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Zellweger spectrum disorders: clinical overview and management approach

Zellweger spectrum disorders: clinical overview and management approach Zellweger spectrum disorders (ZSDs) represent the major subgroup within the peroxisomal biogenesis disorders caused by defects in PEX genes. The Zellweger spectrum is a clinical and biochemical continuum which can roughly be divided into three clinical phenotypes. Patients can present in the neonatal period with severe symptoms or later in life during adolescence or adulthood with only minor features. A defect of functional peroxisomes results in several metabolic abnormalities, which in most cases can be detected in blood and urine. There is currently no curative therapy, but supportive care is available. This review focuses on the management of patients with a ZSD and provides recommendations for supportive therapeutic options for all those involved in the care for ZSD patients. Keywords: Zellweger spectrum disorder, ZSD, Peroxisome biogenesis disorder, PBD, Zellweger syndrome, Neonatal adrenoleukodystrophy, Infantile Refsum disease, Heimler syndrome, PEX, Very long chain fatty acids, VLCFA Background spectrum (with ZS being at the most severe end of the The Zellweger spectrum disorders (ZSDs) are a spectrum) which are now collectively referred to as ZSDs, heterogeneous group of autosomal recessive disorders in order to appreciate the wide variations in presentation characterized by a defect in peroxisome formation [6]. Recently, Heimler syndrome was recognized as a and are caused by mutations in one of 13 PEX genes peroxisome biogenesis disorder within the Zellweger [1–3]. Because of the defect in peroxisome formation, spectrum and added to the (very) mild end of the clinical multiple metabolic (both catabolic and anabolic) pathways spectrum [7]. This review provides a clinical overview of are impaired resulting in metabolic abnormalities. Typic- Zellweger spectrum disorders and focuses on manage- ally, ZSD patients accumulate very long chain fatty acids ment of patients with a ZSD. New developments in the (VLCFAs), phytanic- and pristanic acid, C27-bile acid field of management are discussed. intermediates and pipecolic acid in plasma and have a deficiency of plasmalogens in erythrocytes [4]. Clinically, Disease names and synonyms ZSDs are highly heterogeneous, but the core features are: Zellweger spectrum disorder/Zellweger syndrome liver dysfunction, developmental delay and other neuro- spectrum/Zellweger syndrome/neonatal adrenoleuko- logical abnormalities, adrenocortical dysfunction and dystrophy/infantile Refsum disease/Heimler syndrome hearing- and vision impairment [5]. Before the biochem- (ORPHA79189). ical and molecular basis of ZSDs was known, they were clinically described as three distinct disorders: Zellweger History and definition syndrome (ZS), neonatal adrenoleukodystrophy (NALD) Bowen et al. described a syndrome with failure to thrive, and infantile Refsum disease (IRD). These phenotypes are congenital glaucoma and craniofacial dysmorphic features currently recognized as presentations within a clinical with early death (before 2 years of age) [5]. In 1965 Smith et al. described two siblings with comparable multiple * Correspondence: [email protected] Equal contributors congenital malformations, but also polycystic kidneys and Department of Paediatric Neurology, Emma Children’s Hospital, Academic intrahepatic biliary dysgenesis [8]. In 1967 Passarge et al. Medical Center, University of Amsterdam, Meibergdreef 9, PO BOX introduced the term cerebro-hepato-renal syndrome. 226601105 AZ Amsterdam, The Netherlands Full list of author information is available at the end of the article Since Hans Zellweger, a pediatrician, contributed two of © 2015 Klouwer et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 2 of 11 the originally described patients it was later called Neonatal-infantile presentation Zellweger syndrome [9]. It was not until 1973 that the ZSD patients within this group typically present in the causal link between ZS and peroxisomes was made, when neonatal period with hepatic dysfunction and profound Goldfischer et al. described the absence of peroxisomes in hypotonia resulting in prolonged jaundice and feeding hepatocytes and renal proximal tubules [10]. Although the difficulties. Epileptic seizures are usually present in these clinical presentation is different, the discovery of similar patients. Characteristic dysmorphic features can usually biochemical abnormalities revealed that the earlier be found, of which the facial dysmorphic signs are most described entities infantile Refsum disease and neonatal evident (Fig. 2a). Sensorineural deafness and ocular adrenoleukodystrophy were also peroxisomal disorders abnormalities like retinopathy, cataracts and glaucoma [11, 12]. Based on these findings, peroxisomes which were are typical but not always recognized at first presenta- once considered unimportant organelles, were now tion. Brain magnetic resonance imaging (MRI) may show connected to a group of diseases and became the object of neocortical dysplasia (especially perisylvian polymicro- intensive scientific investigations. It turned out that perox- gyria), generalized decrease in white matter volume, isomes are important organelles in the eukaryotic cell, and delayed myelination, bilaterial ventricular dilatation and are involved in many catabolic and anabolic metabolic germinolytic cysts [23]. Neonatal onset leukodystrophy pathways [4, 13]. At present more than 15 different is rarely described [25]. Calcific stippling (chondrodys- peroxisomal disorders have been identified. The genetic plasia punctata) may be present, especially in the knees basis of ZSDs has largely been resolved and now includes and hips. The neonatal-infantile presentation grossly 13 different PEX genes [14, 15]. The group of diseases is resembles what was originally described as classic ZS. now referred to as Zellweger spectrum disorders and in- Prognosis is poor and survival is usually not beyond the clude the old disease entities of ZS, NALD, IRD but also first year of life. Heimler syndrome which was recently recognized as a ZSD [7, 16]. Childhood presentation These patients show a more varied symptomatology than ZSD patients with a neonatal-infantile presentation. Epidemiology Presentation at the outpatient clinic usually involves The incidence of ZSDs is estimated to be 1 in 50.000 delayed developmental milestone achievement. Ocular newborns in the United States [17]. It is presumed that abnormalities comprise retinitis pigmentosa, cataract ZSDs occur worldwide, but the incidence may differ and glaucoma, often leading to early blindness and tun- between regions. For example, the incidence of (classic) nel vision [26]. Sensorineural deafness is almost always Zellweger syndrome in the French-Canadian region of present and usually discovered by auditory screening Quebec was estimated to be 1 in 12 [18]. A much lower programs. Hepatomegaly and hepatic dysfunction with incidence is reported in Japan, with an estimated coagulopathy, elevated transaminases and (history of) incidence of 1 in 500.000 births [19]. More accurate hyperbilirubinemia are common. Some patients develop incidence data about ZSDs will become available in the epileptic seizures. Craniofacial dysmorphic features are near future, since newborn screening for X-linked generally less pronounced than in the neonatal-infantile adrenoleukodystrophy (X-ALD) will be implemented in group (Fig. 2b, c). Renal calcium oxalate stones and several countries [20, 21]. The screening method is adrenal insufficiency may develop. Early-onset progres- based on C26:0-lysophosphatidylcholine (C26:0-lysoPC) sive leukodystrophy may occur, leading to loss of measurement in dried bloodspots using LC-MS/MS acquired skills and milestones in some individuals. The technology, which will also identify ZSD patients [22]. progressive demyelination is diffuse and affects the cerebrum, midbrain and cerebellum with involvement of Clinical features the hilus of the dentate nucleus and the peridentate Patients with a ZSD can roughly be divided into three white matter [23]. Sequential imaging in three ZSD groups according to the age of presentation: the neonatal- patients showed that the earliest abnormalities related to infantile presentation, the childhood presentation and an demyelination were consistently seen in the hilus of the adolescent-adult (late) presentation [23]. An overview of dentate nucleus and superior cerebellar peduncles, the main presenting symptoms for these groups is sum- chronologically followed by the cerebellar white matter, marized in Fig. 1. The original classification of ZS, NALD brainstem tracts, parieto-occipital white matter, splenium and IRD is less valuable now, especially since additional of the corpus callosum and eventually involvement of the variant phenotypes suggestive for a disease spectrum have whole of the cerebral white matter [27]. The above de- been identified. For discussing prognosis and counseling scribed rapid progressive leukodystrophy, in combination patients or families this classification may in some cases with other symptoms described here, resemble what was still be useful [24]. originally described as NALD. A small subgroup of Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 3 of 11 Fig. 1 Schematic overview of main presenting symptoms in ZSDs per clinical group patients develop a relatively late-onset white matter and are involved in either peroxisome formation, peroxi- disease, but no patients with late-onset rapid progressive somal protein import, or both. As a consequence, muta- white matter disease after the age of five have been tions in PEX genes cause a deficiency of functional reported [28]. Prognosis depends on what organ systems peroxisomes. Cells from ZSD patients either entirely are primarily affected (i.e. liver) and the occurrence of lack functional peroxisomes, or cells can show a reduced progressive cerebral demyelination, but life expectancy is number of functional peroxisomes or a mosaic pattern decreased and most patients die before adolescence. (i.e. a mixed population of cells with functional peroxi- somes and cells without) [1, 32, 33]. Peroxisomes are Adolescent-adult presentation involved in many anabolic and catabolic metabolic pro- Symptoms in this group are less severe, and diagnosis can cesses, like biosynthesis of ether phospholipids and bile be in late child- or even adulthood [29]. Ocular abnormal- acids, α- and β-oxidation of fatty acids and the detoxifi- ities and a sensorineural hearing deficit are the most con- cation of glyoxylate and reactive oxygen species. sistent symptoms. Craniofacial dysmorphic features can Dysfunctional peroxisomes therefore cause biochemical be present, but may also be completely absent (Fig. 2d-f). abnormalities in tissues, but also in readily available Developmental delay is highly variable and some patients materials like plasma and urine [3, 15] (summarized in may have normal intelligence. Daily functioning ranges Table 1). There is a reasonable genotype-phenotype from completely independent to 24 h care. It is important correlation [24]. Approximately 60 % of ZSD patients to emphasize that primary adrenal insufficiency is com- have biallelic PEX1 mutations and almost 90 different mon and is probably under diagnosed [30]. In addition to mutations in PEX1 have been reported so far [34]. some degree of developmental delay, other neurological Detailed and up to date information about PEX gene abnormalities are usually also present: signs of peripheral mutations is available through the dbPEX gene database neuropathy, cerebellar ataxia and pyramidal tract signs. (http://www.dbpex.org). The clinical course is usually slowly progressive, although the disease may remain stable for (many) years [31]. Diagnosis Slowly progressive, clinically silent leukoencephalopathy is If a ZSD is clinically suspected the first step to confirm common, but MRI may be normal in other cases [23]. the diagnosis is by biochemical testing in readily accessible materials like blood and urine. This testing includes meas- Etiology and pathophysiology urement of VLCFAs, the peroxisomal bile acid intermedi- ZSDs are caused by mutations in one of the 13 different ates di- and trihydroxycholestanoic acid (DHCA, THCA), PEX genes. PEX genes encode proteins called peroxins the branched-chain fatty acids phytanic and pristanic acid, Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 4 of 11 Fig. 2 Craniofacial dysmorphic features in ZSD patients developing over time a. Photograph of a 6-month-old girl with typical craniofacial dysmorphia. Note the epicantal folds, high forehead, broad nasal bridge and hypoplastic supraorbital ridges. The anterior fontanel is drawn and enlarged. b-c.Girl with a ZSD at the age of 9 months (b) and at the age of 1 year and two months (c). Less pronounced facial dysmorphism is present: a high forehead is seen, a broad nasal bridge, hypoplastic supraorbital ridges, anteverted nares and more subtle epicantal folds. d-f. Photograph of a male with a ZSD at the age of 5 years (d), 10 years (e) and 15 years (f). No evident facial dysmorphic features can be recognized, although the ears seem to be slightly low-set. Written informed consent was obtained from the parents of all patients for publication of these images and pipecolic acid in plasma, plasmalogen levels in eryth- including culturing the fibroblasts at 40 °C [35]. Further rocytes, and C26:0-lysoPC in dried blood spots. Addition- fibroblast testing is also required to differentiate between ally, bile acids and oxalic acid can be analyzed in urine ZSDs and certain peroxisomal single enzyme deficiencies, [24]. It is important to note that relatively mild ZSD pa- and to perform complementation studies to pinpoint the tients may have (near) normal biochemical tests in plasma defective PEX gene. Subsequent mutation analysis of the and urine [35–37]. If clinical suspicion of a ZSD is high defective PEX gene is done in all patients to confirm the and peroxisomal parameters in blood and urine are nor- diagnosis. A diagnostic flowchart is provided (Fig. 3). With mal, further testing in fibroblasts is recommended, increasing availability and reliability of next generation Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 5 of 11 Table 1 Peroxisome functions and their biochemical consequences and possible clinical relevance in ZSDs Peroxisome function Biochemical consequence Possible clinical relevance β-oxidation of VLCFA (≥C22) Impaired chain shortening of VLCFA, Brain, nerve and adrenal damage due to VLCFA last step in DHA synthesis is impaired tissue accumulation, DHA deficiency affects brain function and vision β-oxidation of methyl-branched chain Impaired chain shortening of DHCA, Pristanic acid accumulation affects brain function, fatty acid, DHCA and THCA THCA and pristanic acid accumulation of DHCA and THCA causes liver toxicity and probably also brain damage α-oxidation of fatty acids Impaired (pre-) degradation of methyl Retinal degeneration, brain and nerve damage branched phytanic acid due to phytanic acid accumulation Fatty acid racemization Reduced convertion of pristanoyl-CoA Tissue accumulation of DHCA, THCA, pristanic- and and C27-bile acyl-CoAs into stereoisomers phytanic acid before β-oxidation Ether phospholipid (plasmalogen) biosynthesis Impaired formation of ether phospholipids Plasmalogen deficiency gives rise to growth- and psychomotor retardation, cataract and bone development anomalies Glyoxylate detoxification Conversion of glyoxylate into oxalate, Accumulation leads to calcium oxalate renal stones a toxic metabolite L-lysine oxidation Impaired L-pipecolic acid degradation Accumulation of pipecolic acid, no clinical consequences known [78] Hydrogen peroxide detoxification Decreased catabolism of hydrogen peroxide Increased reactive oxidant damage sequencing it is possible that genetic tests will become diagnosis. Before prenatal genetic testing can be per- first tier tests in the future. However, biochemical testing formed the familial pathogenic mutation (s) in one of in blood and/or fibroblasts is still required in these cases the PEX genes need (s) to be identified [1]. If the PEX mu- to confirm pathogenicity of the identified mutations and tations are unknown or cannot be detected, biochemical to characterize the extent of the deficiency. prenatal testing for ZSD is possible in chorionic villus biopsy material, cultured chorionic villus cells or cultured Differential diagnosis amniocytes. Biochemical prenatal testing can only be Differential diagnosis varies with the age of presentation performed in case of clear biochemical abnormalities in and most prominent symptoms at presentation (Table 2). cells from the index patient [15]. In newborns, ZSDs with hypotonia are most often con- fused with other conditions presenting with profound Clinical management and treatment hypotonia including chromosomal abnormalities. The Because no curative therapy for patients with a ZSD most important differential disorders to consider when exists, intervention is supportive and based on symp- suspecting a ZSD is the group of single peroxisomal toms. Past- and current supportive therapeutic options enzyme deficiencies. Especially Acyl-CoA oxidase type 1 are summarized in Table 4. (ACOX1) deficiency and D-bifunctional protein (DBP) deficiency show great overlap and in some cases, especially in the neonatal-infantile and childhood period, can be clinically indistinguishable from ZSDs [38, 39]. Docosahexaenoic acid Also MRI-features in DBP-deficiency resemble those of Docosahexaenoic acid (DHA; C22:6ω3) is a long-chain ZSD patients [27]. Differentiation is possible with bio- polyunsaturated fatty acid important for retinal and brain chemical and genetic tests as summarized in Table 3. function [40, 41]. Tetracosahexaenoic acid (C24:6ω3) Dependent on the most prominent presenting symptom undergoes one cycle of peroxisomal beta-oxidation to be such as retinitis pigmentosa, cerebellar ataxia or adrenal converted to DHA [4], leading to reduced levels of DHA insufficiency, other single peroxisomal enzyme deficien- when peroxisomes are absent. Because ZSD patients often cies like classical Refsum disease, alpha-methylacyl-CoA have low levels of DHA in membranes of erythrocytes, racemase deficiency or X-ALD should be considered. supplementation of DHA was suggested to be a possible therapy. Although some studies have claimed a beneficial Genetic counseling and antenatal diagnosis effect of DHA supplementation [42, 43], a randomized Because of the poor outcome and high disease burden double-blind placebo controlled trial showed that DHA associated with the majority of ZSDs, genetic counseling treatment leads to increased DHA levels in plasma, but no should be offered to parents of affected children. Car- improvement of visual function and growth could be riers can be offered prenatal- or preimplantation genetic observed [44]. Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 6 of 11 Fig. 3 Diagnostic flow-chart for ZSDs. a Very long chain fatty acids: C26:0, C24:0/C22:0 ratio, C26:0/C22:0 ratio. b Single enzyme deficiency with pheno- typical ZSD similarities like ACOX1 deficiency and DBP deficiency. c Next generation sequencing (NGS) of all PEX genes is advised when complementa- tion analysis is not practicable Lorenzo’s oil Cholic acid Lorenzo’s oil (i.e. 4:1 mix of glyceryl trioleate and glyceryl Cholic acid is a primary C24 bile acid, involved in for trierucate) therapy was originally developed for the single instance the absorption of fat-soluble vitamins. Cholic peroxisomal enzyme deficiency X-ALD, and was shown to acidisformedfromits precursorTHCAby one lower VLCFAs in plasma [45], but had no effect on disease peroxisomal beta-oxidation cycle. The peroxisomal progression [46, 47]. Some studies reported lowering of C27-bile acid intermediates DHCA and THCA accu- the VLCFA levels in plasma by Lorenzo’s oil in ZS babies mulate in ZSDs and are considered to be more toxic [48, 49]. However, based on data of studies in X-ALD indi- than the primary C24 bile acids due to their altered viduals, there is no reason to expect that Lorenzo’s oil will physical properties and are believed to contribute to be beneficial for ZSD patients at this point. the liver disease in ZSDs (e.g. dysfunction and liver Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 7 of 11 Table 2 Differential diagnosis of ZSDs based on the most levels of fat-soluble vitamins. Furthermore, bile acid prominent presenting symptom treatment in mice was shown to improve hepatic dis- Main presenting symptom Differential diagnosis ease [53]. Limitations of the studies so far, however, are the small number of treated patients and short Hypotonia in newborns Chromosomal abnormalities (Down syndrome, Prader-Willi syndrome) follow-up. Current evidence is insufficient to conclude Congenital infections (cytomegalovirus, that cholic acid treatment is beneficial for patients rubella, herpes simplex, toxoplasmosis) with a ZSD. The Food and Drug Administration Hypoxic ischemic encephalopathy recently approved cholic acid as a safe treatment for ZSD patients in the United States. However, efficiency Cerebral malformations should be demonstrated in large clinical trials before Other metabolic disorders (acid maltase deficiency, carnitine deficiency, this treatment can be implemented. cytochrome-c-oxidase deficiency) Other peroxisomal disorders (acyl-CoA Plasmalogen precursors oxidase type 1 deficiency, D-bifunctional Due to a deficiency of the first peroxisomal steps in the protein deficiency) biosynthesis of plasmalogens [54], ZSD patients may Spinal muscular atrophy have low levels of plasmalogens. Plasmalogens play a Congenital muscular dystrophies critical role in cell membranes and as anti-oxidants [55]. Congenital myopathies It was suggested that supplementation with precursors of plasmalogens (batyl alcohol) could be beneficial for Hereditary motor and sensory neuropathy ZSD patients, as import of these alkylglycerols proceeds Bilateral cataract Idiopathic normally. Several case reports have described an increase Congenital infections in erythrocyte plasmalogen levels after treatment and Other peroxisomal disorders (rhizomelic improvement of clinical symptoms in some patients chondrodysplasia punctata, classical [56–58]. Although never studied systematically, ether Refsum disease, 2-methylacyl-CoA racemase deficiency) lipid therapy could be of interest for ZSD. Other metabolic disorders (galactosemia) Citrate Lowe syndrome The toxic metabolite oxalate accumulates in plasma Sensorineural hearing loss Usher syndrome type I,II and urine from ZSD patients [4]. This causes renal with retinitis pigmentosa Other peroxisomal disorders calcium oxalate stones. In a large cohort of Dutch (classical Refsum disease) ZSD patients a high prevalence of 83 % of renal Mitochondrial disorders calcium oxalate stones was shown [59]. For this rea- Cockayne syndrome son, patients should be screened for the presence of high Alport syndrome levels of oxalic acid in urine yearly. To prevent the forma- Waardenburg syndrome tion of renal stones, patients with hyperoxaluria should start oral citrate treatment. Furthermore, sufficient fluid Adrenocorticol insufficiency Autoimmune adrenalitis intake is recommended [60]. Infectious adrenalitis Adrenal hemorrhage Supportive care Adrenal hypoplasia All ZSD patients need to be screened for adrenal X-linked adrenoleukodystrophy insufficiency [30], epilepsy, low levels of fat-soluble Deficient cholesterol metabolism vitamins, (partly) vitamin K dependent coagulopathy, high levels of phytanic acid, hearing or visual impair- Familial glucocorticoid deficiency ment and enamel hypoplasia. They should be treated according to the identified abnormalities, e.g. supple- fibrosis) [50]. The bile acid intermediates are only mentation of cortisone, anti-epileptic drugs, vitamins partly conjugated and are less well excreted than C24 and/or a phytanic restricted diet. Because supplemen- bile acids contributing to cholestasis. We hypothesize tation of cortisone is associated with severe side that DHCA and THCA cross the blood–brain barrier effects, such as growth suppression and osteoporosis and cause central nerve system damage. Several case [61], only patients with a true insufficiency (i.e. reports have described a beneficial effect of cholic altered Synacthen test) should be treated. A phytanic acid acid in ZS babies, supported by reduced urinary and restricted diet is only necessary when levels of phytanic plasma excretion of DHCA/THCA [51, 52]. Clinically acid are extremely high and is not