Zellweger syndrome (cerebrohepatorenal syndrome), is a rare congenital disorder characterized by the reduction or absence of functional peroxisomes in the cells of an individual. It is one of a family of disorders called leukodystrophies.
Zellweger syndrome is one of three peroxisome biogenesis disorders (PBD) which belong to the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD). The other two disorders are neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD). Although all have a similar molecular basis for disease, Zellweger syndrome is the most severe of these three disorders. Zellweger syndrome is named after Hans Zellweger (1909–1990), a Swiss-American pediatrician, a professor of pediatrics and genetics at the University of Iowa who researched this disorder.
Zellweger syndrome is associated with impaired neuronal migration, neuronal positioning, and brain development. In addition, individuals with Zellweger syndrome can show a reduction in central nervous system (CNS) myelin (particularly cerebral), which is referred to as hypomyelination. Myelin is critical for normal CNS functions, and in this regard, serves to insulate nerve fibers in the brain.
Signs and symptoms of ZS typically become apparent in the newborn period and may include
- feeding problems
- hearing and vision loss
- craniofacial abnormalities (such as a high forehead, hypoplastic supraorbital ridges, epicanthal folds, midface hypoplasia, and a large fontanel)
- skeletal abnormalities
- development delay
- adrenal insufficiency
- hepatomegaly (enlarged liver)
- chondrodysplasia punctata (punctate calcification of the cartilage in specific regions of the body)
- renal cysts
Zellweger syndrome is an autosomal recessive disorder caused by mutations in genes that encode peroxins, proteins required for the normal assembly of peroxisomes. Most commonly, patients have mutations in the PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14, PEX16, PEX19, or PEX26 genes. In almost all cases, patients have mutations that inactivate or greatly reduce the activity of both the maternal and paternal copies of one these aforementioned PEX genes.
As a result of impaired peroxisome function, an individual’s tissues and cells can accumulate very long chain fatty acids (VLCFA) and branched chain fatty acids (BCFA) that are normally degraded in peroxisomes. The accumulation of these lipids can impair the normal function of multiple organ systems, as discussed above. In addition, these individuals can show deficient levels of plasmalogens, ether-phospholipids that are especially important for brain and lung function.
Carrier testing for at-risk relatives and prenatal testing are possible if the two disease-causing mutations in the family are known.
In addition to genetic tests involving the sequencing of PEX genes, biochemical tests have proven highly effective for the diagnosis of Zellweger syndrome and other peroxisomal disorders. Typically, Zellweger syndrome patients show elevated very long chain fatty acids in their blood plasma. Cultured primarily skin fibroblasts obtained from patients show elevated very long chain fatty acids, impaired very long chain fatty acid beta-oxidation, phytanic acid alpha-oxidation, pristanic acid alpha-oxidation, and plasmalogen biosynthesis.
The long-term outlook (prognosis) for infants with Zellweger syndrome is very poor. Most infants do not survive past the first 6 months of life, and usually succumb to respiratory distress, gastrointestinal bleeding, or liver failure. Although no specific treatment for Zellweger syndrome currently exists, significant progress has been made in understanding the molecular and biochemical aspects of the condition, which researchers believe will lead to new research strategies and new therapies in the future.
Currently, no cure for Zellweger syndrome is known, nor is a course of treatment made standard. Infections should be guarded against to prevent such complications as pneumonia and respiratory distress. Other treatment is symptomatic and supportive.