Abstract
Peroxisomal disorders are a group of expanding genetic diseases divided into two major categories: peroxisome biogenesis defects (Zellweger spectrum disorder), and single enzymatic defects. Disorders of Peroxisome Biogenesis occur when there are biallelic pathogenic variants in any of the 13 PEX genes, which code for the peroxins, proteins required for peroxisome biogenesis. This group of disorders includes two distinct phenotypes: Rhizomelic Chondrodysplasia Punctata Type-1 and Zellweger Spectrum Disorders (ZSD), of which Zellweger syndrome is the most severe, neonatal adrenoleukodystrophy is intermediate, and infantile Refsum is the mildest. The spectrum’s most frequent defects are observed in the proteins PEX1 and PEX6, and the most common clinical presentation is Zellweger spectrum, which is often associated with craniofacial dysmorphism with neurologic abnormalities. Typically, the neuroimaging pattern shows several malformative features, including a range of cortical gyral abnormalities such as microgyria and pachygyria, and impairment of the myelination. Nevertheless, we report two siblings with peroxisomal disorder, with unexpected leukodystrophy pattern of the brain mimicking lysosomal storage disease, with classical imaging features of Krabbe disease on brain magnetic resonance image. By whole exome sequencing, we identified two pathogenic variants in compound heterozygosity in PEX6: Chr6:42.933.455 C>T (c.2435G>A), and Chr6:42.935.188 C>T (c.1802G>A). Thus, a final diagnosis of peroxisome disorder was confirmed. The index cases highlight the importance of considering peroxisome disorders as a differential diagnosis for patients with imaging features that resemble Krabbe disease.
Highlights
Peroxisome biogenesis disorders (PBD) are rare autosomal recessive diseases with early-onset, severe systemic involvement, poor outcome, and premature mortality[1,2]
We identified two pathogenic variants in compound heterozygosity in PEX6: Chr6:42.933.455 C>T (c.2435G>A), and Chr6:42.935.188 C>T (c.1802G>A)
After an extensive follow-up with clinical, laboratory, and imaging studies, by whole exome sequencing (WES) we identified two heterozygous variants in the PEX6: p.(Arg812Gln), previously reported as pathogenic in Zellweger Spectrum Disorders (ZSD) individuals[5], and p.(Arg601Gln), a variant with an allele with the relatively high allele frequency of 0.003 in GnomAD Browser and present in homozygous state in 7 among 138,856 individuals in the same databank
Summary
Peroxisome biogenesis disorders (PBD) are rare autosomal recessive diseases with early-onset, severe systemic involvement, poor outcome, and premature mortality[1,2]. Brain magnetic resonance imaging (MRI) studies have demonstrated extensive involvement of the white matter, highlighting several imaging features mimicking the leukodystrophy pattern of the description of Krabbe disease[6,7]. Both children had normal galactocerebrosidase levels, ruling out the diagnosis of Krabbe and had ruled out saposin A deficiency diagnosis. Echocardiogram was normal, and ENMG (electroneuromyography) identified axonal motor polyneuropathy At this time, he performed a brain MRI, which revealed symmetric involvement of the deep WM of the cerebellar hemispheres, notably surrounding the dentate nuclei (figure 2A). He was subsequently diagnosed by Sanger sequencing with the same PEX6 pathogenic variants
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