recommended when there was increased growth and an increase in the levels are moderately increased, as sufficient intake of Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 8 of 11 Table 3 Differences in biochemical characteristics of ZSDs and phenotypical similar single enzyme deficiencies ZSD DBP-D ACOX1-D Remarks Plasma a b b b Very long chain fatty acids ↑ ↑ ↑ False positives possible in ketogenic diets, hemolyzed samples and peanut rich diet. Di- and trihydroxycholestanoic acid ↑ N-↑ N Phytanic acid N-↑ N-↑ N Derived from dietary sources only; dependent on dietary intake. Normal in newborns. Pristanic acid N-↑ N-↑ N Derived from dietary sources only (direct and indirectly via phytanic acid). Normal in newborns. Erythrocytes Plasmalogen level ↓-N N N Blood spot C26:0 lysophosphatidylcholine↑↑ ↑ Fibroblasts Plasmalogen synthesis ↓ NN DHAPAT ↓ NN Alkyl DHAP synthase ↓ NN C26:0 β-oxidation ↓↓ ↓ Pristanic acid β-oxidation ↓↓ N Acyl-CoA oxidase 1 ↓-N N ↓ D-Bifunctional protein ↓-N ↓ N Phytanic acid α-oxidation ↓ NN Phytanoyl CoA hydroxylase ↓ NN Peroxisomes ↓ N N Peroxisomal mosaicism can be present in ZSD. In DBP- and ACOX1-deficiency abnormal peroxisomal morphology may be present. Mutant gene PEX1,2,3,5,6,10,11β,12,13,14,16,19,26 HSD17B4 ACOX Very long chain fatty acids: C26:0, C24:0/C22:0 ratio, C26:0/C22:0 ratio May be minimally abnormal to normal in exceptional cases calories is more decisive. Hearing and visual impair- ment should be (partly) corrected by hearing aids and glasses, with ophthalmologic and audiological evalua- tions yearly. Enamel hypoplasia, present in nearly all patients, should be followed-up by a dentist [62, 63]. Table 4 Supportive therapeutic options in ZSDs Some patients will need a gastrostomy to provide Symptom/disease Treatment/intervention adequate intake of calories. Adrenal insufficiency Cortisone Coagulopathy Vitamin K suppletion Current/future developments Enamel hypoplasia Dentist referral Several compounds that stimulate peroxisomal biogen- Epilepsy Standard antiepileptic drugs esis and function in vitro [64–66] were discovered Hearing impairment Hearing aids, cochlear implant recently and clinical trials are ongoing (clinicaltrails.gov: High phytanic acid plasma level Phytanic acid restricted diet NCT01838941). Hopefully, some of these compounds Hyperoxaluria Oral citrate treatment Sufficient will be able to rescue or improve peroxisomal func- fluid intake tion in patients. The greatest beneficial effect is Insufficient calory intake Gastrostomy expected in patients whose fibroblasts showed a Low levels of fat-soluble Vitamin suppletion temperature sensitivity with worsening of the pheno- vitamins (A, D, E) type when cultured at 40 °C and improvement of Visual impairment Cataract removal, glasses and peroxisomal functions at 30 °C [67, 68]. In addition ophthalmologist referral to these new compounds, the effect of cholic acid is Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 9 of 11 currently under investigation (controlled-trials.com: Unresolved questions ISRCTN96480891) in a large cohort of ZSD patients. The effect of cholic acid is based upon case reports only, Although never tested in ZSD patients, gene therapy but within the coming years the clinical effects will be with or without tissue specific targeting might be a investigated in larger cohorts. In addition, results of potential treatment. Several years ago gene therapy was ongoing trials will be published. An important limitation already proposed for X-ALD [69]. Although promising, to consider when interpreting the data of these trials is gene therapy still needs to be optimized to be feasible the broad spectrum of severe and milder clinical pheno- for patients [70]. First, studies have to be conducted in types and associated biochemical variations within these the recently published mild PEX1 mouse model [71], cohorts. Furthermore, the natural course of the disease before a human trial can be initiated. can lead to false conclusions, as peroxisomal metabolites An orthotopic liver transplantation was described in were shown to fluctuate and decline with age [31]. A large a single 6-month old ZSD patient and hepatocytes prospective natural history study is therefore needed. We transplantation in another 4-year old patient [72, 73]. and others, recently started collecting the data of a large It resulted in decreased concentrations of VLCFAs prospective cohort of ZSD patients (clinicaltrails.gov: and pipecolic acid, and improved bile acid profiles. NCT01668186). However, the effect on long-term disease course has Second, plasma levels of peroxisomal metabolites do not been reported. not correlate well with disease severity, as they generally Although bone marrow transplantation (BMT) is an decrease with age. Furthermore, therapies like DHA and established therapy for the cerebral childhood form of Lorenzo’s oil improved plasma levels of DHA and C26:0, X-ALD [74], there are no reports describing BMT in albeit no effect on the clinical phenotype has been ZSD patients. BMT would be of interest for those observed. This is possibly related to differences in ex- patients who develop leukodystrophy in infancy. However, pression or activity of peroxisomes in the targeted tissue. with the current knowledge it is impossible to predict Therefore, using plasma levels as a surrogate outcome in if patients will develop this rapid progressive leuko- clinical trials is not recommended. New biochemical dystrophy. Recently, a retrospective study revealed outcome parameters that correlate with disease progres- that patients with X-ALD still develop an adrenomye- sion are necessary, such as analysis of markers for lopathy phenotype after BMT [75]. Nevertheless, peroxisomal dysfunctions in lymphocytes. BMT could possibly be beneficial for a subgroup of The pathophysiology of ZSD is still poorly understood. patients within the ZSD spectrum, but first new Similar to the cerebral form of X-ALD, it is still not clear techniques/markers that can predict whether or not when or why ZSD patients develop severe rapid progres- patients will develop a severe progressive leukodystro- sive leukodystrophy. The recently constructed mild phyhavetobe elucidated. PEX1 mouse model [71] and natural history studies will help to answer these questions. Prognosis Conclusions Although a rough genotype-phenotype correlation exists Because of the recently implemented newborn screening, for several PEX genes, such as PEX1 and PEX26 [76, 77], more medical doctors in different specialties (e.g. pediatri- the severity and progression of the disease is difficult to cians, clinical geneticist and neurologists) will encounter predict for individual patients. This will become more patients with a ZSD. ZSDs are clinically heterogeneous relevant as newborn screening is implemented. As a with high morbidity in almost all patient and mortality in consequence of newborn screening for X-ALD by C26:0- some. Although treatment is currently only symptomatic, lysoPC in several countries ZSD will also be diagnosed it is important to initiate proper supportive therapy to at birth. Children with the severe phenotype (neonatal- improve quality of life of these patients. infantile presentation with severe clinical symptoms) have a poor prognosis and these patients usually die Abbreviations within the first year of life. Patients that present in child- ACOX1: acyl-CoA oxidase type 1; BMT: bone marrow transplant; C26:0- hood or adolescence usually have a better prognosis, but lysoPC: C26:0-lysophosphatidylcholine; DBP: d-bifunctional protein; can develop progressive liver disease or leukodystrophy DHA: docosahexanoic acid; DHCA: dihydroxycholestanoic acid; IRD: infantile Refsum disease; MRI: magnetic resonance imaging; NALD: neonatal and deteriorate. If progressive liver disease or leukodys- adrenoleukodystrophy; THCA: trihydroxycholestanoic acid; VLCFAs: very long trophy occurs prognosis is poor. The remaining milder chain fatty acids; X-ALD: x-linked adrenoleukodystrophy; ZS: Zellweger individuals can reach adulthood without progression or syndrome; ZSD: Zellweger spectrum disorder. with long periods of stabilization. When progression occurs, it is mainly related to peripheral neuropathy and Competing interests pyramidal signs, while cognition remains stable [31]. The authors declare that they have no competing interests. Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 10 of 11 Authors’ contributions 18. Levesque S, Morin C, Guay S-P, Villeneuve J, Marquis P, Yik WY, et al. A founder All authors were involved in the conception and writing of the manuscript. mutation in the PEX6 gene is responsible for increased incidence of Zellweger All authors read and approved the final manuscript. syndrome in a French Canadian population. BMC Med Genet. 2012;13:72. 19. Shimozawa N, Nagase T, Takemoto Y, Ohura T, Suzuki Y, Kondo N. Genetic heterogeneity of peroxisome biogenesis disorders among Japanese patients: evidence for a founder haplotype for the most common PEX10 Acknowledgements gene mutation. Am J Med Genet A. 2003;120A:40–3. This work was supported by a grant from ‘Metakids’, ‘Hersenstichting’ and 20. Haynes CA, De Jesús VR. The stability of hexacosanoyl ‘Stichting Steun Emma Kinderziekenhuis AMC’, The Netherlands. We would lysophosphatidylcholine in dried-blood spot quality control materials for X- like to thank the parents of the patients displayed in this review for linked adrenoleukodystrophy newborn screening. Clin Biochem. 2014;48:8–10. providing photographs and the permission for publication. 21. Vogel BH, Bradley SE, Adams DJ, D’Aco K, Erbe RW, Fong C, et al. Newborn screening for X-linked adrenoleukodystrophy in New York State: Diagnostic Author details protocol, surveillance protocol and treatment guidelines. Mol Genet Metab. Department of Paediatric Neurology, Emma Children’s Hospital, Academic 2015;114:599–603. Medical Center, University of Amsterdam, Meibergdreef 9, PO BOX 22. Hubbard WC, Moser AB, Liu AC, Jones RO, Steinberg SJ, Lorey F, et al. 226601105 AZ Amsterdam, The Netherlands. Laboratory Genetic Metabolic Newborn screening for X-linked adrenoleukodystrophy (X-ALD): validation Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, of a combined liquid chromatography-tandem mass spectrometric The Netherlands. (LC-MS/MS) method. Mol Genet Metab. 2009;97:212–20. 23. Poll-The BT, Gärtner J. Clinical diagnosis, biochemical findings and MRI Received: 19 October 2015 Accepted: 22 November 2015 spectrum of peroxisomal disorders. Biochim Biophys Acta. 1822;2012:1421–9. 24. Steinberg SJ, Raymond G V, Braverman NE, Moser AB: Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum. Gene Rev2003. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1448/. Accessed 1 Sep 2015. References 25. Poll-The BT, Gootjes J, Duran M, De Klerk JBC, Wenniger Prick LJM De B, 1. Waterham HR, Ebberink MS. Genetics and molecular basis of human Admiraal RJC, et al. Peroxisome biogenesis disorders with prolonged peroxisome biogenesis disorders. Biochim Biophys Acta. 1822;2012:1430–41. survival: phenotypic expression in a cohort of 31 patients. Am J Med Genet 2. Fujiki Y, Okumoto K, Mukai S, Honsho M, Tamura S. Peroxisome biogenesis A. 2004;126A:333–8. in mammalian cells. Front Physiol. 2014;5:307. 26. Hamel C. Retinitis pigmentosa. Orphanet J Rare Dis. 2006;1:40. 3. Braverman NE, D’Agostino MD, Maclean GE. Peroxisome biogenesis 27. Van der Knaap MS, Wassmer E, Wolf NI, Ferreira P, Topçu M, Wanders RJA, disorders: Biological, clinical and pathophysiological perspectives. et al. MRI as diagnostic tool in early-onset peroxisomal disorders. Neurology. Dev Disabil Res Rev. 2013;17:187–96. 2012;78:1304–8. 4. Wanders RJA, Waterham HR. Biochemistry of mammalian peroxisomes 28. Barth PG, Gootjes J, Bode H, Vreken P, Majoie CBLM, Wanders RJA. Late revisited. Annu Rev Biochem. 2006;75:295–332. onset white matter disease in peroxisome biogenesis disorder. Neurology. 5. Bowen P, Lee CS, Zellweger H, Lindenberg R. A familial syndrome of 2001;57:1949–55. multiple congenital defects. Bull Johns Hopkins Hosp. 1964;114:402–14. 29. Moser AB, Rasmussen M, Naidu S, Watkins PA, McGuinness M, Hajra AK, 6. Poll-The BT, Saudubray JM, Ogier HA, Odièvre M, Scotto JM, Monnens L, et al. Phenotype of patients with peroxisomal disorders subdivided into et al. Infantile Refsum disease: an inherited peroxisomal disorder. sixteen complementation groups. J Pediatr. 