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Identification of a Novel Mutation in PEX10 in a Patient with Attenuated

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Identification of a Novel Mutation in PEX10 in a Patient with Attenuated Blomqvist et al. Journal of Medical Case Reports (2017) 11:218 DOI 10.1186/s13256-017-1365-5 CASE REPORT Open Access Identification of a novel mutation in PEX10 in a patient with attenuated Zellweger spectrum disorder: a case report Maria Blomqvist1*, Karin Ahlberg2, Julia Lindgren1, Sacha Ferdinandusse3 and Jorge Asin-Cayuela1 Abstract Background: The peroxisome biogenesis disorders, which are caused by mutations in any of 13 different PEX genes, include the Zellweger spectrum disorders. Severe defects in one of these PEX genes result in the absence of functional peroxisomes which is seen in classical Zellweger syndrome. These patients present with hypotonia and seizures shortly after birth. Other typical symptoms are dysmorphic features, liver disease, retinal degeneration, sensorineural deafness, polycystic kidneys, and the patient does not reach any developmental milestones. Case presentation: We report a case of a patient with Zellweger spectrum disorder due to a novel mutation in the PEX10 gene, presenting with a mild late-onset neurological phenotype. The patient, an Assyrian girl originating from Iraq, presented with sensorineural hearing impairment at the age of 5 followed by sensorimotor polyneuropathy, cognitive delay, impaired gross and fine motor skills, and tremor and muscle weakness in her teens. Analyses of biochemical markers for peroxisomal disease suggested a mild peroxisomal defect and functional studies in fibroblasts confirmed the existence of a peroxisome biogenesis disorder. Diagnosis was confirmed by next generation sequencing analysis, which showed a novel homozygous mutation (c.530 T > G (p.Leu177Arg) (NM_ 153818.1)) in the PEX10 gene predicted to be pathogenic. Conclusions: This case highlights the importance of performing biochemical, functional, and genetic peroxisomal screening in patients with clinical presentations milder than those usually observed in Zellweger spectrum disorders. Keywords: Zellweger spectrum disorder, Peroxisome biogenesis disorder, PEX10, Case report Background (2) single peroxisomal enzyme defects. PBDs include the Peroxisomes are subcellular organelles present in all Zellweger spectrum disorders (ZSDs) and rhizomelic eukaryotic cells except for mature erythrocytes. A range chondrodysplasia punctata type 1 and 5. ZSDs have auto- of different metabolic functions are specific for this somal recessive inheritance and are caused by mutations organelle, that is, beta-oxidation of very long chain fatty in any of 13 different PEX genes [3]. These PEX genes acids (VLCFA) and pristanic acid, alpha-oxidation of encode for proteins called peroxins that are involved in phytanic acid, biosynthesis of etherphospholipids, bile peroxisome biogenesis and/or protein import [4]. Severe acids and docosahexaenoic acid, and glyoxylate detoxifica- defects in one of these PEX genes result in the absence of tion [1]. The importance of peroxisomes in metabolism is functional peroxisomes which is seen in classical Zellweger evident by the existence of a large group of genetic dis- syndrome, while milder phenotypes are often associated eases associated with impaired peroxisome biogenesis and with partial loss of peroxisomal function. function [2]. Peroxisomal disorders are divided into two Patients with ZSD show neurodevelopmental disease groups: (1) peroxisome biogenesis disorders (PBDs), and that ranges from pronounced neuronal migration deficien- cies with hypotonia, seizures, dysmorphic features, liver * Correspondence: [email protected] disease, retinal degeneration, sensorineural deafness, and 1Institute of Biomedicine, Department of Clinical Chemistry and Transfusion polycystic kidneys to a more attenuated phenotype [2, 3]. Medicine, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden Patients with the classical presentation show elevated Full list of author information is available at the end of the article plasma levels of VLCFAs, pipecolic acid and C27 bile acid © The Author(s). 