# Metabolomic Profiling Reveals Brain Lipid Alterations in PEX7-Deficient Models of Rhizomelic Chondrodysplasia Punctata

## TL;DR

This study shows that PEX7 deficiency causes significant brain lipid changes in mouse models of a rare genetic disorder, highlighting the importance of studying brain-specific metabolites.

## Contribution

The study reveals novel brain-specific lipid alterations in PEX7-deficient models, not captured by plasma-based profiling.

## Key findings

- Pex7-deficient mice show major lipid changes in the brain, including PEs, PCs, acylcarnitines, and sphingomyelins.
- Plasma-based profiling underrepresents the extent of CNS lipid remodeling in RCDP.
- The findings suggest additional pathways may contribute to neurological dysfunction in RCDP.

## Abstract

Rhizomelic chondrodysplasia punctata type 1 (RCDP1) is a peroxisomal disorder characterized by skeletal shortening, intellectual disability, seizures, cataracts, and reduced lifespans. RCDP1 is caused by biallelic loss-of-function variants in PEX7, which encodes a protein required for importing select enzymes into the peroxisome matrix, including those essential for ether lipid synthesis (e.g., plasmalogens) and the branched-chain fatty acid catabolism. Plasmalogen deficiency is a hallmark of RCDP1 and other peroxisomal disorders, including RCDP types 2-5 (RCDP2-5) and Zellweger spectrum disorders (ZSD). Here, we performed comprehensive metabolomic profiling of clinical samples from RCDP patients and Pex7-deficient mouse models. We identified profound neurometabolic disturbances in the cerebral cortex and cerebellum of Pex7-deficient mice involving multiple lipid classes, including phosphatidylethanolamines (PEs), phosphatidylcholines (PCs), acylcarnitines, and sphingomyelins. Notably, many of these neurometabolic alterations were absent in patient and Pex7-deficient mouse plasma, indicating that plasma-based profiling can underrepresent the extent of CNS lipid remodeling. Overall, these findings reveal novel insights into neurometabolic adaptations to plasmalogen deficiency and suggest the potential involvement of additional pathways that may contribute to neurological dysfunction in RCDP.