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Peroxisome Biogenesis Disorders in the Zellweger Spectrum: an Overview of Current Diagnosis, Clinical Manifestations, and Treatment Guidelines

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Peroxisome Biogenesis Disorders in the Zellweger Spectrum: an Overview of Current Diagnosis, Clinical Manifestations, and Treatment Guidelines Molecular Genetics and Metabolism 117 (2016) 313–321 Contents lists available at ScienceDirect Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines Nancy E. Braverman a, Gerald V. Raymond b, William B. Rizzo c, Ann B. Moser d, Mark E. Wilkinson e, Edwin M. Stone e, Steven J. Steinberg f, Michael F. Wangler g, Eric T. Rush h,JosephG.Haciai, Mousumi Bose j,⁎ a McGill University Health Centre, 1001 Décarie Blvd Block E, EM02230, Montreal, QC H4A3J1, Canada b Department of Neurology, University of Minnesota, 516 Delaware Street SE, Minneapolis, MN 55455, USA, c Department of Pediatrics, University of Nebraska Medical Center, 985456 Nebraska Medical Center — MMI 3062, Omaha, NE 68198-5456, USA d Hugo W. Moser Research Institute at Kennedy Krieger, 707 N. Broadway, Baltimore, MD 21205, USA e Carver College of Medicine, Department of Ophthalmology and Visual Sciences, University of Iowa, Stephen A. Wynn Institute for Vision Research, 200 Hawkins Drive, Iowa City, IA 52242, USA f Institute of Genetic Medicine and Department of Neurology, Johns Hopkins University School of Medicine, CMSC1004B, 600 N Wolfe Street, Baltimore, MD 21287, USA g Department of Molecular and Human Genetics, Baylor College of Medicine, Duncan Neurological Research Institute, DNRI-1050, Houston, TX 77030, USA h Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, 985440 Nebraska Medical Center, Omaha, NE 68198, USA i Department of Biochemistry and Molecular Biology, University of Southern California, 1975 Zonal Ave, Los Angeles, CA 90033, USA j Global Foundation for Peroxisomal Disorders, 5147 S. Harvard Avenue, Suite 181, Tulsa, OK 74135, USA article info abstract Article history: Peroxisome biogenesis disorders in the Zellweger spectrum (PBD-ZSD) are a heterogeneous group of genetic Received 31 October 2015 disorders caused by mutations in PEX genes responsible for normal peroxisome assembly and functions. As a Received in revised form 21 December 2015 result of impaired peroxisomal activities, individuals with PBD-ZSD can manifest a complex spectrum of clinical Accepted 21 December 2015 phenotypes that typically result in shortened life spans. The extreme variability in disease manifestation ranging Available online 23 December 2015 from onset of profound neurologic symptoms in newborns to progressive degenerative disease in adults presents practical challenges in disease diagnosis and medical management. Recent advances in biochemical methods for Keywords: Peroxisome biogenesis disorders newborn screening and genetic testing have provided unprecedented opportunities for identifying patients at Zellweger spectrum disorder the earliest possible time and defining the molecular bases for their diseases. Here, we provide an overview of Treatment guidelines current clinical approaches for the diagnosis of PBD-ZSD and provide broad guidelines for the treatment of PEX genes disease in its wide variety of forms. Although we anticipate future progress in the development of more effective Very long-chain fatty acids targeted interventions, the current guidelines are meant to provide a starting point for the management of these Sensorineural hearing loss complex conditions in the context of personalized health care. Retinal dystrophy © 2015 Elsevier Inc. All rights reserved. Contents 1. Definition,nomenclature,andepidemiology............................................... 314 2. Laboratorydiagnosticcriteria...................................................... 315 2.1. Traditionalbiochemicaltesting.................................................. 315 2.2. Geneticdiagnostictesting.................................................... 315 2.3. Newbornscreening....................................................... 315 2.4. PrenataldiagnosisofPBD-ZSD.................................................. 316 Abbreviations: AAV, adeno-associated virus; AED, anti-epileptic drug(s); DHA, docosahexaenoic acid; DHCA, dihydroxycholestanoic acid; ERG, electroretinogram; G-tube, gastrostomy tube; IRD, infantile Refsum disease; LC-MS/MS, liquid chromatography/tandem mass spectrometry; NALD, neonatal adrenoleukodystrophy; OCT, optical coherence tomography; PBD, per- oxisome biogenesis disorder; PBD-ZSD, peroxisome biogenesis disorder-Zellweger spectrum disorder; THCA, trihydroxycholestanoic acid; VLCFA, very long chain fatty acid(s); X-ALD, X- linked adrenoleukodystrophy; ZS, Zellweger syndrome. ⁎ Corresponding author. E-mail addresses: [email protected] (N.E. Braverman), [email protected] (G.V. Raymond), [email protected] (W.B. Rizzo), [email protected] (A.B. Moser), [email protected] (M.E. Wilkinson), [email protected] (E.M. Stone), [email protected] (S.J. Steinberg), [email protected] (M.F. Wangler), [email protected] (E.T. Rush), [email protected] (J.G. Hacia), [email protected] (M. Bose). http://dx.doi.org/10.1016/j.ymgme.2015.12.009 1096-7192/© 2015 Elsevier Inc. All rights reserved. 