2017 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. intermediates together with diminished erythrocyte ether- phospholipids (plasmalogens). Phytanic and pristanic acid levels are normal at birth, but can be elevated depending on dietary intake. Cultured fibroblasts from these patients show increased levels of VLCFAs, deficient plasmalogen Blomqvist et al. Journal of Medical Case Reports (2017) 11:218 Page 3 of 6 Table 2 Fibroblast studies a markedly reduced number of peroxisomes was observed. Biomarker fibroblasts Patient Normal range Culturing patient fibroblasts at 40 °C for 2 weeks resulted C22:0 (μmol/g protein) 3.79 2.46–6.59 in a complete absence of peroxisomal staining with cata- C24:0 (μmol/g protein) 8.16 6.37–13.87 lase immunofluorescence microscopy analysis, indicating the lack of import-competent peroxisomes at this elevated C26:0 (μmol/g protein) 0.22 0.16–0.41 temperature (Fig. 2). These results showed that our patient – C24:0/C22:0 2.15 1.68 2.92 suffered from a Zellweger spectrum defect. C26:0/C22:0 0.06 0.03–0.10 Mutation analysis was performed by using a custom- Dihydroxyacetonephosphate-acyltransferase 10.6 5.9–15.5 made next generation sequencing (NGS) gene panel activity (DHAPAT) (nmol/(2 hour.mg protein) (SureSelectQXT, Agilent Technologies, Santa Clara, CA, USA). The panel targets coding exons of 21 genes de- scribed to be involved in peroxisomal disorders includ- were moderately increased resulting in an increased ing the 13 PEX genes (+/- 25 bases, according to RefSeq C26:0/C22:0 ratio. The C24:0/C22:0 ratio was borderline database and assembly Feb. 2009 (GRCh37/hg19)). normal. Her phytanic and pristanic acid levels were Variants of interest were filtered according to allele significantly increased at both sampling occasions. Her frequency, exonic/splice site location and autosomal erythrocyte plasmalogen levels were normal. Because of recessive or X-linked pattern of inheritance. NGS ana- the abnormal VLCFA and phytanic and pristanic acid lysis identified only one variant of potential clinical sig- levels further peroxisomal studies in fibroblasts were nificance, namely a homozygous mutation (c.530 T > G performed. Remarkably, her VLCFAs and DHAPAT (p.Leu177Arg) (NM_153818.1)) in the PEX10 gene. This activity in cultured fibroblasts were normal (Table 2). variant is not present in HGMD® Professional database Immunofluorescence microscopy analysis using anti- (Biobase, Qiagen®, Redwood City, CA, USA) or ClinVar bodies raised against catalase, a peroxisomal matrix [8], but has a very low allele frequency in the normal protein, did show abnormal peroxisomal staining but population according to 1000 genome database [9], is not in all cells. When cultured at 37 °C most cells re- classified as probably damaging by PolyPhen and dele- vealed a normal peroxisomal staining, but in some cells terious by SIFT and affects a highly conserved amino Fig. 2 Immunofluorescence microscopy analysis using antibodies raised against catalase, a peroxisomal matrix enzyme, in skin fibroblasts of a control subject (left panels) and the patient, F1453 (right panels) cultured at 37 °C (upper panels) and 40 °C (lower panels) for 2 weeks. At 37 °C cells of the patient reveal a normal peroxisomal staining in most cells (a representative picture is shown), whereas at 40 °C catalase staining becomes cytosolic confirming the peroxisome biogenesis defect in the patient acid. The result was verified by Sanger sequencing and targeted sequencing on the parents showed the ex- pected segregation pattern (Fig. 3). To confirm the PEX10 defect in the patient we performed complementation stud- patients with mild mutations in PEX10 [14, 18] as well as Abbreviations other PEX genes. Culturing fibroblasts at 40 °C usually IRD: Infantile Refsum disease; MRI: Magnetic resonance imaging; NGS: Next generation sequencing; PBD: Peroxisomal biogenesis disorders; aggravates the defect, an effect that was also found in our PTS1: peroxisome targeting sequence 1; VLCFA: Very long chain fatty acids; study where a complete absence of peroxisomal staining ZSD: Zellweger spectrum disorders with catalase immunofluorescence microscopy analysis Acknowledgements was observed. This result showed that there is a lack of We wish to thank the patient and her parents for consenting to the import-competent peroxisomes at this elevated tem- publication of this case report and Dr Liz Ivarsson for providing the MRI. perature. Overall, the results observed in fibroblasts suggest that the mutated PEX10 protein can partly be Funding There was no source of funding for this case report. correctly targeted to the peroxisomal membrane and has residual activity, which is in line with the biochem- Availability of data and materials ical and clinical presentation of our patient. All laboratory data and MRI relevant to this case report can be found in the “Case presentation” section of this report. Proteins synthesized in the cytosol containing the PTS1-tag form a complex with PEX5 prior to import Authors’ contributions
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