A Novel PEX13 Variant Causes Zellweger Spectrum Disorder with Mild/Intermediate Phenotype and Cystic Leukoencephalopathy

Background/Purpose: Zellweger spectrum disorders (ZSD) are rare autosomal recessive diseases of peroxisome biogenesis. Phenotypic manifestations include severe classic Zellweger syndrome presenting in neonates, as well as milder courses with variable organ involvement and slower progression. Very few patients with PEX13 variants have been identified so far. PEX13 encodes an integral peroxisomal membrane protein, peroxin 13. While not all functions of the PEX13 protein are yet understood, recent studies suggest a role beyond peroxisome biogenesis and an association with mitochondrial function and autophagy pathways.

Methods: Two siblings from a consanguineous family presented with congenital cataracts, slowly progressive spasticity, and mental decline. At the age of 15 (female) and 22 (male) years, they continue to show slowly progressing neurodegeneration. A primary cell line of skin fibroblasts from the female patient was established and used for functional analysis.

Results: cMRI studies show a progressive leukoencephalopathy with supratentorial bihemispheric porencephalic cysts, slowly increasing over the course of several years. After negative trio exome analysis, trio genome sequencing of the girl and parents revealed a homozygous 3′UTR variant of unknown significance in PEX13. The same variant was confirmed in the affected brother. One healthy brother does not carry the variant.

Conclusion: Here, we show a novel 3′UTR variant in PEX13 leading to a ZS phenotype comprising typical aspects of a mild/intermediate ZSD. In contrast, cMRI images of both siblings unusually show a cystic leukoencephalopathy as seen in viral infections and not previously reported in ZSD. This new phenotype suggests a complex underlying pathophysiology that goes beyond peroxisome biogenesis. Additionally, this case highlights not only the power of genome sequencing but also the critical need to consider noncoding regions and domains whose functions remain largely enigmatic and require further exploration.

Publication History

Article published online:
26 September 2025