Evaluation of C26:0‐lysophosphatidylcholine and C26:0‐carnitine as diagnostic markers for Zellweger spectrum disorders

Abstract

Introduction Zellweger spectrum disorders (ZSD) are a group of genetic metabolic disorders caused by a defect in peroxisome biogenesis. This results in multiple metabolic abnormalities, including elevated very long-chain fatty acid (VLCFA) levels. Elevated levels of C26:0-lysophosphatidylcholine (C26:0-lysoPC) have been shown in dried blood spots (DBS) from ZSD patients. However, little is known about the sensitivity and specificity of this marker and C26:0-carnitine, another VLCFA-marker, in ZSD. We investigated C26:0-lysoPC and C26:0-carnitine as diagnostic markers for ZSD in DBS and fibroblasts. Methods C26:0-lysoPC levels in 91 DBS from 37 different ZSD patients were determined and compared to the levels in 209 control DBS. C26:0-carnitine levels were measured in 41 DBS from 29 ZSD patients and 97 control DBS. We measured C26:0-lysoPC levels in fibroblasts from 24 ZSD patients and 61 control individuals. Results Elevated C26:0-lysoPC levels (>72 nmol/L) were found in 86/91 ZSD DBS (n=33/37 patients) corresponding to a sensitivity of 89.2%. Median level was 567 nmol/l (range 28-3133 nmol/l). Consistently elevated C26:0-carnitine levels (>0.077 μmol/L) in DBS were found in 16 out of 29 ZSD patients corresponding to a sensitivity of 55.2%. C26:0-lysoPC levels were elevated in 21/24 ZSD fibroblast lines. Discussion C26:0-lysoPC in DBS is a sensitive and useful marker for VLCFA accumulation in patients with a ZSD. C26:0-carnitine in DBS is elevated in some ZSD patients, but is less useful as a diagnostic marker. Implementation of C26:0-lysoPC measurement in the diagnostic work-up when suspecting a ZSD is advised. This marker has the potential to be used for newborn screening for ZSD.

Lipidomics unveils lipid dyshomeostasis and low circulating plasmalogens as biomarkers in a monogenic mitochondrial disorder

“…with a very-long-chain (VLCFAs; >20 C), which cannot be oxidized by mitochondria, or with an odd chain, generated from dietary phytanic acid metabolism (18), and (ii) C24 BAs conjugated with glycine (glyco-BA) or taurine (tauro-BA) (19,26). In parallel, plasma samples were also analyzed by a certified laboratory for established biomarkers in inherited peroxisomal disorders, specifically C26:0-lysophosphatidylcholine (LPC 26:0) (27,28) and the BA intermediates di-and trihydroxycholestanoic (DHCA and THCA) (29).…”

Mild Zellweger syndrome due to functionally confirmed novel PEX1 variants

“…Therefore, there is a need of better biochemical markers in diagnostic work-up in patients suspected to suffer from ZSD. Recently, Klouwer et al commenced a novel serum biomarker, C26:0-lysoPC, and it has been reported as a sensitive marker in ZSD patients, more sensitive than other biochemical markers such as serum VLCFA and phytanic acid (Klouwer et al 2017). Yet, even if all test results are normal in plasma and urine, but a high level of suspicion for a ZSD remains, additional testing in fibroblasts should be considered to definitely rule out a peroxisomal disorder (Klouwer et al 2016).…”

“…Surprisingly, we found normal results of serum VLCFA and phytanic acid (Table 1). We therefore continued and performed VLCFA measurement in skin fibroblasts and C26:0-lysoPC in dried blood spot as described by Klouwer et al (2017) in the Laboratory of Genetic Metabolic Diseases in Amsterdam. Both results (Table 1) were in line with the diagnosis of ZSD.…”

Lipids and synaptic functions

“…Defects in lipid catabolic pathways have been involved for decades in numerous inborn errors of metabolism (IEM), especially lysosomal storage diseases and peroxisome biogenesis disorders. These catabolic defects lead to the accumulation of lipid substrates that have become useful diagnostic biological markers such as lysosphingolipids (Pettazzoni et al 2017) and C26:0-lysophosphatidylcholine (Klouwer et al 2017). Conversely, IEM related to defects in the biosynthesis and remodelling of glycerophospholipids, sphingolipids and fatty acids have only been delineated recently (Lamari et al 2013) but rapidly expanded to over 100 diseases thanks to the increased access to next-generation sequencing tools.…”