The cholic acid extension study in Zellweger spectrum disorders: Results and implications for therapy.

Femke C C Klouwer,Frédéric M Vaz,Kiran V K Koelfat,Bart G P Koot,Frank G Schaap,Marc Engelen,Elles M Kemper,Martin Lenicek,Kevin Berendse,Hans R Waterham,Sacha Ferdinandusse,Peter L M Jansen,Ronald J A Wanders,Bwee Tien Poll‐The

doi:10.1002/jimd.12042

Abstract

Currently, no therapies are available for Zellweger spectrum disorders (ZSDs), a group of genetic metabolic disorders characterised by a deficiency of functional peroxisomes. In a previous study, we showed that oral cholic acid (CA) treatment can suppress bile acid synthesis in ZSD patients and, thereby, decrease plasma levels of toxic C27 -bile acid intermediates, one of the biochemical abnormalities in these patients. However, no effect on clinically relevant outcome measures could be observed after 9 months of CA treatment. It was noted that, in patients with advanced liver disease, caution is needed because of possible hepatotoxicity. An extension study of the previously conducted pretest-posttest design study was conducted including 17 patients with a ZSD. All patients received oral CA for an additional period of 12 months, encompassing a total of 21 months of treatment. Multiple clinically relevant parameters and markers for bile acid synthesis were assessed after 15 and 21 months of treatment. Bile acid synthesis was still suppressed after 21 months of CA treatment, accompanied with reduced levels of C27 -bile acid intermediates in plasma. These levels significantly increased again after discontinuation of CA. No significant changes were found in liver tests, liver elasticity, coagulation parameters, fat-soluble vitamin levels or body weight. Although CA treatment did lead to reduced levels of toxic C27 -bile acid intermediates in ZSD patients without severe liver fibrosis or cirrhosis, no improvement of clinically relevant parameters was observed after 21 months of treatment. We discuss the implications for CA therapy in ZSD based on these results.

Highlights

No therapies are available for Zellweger spectrum disorders (ZSDs), a group of genetic metabolic disorders characterised by a deficiency of functional peroxisomes
Since peroxisomes are responsible for a variety of metabolic functions, ZSDs are characterised by multiple biochemical abnormalities, including the accumulation of C27-bile acid intermediates [3α,7αdihydroxycholestanoic acid (DHCA) and 3α,7α,12αtrihydroxycholestanoic acid (THCA)], very long-chain fatty acids (VLCFAs), branched-chain fatty acids like phytanic acid and pristanic acid, and plasmalogen deficiency (Wanders and Waterham 2006)
We investigated the effect of 21 months of cholic acid (CA) treatment on biochemical parameters and clinically relevant outcome measures in 17 patients with a ZSD

Summary

Introduction

No therapies are available for Zellweger spectrum disorders (ZSDs), a group of genetic metabolic disorders characterised by a deficiency of functional peroxisomes. Since peroxisomes are responsible for a variety of metabolic functions, ZSDs are characterised by multiple biochemical abnormalities, including the accumulation of C27-bile acid intermediates [3α,7αdihydroxycholestanoic acid (DHCA) and 3α,7α,12αtrihydroxycholestanoic acid (THCA)], very long-chain fatty acids (VLCFAs), branched-chain fatty acids like phytanic acid and pristanic acid, and plasmalogen deficiency (Wanders and Waterham 2006). Signs of liver disease can be completely absent in ZSD patients with a relatively mild phenotype. It is still largely unknown which biochemical abnormalities, either alone or in combination, contribute to the individual clinical manifestations, some correlations have been hypothesised (Braverman et al 2013; Klouwer et al 2015). The C27-bile acid intermediates are toxic and thought to contribute to the liver disease (Ferdinandusse et al 2009; Wanders and Ferdinandusse 2012); a role for other biochemical abnormalities in this process cannot be ruled out

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