1995;127:13–22. Comparison with Zellweger syndrome and neonatal adrenoleukodystrophy. 30. Berendse K, Engelen M, Linthorst GE, van Trotsenburg ASP, Poll-The BT. Eur J Pediatr. 1987;146:477–83. High prevalence of primary adrenal insufficiency in Zellweger spectrum 7. Ratbi I, Falkenberg KD, Sommen M, Al-Sheqaih N, Guaoua S, Vandeweyer G, disorders. Orphanet J Rare Dis. 2014;9:133. Urquhart JE, Chandler KE, Williams SG, Roberts NA, El Alloussi M, Black GC, 31. Berendse K, Engelen M, Ferdinandusse S, Majoie CBLM, Waterham HR, Vaz FM, Ferdinandusse S, Ramdi H, Heimler A, Fryer A, Lynch S-A, Cooper N, Ong KR, Koelman JHTM, Barth PG, Wanders RJA, Poll-The BT: Zellweger spectrum Smith CEL, Inglehearn CF, Mighell AJ, Elcock C, Poulter JA, Tischkowitz M, disorders: clinical manifestations in patients surviving into adulthood. Davies SJ, Sefiani A, Mironov AA, Newman WG, Waterham HR, et al.: Heimler J Inherit Metab Dis 2015, in press. Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome- Biogenesis Genes PEX1 and PEX6. Am J Hum Genet 2015, in press. 32. Pineda M, Girós M, Roels F, Espeel M, Ruiz M, Moser A, et al. Diagnosis and 8. Smith DW, Opitz JM, Inhorn SL. A syndrome of multiple developmental follow-up of a case of peroxisomal disorder with peroxisomal mosaicism. defects including polycystic kidneys and intrahepatic biliary dysgenesis J Child Neurol. 1999;14:434–9. in 2 siblings. J Pediatr. 1965;67:617–24. 33. Gootjes J, Schmohl F, Mooijer PAW, Dekker C, Mandel H, Topcu M, et al. Identification of the molecular defect in patients with peroxisomal mosaicism 9. Opitz JM, Zu Rhein GM, Vitale L, Shahidi NJ, Howe JJ, Chon SM, et al. The using a novel method involving culturing of cells at 40 degrees C: implications Zellweger Syndrome (cerebro-hepato-renal syndrome). Birth Defects Orig for other inborn errors of metabolism. Hum Mutat. 2004;24:130–9. Art Set. 1969;2:144–58. 34. Ebberink MS, Mooijer PAW, Gootjes J, Koster J, Wanders RJA, Waterham HR. 10. Goldfischer S, Moore CL, Johnson AB, Spiro AJ, Valsamis MP, Wisniewski HK, Genetic classification and mutational spectrum of more than 600 patients et al. Peroxisomal and mitochondrial defects in the cerebro-hepato-renal with a Zellweger syndrome spectrum disorder. Hum Mutat. 2011;32:59–69. syndrome. Science. 1973;182:62–4. 35. Zeharia A, Ebberink MS, Wanders RJA, Waterham HR, Gutman A, Nissenkorn A, 11. Poulos A, Sharp P, Whiting M. Infantile Refsum’s disease (phytanic acid et al. A novel PEX12 mutation identified as the cause of a peroxisomal storage disease): a variant of Zellweger’s syndrome? Clin Genet. biogenesis disorder with mild clinical phenotype, mild biochemical 1984;26:579–86. abnormalities in fibroblasts and a mosaic catalase immunofluorescence 12. Kelley RI, Moser HW. Hyperpipecolic acidemia in neonatal pattern, even at 40 degrees C. J Hum Genet. 2007;52:599–606. adrenoleukodystrophy. Am J Med Genet. 1984;19:791–5. 13. Van Veldhoven PP. Biochemistry and genetics of inherited disorders of 36. Steinberg SJ, Snowden A, Braverman NE, Chen L, Watkins PA, Clayton PT, et al. peroxisomal fatty acid metabolism. J Lipid Res. 2010;51:2863–95. A PEX10 defect in a patient with no detectable defect in peroxisome assembly 14. Reuber BE, Germain-Lee E, Collins CS, Morrell JC, Ameritunga R, Moser HW, or metabolism in cultured fibroblasts. J Inherit Metab Dis. 2009;32:109–19. et al. Mutations in PEX1 are the most common cause of peroxisome 37. Ebberink MS, Csanyi B, Chong WK, Denis S, Sharp P, Mooijer PAW, et al. biogenesis disorders. Nat Genet. 1997;17:445–8. Identification of an unusual variant peroxisome biogenesis disorder caused 15. Wanders RJA, Waterham HR. Peroxisomal disorders I: biochemistry and by mutations in the PEX16 gene. J Med Genet. 2010;47:608–15. genetics of peroxisome biogenesis disorders. Clin Genet. 2005;67:107–33. 38. Ferdinandusse S, Denis S, Hogenhout EM, Koster J, van Roermund CWT, IJlst L, 16. Collins CS, Gould SJ. Identification of a common PEX1 mutation in et al. Clinical, biochemical, and mutational spectrum of peroxisomal Zellweger syndrome. Hum Mutat. 1999;14:45–53. acyl-coenzyme A oxidase deficiency. Hum Mutat. 2007;28:904–12. 17. Gould S, Raymond G, Valle D: The Peroxisome biogenesis disorders. In The 39. Ferdinandusse S, Denis S, Mooyer PAW, Dekker C, Duran M, Soorani-Lunsing RJ, Metabolic and Molecular Bases of Inherited Disease. 8th edition. New York, et al. Clinical and biochemical spectrum of D-bifunctional protein deficiency. NY: McGraw-Hill; 2001:3181–3218. Ann Neurol. 2006;59:92–104. Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 11 of 11 40. Horrocks LA, Yeo YK. Health benefits of docosahexaenoic acid (DHA). 66. Wei H, Kemp S, McGuinness MC, Moser AB, Smith KD. Pharmacological Pharmacol Res. 1999;40:211–25. induction of peroxisomes in peroxisome biogenesis disorders. Ann Neurol. 41. Birch EE, Hoffman DR, Uauy R, Birch DG, Prestidge C. Visual acuity and the 2000;47:286–96. essentiality of docosahexaenoic acid and arachidonic acid in the diet of 67. Imamura A, Tamura S, Shimozawa N, Suzuki Y, Zhang Z, Tsukamoto T, et al. term infants. Pediatr Res. 1998;44:201–9. Temperature-sensitive mutation in PEX1 moderates the phenotypes of 42. Martínez M, Vázquez E, García-Silva MT, Manzanares J, Bertran JM, Castelló F, peroxisome deficiency disorders. Hum Mol Genet. 1998;7:2089–94. et al. Therapeutic effects of docosahexaenoic acid ethyl ester in patients with 68. Shimozawa N, Suzuki Y, Zhang Z, Imamura A, Toyama R, Mukai S, et al. generalized peroxisomal disorders. Am J Clin Nutr. 2000;71 Suppl 1:376S–85S. Nonsense and temperature-sensitive mutations in PEX13 are the cause of 43. Noguer MT, Martinez M. Visual follow-up in peroxisomal-disorder patients complementation group H of peroxisome biogenesis disorders. Hum Mol treated with docosahexaenoic Acid ethyl ester. Invest Ophthalmol Vis Sci. Genet. 1999;8:1077–83. 2010;51:2277–85. 69. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Bougnères P, Schmidt M, Kalle C, et al. Lentiviral hematopoietic cell gene therapy for X-linked 44. Paker M, Sunness JS, Brereton NH, Speedie LJ, Albanna L, Dharmaraj S, et al. Docosahexaenoic acid therapy in peroxisomal diseases: results of a double- adrenoleukodystrophy. Methods Enzymol. 2012;507:187–98. blind, randomized trial. Neurology. 2010;75:826–30. 70. Toscano MG, Romero Z, Muñoz P, Cobo M, Benabdellah K, Martin F. Physiological and tissue-specific vectors for treatment of inherited diseases. 45. Moser AB, Borel J, Odone A, Naidu S, Cornblath D, Sanders DBMH. A new Gene Ther. 2011;18:117–27. dietary therapy for adrenoleukodystrophy: biochemical and preliminary 71. Hiebler S, Masuda T, Hacia JG, Moser AB, Faust PL, Liu A, et al. The Pex1- clinical results in 36 patients. Ann Neurol. 1987;21:240–9. G844D mouse: a model for mild human Zellweger spectrum disorder. Mol 46. Aubourg P, Adamsbaum C, Lavallard-Rousseau MC, Rocchiccioli F, Cartier N, Genet Metab. 2014;111:522–32. Jambaque I, et al. A two-year trial of oleic and erucic acids (“Lorenzo’s Oil”) 72. Sokal EM, Smets F, Bourgois A, Van Maldergem L, Buts JP, Reding R, et al. as treatment for adrenomyeloneuropathy. NEJM. 1993;329:745–52. Hepatocyte transplantation in a 4-year-old girl with peroxisomal biogenesis 47. Van Geel BM, Assies J, Haverkort EB, Koelman JHTM, Verbeeten B, Wanders RJA, disease: technique, safety, and metabolic follow-up. Transplantation. et al. Progression of abnormalities in adrenomyeloneuropathy and 2003;76:735–8. neurologically asymptomatic X-linked adrenoleukodystrophy despite 73. Van Maldergem L, Moser AB, Vincent M-F, Roland D, Reding R, Otte JB et al. treatment with “Lorenzo’soil.”. J Neurol Neurosurg Psychiatry. 1999;67:290–9. Orthotopic liver transplantation from a living-related donor in an infant with 48. Tanaka K, Shimizu T, Ohtsuka Y, Yamashiro Y, Oshida K. Early dietary a peroxisome biogenesis defect of the infantile Refsum disease type. J treatments with Lorenzo’s oil and docosahexaenoic acid for neurological Inherit Metab Dis. 2005;28:593–600. development in a case with Zellweger syndrome. Brain Dev. 2007;29:586–9. 74. Aubourg P, Blanche S, Jambaqué I, Rocchiccioli F, Kalifa G, Naud-Saudreau C 49. Arai Y, Kitamura Y, Hayashi M, Oshida K, Shimizu T, Yamashiro Y. Effect of et al. Reversal of early neurologic and neuroradiologic manifestations of dietary Lorenzo’s oil and docosahexaenoic acid treatment for Zellweger X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J syndrome. Congenit Anom (Kyoto). 2008;48:180–2. Med. 1990;322:1860–6. 50. Ferdinandusse S, Denis S, Dacremont G, Wanders RJA. Toxicity of 75. Van Geel BM, Poll-The BT, Verrips A, Boelens JJ, Kemp S, Engelen M. peroxisomal C27-bile acid intermediates. Mol Genet Metab. 2009;96:121–8. Hematopoietic cell transplantation does not prevent myelopathy in X-linked 51. Setchell KDR, Bragetti P, Zimmer-Nechemias L, Daugherty C, Pelli MA, adrenoleukodystrophy: a retrospective study. J Inherit Metab Dis. Vaccaro R, et al. Oral bile acid treatment and the patient with zellweger 2015;38:359–61. syndrome. Hepatology. 1992;15:198–207. 76. Bader PI, Dougherty S, Cangany N, Raymond G, Jackson CE. Infantile Refsum 52. Maeda K, Kimura A, Yamato Y, Nittono H, Takei H, Sato T, Mitsubuchi H, disease in four Amish sibs. Am J Med Genet. 2000;90:110–4. Murai T, Kurosawa T: Oral Bile Acid Treatment in Two Japanese Patients 77. Rosewich H, Ohlenbusch A, Gärtner J. Genetic and clinical aspects of Zellweger With Zellweger Syndrome. J Pediatr Gastroenterol Nutr. 2002, 35:227–230 spectrum patients with PEX1 mutations. J Med Genet. 2005;42:e58. 53. Keane MH, Overmars H, Wikander TM, Ferdinandusse S, Duran M, Wanders RJ A, 78. Vallat C, Denis S, Bellet H, Jakobs C, Wanders RJA, Mion H. Major et al. Bile acid treatment alters hepatic disease and bile acid transport in hyperpipecolataemia in a normal adult. J Inherit Metab Dis. 1996;19:624–6. peroxisome-deficient PEX2 Zellweger mice. Hepatology. 2007;45:982–97. 54. De Vet EC, van den Bosch H. Alkyl-dihydroxyacetonephosphate synthase. Cell Biochem Biophys. 2000;32:117–21. 55. Braverman NE, Moser AB. Functions of plasmalogen lipids in health and disease. Biochim Biophys Acta. 1822;2012:1442–52. 56. Holmes RD, Wilson GN, Hajra A. Oral ether lipid therapy in patients with peroxisomal disorders. J Inherit Metab Dis. 1987;10:239–41. 57. Das AK, Holmes RD, Wilson GN, Hajra AK. Dietary ether lipid incorporation into tissue plasmalogens of humans and rodents. Lipids. 1992;27:401–5. 58. Wilson GN, Holmes RG, Custer J, Lipkowitz JL, Stover J, Datta N, et al. Zellweger syndrome: diagnostic assays, syndrome delineation, and potential therapy. Am J Med Genet. 1986;24:69–82. 59. Van Woerden CS, Groothoff JW, Wijburg FA, Duran M, Wanders RJA, Barth PG, et al. High incidence of hyperoxaluria in generalized peroxisomal disorders. Mol Genet Metab. 2006;88:346–50. 60. Leumann E, Hoppe B, Neuhaus T, Blau N. Efficacy of oral citrate administration in primary hyperoxaluria. Nephrol Dial Transplant. 1995;10 Suppl 8:14–6. Submit your next manuscript to BioMed Central 61. Buchman AL. Side effects of corticosteroid therapy. J Clin Gastroenterol. 2001;33:289–94. and we will help you at every step: 62. Lertsirivorakul J, Wongswadiwat M, Treesuwan P. Oral manifestations and • We accept pre-submission inquiries dental management of a child with Zellweger syndrome. Spec Care Dent. 2012;34:46–50. � Our selector tool helps you to find the most relevant journal 63. Acharya BS, Ritwik P, Velasquez GM, Fenton SJ. Medical-dental findings and � We provide round the clock customer support management of a child with infantile Refsum disease: a case report. Spec � Convenient online submission Care Dentist. 2012;32:112–7. 64. Zhang R, Chen L, Jiralerspong S, Snowden A, Steinberg S, Braverman N. � Thorough peer review Recovery of PEX1-Gly843Asp peroxisome dysfunction by small-molecule � Inclusion in PubMed and all major indexing services compounds. Proc Natl Acad Sci U S A. 2010;107:5569–74. � Maximum visibility for your research 65. Berendse K, Ebberink MS, Ljlst L, Wanders RJA, Waterham HR, Poll The BT. Arginine improves peroxisome functioning in cells from patients with a Submit your manuscript at mild peroxisome biogenesis disorder. Orphanet J Rare Dis. 2013;8:138. www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Orphanet Journal of Rare Diseases Springer Journals

