, but in whom a As a result of the elevated pristanic acid levels, the full de#ciency of alkyl-DHAP synthase (ADHAPS) was single patient with SCPx de#ciency identi#ed so identi#ed as caused by mutations in the encoding far began a phytanic acid-restricted diet, which led gene AGPS. RCDP type 1 due to mutations in PEX7 to decreased pristanic acid levels at a marginally has remained the most frequent form of RCDP with elevated level. Since the beginning of the diet, no type 2 and type 3 described in only 10 and 5 patients, progression of symptoms has been observed. respectively.

2-Methylacyl-CoA racemase de!ciency Laboratory diagnosis 2-Methylacyl-CoA racemase de#ciency was #rst First-line testing of RCDP type 2 and type 3 includes described in 200025 in two patients whose clinical plasmalogen analysis in erythrocytes. In all patients presentation was dominated by a late-onset sensory we have identi#ed through the years erythrocyte motor neuropathy. Subsequently, this defect has plasmalogen levels have been found to be very much been found in a few additional patients. Interestingly, de#cient (< 10%). Subsequent studies in #broblasts Setchell et al.46 described a completely di$erent followed up by molecular studies are needed to phenotype of AMACR de#ciency dominated by severe pinpoint the true enzymatic and molecular defect. liver abnormalities early in life. Recently, Kapina et al.47 described yet another clinical presentation of AMACR de#ciency, characterized by stroke-like episodes and Fatty acid alpha-oxidation recurrent rhabdomyolysis. Refsum disease Laboratory diagnosis Refsum disease was #rst described in the 1940s. The full constellation of cardinal features, as described Patients identi#ed so far have shown clear by Refsum, which includes retinitis pigmentosa (RP), peroxisomal abnormalities in plasma characterized cerebellar ataxia and chronic polyneuropathy, is rarely by elevated pristanic acid and di- and seen in individual Refsum patients. Indeed, detailed trihydroxycholestanoic acid, but normal VLCFA levels. studies by Wierzbicki et al.50 have shown that RP is Urine analysis has also revealed clear abnormalities an early clinical sign present in all Refsum patients, showing large amounts of abnormal bile alcohols. with ataxia and polyneuropathy, which develop later, observed in only around 70% and 50% of patients Treatment respectively. Interestingly, virtually every individual ultimately diagnosed as having Refsum disease No therapeutic e$orts have been tried in AMACR experiences visual symptoms #rst. Night blindness de#ciency so far. and loss of visual capacity, especially when combined

