Zellweger spectrum disorders
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A hypotonic newborn with distinctive facial features (high forehead, large fontanelles) has hepatomegaly, seizures, and stippled calcifications in the epiphyses.
AR; PEX genes (peroxisome biogenesis)
- Most common: PEX1
Spectrum:
- Zellweger syndrome (severe): Neonatal, profound hypotonia, seizures, death in first year
- Neonatal adrenoleukodystrophy (intermediate)
- Infantile Refsum disease (mildest)
- Craniofacial dysmorphism
- Profound hypotonia
- Hepatomegaly, liver dysfunction
- Stippled epiphyses (chondrodysplasia punctata)
- Elevated VLCFA, phytanic acid, pipecolic acid
- Biochemistry: elevated plasma very-long-chain fatty acids (VLCFA) is the primary screen; supportive elevations in phytanic acid, pristanic acid, pipecolic acid, and abnormal bile acid intermediates
- Reduced red-cell plasmalogens (reflecting impaired peroxisome biogenesis); not on standard newborn screening
- Confirm with molecular testing of PEX genes (PEX1 most common)
- Supportive only; no disease-modifying therapy. Seizure control, nutritional/feeding support, fat-soluble vitamin and bile acid supplementation as indicated
- Monitor and manage liver dysfunction, coagulopathy, hearing and vision deficits, and adrenal function
- Genetic counseling and carrier testing for at-risk relatives; severe (Zellweger) form has poor survival beyond the first year
"PeroxZeZome BiogeneZeZ iZZue in Zellweger": Zellweger is a disorder of peroxisome biogenesis due to mutated PEX genes. PEX1 is the #1 most common gene.
"Zero wiggle in Zell-wiggle": profound neonatal hypotonia. "Zellweger has near-Zero likelihood of survival": most die at age Zero (within the first year). "Wide Gap in Zelle-WeGer": large anterior fontanelle.
"Ztippling in Zellweger": patellar stippling (chondrodysplasia punctata) on X-ray. "Guy RAZ sings his ABCs from mild to severe": the three historical phenotypes of the Zellweger spectrum run mildest to most severe, R to Z: infantile Refsum disease (mildest), neonatal Adrenoleukodystrophy (intermediate), Zellweger syndrome (most severe). All three share one mechanism, a defect in peroxisome biogenesis from PEX variants, and differ only in severity rather than in which metabolic step is affected.