Zellweger syndrome

Zellweger syndrome (also known as cerebrohepatorenal syndrome) is the most severe form of the Zellweger spectrum disorders (ZSDs), a group of rare inherited metabolic conditions caused by defects in peroxisome biogenesis. Peroxisomes are small cellular organelles essential for the breakdown of very long-chain fatty acids, the synthesis of plasmalogens (important components of cell membranes, particularly in the brain), and bile acid metabolism. In Zellweger syndrome, peroxisomes are absent or severely reduced in number and function, leading to the accumulation of toxic substances and deficiency of essential lipids throughout the body. The disease affects multiple organ systems and is typically apparent at birth. Key clinical features include severe hypotonia (low muscle tone), distinctive craniofacial abnormalities (high forehead, large anterior fontanelle, flat facial profile, broad nasal bridge, and epicanthal folds), seizures, hepatomegaly with liver dysfunction, and profound neurological impairment including absent or severely reduced reflexes. Affected infants often have renal cortical cysts, eye abnormalities (such as cataracts, glaucoma, retinal dystrophy, and optic nerve hypoplasia), sensorineural hearing loss, and skeletal abnormalities including chondrodysplasia punctata (stippled calcifications in cartilage). Brain MRI typically reveals neuronal migration defects such as polymicrogyria or pachygyria. Zellweger syndrome is caused by biallelic pathogenic variants in any of at least 13 PEX genes (most commonly PEX1, PEX6, PEX12, and PEX26), which encode peroxins required for peroxisome assembly. The prognosis is very poor, with most affected infants surviving only weeks to months, rarely beyond the first year of life. There is currently no cure or disease-modifying treatment. Management is supportive and symptomatic, including nutritional support (often via gastrostomy tube), seizure management with anticonvulsant medications, monitoring and treatment of liver and kidney dysfunction, hearing aids for hearing loss, and ophthalmologic care. Genetic counseling is recommended for affected families.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

Common questions about Zellweger syndrome