Profiles of very-long-chain fatty acids in plasma, fibroblasts, and blood cells in Zellweger syndrome, X-linked adrenoleukodystrophy, and rhizomelic chondrodysplasia punctata

Schutgens, R. B. H.; Bouman, I. W.; Nijenhuis, A. A.; Wanders, R. J. A.; Frumau, M. E. J.

doi:10.1093/clinchem/39.8.1632

Cited by 43 publications

(18 citation statements)

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“…Increase of C26/C22 in the PBD LCL in their study (0.65) was less pronounced than for our patients (1.21/1.39), although the authors noted a generally higher amount of C26:0 accumulation in lymphoblast membranes than in fibroblasts. Indeed, C26/C22 values in control fibroblasts are approximately tenfold lower than in LCL in our and Santos' study (Santos et al 1993) in some reports (Schutgens et al 1993;Valianpour et al 2003). Other analyses in fibroblasts have C26/C22 levels in fibroblasts comparable to our findings in LCL (Dacremont et al 1995;Santos et al 1993).…”

Section: Discussionsupporting

confidence: 85%

“…Earlier studies of peroxisomal metabolites in cultivated cells from PBD patients included various reports in fibroblasts (Dacremont et al 1995;Molzer 1993;Santos et al 1993;Schutgens et al 1993) and one report in LCL (Santos et al 1993). For XALD patients, additional cell types have been analyzed, including blood leukocytes (Molzer 1993;Schutgens et al 1993;Unterberger et al 2007) and LCL in one report (Uto et al 2008).…”

Section: Discussionmentioning

confidence: 99%

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Lymphoblastoid Cell Lines for Diagnosis of Peroxisome Biogenesis Disorders

et al. 2011

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Peroxisome biogenesis disorders (PBDs) are a group of autosomal-recessive developmental and progressive metabolic diseases leading to the Zellweger spectrum (ZS) phenotype in most instances. Diagnosis of clinically suspected cases can be difficult because of extensive genetic heterogeneity and large spectrum of disease severity. Furthermore, a second group of peroxisomal diseases caused by deficiencies of single peroxisomal enzymes can show an indistinguishable clinical phenotype. The diagnosis of these peroxisomal disorders relies on the clinical presentation, the biochemical parameters in plasma and erythrocyte membranes, and genetic testing as the final step. Analysis of patients' cells is frequently required during the diagnostic process, e.g., for complementation analysis to identify the affected gene before sequencing. In the cases with unclear clinical or biochemical presentation, patients' cells are analyzed to prove PBD or to demonstrate biochemical abnormalities that might be elusive in plasma. Cell lines from skin fibroblast that are usually generated for diagnostic workup are not available in all instances, mainly because the required skin biopsy is invasive and sometimes denied by parents. An alternative cellular system has not been analyzed sufficiently. In this study, we evaluated the alternative use of lymphoblastoid cell lines (LCLs), derived from a peripheral blood sample, in the diagnostic process for PBD. LCLs were suitable for immunofluorescence visualization of peroxisomal enzymes, complementation analysis, and the biochemical analysis to differentiate between control and PBD LCL. LCLs are therefore an easily obtainable alternative cellular system for a detailed PBD diagnostic workup with a reliability of diagnostic results equal to those of skin fibroblasts.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Lymphoblastoid Cell Lines for Diagnosis of Peroxisome Biogenesis Disorders

et al. 2011

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“… 37 Alternatively, the ratio of C26:0/C22:0 or C24:0/C22:0 can be used, because C22:0 remains unchanged or is even slightly reduced in plasma samples of X-ALD patients. 38 , 39 …”

Section: Diagnosis Of X-aldmentioning

confidence: 99%

The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis

Wiesinger

Eichler

Berger

2015

TACG

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X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding a peroxisomal ABC transporter. In this review, we compare estimates of incidence derived from different populations in order to provide an overview of the worldwide incidence of X-ALD. X-ALD presents with heterogeneous phenotypes ranging from adrenomyeloneuropathy (AMN) to inflammatory demyelinating cerebral ALD (CALD). A large number of different mutations has been described, providing a unique opportunity for analysis of functional domains within ABC transporters. Yet the molecular basis for the heterogeneity of clinical symptoms is still largely unresolved, as no correlation between genotype and phenotype exists in X-ALD. Beyond ABCD1, environmental triggers and other genetic factors have been suggested as modifiers of the disease course. Here, we summarize the findings of numerous reports that aimed at identifying modifier genes in X-ALD and discuss potential problems and future approaches to address this issue. Different options for prenatal diagnosis are summarized, and potential pitfalls when applying next-generation sequencing approaches are discussed. Recently, the measurement of very long-chain fatty acids in lysophosphatidylcholine for the identification of peroxisomal disorders was included in newborn screening programs.

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“…This lysoPC was highly decreased in the overdose group (compared to the control or the therapeutic dose groups) and was statistically significant before and after adjusting for age and sex in logistic regression models. Interestingly, lysoPC-C26:0, the unsaturated native of lysoPC-C26:1, was recently reported as a candidate biomarker for X-linked adrenoleukodystrophy (X-ALD) [19] and other peroxisomal disorders of peroxisomal β-oxidation like Zellweger syndrome [41] . Indeed, APAP has been reported to directly or indirectly perturb peroxisomal activity and activation of PPAR-alpha, a major regulator of mitochondrial and peroxisomal β-oxidation is known to protect against APAP hepatotoxicity in the mouse model [35] .…”

Section: Discussionmentioning

confidence: 99%

Targeted metabolomic profiling indicates structure-based perturbations in serum phospholipids in children with acetaminophen overdose

et al. 2016

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Phospholipids are an important class of lipids that act as building blocks of biological cell membranes and participate in a variety of vital cellular functions including cell signaling. Previous studies have reported alterations in phosphatidylcholine (PC) and lysophosphatidylcholine (lysoPC) metabolism in acetaminophen (APAP)-treated animals or cell cultures. However, little is known about phospholipid perturbations in humans with APAP toxicity. In the current study, targeted metabolomic analysis of 180 different metabolites including 14 lysoPCs and 73 PCs was performed in serum samples from children and adolescents hospitalized for APAP overdose. Metabolite profiles in the overdose group were compared to those of healthy controls and hospitalized children receiving low dose APAP for treatment of pain or fever (therapeutic group). PCs and lysoPCs with very long chain fatty acids (VLCFAs) were significantly decreased in the overdose group, while those with comparatively shorter chain lengths were increased in the overdose group compared to the therapeutic and control groups. All ether linked PCs were decreased in the overdose group compared to the controls. LysoPC-C26:1 was highly reduced in the overdose group and could discriminate between the overdose and control groups with 100% sensitivity and specificity. The PCs and lysoPCs with VLCFAs showed significant associations with changes in clinical indicators of drug metabolism (APAP protein adducts) and liver injury (alanine aminotransferase, or ALT). Thus, a structure-dependent reduction in PCs and lysoPCs was observed in the APAP-overdose group, which may suggest a structure-activity relationship in inhibition of enzymes involved in phospholipid metabolism in APAP toxicity.

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Profiles of very-long-chain fatty acids in plasma, fibroblasts, and blood cells in Zellweger syndrome, X-linked adrenoleukodystrophy, and rhizomelic chondrodysplasia punctata

Cited by 43 publications

References 0 publications

Lymphoblastoid Cell Lines for Diagnosis of Peroxisome Biogenesis Disorders

Lymphoblastoid Cell Lines for Diagnosis of Peroxisome Biogenesis Disorders

The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis

Targeted metabolomic profiling indicates structure-based perturbations in serum phospholipids in children with acetaminophen overdose

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