22/05/2026
From Molecular to Clinical aspect of Rhizomelic Chondrodysplasia Punctata (RCDP)🧬🧠
Meet Rayan
At two months old, his brain began to misfire: subtle seizures, floppy muscles, and an MRI that revealed fragile, damaged white matter.
The cause wasn’t a large deletion or a dramatic mutation. It was hiding inside a slippery, seven‑letter stutter in his DNA!
In the PEX7 gene, there’s a short word: TGCGGTG
If you look at healthy genomes (check ensembl), you’ll see that word repeated twice, it's a normal genetic stutter in this gene. Almost all of us have it.
But Liam inherited an allele where the stutter kept going, not twice but three times: TGCGGTG TGCGGTG TGCGGTG
That third copy threw the entire gene out of frame.
The PEX7 protein which is a critical import receptor for peroxisomes was truncated almost immediately (p.Ala7GlyfsTer42).
No functional PEX7 means nothing gets into the peroxisome, which subsequently leading to:
The Left Path (Anabolism): The enzymes DHAPAT and AGPS fail to enter the peroxisome. These enzymes catalyze ether lipid synthesis. Their absence causes a profound plasmalogen deficiency. Because plasmalogens are major structural phospholipids in myelin sheaths, this deficiency leads directly to defective myelination.
The Right Path (Catabolism): The enzyme Phytanoyl-CoA hydroxylase (PHYH) is denied entry into the peroxisome. PHYH is required for the alpha oxidation of branched-chain fatty acids, this blockade causes an upstream accumulation of phytanic acid, which is highly cytotoxic to neurons and nervous tissue.
This all explains the white matter changes in the brain and severe developmental delay in RCDP1 patients, merging the genotypic and phenotypic data.