Zellweger spectrum disorders: clinical overview and management approach

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Medicine & Public Health; Medicine/Public Health, general; Pharmacology/Toxicology; Human Genetics
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Abstract

Zellweger spectrum disorders (ZSDs) represent the major subgroup within the peroxisomal biogenesis disorders caused by defects in PEX genes. The Zellweger spectrum is a clinical and biochemical continuum which can roughly be divided into three clinical phenotypes. Patients can present in the neonatal period with severe symptoms or later in life during adolescence or adulthood with only minor features. A defect of functional peroxisomes results in several metabolic abnormalities, which in most cases can be detected in blood and urine. There is currently no curative therapy, but supportive care is available. This review focuses on the management of patients with a ZSD and provides recommendations for supportive therapeutic options for all those involved in the care for ZSD patients. Keywords: Zellweger spectrum disorder, ZSD, Peroxisome biogenesis disorder, PBD, Zellweger syndrome, Neonatal adrenoleukodystrophy, Infantile Refsum disease, Heimler syndrome, PEX, Very long chain fatty acids, VLCFA Background spectrum (with ZS being at the most severe end of the The Zellweger spectrum disorders (ZSDs) are a spectrum) which are now collectively referred to as ZSDs, heterogeneous group of autosomal recessive disorders in order to appreciate the wide variations in presentation characterized by a defect in peroxisome formation [6]. Recently, Heimler syndrome was recognized as a and are caused by mutations in one of 13 PEX genes peroxisome biogenesis disorder within the Zellweger [1–3]. Because of the defect in peroxisome formation, spectrum and added to the (very) mild end of the clinical multiple metabolic (both catabolic and anabolic) pathways spectrum [7]. This review provides a clinical overview of are impaired resulting in metabolic abnormalities. Typic- Zellweger spectrum disorders and focuses on manage- ally, ZSD patients accumulate very long chain fatty acids ment of patients with a ZSD. New developments in the (VLCFAs), phytanic- and pristanic acid, C27-bile acid field of management are discussed. intermediates and pipecolic acid in plasma and have a deficiency of plasmalogens in erythrocytes [4]. Clinically, Disease names and synonyms ZSDs are highly heterogeneous, but the core features are: Zellweger spectrum disorder/Zellweger syndrome liver dysfunction, developmental delay and other neuro- spectrum/Zellweger syndrome/neonatal adrenoleuko- logical abnormalities, adrenocortical dysfunction and dystrophy/infantile Refsum disease/Heimler syndrome hearing- and vision impairment [5]. Before the biochem- (ORPHA79189). ical and molecular basis of ZSDs was known, they were clinically described as three distinct disorders: Zellweger History and definition syndrome (ZS), neonatal adrenoleukodystrophy (NALD) Bowen et al. described a syndrome with failure to thrive, and infantile Refsum disease (IRD). These phenotypes are congenital glaucoma and craniofacial dysmorphic features currently recognized as presentations within a clinical with early death (before 2 years of age) [5]. In 1965 Smith et al. described two siblings with comparable multiple * Correspondence: [email protected] Equal contributors congenital malformations, but also polycystic kidneys and Department of Paediatric Neurology, Emma Children’s Hospital, Academic intrahepatic biliary dysgenesis [8]. In 1967 Passarge et al. Medical Center, University of Amsterdam, Meibergdreef 9, PO BOX introduced the term cerebro-hepato-renal syndrome. 226601105 AZ Amsterdam, The Netherlands Full list of author information is available at the end of the article Since Hans Zellweger, a pediatrician, contributed two of © 2015 Klouwer et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 2 of 11 the originally described patients it was later called Neonatal-infantile presentation Zellweger syndrome [9]. It was not until 1973 that the ZSD patients within this group typically present in the causal link between ZS and peroxisomes was made, when neonatal period with hepatic dysfunction and profound Goldfischer et al. described the absence of peroxisomes in hypotonia resulting in prolonged jaundice and feeding hepatocytes and renal proximal tubules [10]. Although the difficulties. Epileptic seizures are usually present in these clinical presentation is different, the discovery of similar patients. Characteristic dysmorphic features can usually biochemical abnormalities revealed that the earlier be found, of which the facial dysmorphic signs are most described entities infantile Refsum disease and neonatal evident (Fig. 2a). Sensorineural deafness and ocular adrenoleukodystrophy were also peroxisomal disorders abnormalities like retinopathy, cataracts and glaucoma [11, 12]. Based on these findings, peroxisomes which were are typical but not always recognized at first presenta- once considered unimportant organelles, were now tion. Brain magnetic resonance imaging (MRI) may show connected to a group of diseases and became the object of neocortical dysplasia (especially perisylvian polymicro- intensive scientific investigations. It turned out that perox- gyria), generalized decrease in white matter volume, isomes are important organelles in the eukaryotic cell, and delayed myelination, bilaterial ventricular dilatation and are involved in many catabolic and anabolic metabolic germinolytic cysts [23]. Neonatal onset leukodystrophy pathways [4, 13]. At present more than 15 different is rarely described [25]. Calcific stippling (chondrodys- peroxisomal disorders have been identified. The genetic plasia punctata) may be present, especially in the knees basis of ZSDs has largely been resolved and now includes and hips. The neonatal-infantile presentation grossly 13 different PEX genes [14, 15]. The group of diseases is resembles what was originally described as classic ZS. now referred to as Zellweger spectrum disorders and in- Prognosis is poor and survival is usually not beyond the clude the old disease entities of ZS, NALD, IRD but also first year of life. Heimler syndrome which was recently recognized as a ZSD [7, 16]. Childhood presentation These patients show a more varied symptomatology than ZSD patients with a neonatal-infantile presentation. Epidemiology Presentation at the outpatient clinic usually involves The incidence of ZSDs is estimated to be 1 in 50.000 delayed developmental milestone achievement. Ocular newborns in the United States [17]. It is presumed that abnormalities comprise retinitis pigmentosa, cataract ZSDs occur worldwide, but the incidence may differ and glaucoma, often leading to early blindness and tun- between regions. For example, the incidence of (classic) nel vision [26]. Sensorineural deafness is almost always Zellweger syndrome in the French-Canadian region of present and usually discovered by auditory screening Quebec was estimated to be 1 in 12 [18]. A much lower programs. Hepatomegaly and hepatic dysfunction with incidence is reported in Japan, with an estimated coagulopathy, elevated transaminases and (history of) incidence of 1 in 500.000 births [19]. More accurate hyperbilirubinemia are common. Some patients develop incidence data about ZSDs will become available in the epileptic seizures. Craniofacial dysmorphic features are near future, since newborn screening for X-linked generally less pronounced than in the neonatal-infantile adrenoleukodystrophy (X-ALD) will be implemented in group (Fig. 2b, c). Renal calcium oxalate stones and several countries [20, 21]. The screening method is adrenal insufficiency may develop. Early-onset progres- based on C26:0-lysophosphatidylcholine (C26:0-lysoPC) sive leukodystrophy may occur, leading to loss of measurement in dried bloodspots using LC-MS/MS acquired skills and milestones in some individuals. The technology, which will also identify ZSD patients [22]. progressive demyelination is diffuse and affects the cerebrum, midbrain and cerebellum with involvement of Clinical features the hilus of the dentate nucleus and the peridentate Patients with a ZSD can roughly be divided into three white matter [23]. Sequential imaging in three ZSD groups according to the age of presentation: the neonatal- patients showed that the earliest abnormalities related to infantile presentation, the childhood presentation and an demyelination were consistently seen in the hilus of the adolescent-adult (late) presentation [23]. An overview of dentate nucleus and superior cerebellar peduncles, the main presenting symptoms for these groups is sum- chronologically followed by the cerebellar white matter, marized in Fig. 1. The original classification of ZS, NALD brainstem tracts, parieto-occipital white matter, splenium and IRD is less valuable now, especially since additional of the corpus callosum and eventually involvement of the variant phenotypes suggestive for a disease spectrum have whole of the cerebral white matter [27]. The above de- been identified. For discussing prognosis and counseling scribed rapid progressive leukodystrophy, in combination patients or families this classification may in some cases with other symptoms described here, resemble what was still be useful [24]. originally described as NALD. A small subgroup of Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 3 of 11 Fig. 1 Schematic overview of main presenting symptoms in ZSDs per clinical group patients develop a relatively late-onset white matter and are involved in either peroxisome formation, peroxi- disease, but no patients with late-onset rapid progressive somal protein import, or both. As a consequence, muta- white matter disease after the age of five have been tions in PEX genes cause a deficiency of functional reported [28]. Prognosis depends on what organ systems peroxisomes. Cells from ZSD patients either entirely are primarily affected (i.e. liver) and the occurrence of lack functional peroxisomes, or cells can show a reduced progressive cerebral demyelination, but life expectancy is number of functional peroxisomes or a mosaic pattern decreased and most patients die before adolescence. (i.e. a mixed population of cells with functional peroxi- somes and cells without) [1, 32, 33]. Peroxisomes are Adolescent-adult presentation involved in many anabolic and catabolic metabolic pro- Symptoms in this group are less severe, and diagnosis can cesses, like biosynthesis of ether phospholipids and bile be in late child- or even adulthood [29]. Ocular abnormal- acids, α- and β-oxidation of fatty acids and the detoxifi- ities and a sensorineural hearing deficit are the most con- cation of glyoxylate and reactive oxygen species. sistent symptoms. Craniofacial dysmorphic features can Dysfunctional peroxisomes therefore cause biochemical be present, but may also be completely absent (Fig. 2d-f). abnormalities in tissues, but also in readily available Developmental delay is highly variable and some patients materials like plasma and urine [3, 15] (summarized in may have normal intelligence. Daily functioning ranges Table 1). There is a reasonable genotype-phenotype from completely independent to 24 h care. It is important correlation [24]. Approximately 60 % of ZSD patients to emphasize that primary adrenal insufficiency is com- have biallelic PEX1 mutations and almost 90 different mon and is probably under diagnosed [30]. In addition to mutations in PEX1 have been reported so far [34]. some degree of developmental delay, other neurological Detailed and up to date information about PEX gene abnormalities are usually also present: signs of peripheral mutations is available through the dbPEX gene database neuropathy, cerebellar ataxia and pyramidal tract signs. (http://www.dbpex.org). The clinical course is usually slowly progressive, although the disease may remain stable for (many) years [31]. Diagnosis Slowly progressive, clinically silent leukoencephalopathy is If a ZSD is clinically suspected the first step to confirm common, but MRI may be normal in other cases [23]. the diagnosis is by biochemical testing in readily accessible materials like blood and urine. This testing includes meas- Etiology and pathophysiology urement of VLCFAs, the peroxisomal bile acid intermedi- ZSDs are caused by mutations in one of the 13 