322 © 2012 The Author(s) Journal Compilation © 2012 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences Hamdan Medical Journal 2012; 5:313–326 (http://dx.doi.org/10.7707/hmj.v5i3.212) REVIEW FOR THE SHEIKH HAMDAN BIN RASHID AL MAKTOUM AWARD FOR MEDICAL SCIENCES with anosmia, should lead to prompt analysis of Laboratory diagnosis plasma phytanic acid in order to start therapy. Urinary oxalate analysis is the method of choice to Furthermore, electroretinography (ERG) should be check for PH-I. In PH-I patients overproduction of done, which shows either reduction or a complete oxalate in the liver results in very high urinary oxalate loss of rod and cone responses. excretion, typically amounting to > 1 mmol/1.73 m2 per day. A raised urinary glycolate level is strongly Laboratory diagnosis suggestive of PH-I, but glycolate may also be entirely normal in PH-I patients. Although measurement of First-line testing for Refsum disease includes phytanic AGT enzyme activity in a liver biopsy specimen has acid analysis in plasma, which is abnormal in all long been the gold standard for the diagnosis of PH-I, Refsum patients identi#ed so far. Subsequent work direct molecular analysis of the alanine glyoxylate in #broblasts, followed up by molecular studies, aminotransferase (AGXT) gene is rapidly becoming has to be done to pinpoint the enzymatic and the #rst choice for diagnosis. This is because in a molecular defect. signi#cant proportion of PH-I patients AGT enzyme activity is not de#cient, at least not in vitro in a Treatment liver homogenate, since the enzyme is targeted to mitochondria rather than to peroxisomes.51 No curative therapy currently exists for Refsum disease. Plasma phytanic acid concentrations can be reduced by 50–70%, typically to about Treatment 100–300 µmol/l, by restricting dietary intake of Overall, the treatment of PH-I greatly depends on phytanic acid or eliminating phytanic acid by the degree of renal function. Conservative measures plasmapheresis or lipid apheresis. This reduction in should be initiated as soon as possible with the plasma phytanic acid successfully resolves symptoms goal of preserving renal function. The following of ichthyosis, sensory neuropathy and ataxia in measures apply to all types of PH-I: (1) high %uid approximately that order. However, it remains intake has been proven to be e$ective in kidney uncertain whether or not treatment a$ects the stone diseases including PH-I; (2) alkalinization of the progression of the retinitis pigmentosa, anosmia urine with alkali citrate can reduce urinary calcium and deafness. Sudden weight loss should be oxalate saturation by forming complexes with avoided in order to prevent mobilization of phytanic calcium, consequently decreasing calcium oxalate acid into plasma. Post-operative care requires precipitation; and (3) dialysis, both peritoneal dialysis parenteral nutrition. and haemodialysis, has been used either alone or in combination in order to maximize oxalate removal. Disorders of glyoxylate metabolism In all patients with PH-I, pyridoxine should be tried. Indeed, one-third of patients with PH-I respond to Hyperoxaluria type 1 pharmacological doses of pyridoxine. Pyridoxine at the usual daily dose of 1000 mg/m2 body surface Only a single form of hyperoxaluria is due to a area can bring about a substantial reduction in the de#cient activity of a peroxisomal enzyme (alanine production and excretion of oxalate except in patients glyoxylate aminotransferase). This form of primary with pyridoxine-resistant forms of the disease. In the hyperoxaluria is called type I (PH-I). The phenotypic latter group of patients, liver transplantation and/ variability of PH-I is large, ranging from severe early- or combined liver–kidney transplantation is the only onset oxalosis and early death to adult presentations option left. Pre-emptive isolated liver transplantation that resemble idiopathic kidney stone disease. may be an option in selected patients, but in most PH-I often goes undetected for years until severe, cases the liver is replaced only after su"cient kidney irreversible kidney damage has occurred. In general, damage has occurred, thus opting for combined liver– PH-I has a bad prognosis, especially in its severe form, kidney transplantation. It has been used successfully unless liver (plus kidney) transplantation is performed. with excellent outcome even in small infants.52,53 A PH-I should be considered in all cases of familial stone sequential procedure (#rst liver transplantation, then disease and renal failure of unknown cause. dialysis until su"cient oxalate has been cleared from the body, followed by kidney transplantation) may be

