Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene.
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.
Ebberink
Merel S
MS
Academic Medical Centre, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Department of Paediatrics/Emma Children's Hospital, Amsterdam, The Netherlands.
Csanyi
Barbara
B
Chong
Wui K
WK
Denis
Simone
S
Sharp
Peter
P
Mooijer
Petra A W
PA
Dekker
Conny J M
CJ
Spooner
Claire
C
Ngu
Lock H
LH
De Sousa
Carlos
C
Wanders
Ronald J A
RJ
Fietz
Michael J
MJ
Clayton
Peter T
PT
Waterham
Hans R
HR
Ferdinandusse
Sacha
S
D000293:Adolescent; D002374:Catalase / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D005455:Fluorescent Antibody Technique; D005816:Genetic Complementation Test; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D020675:Peroxisomes / Q000235:genetics* / Q000473:pathology*
D008565:Membrane Proteins; C486345:PEX16 protein, human; D002374:Catalase