Mild Zellweger syndrome due to functionally confirmed novel PEX1 variants

Patryk Lipiński,Ronald J A Wanders,Rafał Płoski,Sacha Ferdinandusse,Frederic M Vaz,Elżbieta Jurkiewicz,Anna Tylki-Szymańska,Maria Wypchło,Piotr Stawiński,Teresa Joanna Stradomska,Małgorzata Rydzanicz

doi:10.1007/s13353-019-00523-w

Abstract

Zellweger spectrum disorders (ZSD) constitute a group of rare autosomal recessive disorders characterized by a defect in peroxisome biogenesis due to mutations in one of 13 PEX genes. The broad clinical heterogeneity especially in late-onset presenting patients and a mild phenotype complicates and delays the diagnostic process. Here, we report a case of mild ZSD, due to novel PEX1 variants. The patient presented with an early hearing loss, bilateral cataracts, and leukodystrophy on magnetic resonance (MR) images. Normal results of serum very-long-chain fatty acids (VLCFA) and phytanic acid were found. Molecular diagnostics were performed to uncover the etiology of the clinical phenotype. Using whole exome sequencing, there have been found two variants in the PEX1 gene—c.3450T>A (p.Cys1150*) and c.1769T>C (p.Leu590Pro). VLCFA measurement in skin fibroblasts and C26:0-lysoPC in dried blood spot therefore was performed. Both results were in line with the diagnosis of ZSD. To conclude, normal results of routine serum VLCFA and branched-chain fatty acid measurement do not exclude mild forms of ZSD. The investigation of C26:0-lysoPC should be included in the diagnostic work-up in patients with cataract, hearing loss, and leukodystrophy on MR images suspected to suffer from ZSD.

Highlights

Zellweger spectrum disorders (ZSD) constitute a group of rare autosomal recessive disorders characterized by a defect in peroxisome biogenesis due to mutations in one of 13 PEX genes
The patient presented with an early hearing loss, bilateral cataracts, and leukodystrophy on magnetic resonance (MR) images
The investigation of 0-lysoPC C26 (C26):0-lysoPC should be included in the diagnostic work-up in patients with cataract, hearing loss, and leukodystrophy on MR images suspected to suffer from ZSD

Summary

Introduction

Zellweger spectrum disorders constitute a group of rare autosomal recessive disorders characterized by a defect in peroxisome biogenesis due to mutations in one of 13 PEX genes (Klouwer et al 2015). The family history revealed that patient’s older sister had presented with similar signs including more pronounced intellectual disability, bilateral hearing loss, and cataracts but no diagnosis was established. Delayed psychomotor development; hearing loss Partial wheelchair dependency due to spastic paresis; mild intellectual disability; slowing head circumference growth Bilateral cataracts. We 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

Discussion

Conclusions

Compliance with ethical standards