© 2012 The Author(s) 323 Journal Compilation © 2012 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences Hamdan Medical Journal 2012; 5:313–326 (http://dx.doi.org/10.7707/hmj.v5i3.212) REVIEW FOR THE SHEIKH HAMDAN BIN RASHID AL MAKTOUM AWARD FOR MEDICAL SCIENCES proposed in individual end-stage renal disease (ESRD) Acknowledgements patients. The author gratefully acknowledges Mrs Maddy Festen for the expert preparation of the manuscript Disorder of bile acid conjugation and Mr Jos Ruiter for artwork. The author would like to thank Professors Aubourg, Barth, Borst, Heymans, Bile acid-CoA, amino acid N-acyltransferase Moser, Poll-Thé, Schutgens, Tager, Van den Bosch de!ciency and Van der Knaap for inspiration and guidance throughout the last 30 years. Furthermore, he Bile acid-CoA, amino acid N-acyltransferase de#ciency gratefully acknowledges the many post-doctorate was #rst identi#ed by Setchell et al.54 followed workers and PhD students without whom the work by subsequent cases described by Carlton et al.55 done would have been impossible to achieve. These Indeed, Carlton et al. described the identi#cation include Drs Brites, Ebberink, Ferdinandusse, Gloerich, of patients from the Amish community with bona Gootjes, Jacobs, Jansen, Kemp, Komen, Lageweg, !de mutations in the BAAT gene. Patients were Van den Brink, Van Grunsven, Van Roermund, Verleur, homozygous for a c.226AqG mutation (M76V) and Visser, Waterham and Wolvetang. showed increased serum bile acids, which were virtually fully unconjugated. Clinical features of these patients included fat malabsorption, failure References to thrive, coagulopathy, pruritus and chronic upper 1 Bowen P, Lee CSM, Zellweger H, et al. A familial respiratory infection. They did not have jaundice and syndrome of multiple congenital defects. Bull Johns had normal serum L-glutamyltransferase (gamma-GT) Hopkins Hosp 1964; 114:402–14. concentrations . In 2007, Heubi et al.56 reported six 2 Smith DW, Opitz JM, Inhorn SL. A syndrome of multiple additional patients with BAAT de#ciency. developmental defects including polycystic kidneys and intrahepatic biliary dysgenesis in 2 siblings. J Pediatr 1965; 67:617–24. Laboratory diagnosis http://dx.doi.org/10.1016/S0022-3476(65)80433-4 3 Passarge E, McAdams AJ. Cerebro-hepato-renal Laboratory diagnosis of BAAT de#ciency involves syndrome. A newly recognized hereditary disorder of analysis of bile acids in plasma and urine, preferably multiple congenital defects, including sudanophilic leukodystrophy, cirrhosis of the liver, and polycystic by tandem mass spectrometry, characterized by the kidneys. J Pediatr 1967; 71:691–702. virtually complete absence of glycine and taurine bile http://dx.doi.org/10.1016/S0022-3476(67)80205-1 acid conjugates in body %uids. Subsequent molecular 4 Opitz JM, Zu Rhein GM, Vitale L, et al. The Zellweger testing needs to be done to establish BAAT de#ciency syndrome (cerebro-hepato-renal syndrome). Birth with certainty. Defects Orig Art Ser 1969; 2:144–58. 5 McKusick V. The Zellweger syndrome: editorial comment. Birth Defects Orig Art Ser 1969; 2:144–58. Treatment 6 Gold#scher S, Moore CL, Johnson AB, et al. Peroxisomal and mitochondrial defects in the cerebro-hepato- renal In patients with BAAT de#ciency, symptoms syndrome. Science 1973; 182:62–4. such as fat malabsorption, failure to thrive and http://dx.doi.org/10.1126/science.182.4107.62 coagulopathy reportedly respond to treatment with 7 Bernard W, Rouiller C. Close topographical relationship between mitochondria and ergastoplasm of liver cells 55 ursodeoxycholic acid. in a de#nite phase of cellular activity. J Biophys Biochem Cytol 1956; 2:73–8. http://dx.doi.org/10.1083/jcb.2.4.73 8 de Duve C, Baudhuin P. Peroxisomes (microbodies and Prenatal diagnosis related particles). Physiol Rev 1966; 46:323–57. Without going into any detail it is su"cient to 9 Baudhuin P, Beaufay H, de Duve DC. Combined biochemical and morphological study of particulate state that prenatal diagnosis is now possible in all fractions from rat liver. Analysis of preparations enriched peroxisomal diseases identi#ed so far. With the in lysosomes or in particles containing urate oxidase, identi#cation of the molecular defect in virtually all D-amino acid oxidase, and catalase. J Cell Biol 1965; peroxisomal disorders, especially the disorders of 26:219–43. http://dx.doi.org/10.1083/jcb.26.1.219 peroxisome biogenesis in recent years, methods have 10 Lazarow PB, de Duve C. A fatty acyl-CoA oxidizing system in rat liver peroxisomes; enhancement by now shifted from biochemical and cell biological clo#brate, a hypolipidemic drug. Proc Natl Acad Sci U S A methods to molecular methods. These methods all 1976; 73:2043–6. can be applied to chorionic villous biopsy specimens, http://dx.doi.org/10.1073/pnas.73.6.2043 thus allowing early detection of a$ected fetuses.

324 © 2012 The Author(s) Journal Compilation © 2012 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences Hamdan Medical Journal 2012; 5:313–326 (http://dx.doi.org/10.7707/hmj.v5i3.212) REVIEW FOR THE SHEIKH HAMDAN BIN RASHID AL MAKTOUM AWARD FOR MEDICAL SCIENCES

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