Zellweger spectrum disorders (ZSDs) represent the major subgroup within the peroxisomal biogenesis disorders caused by defects in PEX genes. The Zellweger spectrum is a clinical and biochemical continuum which can roughly be divided into three clinical phenotypes. Patients can present in the neonatal period with severe symptoms or later in life during adolescence or adulthood with only minor features. A defect of functional peroxisomes results in several metabolic abnormalities, which in most cases can be detected in blood and urine. There is currently no curative therapy, but supportive care is available. This review focuses on the management of patients with a ZSD and provides recommendations for supportive therapeutic options for all those involved in the care for ZSD patients.

IntroductionWe describe the natural history of patients with a Zellweger spectrum disorder (ZSD) surviving into adulthood.MethodsRetrospective cohort study in patients with a genetically confirmed ZSD.ResultsAll patients (n = 19; aged 16–35 years) had a follow-up period of 1–24.4 years (mean 16 years). Seven patients had a progressive disease course, while 12 remained clinically stable during follow-up. Disease progression usually manifests in adolescence as a gait disorder, caused by central and/or peripheral nervous system involvement. Nine were capable of living a partly independent life with supported employment. Systematic MRI review revealed T2 hyperintense white matter abnormalities in the hilus of the dentate nucleus and/or peridentate region in nine out of 16 patients. Biochemical analyses in blood showed abnormal peroxisomal biomarkers in all patients in infancy and childhood, whereas in adolescence/adulthood we observed normalization of some metabolites.ConclusionsThe patients described here represent a distinct subgroup within the ZSDs who survive into adulthood. Most remain stable over many years. Disease progression may occur and is mainly due to cerebral and cerebellar white matter abnormalities, and peripheral neuropathy.

IntroductionZellweger spectrum disorders (ZSDs) are characterized by a failure in peroxisome formation, caused by autosomal recessive mutations in different PEX genes. At least some of the progressive and irreversible clinical abnormalities in patients with a ZSD, particularly liver dysfunction, are likely caused by the accumulation of toxic bile acid intermediates. We investigated whether cholic acid supplementation can suppress bile acid synthesis, reduce accumulation of toxic bile acid intermediates and improve liver function in these patients.MethodsAn open label, pretest-posttest design study was conducted including 19 patients with a ZSD. Participants were followed longitudinally during a period of 2.5 years prior to the start of the intervention. Subsequently, all patients received oral cholic acid and were followed during 9 months of treatment. Bile acids, peroxisomal metabolites, liver function and liver stiffness were measured at baseline and 4, 12 and 36 weeks after start of cholic acid treatment.ResultsDuring cholic acid treatment, bile acid synthesis decreased in the majority of patients. Reduced levels of bile acid intermediates were found in plasma and excretion of bile acid intermediates in urine was diminished. In patients with advanced liver disease (n = 4), cholic acid treatment resulted in increased levels of plasma transaminases, bilirubin and cholic acid with only a minor reduction in bile acid intermediates.ConclusionsOral cholic acid therapy can be used in the majority of patients with a ZSD, leading to at least partial suppression of bile acid synthesis. However, caution is needed in patients with advanced liver disease due to possible hepatotoxic effects.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-016-9962-9) contains supplementary material, which is available to authorized users.

BackgroundZellweger spectrum disorders (ZSDs) are multisystem genetic disorders caused by a lack of functional peroxisomes, due to mutations in one of the PEX genes, encoding proteins involved in peroxisome biogenesis. The phenotypic spectrum of ZSDs ranges from an early lethal form to much milder presentations. In cultured skin fibroblasts from mildly affected patients, peroxisome biogenesis can be partially impaired which results in a mosaic catalase immunofluorescence pattern. This peroxisomal mosaicism has been described for specific missense mutations in various PEX genes. In cell lines displaying peroxisomal mosaicism, peroxisome biogenesis can be improved when these are cultured at 30°C. This suggests that these missense mutations affect the folding and/or stability of the encoded protein. We have studied if the function of mutant PEX1, PEX6 and PEX12 can be improved by promoting protein folding using the chemical chaperone arginine.MethodsFibroblasts from three PEX1 patients, one PEX6 and one PEX12 patient were cultured in the presence of different concentrations of arginine. To determine the effect on peroxisome biogenesis we studied the following parameters: number of peroxisome-positive cells, levels of PEX1 protein and processed thiolase, and the capacity to β-oxidize very long chain fatty acids and pristanic acid.ResultsPeroxisome biogenesis and function in fibroblasts with mild missense mutations in PEX1, 6 and 12 can be improved by arginine.ConclusionArginine may be an interesting compound to promote peroxisome function in patients with a mild peroxisome biogenesis disorder.

Zellweger spectrum disorders are a group of autosomal recessive disorders characterized by impaired peroxisome functions. The clinical spectrum is broad, ranging from the classical most severe Zellweger syndrome to patients with a relatively mild phenotype. Treatment options are limited to symptomatic and supportive therapy. During routine follow-up we discovered patients with asymptomatic primary adrenal insufficiency. It is important to detect impaired adrenal function because it has treatment implications. Primary adrenal insufficiency was found in 7/24 patients examined, with 4/7 being asymptomatic. Systematic evaluation of adrenal function, through a Synacthen test, should be included in the clinical management of these patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0133-5) contains supplementary material, which is available to authorized users.

Although CA treatment did lead to reduced levels of toxic C-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.

Introduction 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. Methods 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. Results 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. Conclusions 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.

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