different ates di- and trihydroxycholestanoic acid (DHCA, THCA), PEX genes. PEX genes encode proteins called peroxins the branched-chain fatty acids phytanic and pristanic acid, Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 4 of 11 Fig. 2 Craniofacial dysmorphic features in ZSD patients developing over time a. Photograph of a 6-month-old girl with typical craniofacial dysmorphia. Note the epicantal folds, high forehead, broad nasal bridge and hypoplastic supraorbital ridges. The anterior fontanel is drawn and enlarged. b-c.Girl with a ZSD at the age of 9 months (b) and at the age of 1 year and two months (c). Less pronounced facial dysmorphism is present: a high forehead is seen, a broad nasal bridge, hypoplastic supraorbital ridges, anteverted nares and more subtle epicantal folds. d-f. Photograph of a male with a ZSD at the age of 5 years (d), 10 years (e) and 15 years (f). No evident facial dysmorphic features can be recognized, although the ears seem to be slightly low-set. Written informed consent was obtained from the parents of all patients for publication of these images and pipecolic acid in plasma, plasmalogen levels in eryth- including culturing the fibroblasts at 40 °C [35]. Further rocytes, and C26:0-lysoPC in dried blood spots. Addition- fibroblast testing is also required to differentiate between ally, bile acids and oxalic acid can be analyzed in urine ZSDs and certain peroxisomal single enzyme deficiencies, [24]. It is important to note that relatively mild ZSD pa- and to perform complementation studies to pinpoint the tients may have (near) normal biochemical tests in plasma defective PEX gene. Subsequent mutation analysis of the and urine [35–37]. If clinical suspicion of a ZSD is high defective PEX gene is done in all patients to confirm the and peroxisomal parameters in blood and urine are nor- diagnosis. A diagnostic flowchart is provided (Fig. 3). With mal, further testing in fibroblasts is recommended, increasing availability and reliability of next generation Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 5 of 11 Table 1 Peroxisome functions and their biochemical consequences and possible clinical relevance in ZSDs Peroxisome function Biochemical consequence Possible clinical relevance β-oxidation of VLCFA (≥C22) Impaired chain shortening of VLCFA, Brain, nerve and adrenal damage due to VLCFA last step in DHA synthesis is impaired tissue accumulation, DHA deficiency affects brain function and vision β-oxidation of methyl-branched chain Impaired chain shortening of DHCA, Pristanic acid accumulation affects brain function, fatty acid, DHCA and THCA THCA and pristanic acid accumulation of DHCA and THCA causes liver toxicity and probably also brain damage α-oxidation of fatty acids Impaired (pre-) degradation of methyl Retinal degeneration, brain and nerve damage branched phytanic acid due to phytanic acid accumulation Fatty acid racemization Reduced convertion of pristanoyl-CoA Tissue accumulation of DHCA, THCA, pristanic- and and C27-bile acyl-CoAs into stereoisomers phytanic acid before β-oxidation Ether phospholipid (plasmalogen) biosynthesis Impaired formation of ether phospholipids Plasmalogen deficiency gives rise to growth- and psychomotor retardation, cataract and bone development anomalies Glyoxylate detoxification Conversion of glyoxylate into oxalate, Accumulation leads to calcium oxalate renal stones a toxic metabolite L-lysine oxidation Impaired L-pipecolic acid degradation Accumulation of pipecolic acid, no clinical consequences known [78] Hydrogen peroxide detoxification Decreased catabolism of hydrogen peroxide Increased reactive oxidant damage sequencing it is possible that genetic tests will become diagnosis. Before prenatal genetic testing can be per- first tier tests in the future. However, biochemical testing formed the familial pathogenic mutation (s) in one of in blood and/or fibroblasts is still required in these cases the PEX genes need (s) to be identified [1]. If the PEX mu- to confirm pathogenicity of the identified mutations and tations are unknown or cannot be detected, biochemical to characterize the extent of the deficiency. prenatal testing for ZSD is possible in chorionic villus biopsy material, cultured chorionic villus cells or cultured Differential diagnosis amniocytes. Biochemical prenatal testing can only be Differential diagnosis varies with the age of presentation performed in case of clear biochemical abnormalities in and most prominent symptoms at presentation (Table 2). cells from the index patient [15]. In newborns, ZSDs with hypotonia are most often con- fused with other conditions presenting with profound Clinical management and treatment hypotonia including chromosomal abnormalities. The Because no curative therapy for patients with a ZSD most important differential disorders to consider when exists, intervention is supportive and based on symp- suspecting a ZSD is the group of single peroxisomal toms. Past- and current supportive therapeutic options enzyme deficiencies. Especially Acyl-CoA oxidase type 1 are summarized in Table 4. (ACOX1) deficiency and D-bifunctional protein (DBP) deficiency show great overlap and in some cases, especially in the neonatal-infantile and childhood period, can be clinically indistinguishable from ZSDs [38, 39]. Docosahexaenoic acid Also MRI-features in DBP-deficiency resemble those of Docosahexaenoic acid (DHA; C22:6ω3) is a long-chain ZSD patients [27]. Differentiation is possible with bio- polyunsaturated fatty acid important for retinal and brain chemical and genetic tests as summarized in Table 3. function [40, 41]. Tetracosahexaenoic acid (C24:6ω3) Dependent on the most prominent presenting symptom undergoes one cycle of peroxisomal beta-oxidation to be such as retinitis pigmentosa, cerebellar ataxia or adrenal converted to DHA [4], leading to reduced levels of DHA insufficiency, other single peroxisomal enzyme deficien- when peroxisomes are absent. Because ZSD patients often cies like classical Refsum disease, alpha-methylacyl-CoA have low levels of DHA in membranes of erythrocytes, racemase deficiency or X-ALD should be considered. supplementation of DHA was suggested to be a possible therapy. Although some studies have claimed a beneficial Genetic counseling and antenatal diagnosis effect of DHA supplementation [42, 43], a randomized Because of the poor outcome and high disease burden double-blind placebo controlled trial showed that DHA associated with the majority of ZSDs, genetic counseling treatment leads to increased DHA levels in plasma, but no should be offered to parents of affected children. Car- improvement of visual function and growth could be riers can be offered prenatal- or preimplantation genetic observed [44]. Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 6 of 11 Fig. 3 Diagnostic flow-chart for ZSDs. a Very long chain fatty acids: C26:0, C24:0/C22:0 ratio, C26:0/C22:0 ratio. b Single enzyme deficiency with pheno- typical ZSD similarities like ACOX1 deficiency and DBP deficiency. c Next generation sequencing (NGS) of all PEX genes is advised when complementa- tion analysis is not practicable Lorenzo’s oil Cholic acid Lorenzo’s oil (i.e. 4:1 mix of glyceryl trioleate and glyceryl Cholic acid is a primary C24 bile acid, involved in for trierucate) therapy was originally developed for the single instance the absorption of fat-soluble vitamins. Cholic peroxisomal enzyme deficiency X-ALD, and was shown to acidisformedfromits precursorTHCAby one lower VLCFAs in plasma [45], but had no effect on disease peroxisomal beta-oxidation cycle. The peroxisomal progression [46, 47]. Some studies reported lowering of C27-bile acid intermediates DHCA and THCA accu- the VLCFA levels in plasma by Lorenzo’s oil in ZS babies mulate in ZSDs and are considered to be more toxic [48, 49]. However, based on data of studies in X-ALD indi- than the primary C24 bile acids due to their altered viduals, there is no reason to expect that Lorenzo’s oil will physical properties and are believed to contribute to be beneficial for ZSD patients at this point. the liver disease in ZSDs (e.g. dysfunction and liver Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 7 of 11 Table 2 Differential diagnosis of ZSDs based on the most levels of fat-soluble vitamins. Furthermore, bile acid prominent presenting symptom treatment in mice was shown to improve hepatic dis- Main presenting symptom Differential diagnosis ease [53]. Limitations of the studies so far, however, are the small number of treated patients and short Hypotonia in newborns Chromosomal abnormalities (Down syndrome, Prader-Willi syndrome) follow-up. Current evidence is insufficient to conclude Congenital infections (cytomegalovirus, that cholic acid treatment is beneficial for patients rubella, herpes simplex, toxoplasmosis) with a ZSD. The Food and Drug Administration Hypoxic ischemic encephalopathy recently approved cholic acid as a safe treatment for ZSD patients in the United States. However, efficiency Cerebral malformations should be demonstrated in large clinical trials before Other metabolic disorders (acid maltase deficiency, carnitine deficiency, this treatment can be implemented. cytochrome-c-oxidase deficiency) Other peroxisomal disorders (acyl-CoA Plasmalogen precursors oxidase type 1 deficiency, D-bifunctional Due to a deficiency of the first peroxisomal steps in the protein deficiency) biosynthesis of plasmalogens [54], ZSD patients may Spinal muscular atrophy have low levels of plasmalogens. Plasmalogens play a Congenital muscular dystrophies critical role in cell membranes and as anti-oxidants [55]. Congenital myopathies It was suggested that supplementation with precursors of plasmalogens (batyl alcohol) could be beneficial for Hereditary motor and sensory neuropathy ZSD patients, as import of these alkylglycerols proceeds Bilateral cataract Idiopathic normally. Several case reports have described an increase Congenital infections in erythrocyte plasmalogen levels after treatment and Other peroxisomal disorders (rhizomelic improvement of clinical symptoms in some patients chondrodysplasia punctata, classical [56–58]. Although never studied systematically, ether Refsum disease, 2-methylacyl-CoA racemase deficiency) lipid therapy could be of interest for ZSD. Other metabolic disorders (galactosemia) Citrate Lowe syndrome The toxic metabolite oxalate accumulates in plasma Sensorineural hearing loss Usher syndrome type I,II and urine from ZSD patients [4]. This causes renal with retinitis pigmentosa Other peroxisomal disorders calcium oxalate stones. In a large cohort of Dutch (classical Refsum disease) ZSD patients a high prevalence of 83 % of renal Mitochondrial disorders calcium oxalate stones was shown [59]. For this rea- Cockayne syndrome son, patients should be screened for the presence of high Alport syndrome levels of oxalic acid in urine yearly. To prevent the forma- Waardenburg syndrome tion of renal stones, patients with hyperoxaluria should start oral citrate treatment. Furthermore, sufficient fluid Adrenocorticol insufficiency Autoimmune adrenalitis intake is recommended [60]. Infectious adrenalitis Adrenal hemorrhage Supportive care Adrenal hypoplasia All ZSD patients need to be screened for adrenal X-linked adrenoleukodystrophy insufficiency [30], epilepsy, low levels of fat-soluble Deficient cholesterol metabolism vitamins, (partly) vitamin K dependent coagulopathy, high levels of phytanic acid, hearing or visual impair- Familial glucocorticoid deficiency ment and enamel hypoplasia. They should be treated according to the identified abnormalities, e.g. supple- fibrosis) [50]. The bile acid intermediates are only mentation of cortisone, anti-epileptic drugs, vitamins partly conjugated and are less well excreted than C24 and/or a phytanic restricted diet. Because supplemen- bile acids contributing to cholestasis. We hypothesize tation of cortisone is associated with severe side that DHCA and THCA cross the blood–brain barrier effects, such as growth suppression and osteoporosis and cause central nerve system damage. Several case [61], only patients with a true insufficiency (i.e. reports have described a beneficial effect of cholic altered Synacthen test) should be treated. A phytanic acid acid in ZS babies, supported by reduced urinary and restricted diet is only necessary when levels of phytanic plasma excretion of DHCA/THCA [51, 52]. Clinically acid are extremely high and is not recommended when there was increased growth and an increase in the levels are moderately increased, as sufficient intake of Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 8 of 11 Table 3 Differences in biochemical characteristics of ZSDs and phenotypical similar single enzyme deficiencies ZSD DBP-D ACOX1-D Remarks Plasma a b b b Very long chain fatty acids ↑ ↑ ↑ False positives possible in ketogenic diets, hemolyzed samples and peanut rich diet. Di- and trihydroxycholestanoic acid ↑ N-↑ N Phytanic acid N-↑ N-↑ N Derived from dietary sources only; dependent on dietary intake. Normal in newborns. Pristanic acid N-↑ N-↑ N Derived from dietary sources only (direct and indirectly via phytanic acid). Normal in newborns. Erythrocytes Plasmalogen level ↓-N N N Blood spot C26:0 lysophosphatidylcholine↑↑ ↑ Fibroblasts Plasmalogen synthesis ↓ NN DHAPAT ↓ NN Alkyl DHAP synthase ↓ NN C26:0 β-oxidation ↓↓ ↓ Pristanic acid β-oxidation ↓↓ N Acyl-CoA oxidase 1 ↓-N N ↓ D-Bifunctional protein ↓-N ↓ N Phytanic acid α-oxidation ↓ NN Phytanoyl CoA hydroxylase ↓ NN Peroxisomes ↓ N N Peroxisomal mosaicism can be present in ZSD. In DBP- and ACOX1-deficiency abnormal peroxisomal morphology may be present. Mutant gene PEX1,2,3,5,6,10,11β,12,13,14,16,19,26 HSD17B4 ACOX Very long chain fatty acids: C26:0, C24:0/C22:0 ratio, C26:0/C22:0 ratio May be minimally abnormal to normal in exceptional cases calories is more decisive. Hearing and visual impair- ment should be (partly) corrected by hearing aids and glasses, with ophthalmologic and audiological evalua- tions yearly. Enamel hypoplasia, present in nearly all patients, should be followed-up by a dentist [62, 63]. Table 4 Supportive therapeutic options in ZSDs Some patients will need a gastrostomy to provide Symptom/disease Treatment/intervention adequate intake of calories. Adrenal insufficiency Cortisone Coagulopathy Vitamin K suppletion Current/future developments Enamel hypoplasia Dentist referral Several compounds that stimulate peroxisomal biogen- Epilepsy Standard antiepileptic drugs esis and function in vitro [64–66] were discovered Hearing impairment Hearing aids, cochlear implant recently and clinical trials are ongoing (clinicaltrails.gov: High phytanic acid plasma level Phytanic acid restricted diet NCT01838941). Hopefully, some of these compounds Hyperoxaluria Oral citrate treatment Sufficient will be able to rescue or improve peroxisomal func- fluid intake tion in patients. The greatest beneficial effect is Insufficient calory intake Gastrostomy expected in patients whose fibroblasts showed a Low levels of fat-soluble Vitamin suppletion temperature sensitivity with worsening of the pheno- vitamins (A, D, E) type when cultured at 40 °C and improvement of Visual impairment Cataract removal, glasses and peroxisomal functions at 30 °C [67, 68]. In addition ophthalmologist referral to these new compounds, the effect of cholic acid is Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 9 of 11 currently under investigation (controlled-trials.com: Unresolved questions ISRCTN96480891) in a large cohort of ZSD patients. The effect of cholic acid is based upon case reports only, Although never tested in ZSD patients, gene therapy but within the coming years the clinical effects will be with or without tissue specific targeting might be a investigated in larger cohorts. In addition, results of potential treatment. Several years ago gene therapy was ongoing trials will be published. An important limitation already proposed for X-ALD [69]. Although promising, to consider when interpreting the data of these trials is gene therapy still needs to be optimized to be feasible the broad spectrum of severe and milder clinical pheno- for patients [70]. First, studies have to be conducted in types and associated biochemical variations within these the recently published mild PEX1 mouse model [71], cohorts. Furthermore, the natural course of the disease before a human trial can be initiated. can lead to false conclusions, as peroxisomal metabolites An orthotopic liver transplantation was described in were shown to fluctuate and decline with age [31]. A large a single 6-month old ZSD patient and hepatocytes prospective natural history study is therefore needed. We transplantation in another 4-year old patient [72, 73]. and others, recently started collecting the data of a large It resulted in decreased concentrations of VLCFAs prospective cohort of ZSD patients (clinicaltrails.gov: and pipecolic acid, and improved bile acid profiles. NCT01668186). However, the effect on long-term disease course has Second, plasma levels of peroxisomal metabolites do not been reported. not correlate well with disease severity, as they generally Although bone marrow transplantation (BMT) is an decrease with age. Furthermore, therapies like DHA and established therapy for the cerebral childhood form of Lorenzo’s oil improved plasma levels of DHA and C26:0, X-ALD [74], there are no reports describing BMT in albeit no effect on the clinical phenotype has been ZSD patients. BMT would be of interest for those observed. This is possibly related to differences in ex- patients who develop leukodystrophy in infancy. However, pression or activity of peroxisomes in the targeted tissue. with the current knowledge it is impossible to predict Therefore, using plasma levels as a surrogate outcome in if patients will develop this rapid progressive leuko- clinical trials is not recommended. New biochemical dystrophy. Recently, a retrospective study revealed outcome parameters that correlate with disease progres- that patients with X-ALD still develop an adrenomye- sion are necessary, such as analysis of markers for lopathy phenotype after BMT [75]. Nevertheless, peroxisomal dysfunctions in lymphocytes. BMT could possibly be beneficial for a subgroup of The pathophysiology of ZSD is still poorly understood. patients within the ZSD spectrum, but first new Similar to the cerebral form of X-ALD, it is still not clear techniques/markers that can predict whether or not when or why ZSD patients develop severe rapid progres- patients will develop a severe progressive leukodystro- sive leukodystrophy. The recently constructed mild phyhavetobe elucidated. PEX1 mouse model [71] and natural history studies will help to answer these questions. Prognosis Conclusions Although a rough genotype-phenotype correlation exists Because of the recently implemented newborn screening, for several PEX genes, such as PEX1 and PEX26 [76, 77], more medical doctors in different specialties (e.g. pediatri- the severity and progression of the disease is difficult to cians, clinical geneticist and neurologists) will encounter predict for individual patients. This will become more patients with a ZSD. ZSDs are clinically heterogeneous relevant as newborn screening is implemented. As a with high morbidity in almost all patient and mortality in consequence of newborn screening for X-ALD by C26:0- some. Although treatment is currently only symptomatic, lysoPC in several countries ZSD will also be diagnosed it is important to initiate proper supportive therapy to at birth. Children with the severe phenotype (neonatal- improve quality of life of these patients. infantile presentation with severe clinical symptoms) have a poor prognosis and these patients usually die Abbreviations within the first year of life. Patients that present in child- ACOX1: acyl-CoA oxidase type 1; BMT: bone marrow transplant; C26:0- hood or adolescence usually have a better prognosis, but lysoPC: C26:0-lysophosphatidylcholine; DBP: d-bifunctional protein; can develop progressive liver disease or leukodystrophy DHA: docosahexanoic acid; DHCA: dihydroxycholestanoic acid; IRD: infantile Refsum disease; MRI: magnetic resonance imaging; NALD: neonatal and deteriorate. If progressive liver disease or leukodys- adrenoleukodystrophy; THCA: trihydroxycholestanoic acid; VLCFAs: very long trophy occurs prognosis is poor. The remaining milder chain fatty acids; X-ALD: x-linked adrenoleukodystrophy; ZS: Zellweger individuals can reach adulthood without progression or syndrome; ZSD: Zellweger spectrum disorder. with long periods of stabilization. When progression occurs, it is mainly related to peripheral neuropathy and Competing interests pyramidal signs, while cognition remains stable [31]. The authors declare that they have no competing interests. Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 10 of 11 Authors’ contributions 18. Levesque S, Morin C, Guay S-P, Villeneuve J, Marquis P, Yik WY, et al. A founder All authors were involved in the conception and writing of the manuscript. mutation in the PEX6 gene is responsible for increased incidence of Zellweger All authors read and approved the final manuscript. syndrome in a French Canadian population. BMC Med Genet. 2012;13:72. 19. Shimozawa N, Nagase T, Takemoto Y, Ohura T, Suzuki Y, Kondo N. Genetic heterogeneity of peroxisome biogenesis disorders among Japanese patients: evidence for a founder haplotype for the most common PEX10 Acknowledgements gene mutation. Am J Med Genet A. 2003;120A:40–3. This work was supported by a grant from ‘Metakids’, ‘Hersenstichting’ and 20. Haynes CA, De Jesús VR. The stability of hexacosanoyl ‘Stichting Steun Emma Kinderziekenhuis AMC’, The Netherlands. We would lysophosphatidylcholine in dried-blood spot quality control materials for X- like to thank the parents of the patients displayed in this review for linked adrenoleukodystrophy newborn screening. Clin Biochem. 2014;48:8–10. providing photographs and the permission for publication. 21. Vogel BH, Bradley SE, Adams DJ, D’Aco K, Erbe RW, Fong C, et al. Newborn screening for X-linked adrenoleukodystrophy in New York State: Diagnostic Author details protocol, surveillance protocol and treatment guidelines. Mol Genet Metab. Department of Paediatric Neurology, Emma Children’s Hospital, Academic 2015;114:599–603. Medical Center, University of Amsterdam, Meibergdreef 9, PO BOX 22. Hubbard WC, Moser AB, Liu AC, Jones RO, Steinberg SJ, Lorey F, et al. 226601105 AZ Amsterdam, The Netherlands. Laboratory Genetic Metabolic Newborn screening for X-linked adrenoleukodystrophy (X-ALD): validation Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, of a combined liquid chromatography-tandem mass spectrometric The Netherlands. (LC-MS/MS) method. Mol Genet Metab. 2009;97:212–20. 23. Poll-The BT, Gärtner J. Clinical diagnosis, biochemical findings and MRI Received: 19 October 2015 Accepted: 22 November 2015 spectrum of peroxisomal disorders. Biochim Biophys Acta. 1822;2012:1421–9. 24. Steinberg SJ, Raymond G V, Braverman NE, Moser AB: Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum. Gene Rev2003. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1448/. Accessed 1 Sep 2015. References 25. Poll-The BT, Gootjes J, Duran M, De Klerk JBC, Wenniger Prick LJM De B, 1. Waterham HR, Ebberink MS. Genetics and molecular basis of human Admiraal RJC, et al. Peroxisome biogenesis disorders with prolonged peroxisome biogenesis disorders. Biochim Biophys Acta. 1822;2012:1430–41. survival: phenotypic expression in a cohort of 31 patients. Am J Med Genet 2. Fujiki Y, Okumoto K, Mukai S, Honsho M, Tamura S. Peroxisome biogenesis A. 2004;126A:333–8. in mammalian cells. Front Physiol. 2014;5:307. 26. Hamel C. Retinitis pigmentosa. Orphanet J Rare Dis. 2006;1:40. 3. Braverman NE, D’Agostino MD, Maclean GE. Peroxisome biogenesis 27. Van der Knaap MS, Wassmer E, Wolf NI, Ferreira P, Topçu M, Wanders RJA, disorders: Biological, clinical and pathophysiological perspectives. et al. MRI as diagnostic tool in early-onset peroxisomal disorders. Neurology. Dev Disabil Res Rev. 2013;17:187–96. 2012;78:1304–8. 4. Wanders RJA, Waterham HR. Biochemistry of mammalian peroxisomes 28. Barth PG, Gootjes J, Bode H, Vreken P, Majoie CBLM, Wanders RJA. Late revisited. Annu Rev Biochem. 2006;75:295–332. onset white matter disease in peroxisome biogenesis disorder. Neurology. 5. Bowen P, Lee CS, Zellweger H, Lindenberg R. A familial syndrome of 2001;57:1949–55. multiple congenital defects. Bull Johns Hopkins Hosp. 1964;114:402–14. 29. Moser AB, Rasmussen M, Naidu S, Watkins PA, McGuinness M, Hajra AK, 6. Poll-The BT, Saudubray JM, Ogier HA, Odièvre M, Scotto JM, Monnens L, et al. Phenotype of patients with peroxisomal disorders subdivided into et al. Infantile Refsum disease: an inherited peroxisomal disorder. sixteen complementation groups. J Pediatr. 