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Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene
  1. Merel S Ebberink1,
  2. Barbara Csanyi2,
  3. Wui K Chong3,
  4. Simone Denis1,
  5. Peter Sharp4,
  6. Petra A W Mooijer1,
  7. Conny J M Dekker1,
  8. Claire Spooner5,
  9. Lock H Ngu6,
  10. Carlos De Sousa7,
  11. Ronald J A Wanders1,
  12. Michael J Fietz4,
  13. Peter T Clayton2,
  14. Hans R Waterham1,
  15. Sacha Ferdinandusse1
  1. 1Academic Medical Centre, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Department of Paediatrics/Emma Children's Hospital, Amsterdam, The Netherlands
  2. 2Biochemistry Research Group, UCL Institute of Child Health, Great Ormond Street Hospital for Children NHS Trust, London, UK
  3. 3Department of Radiology, Great Ormond Street Hospital for Children NHS Trust, London, UK
  4. 4National Referral Laboratory, SA Pathology, North Adelaide, Australia
  5. 5Starship Children's Hospital, Auckland District Health Board, Auckland, New Zealand
  6. 6Genetics Department, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia
  7. 7Department of Neurology, Great Ormond Street Hospital for Children NHS Trust, London, UK
  1. Correspondence to Sacha Ferdinandusse, Laboratory Genetic Metabolic Diseases (F0-220), Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; s.ferdinandusse{at}


Background Zellweger syndrome spectrum disorders are caused by mutations in any of at least 12 different PEX genes. This includes PEX16, which encodes an integral peroxisomal membrane protein involved in peroxisomal membrane assembly. PEX16-defective patients have been reported to have a severe clinical presentation. Fibroblasts from these patients displayed a defect in the import of peroxisomal matrix and membrane proteins, resulting in a total absence of peroxisomal remnants.

Objective To report on six patients with an unexpected mild variant peroxisome biogenesis disorder due to mutations in the PEX16 gene. Patients presented in the preschool years with progressive spastic paraparesis and ataxia (with a characteristic pattern of progressive leucodystrophy and brain atrophy on MRI scan) and later developed cataracts and peripheral neuropathy. Surprisingly, their fibroblasts showed enlarged, import-competent peroxisomes.

Results Plasma analysis revealed biochemical abnormalities suggesting a peroxisomal disorder. Biochemical variables in fibroblasts were only mildly abnormal or within the normal range. Immunofluorescence microscopy revealed the presence of import-competent peroxisomes, which were increased in size but reduced in number. Subsequent sequencing of all known PEX genes revealed five novel apparent homozygous mutations in the PEX16 gene.

Conclusions An unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene, with a relatively mild clinical phenotype and an unexpected phenotype in fibroblasts, was identified. Although PEX16 is involved in peroxisomal membrane assembly, PEX16 defects can present with enlarged import-competent peroxisomes in fibroblasts. This is important for future diagnostics of patients with a peroxisomal disorder.

  • Zellweger syndrome
  • peroxisome
  • leucodystrophy
  • metabolic disorders

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  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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