Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene

Merel Ebberink (1) , Barbara Csanyi (2) , Simone Denis (3) , Peter Sharp (4) , Petra Mooijer (3) , Conny Dekker (3) , Peter Clayton (3) , Michael Fietz (3) , Ronald Wanders (3) , Hans Waterham (3) , Sacha Ferdinandusse (3)

1 AMC - Academic Medical Center - Academisch Medisch Centrum [Amsterdam]
2 Biochemistry Research Group, UCL Institute of Child Health, London, United Kingdom
3 Academic Medical Centre, University of Amsterdam, Laboratory Genetic Metabolic Diseases
4 National Referral Laboratory, SA Pathology, North Adelaide

Zellweger syndrome spectrum disorders are caused by mutations in any of at least 12 different genes. This includes , 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 of these patients displayed a defect in import of peroxisomal matrix and membrane proteins, resulting in a total absence of peroxisomal remnants. Here, we report 6 patients with an unexpected mild variant peroxisome biogenesis disorder due to mutations in the gene. Patients presented in the preschool years with progressive spastic paraparesis and ataxia (with a characteristic pattern of progressive leukodystrophy and brain atrophy on MRI scan) and later developed cataracts and peripheral neuropathy. Surprisingly, their fibroblasts showed enlarged, import-competent peroxisomes. Plasma analysis revealed biochemical abnormalities suggesting a peroxisomal disorder. Biochemical parameters in fibroblasts were only mildly abnormal or within the normal range. Immunofluorescence microscopy analyses revealed the presence of import-competent peroxisomes, which were increased in size but reduced in number. Subsequent sequencing of all known genes revealed five novel apparent homozygous mutations in the gene. We identified an unusual variant peroxisome biogenesis disorder caused by mutations in the gene, with a relatively mild clinical phenotype and an unexpected phenotype in fibroblasts. 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.

Mots clés: Metabolic disorders

Merel Ebberink, Barbara Csanyi, Simone Denis, Peter Sharp, Petra Mooijer, et al.. Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene. Journal of Medical Genetics, 2010, 47 (9), pp.608. ⟨10.1136/jmg.2009.074302⟩. ⟨hal-00557382⟩