1995;127:13–22. Comparison with Zellweger syndrome and neonatal adrenoleukodystrophy. 30. Berendse K, Engelen M, Linthorst GE, van Trotsenburg ASP, Poll-The BT. Eur J Pediatr. 1987;146:477–83. High prevalence of primary adrenal insufficiency in Zellweger spectrum 7. Ratbi I, Falkenberg KD, Sommen M, Al-Sheqaih N, Guaoua S, Vandeweyer G, disorders. Orphanet J Rare Dis. 2014;9:133. Urquhart JE, Chandler KE, Williams SG, Roberts NA, El Alloussi M, Black GC, 31. Berendse K, Engelen M, Ferdinandusse S, Majoie CBLM, Waterham HR, Vaz FM, Ferdinandusse S, Ramdi H, Heimler A, Fryer A, Lynch S-A, Cooper N, Ong KR, Koelman JHTM, Barth PG, Wanders RJA, Poll-The BT: Zellweger spectrum Smith CEL, Inglehearn CF, Mighell AJ, Elcock C, Poulter JA, Tischkowitz M, disorders: clinical manifestations in patients surviving into adulthood. Davies SJ, Sefiani A, Mironov AA, Newman WG, Waterham HR, et al.: Heimler J Inherit Metab Dis 2015, in press. Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome- Biogenesis Genes PEX1 and PEX6. Am J Hum Genet 2015, in press. 32. Pineda M, Girós M, Roels F, Espeel M, Ruiz M, Moser A, et al. Diagnosis and 8. Smith DW, Opitz JM, Inhorn SL. A syndrome of multiple developmental follow-up of a case of peroxisomal disorder with peroxisomal mosaicism. defects including polycystic kidneys and intrahepatic biliary dysgenesis J Child Neurol. 1999;14:434–9. in 2 siblings. J Pediatr. 1965;67:617–24. 33. Gootjes J, Schmohl F, Mooijer PAW, Dekker C, Mandel H, Topcu M, et al. Identification of the molecular defect in patients with peroxisomal mosaicism 9. Opitz JM, Zu Rhein GM, Vitale L, Shahidi NJ, Howe JJ, Chon SM, et al. The using a novel method involving culturing of cells at 40 degrees C: implications Zellweger Syndrome (cerebro-hepato-renal syndrome). Birth Defects Orig for other inborn errors of metabolism. Hum Mutat. 2004;24:130–9. Art Set. 1969;2:144–58. 34. Ebberink MS, Mooijer PAW, Gootjes J, Koster J, Wanders RJA, Waterham HR. 10. Goldfischer S, Moore CL, Johnson AB, Spiro AJ, Valsamis MP, Wisniewski HK, Genetic classification and mutational spectrum of more than 600 patients et al. Peroxisomal and mitochondrial defects in the cerebro-hepato-renal with a Zellweger syndrome spectrum disorder. Hum Mutat. 2011;32:59–69. syndrome. Science. 1973;182:62–4. 35. Zeharia A, Ebberink MS, Wanders RJA, Waterham HR, Gutman A, Nissenkorn A, 11. Poulos A, Sharp P, Whiting M. Infantile Refsum’s disease (phytanic acid et al. A novel PEX12 mutation identified as the cause of a peroxisomal storage disease): a variant of Zellweger’s syndrome? Clin Genet. biogenesis disorder with mild clinical phenotype, mild biochemical 1984;26:579–86. abnormalities in fibroblasts and a mosaic catalase immunofluorescence 12. Kelley RI, Moser HW. Hyperpipecolic acidemia in neonatal pattern, even at 40 degrees C. J Hum Genet. 2007;52:599–606. adrenoleukodystrophy. Am J Med Genet. 1984;19:791–5. 13. Van Veldhoven PP. Biochemistry and genetics of inherited disorders of 36. Steinberg SJ, Snowden A, Braverman NE, Chen L, Watkins PA, Clayton PT, et al. peroxisomal fatty acid metabolism. J Lipid Res. 2010;51:2863–95. A PEX10 defect in a patient with no detectable defect in peroxisome assembly 14. Reuber BE, Germain-Lee E, Collins CS, Morrell JC, Ameritunga R, Moser HW, or metabolism in cultured fibroblasts. J Inherit Metab Dis. 2009;32:109–19. et al. Mutations in PEX1 are the most common cause of peroxisome 37. Ebberink MS, Csanyi B, Chong WK, Denis S, Sharp P, Mooijer PAW, et al. biogenesis disorders. Nat Genet. 1997;17:445–8. Identification of an unusual variant peroxisome biogenesis disorder caused 15. Wanders RJA, Waterham HR. Peroxisomal disorders I: biochemistry and by mutations in the PEX16 gene. J Med Genet. 2010;47:608–15. genetics of peroxisome biogenesis disorders. Clin Genet. 2005;67:107–33. 38. Ferdinandusse S, Denis S, Hogenhout EM, Koster J, van Roermund CWT, IJlst L, 16. Collins CS, Gould SJ. Identification of a common PEX1 mutation in et al. Clinical, biochemical, and mutational spectrum of peroxisomal Zellweger syndrome. Hum Mutat. 1999;14:45–53. acyl-coenzyme A oxidase deficiency. Hum Mutat. 2007;28:904–12. 17. Gould S, Raymond G, Valle D: The Peroxisome biogenesis disorders. In The 39. Ferdinandusse S, Denis S, Mooyer PAW, Dekker C, Duran M, Soorani-Lunsing RJ, Metabolic and Molecular Bases of Inherited Disease. 8th edition. New York, et al. Clinical and biochemical spectrum of D-bifunctional protein deficiency. NY: McGraw-Hill; 2001:3181–3218. Ann Neurol. 2006;59:92–104. Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 Page 11 of 11 40. Horrocks LA, Yeo YK. Health benefits of docosahexaenoic acid (DHA). 66. Wei H, Kemp S, McGuinness MC, Moser AB, Smith KD. Pharmacological Pharmacol Res. 1999;40:211–25. induction of peroxisomes in peroxisome biogenesis disorders. Ann Neurol. 41. Birch EE, Hoffman DR, Uauy R, Birch DG, Prestidge C. Visual acuity and the 2000;47:286–96. essentiality of docosahexaenoic acid and arachidonic acid in the diet of 67. Imamura A, Tamura S, Shimozawa N, Suzuki Y, Zhang Z, Tsukamoto T, et al. term infants. Pediatr Res. 1998;44:201–9. Temperature-sensitive mutation in PEX1 moderates the phenotypes of 42. Martínez M, Vázquez E, García-Silva MT, Manzanares J, Bertran JM, Castelló F, peroxisome deficiency disorders. Hum Mol Genet. 1998;7:2089–94. et al. Therapeutic effects of docosahexaenoic acid ethyl ester in patients with 68. Shimozawa N, Suzuki Y, Zhang Z, Imamura A, Toyama R, Mukai S, et al. generalized peroxisomal disorders. Am J Clin Nutr. 2000;71 Suppl 1:376S–85S. Nonsense and temperature-sensitive mutations in PEX13 are the cause of 43. Noguer MT, Martinez M. Visual follow-up in peroxisomal-disorder patients complementation group H of peroxisome biogenesis disorders. Hum Mol treated with docosahexaenoic Acid ethyl ester. Invest Ophthalmol Vis Sci. Genet. 1999;8:1077–83. 2010;51:2277–85. 69. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Bougnères P, Schmidt M, Kalle C, et al. Lentiviral hematopoietic cell gene therapy for X-linked 44. Paker M, Sunness JS, Brereton NH, Speedie LJ, Albanna L, Dharmaraj S, et al. Docosahexaenoic acid therapy in peroxisomal diseases: results of a double- adrenoleukodystrophy. Methods Enzymol. 2012;507:187–98. blind, randomized trial. Neurology. 2010;75:826–30. 70. Toscano MG, Romero Z, Muñoz P, Cobo M, Benabdellah K, Martin F. Physiological and tissue-specific vectors for treatment of inherited diseases. 45. Moser AB, Borel J, Odone A, Naidu S, Cornblath D, Sanders DBMH. A new Gene Ther. 2011;18:117–27. dietary therapy for adrenoleukodystrophy: biochemical and preliminary 71. Hiebler S, Masuda T, Hacia JG, Moser AB, Faust PL, Liu A, et al. The Pex1- clinical results in 36 patients. Ann Neurol. 1987;21:240–9. G844D mouse: a model for mild human Zellweger spectrum disorder. Mol 46. Aubourg P, Adamsbaum C, Lavallard-Rousseau MC, Rocchiccioli F, Cartier N, Genet Metab. 2014;111:522–32. Jambaque I, et al. A two-year trial of oleic and erucic acids (“Lorenzo’s Oil”) 72. Sokal EM, Smets F, Bourgois A, Van Maldergem L, Buts JP, Reding R, et al. as treatment for adrenomyeloneuropathy. NEJM. 1993;329:745–52. Hepatocyte transplantation in a 4-year-old girl with peroxisomal biogenesis 47. Van Geel BM, Assies J, Haverkort EB, Koelman JHTM, Verbeeten B, Wanders RJA, disease: technique, safety, and metabolic follow-up. Transplantation. et al. Progression of abnormalities in adrenomyeloneuropathy and 2003;76:735–8. neurologically asymptomatic X-linked adrenoleukodystrophy despite 73. Van Maldergem L, Moser AB, Vincent M-F, Roland D, Reding R, Otte JB et al. treatment with “Lorenzo’soil.”. J Neurol Neurosurg Psychiatry. 1999;67:290–9. Orthotopic liver transplantation from a living-related donor in an infant with 48. Tanaka K, Shimizu T, Ohtsuka Y, Yamashiro Y, Oshida K. Early dietary a peroxisome biogenesis defect of the infantile Refsum disease type. J treatments with Lorenzo’s oil and docosahexaenoic acid for neurological Inherit Metab Dis. 2005;28:593–600. development in a case with Zellweger syndrome. Brain Dev. 2007;29:586–9. 74. Aubourg P, Blanche S, Jambaqué I, Rocchiccioli F, Kalifa G, Naud-Saudreau C 49. Arai Y, Kitamura Y, Hayashi M, Oshida K, Shimizu T, Yamashiro Y. Effect of et al. Reversal of early neurologic and neuroradiologic manifestations of dietary Lorenzo’s oil and docosahexaenoic acid treatment for Zellweger X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J syndrome. Congenit Anom (Kyoto). 2008;48:180–2. Med. 1990;322:1860–6. 50. Ferdinandusse S, Denis S, Dacremont G, Wanders RJA. Toxicity of 75. Van Geel BM, Poll-The BT, Verrips A, Boelens JJ, Kemp S, Engelen M. peroxisomal C27-bile acid intermediates. Mol Genet Metab. 2009;96:121–8. Hematopoietic cell transplantation does not prevent myelopathy in X-linked 51. Setchell KDR, Bragetti P, Zimmer-Nechemias L, Daugherty C, Pelli MA, adrenoleukodystrophy: a retrospective study. J Inherit Metab Dis. Vaccaro R, et al. Oral bile acid treatment and the patient with zellweger 2015;38:359–61. syndrome. Hepatology. 1992;15:198–207. 76. Bader PI, Dougherty S, Cangany N, Raymond G, Jackson CE. Infantile Refsum 52. Maeda K, Kimura A, Yamato Y, Nittono H, Takei H, Sato T, Mitsubuchi H, disease in four Amish sibs. Am J Med Genet. 2000;90:110–4. Murai T, Kurosawa T: Oral Bile Acid Treatment in Two Japanese Patients 77. Rosewich H, Ohlenbusch A, Gärtner J. Genetic and clinical aspects of Zellweger With Zellweger Syndrome. J Pediatr Gastroenterol Nutr. 2002, 35:227–230 spectrum patients with PEX1 mutations. J Med Genet. 2005;42:e58. 53. Keane MH, Overmars H, Wikander TM, Ferdinandusse S, Duran M, Wanders RJ A, 78. Vallat C, Denis S, Bellet H, Jakobs C, Wanders RJA, Mion H. Major et al. Bile acid treatment alters hepatic disease and bile acid transport in hyperpipecolataemia in a normal adult. J Inherit Metab Dis. 1996;19:624–6. peroxisome-deficient PEX2 Zellweger mice. Hepatology. 2007;45:982–97. 54. De Vet EC, van den Bosch H. Alkyl-dihydroxyacetonephosphate synthase. Cell Biochem Biophys. 2000;32:117–21. 55. Braverman NE, Moser AB. Functions of plasmalogen lipids in health and disease. Biochim Biophys Acta. 1822;2012:1442–52. 56. Holmes RD, Wilson GN, Hajra A. Oral ether lipid therapy in patients with peroxisomal disorders. J Inherit Metab Dis. 1987;10:239–41. 57. Das AK, Holmes RD, Wilson GN, Hajra AK. Dietary ether lipid incorporation into tissue plasmalogens of humans and rodents. Lipids. 1992;27:401–5. 58. Wilson GN, Holmes RG, Custer J, Lipkowitz JL, Stover J, Datta N, et al. Zellweger syndrome: diagnostic assays, syndrome delineation, and potential therapy. Am J Med Genet. 1986;24:69–82. 59. Van Woerden CS, Groothoff JW, Wijburg FA, Duran M, Wanders RJA, Barth PG, et al. High incidence of hyperoxaluria in generalized peroxisomal disorders. Mol Genet Metab. 2006;88:346–50. 60. Leumann E, Hoppe B, Neuhaus T, Blau N. Efficacy of oral citrate administration in primary hyperoxaluria. Nephrol Dial Transplant. 1995;10 Suppl 8:14–6. Submit your next manuscript to BioMed Central 61. Buchman AL. Side effects of corticosteroid therapy. J Clin Gastroenterol. 2001;33:289–94. and we will help you at every step: 62. Lertsirivorakul J, Wongswadiwat M, Treesuwan P. Oral manifestations and • We accept pre-submission inquiries dental management of a child with Zellweger syndrome. Spec Care Dent. 2012;34:46–50. � Our selector tool helps you to find the most relevant journal 63. Acharya BS, Ritwik P, Velasquez GM, Fenton SJ. Medical-dental findings and � We provide round the clock customer support management of a child with infantile Refsum disease: a case report. Spec � Convenient online submission Care Dentist. 2012;32:112–7. 64. Zhang R, Chen L, Jiralerspong S, Snowden A, Steinberg S, Braverman N. � Thorough peer review Recovery of PEX1-Gly843Asp peroxisome dysfunction by small-molecule � Inclusion in PubMed and all major indexing services compounds. Proc Natl Acad Sci U S A. 2010;107:5569–74. � Maximum visibility for your research 65. Berendse K, Ebberink MS, Ljlst L, Wanders RJA, Waterham HR, Poll The BT. Arginine improves peroxisome functioning in cells from patients with a Submit your manuscript at mild peroxisome biogenesis disorder. Orphanet J Rare Dis. 2013;8:138. www.biomedcentral.com/submit

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