Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups

Moser, Ann B.; Rasmussen, Magnhild; Naidu, Sakkubai; Watkins, Paul A.; McGuinness, Mark; Hajra, Amiya K.; Chen, Grace; Raymond, Gerald V.; Liu, Angela; Gordon, Donald C.; Garnaas, Karen; Walton, David S.; Skjeldal, Ola H.; Guggenheim, Mary Anne; Jackson, Laird G.; Elias, Ellen Roy; Moser, Hugo W.

doi:10.1016/s0022-3476(95)70250-4

Cited by 234 publications

(125 citation statements)

References 45 publications

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“…A series of inherited human genetic disorders have been described in which patients ' tissues lack plasmalogens [6,7] but the primary defect in most of these patients is a defect in peroxisome assembly and function. Because of the combined loss of peroxisomal function and plasmalogen deficiency, it has not been possible to determine which clinical manifestations are due to a plasmalogen deficit.…”

Section: Introductionmentioning

confidence: 99%

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Plasmalogens as endogenous antioxidants: somatic cell mutants reveal the importance of the vinyl ether

Zoeller

Lake

Nagan

et al. 1999

Biochemical Journal

173

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Exposure of plasmalogen-deficient variants of the murine cell line RAW 264.7 to short-term (0-100 min) treatment with electron transport inhibitors antimycin A or cyanide (chemical hypoxia) resulted in a more rapid loss of viability than in the parent strain. Results suggested that plasmalogen-deficient cells were more sensitive to reactive oxygen species (ROS) generated during chemical hypoxia ; the mutants could be rescued from chemical hypoxia by using the antioxidant Trolox, an α-tocopherol analogue, and they were more sensitive to ROS generation by plumbagin or by rose bengal treatment coupled with irradiation. In addition, the use of buffers containing #H # O greatly enhanced the cytotoxic effect of chemical hypoxia, suggesting the involvement of singlet oxygen. We used the unique enzymic deficiencies displayed by the mutants to differentially restore either plasmenylethanolamine (the major plasma-

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Section: Introductionmentioning

confidence: 99%

“…Because of the combined loss of peroxisomal function and plasmalogen deficiency, it has not been possible to determine which clinical manifestations are due to a plasmalogen deficit. Patients with a defect in ether lipid biosynthesis and normal peroxisome function have also been described [6,8].…”

Section: Introductionmentioning

confidence: 99%

Plasmalogens as endogenous antioxidants: somatic cell mutants reveal the importance of the vinyl ether

Zoeller

Lake

Nagan

et al. 1999

Biochemical Journal

173

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“…Similar DHA-EE therapy of a severely affected Zellweger patient by Suzuki et al (1996) could not prevent neurological deterioration, suggesting that pa-tients with a milder phenotype would be better candidates for DHA supplementation. It should be noted that Zellweger syndrome is a descriptive term and that recent molecular tools have shown that these patients belong to 10 different complementation groups (Moser et al, 1995).…”

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confidence: 99%

Docosahexaenoic Acid Deficit Is Not a Major Pathogenic Factor in Peroxisome-Deficient Mice

Janssen

Baes

Gressèns

et al. 2000

Laboratory Investigation

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SUMMARY: Docosahexaenoic acid (DHA), a major component of membrane phospholipids in brain and retina, is profoundly reduced in patients with peroxisome biogenesis disorders (Zellweger syndrome). Supplementing newborn patients with DHA resulted in improved muscular tone and visual functions. The purpose of this study was to investigate (a) whether DHA levels were also reduced in newborn PEX5 knockout mice, the mouse model of Zellweger syndrome that we recently generated; (b) whether these levels could be normalized by supplying DHA; and (c) whether this results in longer survival. The DHA concentration in brain of newborn PEX5 Ϫ/Ϫ mice was reduced by 40% as compared with levels in normal littermates; in liver, no differences were noticed. The daily administration of 10 mg of DHA-ethyl ester (EE) to pregnant heterozygous mothers during the last 8 days of gestation resulted in a normalization of brain DHA levels in Zellweger pups. However, no clinical improvement was observed in these pups, and the neuronal migration defect was unaltered. These data suggest that the accretion of DHA in the brain at the end of embryonic development is not only supported by the maternal supply but also depends on synthesis in the fetal brain. Furthermore, the DHA deficit does not seem to be a major pathogenic factor in the newborn Zellweger mice. (Lab Invest 2000, 80:31-35).

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“…In the past, ZSS patient fibroblasts were often fused with other fibroblasts of known disrupted PEX genes and analyzed for the restoration of catalase in the peroxisome of the heterokaryons. 16,17 If the defective genes in the two fibroblast cell lines are different, they would be able to complement each other and peroxisomal function would be restored. Consequently, catalase would be found in the peroxisome in the heterokaryons.…”

Section: Complementation Analysis Through Transfectionmentioning

confidence: 99%

Rational diagnostic strategy for Zellweger syndrome spectrum patients

2009

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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.

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Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups

Cited by 234 publications

References 45 publications

Plasmalogens as endogenous antioxidants: somatic cell mutants reveal the importance of the vinyl ether

Plasmalogens as endogenous antioxidants: somatic cell mutants reveal the importance of the vinyl ether

Docosahexaenoic Acid Deficit Is Not a Major Pathogenic Factor in Peroxisome-Deficient Mice

Rational diagnostic strategy for Zellweger syndrome spectrum patients

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