Peroxisomal Biogenesis Disorder-Zellweger Spectrum Disorder (PBD-ZSD)

The Challenge: Understanding Peroxisomal Biogenesis Disorder-Zellweger Spectrum Disorder (PBD-ZSD)

Peroxisomal biogenesis disorder-Zellweger spectrum disorder (PBD-ZSD) represents a group of rare genetic disorders with multisystem manifestations affecting primarily neonates and infants. They are caused by the loss of peroxisome function, which is responsible for many key metabolic functions, such as breaking down fats and getting rid of waste so the body can function properly. However, the broader metabolic impact of peroxisomal dysfunction and the utility of metabolomic methods are unknown. Most importantly, the full range of diseases is still being discovered and described. Patients with PBD-ZSD can develop hypotonia, hearing and vision loss, leukodystrophy, neuropathy, and hepatic dysfunction. In severe cases, individuals have congenital malformations and develop neonatal seizures. The possible wider phenotypic range of PBD-ZSD supported by sequencing studies suggests that novel methods for detecting peroxisomal abnormalities in plasma could be a valuable tool in pediatric diagnostics to identify additional cases and better understand peroxisomal biochemistry in the pediatric population.

Metabolon Insight: Dissecting the Metabolome of Patients with PBD-ZSD

The Metabolon Global Discovery Panel was used in this study to profile plasma samples from 1,011 individuals with clinically and molecularly characterized PBD-ZSD (n = 19) and controls.¹ The goal was to discover distinctive alterations in the metabolic components of signaling pathways underlying PBD-ZSD.

The Solution: Metabolomics Identifies a Metabolomic Pattern for PBD-ZSD

Metabolon performed untargeted metabolomic profiling of plasma samples, detecting more than 650 named compounds. The research group then identified a pattern of abnormalities associated with PBD-ZSD. Subjects with PBD-ZSD had elevated levels of long-chain dicarboxylic acids and reductions in phosphatidylcholines, phosphatidylethanolamines, and plasmalogens. Among the detected metabolites, 1-lignoceroyl-GPC (24:0) was the most significantly enriched metabolite in subjects with PBD-ZSD with an average z-score of 3.69, followed by 7α-hydroxy-3-oxo-4-cholestenoic acid, which had an average z-score of 2.11. The most novel finding of this study was that nine sphingomyelins were significantly reduced in the PBD-ZSD samples.

After the identification of this metabolite pattern in the PBD-ZSD metabolome, the research team applied the metabolomic pattern they observed to aid in the diagnosis of a case. This case was an undiagnosed infant whose metabolome exhibited reductions in sphingomyelins in plasma and other features of the PBD-ZSD metabolome. This supported the use of metabolomics as a screening tool for PBD-ZSD. Remarkably, the PBD-ZSD metabolomic pattern was more pronounced in younger subjects and less prominent in older PBD-ZSD subjects. The researchers observed a strong correlation between age and all the biomarkers of the PBD-ZSD metabolome such that the abnormalities were attenuated in older subjects. This suggests that earlier onset of disease could result in more severe phenotypes.

The Benefit: Identifying Biomarkers for PBD-ZSD to Accelerate Diagnosis

The Metabolon Global Discovery Panel was utilized to establish a PBD-ZSD metabolomic signature that includes novel biomarkers for PBD-ZSD. Individuals with PBD-ZSD had reduced levels of plasma sphingomyelin, a novel biomarker that will require further investigation and can be used to identify additional peroxisomal phenotypes in the future. Utilizing this methodology as a screening approach to identify individuals with PBD-ZSD could lead to earlier diagnosis. Metabolomics also has the potential to expand our understanding of the range of severity across this metabolic disorder.