Rational diagnostic strategy for Zellweger syndrome spectrum patients

Abstract

Zellweger syndrome spectrum (ZSS) comprises a clinically and genetically heterogeneous disease entity, which is caused by mutations in any of the 12 different human PEX genes leading to impaired biogenesis of the peroxisome. Patients potentially suffering from ZSS are diagnosed biochemically by measuring elevated levels of very long chain fatty acids, pristanic acid and phytanic acid in plasma and serum and reduced levels of ether phospholipids in erythrocytes. Published reports on diagnostic procedures for ZSS patients are restricted either to biochemical markers or to defined mutations in a subset of PEX genes. Clarification of the primary genetic defect in an affected patient is crucial for genetic counselling, carrier testing or prenatal diagnosis. In this study, we present a rational diagnostic strategy for patients suspected of ZSS. By combining cell biology and molecular genetic methods in an appropriate sequence, we were able to detect the underlying mutation in various PEX genes within adequate time and cost. We applied this method on 90 patients who presented at our institute, Department of Pediatrics and Pediatric Neurology at Georg August University, and detected 174 mutant alleles within six different PEX genes, including two novel deletions and three new missense mutations in PEX6. Furthermore, this strategy will extend our knowledge on genotype -phenotype correlation in various PEX genes. It will contribute to a better understanding of ZSS pathogenesis, allowing the investigation of the effects of diverse mutations on the interaction between PEX proteins and peroxisomal function in vivo.

Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines

“…The biochemical assays most frequently used in fibroblasts involve quantifying phytanic and pristanic acid oxidation, VLCFA accumulation and/or oxidation and plasmalogen biosynthesis [19]. Cultured skin fibroblasts are also valuable for establishing the subcellular localization of peroxisomal matrix proteins, such as catalase, which can distinguish PBD-ZSD from phenotypically similar peroxisomal single enzyme deficiencies [25]. …”

Infantile Refsum Disease: Influence of Dietary Treatment on Plasma Phytanic Acid Levels

“…Indeed, older individuals were shown to have lower plasma ratios of C24:0/C22:0 and C26:0/C22:0 fatty acids when compared with children under one year (Hall et al 1988). Since normal VLCFA plasma levels do not exclude the diagnosis of IRD, this clinical case highlights the need of repeated plasma VLCFA measurements or analysis of additional biochemical parameters, including plasma phytanic acid or erythrocyte plasmalogens, to increase the diagnostic rate of IRD patients (Krause et al 2009). …”

Clinical utility gene card for: Zellweger syndrome spectrum

“…Krause et al 13 in which the two most common mutations in the most frequently affected PEX gene (PEX1) are analysed first, followed, when negative, by PEX cDNA transfection complementation assays of patient´s cells and mutation analysis of the PEX gene thus identified, or a variation thereof including consecutive PEX cDNA complementation testing. 14 3.…”