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

Femke C C Klouwer,Hans R Waterham,Henk Van Lenthe,Ronald J A Wanders,Sacha Ferdinandusse,Bwee Tien Poll‐The,Frédéric M Vaz,Wim Kulik

doi:10.1007/s10545-017-0064-0

Femke C C Klouwer, Hans R Waterham + Show 6 more

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https://doi.org/10.1007/s10545-017-0064-0

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Abstract

IntroductionZellweger 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.MethodsC26:0-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.ResultsElevated 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.DiscussionC26:0-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.

Highlights

Zellweger spectrum disorders (ZSD) are a group of genetic metabolic disorders caused by a defect in peroxisome biogenesis
We show that the C26:0-lysoPC concentration in dried blood spots (DBS) is a sensitive marker for very long-chain fatty acid (VLCFA) accumulation in ZSD patients
C26:0-lysoPC in DBS was even more sensitive than other known peroxisomal plasma markers like VLCFA, bile acid intermediates, phytanic acid, and pristanic acid. This is of great importance, since more ZSD patients with a relatively mild or atypical phenotype have been recognized over recent years, causing diagnostic challenges (Klouwer et al 2016)

Summary

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. 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%. 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%. 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. There is a need for new and more sensitive biomarkers for ZSD, preferably suitable for (neonatal) screening programs

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