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 Zellweger syndrome (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 peroxisomes. 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 peroxisome 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 catalase – 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 metabolism 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