314 N.E. Braverman et al. / Molecular Genetics and Metabolism 117 (2016) 313–321 3. Managementandtreatmentguidelines.................................................. 316 3.1. Clinicalevaluationsfollowinginitialdiagnosis........................................... 316 3.2. Feedingandnutrition...................................................... 317 3.3. Liver.............................................................. 318 3.4. Hearing............................................................. 318 3.5. Vision............................................................. 318 3.6. Neurologicalfunction...................................................... 318 3.7. Bone.............................................................. 318 3.8. Teeth.............................................................. 318 3.9. Adrenal insufficiency....................................................... 318 3.10. Kidney............................................................ 318 3.11. Otherrecommendations.................................................... 318 4. Futuredirections............................................................ 319 5. Concludingremarks.......................................................... 319 Acknowledgments.............................................................. 319 References................................................................. 319 1. Definition, nomenclature, and epidemiology syndromes were historically described: Zellweger syndrome (ZS), also referred to as cerebrohepatorenal syndrome; neonatal adreno- Peroxisomes are membrane-bound organelles found within almost leukodystrophy (NALD), and infantile Refsum disease (IRD) [12]. all eukaryotic cells [1]. They are formed through replication by fission We recommend replacing these names with the overall classification (the major pathway for peroxisome formation) or can originate from of peroxisome biogenesis disorders in the Zellweger spectrum (PBD- the endoplasmic reticulum (ER) through a de novo process [2].Contained ZSD), ranging from severe (ZS), intermediate (NALD), and mild (IRD) within the peroxisome matrix of mammalian cells are over 70 distinct phenotypes, respectively. The purpose of this recommendation is to enzymes required for normal lipid metabolism and a host of other highlight the fact that the individual clinical pictures are along a spec- biochemical processes critical for normal health and development [3]. trum of disease severity and often do not fit into the original assigned Peroxisome biogenesis disorders (PBDs) are autosomal recessive categories. Additionally, we now also recognize a group of PBD-ZSD pa- disorders that are characterized by defective peroxisome biosynthesis, tients who do not exhibit the vision and hearing loss usually described assembly, and biochemical functions [4]. Although it is estimated that in PBD-ZSD, and instead present with peripheral neuropathy and/or 1 in 50,000 births are affected by PBDs in North America [5], these cerebellar ataxia [13–15]. Other variant phenotypes continue to be estimates may increase with the introduction of newborn screening described [16,17]. These patients would be diagnosed as intermediate for peroxisomal disorders across the United States [6]. PBDs are primar- or mild within the PBD-ZSD spectrum. Table 1 summarizes the clinical ily caused by mutations in any of 14 different PEX genes, which code features observed in PBD-ZSD based on disease severity and age of for peroxins, proteins involved in peroxisome assembly [5,7].While symptom appearance. Symptom expression in most patients has an mutations in PEX1 account for nearly 70% of all PBD-ZSD cases, another age-dependent component related to disease severity and considerable 26% of cases are caused by mutations in PEX6, PEX10, PEX12,orPEX26, overlap exists among patients with severe, intermediate and milder with the majority of these cases involving PEX6 mutations [8,9]. phenotypes. Although the relative proportions of certain features PBDs are divided into 2 groups: Zellweger spectrum disorder (PBD- were reported in one cohort with a subset of PEX genotypes [18], the ZSD) and rhizomelic chondrodysplasia punctata type 1 [10,11]. prevalence and timing of all outcomes amongst PBD-ZSD patients is The treatment guidelines presented here will refer only to PBD-ZSD. not yet adequately described, nor is the risk known for individual Prior to the discovery of
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