Getting the Right Diagnosis: Blood Tests and Genetics in IRD

Navigating the diagnostic process for Infantile Refsum Disease (IRD) can be confusing, especially when different tests seem to contradict one another. It is important to understand that traditional blood tests are not always “black and white” in milder cases of the Zellweger Spectrum ^[1][2].

The “Normal” Test Pitfall

For years, the “gold standard” for diagnosing these disorders was a blood test for Very Long Chain Fatty Acids (VLCFAs). However, in children with the IRD phenotype, these levels can sometimes be completely normal ^[1][2].

This happens because IRD is often caused by hypomorphic mutations—genetic “typos” that leave the peroxisomes partially functional ^[3][4]. These “leaky” peroxisomes might work just well enough to keep blood levels of fatty acids near the normal range, even while the body is struggling elsewhere ^[1][5]. Because of this, doctors are moving toward a “genomics-first” approach, where genetic testing is prioritized over biochemical blood work ^[1][2].

Decoding the Genetics Report

When you receive a genetic report (often using Next-Generation Sequencing or Whole Exome Sequencing), you may see several technical terms:

• Pathogenic / Likely Pathogenic: This means the variant is known to cause disease ^[6].
• Variant of Uncertain Significance (VUS): This means the lab found a change in the DNA, but they don’t have enough data yet to know if it causes disease or is just a natural variation ^[6][7]. Next Steps: If a VUS is found, your doctor will likely request blood samples from both biological parents. Seeing how the genes were inherited can often clarify if the VUS is the actual cause of the disease.
• Compound Heterozygous: Since IRD is an autosomal recessive condition, a child must have two mutated copies of a gene (like PEX1 or PEX6). “Compound heterozygous” means they have two different mutations in the same gene—one inherited from each parent ^[8][9].
• In Trans: This is a crucial note on a report confirming that the two mutations are on opposite sides of the gene pair (one from mom, one from dad), which confirms the diagnosis ^[10].

Beyond the Basics: Advanced Testing

If genetic results are unclear or blood tests are normal, doctors may use more sensitive tools:

1. C26:0-lysoPC: This is a newer, much more sensitive biomarker than traditional VLCFA tests. It can often detect IRD even when standard fatty acid tests fail ^[11][12].
2. Fibroblast Assay (Skin Biopsy): A small sample of skin cells is grown in a lab to see exactly how well the peroxisomes are importing proteins. This “functional” test can prove a diagnosis when blood and genetic tests are inconclusive ^[10][13].

Diagnostic Completeness Checklist

A thorough diagnostic report for IRD should ideally include the following data points. If any are missing, ask your team if further testing is needed:

• [ ] Specific Gene Identified: (e.g., PEX1, PEX6, PEX10, PEX26) ^[13].
• [ ] Variant Classification: (e.g., Pathogenic, Likely Pathogenic) ^[6].
• [ ] Zygosity: (e.g., Compound Heterozygous or Homozygous) ^[9].
• [ ] Biochemical Confirmation: (e.g., VLCFA, C26:0-lysoPC, or Phytanic acid levels) ^[11][1].
• [ ] Functional Evidence: (If genetics were unclear, results from a fibroblast/skin biopsy study) ^[10].