Zellweger syndrome is caused by genetic mutations that disrupt the normal formation and function of peroxisomes, which are tiny structures inside cells responsible for important metabolic tasks. Specifically, it results from mutations in any one of more than a dozen genes known as PEX genes. These genes encode proteins called peroxins, which are essential for the biogenesis (creation and maintenance) of peroxisomes. When these genes are defective, peroxisomes cannot form properly or function correctly, leading to a cascade of metabolic problems that affect multiple organs and systems in the body.
Peroxisomes play a critical role in breaking down very long chain fatty acids, detoxifying harmful substances, and synthesizing important molecules like plasmalogens, which are vital for brain and lung function. In Zellweger syndrome, because peroxisomes are either absent or severely impaired, these metabolic processes fail. This causes toxic substances to accumulate and essential molecules to be deficient, which in turn leads to widespread cellular damage, especially in the brain, liver, and kidneys.
The genetic mutations causing Zellweger syndrome are inherited in an autosomal recessive pattern. This means a child must inherit two defective copies of a PEX gene—one from each parent—to develop the disorder. Parents who carry one mutated gene typically do not show symptoms but can pass the mutation to their children. The mutations can vary widely, including missense mutations, nonsense mutations, deletions, or stop-loss variants, all of which disrupt the normal production or function of peroxins.
Among the PEX genes, PEX1 mutations are the most common cause, but mutations in other genes like PEX5, PEX6, and PEX2 have also been identified. Each gene mutation affects peroxisome assembly or function in slightly different ways, contributing to the spectrum of severity seen in Zellweger syndrome and related disorders. The severity of the syndrome can range from very severe forms that cause death in infancy to milder forms with longer survival but still significant neurological and developmental impairments.
Because peroxisomes are involved in multiple metabolic pathways, the symptoms of Zellweger syndrome are diverse and affect many body systems. The brain is particularly vulnerable, leading to neurodevelopmental delays, seizures, and structural brain abnormalities. The liver and kidneys also suffer damage due to the buildup of toxic substances. Vision and hearing impairments are common, as are distinctive facial features and skeletal abnormalities.
In families with consanguinity (parents who are closely related), the risk of inheriting two defective copies of a PEX gene increases, making Zellweger syndrome more likely. Genetic testing can identify the specific mutations in affected individuals, which helps confirm the diagnosis and allows for carrier testing in family members.
In summary, Zellweger syndrome is caused by inherited mutations in PEX genes that disrupt peroxisome biogenesis, leading to metabolic dysfunction and multisystem disease. The underlying problem is the failure of peroxisomes to form or function properly, which causes toxic buildup and deficiency of critical molecules, resulting in the severe symptoms characteristic of this disorder.
