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Zellweger syndrome, also called 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 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.
Molecular basis of disease
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, and 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 below. In addition, these individuals can show deficient levels of plasmalogens, ether-phospholipids that are especially important for brain and lung function.
Clinical manifestations of disease
Zellweger syndrome is one of three peroxisome biogenesis disorders 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 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. Patients can also show postdevelopmental sensorineuronal degeneration that leads to a progressive loss of hearing and vision.
Zellweger syndrome can also affect the function of many other organ systems. Patients can show craniofacial abnormalities (such as a high forehead, hypoplastic supraorbital ridges, epicanthal folds, midface hypoplasia, and a large fontanel), hepatomegaly (enlarged liver), chondrodysplasia punctata (punctate calcification of the cartilage in specific regions of the body), eye abnormalities, and renal cysts. Newborns may present with profound hypotonia (low muscle tone), seizures, apnea, and an inability to eat.
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.
Currently, there is no cure for Zellweger syndrome, nor is there a standard course of treatment. Infections should be guarded against to prevent such complications as pneumonia and respiratory distress. Other treatment is symptomatic and supportive. Patients usually do not survive beyond one year of age.
Additional resources for patients and families
- European Leukodystrophy Foundation
- March of Dimes Foundation
- The Global Foundation for Peroxisomal Disorders
- United Leukodystrophy Foundation
- Zellwegers Support Network
- PMID 2454948 (PMID 2454948)
- Who Named It synd/1670
- PMID 1915492 (PMID 1915492)
- OMIM 214100
- PMID 17055079 (PMID 17055079)
- GeneReviews: Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum
- PMID 17041890 (PMID 17041890&query_hl=14&itool=pubmed_docsum 17041890)
- PMID 15542397 (PMID 15542397)
- PMID 19105186 (PMID 19105186)
- Health Link at Medical College of Wisconsin
- Template:Office of Rare Diseases
Template:Phakomatoses and other congenital malformations not elsewhere classified Template:Peroxisomal disorders
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