Klouwer et al. Orphanet Journal of Rare Diseases (2015) 10:151 DOI 10.1186/s13023-015-0368-9 REVIEW Open Access Zellweger spectrum disorders: clinical overview and management approach Femke C. C. Klouwer1,2†, Kevin Berendse1,2†, Sacha Ferdinandusse2, Ronald J. A. Wanders2, Marc Engelen1 and Bwee Tien Poll-The1* 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 * Correspondence: [email protected] et al. described two siblings with comparable multiple †Equal contributors congenital malformations, but also polycystic kidneys and 1 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 226601105 AZ Amsterdam, The Netherlands introduced the term cerebro-hepato-renal syndrome. 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