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A PEX10 defect in a patient with no detectable defect in peroxisome assembly or metabolism in cultured fibroblasts
Author(s) -
Steinberg S. J.,
Snowden A.,
Braverman N. E.,
Chen L.,
Watkins P. A.,
Clayton P. T.,
Setchell K. D. R.,
Heubi J. E.,
Raymond G. V.,
Moser A. B.,
Moser H. W.
Publication year - 2009
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-008-0969-8
Subject(s) - complementation , frameshift mutation , biology , missense mutation , zellweger syndrome , peroxisome , exon , mutation , peroxisomal disorder , gene , phenotype , human genetics , genetics , compound heterozygosity , microbiology and biotechnology
Summary Zellweger spectrum disorders (ZSD) are diagnosed by biochemical assay in blood, urine and cultured fibroblasts and PEX gene mutation identification. In most cases studies in fibroblasts corroborate results obtained in body fluids. In 1996 Clayton and colleagues described a 10‐year old girl with evidence of a peroxisome disorder, based on elevated bile acid metabolites and phytanate. At the time it was not possible to distinguish whether she had a ZSD or a single peroxisomal protein defect. Studies in our laboratory showed that she also had elevated plasma pipecolate, supporting the former diagnosis. Despite the abnormal metabolites detected in blood (phytanate, bile acid intermediates and pipecolate), analysis of multiple peroxisomal pathways in fibroblasts yielded normal results. In addition, she had a milder clinical phenotype than usually associated with ZSD. Since complementation analysis to determine the gene defect was not possible, we screened this patient following the PEX Gene Screen algorithm (PGS). The PGS provides a template for sequencing PEX gene exons independent of complementation analysis. Two mutations in PEX10 were identified, a frameshift mutation inherited from her father and a de novo missense mutation in a conserved functional domain on the other allele. This case highlights that molecular analysis may be essential to the diagnosis of patients at the milder end of the ZSD spectrum. Furthermore, it supports the concept that some tissues are less affected by certain PEX gene defects than brain and liver.