Definition
Zellweger syndrome is a severe and fatal genetic disorder affecting the brain, liver, and kidneys. It can be inherited by children of individuals that carry mutations for a specific gene.
Description
Zellweger syndrome is a fatal disorder that damages the brain, liver, and kidneys. There are related syndromes that have Zellweger-like symptoms and involve defects in the distinct cytoplasm organelles of cells called the peroxisomes; these include neonatal adrenoleukodystrophy, infantile Refsum disease, and hyperpipecolic acidemia. Zellweger syndrome is the most severe of these related syndromes.
Demographics
The incidence of Zellweger syndrome worldwide is roughly one in 100,000 births.
Causes and symptoms
Mutations in one of the many genes that cause Zellweger syndrome lead to a dysfunctional protein that is important for the cells' ability to import newly synthesized proteins into small cytoplasmic organelles called peroxisomes. Zellweger syndrome is characterized by the reduction or absence of these peroxisomes. Key enzymes that are critical for various chemical reactions, in particular oxidation, are contained within the peroxisomes.
Functional and structural abnormalities of the peroxisomes can lead to the disease development observed in Zellweger syndrome. Because peroxisomes are abundant in the liver and the kidney, these organs are affected in Zellweger syndrome. Toxic molecules that enter the bloodstream are detoxified by the peroxisomes, although there are additional mechanisms for detoxification. For example, when consuming large amounts of ethanol from alcoholic beverages, roughly 5–25% of the ethanol can be oxidized by the peroxisomes. Peroxisomes can also function in the organic creation of key compounds and play important roles in the various chemical reactions.
Zellweger syndrome is caused by mutations in any one of several different genes involved in the function of the peroxisome. These include peroxin-1 (PEX1), peroxin-2 (PEX2) peroxin-3 (PEX3), peroxin-5 (PEX5), peroxin-6 (PEX6), and peroxin-12 (PEX12). Each of these gene locations are biochemically and genetically distinct and are found on different chromosomes.
The observable clinical features of Zellweger syndrome can include facial, developmental, and ocular (eye) defects. Characteristic features commonly include a high forehead, upslanting eyes, and skin folds, called epicanthal folds, along the medial (nasal) borders of the palpebral fissures (space between upper and lower eyelids) of the eyes. Typically, babies with Zellweger syndrome have severe weakness, hyptonia (loss of muscle tone), and often have neonatal seizures. There are also several ocular abnormalities that can affect eyesight.
Diagnosis
Absent peroxisomes in the liver and kidney was initially demonstrated by American pathologist S. L. Goldfischer in 1985. The absence of these organelles in the liver is currently thought to be the hallmark of this disorder. Patients with Zellweger syndrome have been found to have remarkably fewer peroxisomes in both the brain and cultured skin fibroblasts. Fibroblasts are a type of skin cell and, in Zellweger syndrome, these cells appear to have ghost-like peroxisomes, which are caused by an absence of specific proteins inside the organelles that are recruited into the membranes.
Peroxisomes play an important role in organ development. Brain abnormalities can be explained by the disrupted migration of nerve cells called neurons (or neuroblasts at this stage of development) around the third month of gestation. This defect occurs in a specific area of the brain called the cerebrum and leads to small or thick convolutions in brain tissue. This brain abnormality allows Zellweger syndrome to be distinguished from other diseases that involve brain abnormalities. Other tissues involved in the disease development include the liver, kidney, cartilage, heart, and muscle. Most patients have cysts on their kidneys.
Zellweger syndrome is diagnosed by measuring metabolic compounds in blood samples from patients. Various fatty acids, plasmalogens, pipecolic acid, and bile acid intermediates are usually studied. Aside from plasmalogen levels, which are diminished, these compounds are typically increased in affected individuals. It is also possible to detect fatty acid levels and plasmalogen synthesis before birth by obtaining cells in the fluid of the amnion, a process called amniocentesis. Thus, pregnant mothers who have previously had an affected baby can opt to have prenatal diagnosis to determine if the fetus is affected.
Treatment team
Physicians, nurses, and therapists provide the basis of the treatment team for a person with Zellweger's syndrome. Geneticists also provide diagnostic and genetic counseling services. Support services are available for families.
Treatment
There is no cure for Zellweger syndrome and treatment is based solely on lessening the symptoms and supporting the involved organs.
Recovery and rehabilitation
Physical, occupational, respiratory, and speech therapists can provide supportive strategies and devices to maintain posture, independent breathing, speech, eating, and other daily activities according to the infant or child's developmental stage for as long as practically possible.
Clinical trials
As of 2004, there is one clinical trial sponsored by the FDA Office of Orphan Products Development for the treatment of Zellweger syndrome (which is under review by the National Institutes of Health). It involves determining the effectiveness of giving oral bile acids (cholic acid, chenodeoxycholic acid, and ursodeoxycholic acid) as therapy for affected individuals.
Prognosis
Persons with Zellweger syndrome rarely live more than one year after diagnosis, with death due mostly to severe feeding difficulties, liver complications, respiratory distress, and cardiac defects.
Special concerns
Because Zellweger syndrome is usually fatal within the first year of life, genetic counseling and prenatal diagnosis are usually assigned a high priority for parents identified or concerned that they may be at risk for having a baby with the syndrome.
Resources
PERIODICALS
Collins, C. S., and S. J. Gould. "Identification of a Common PEX1 Mutation in Zellweger Syndrome." Hum Mutat (1999) 14: 45–53.
Depreter, M., M. Espeel, and F. Roels. "Human Peroxisomal Disorders." Microsc Res Tech (2003) 61: 203–23.
Gootjes, J., et al. "Biochemical Markers Predicting Survival in Peroxisome Diogenesis Disorders." Neurology (2002) 59: 1746–9.
Gould, S. J., G. V. Raymond, and D. Valle. "The Peroxisome Biogenesis Disorders." In The Metabolic and Molecular Bases of Inherited Disease, C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, editors, 8th ed. New York: McGraw-Hill, 3181–218.
OTHER
Johns Hopkins University School of Medicine. The Peroxisome. January 3, 2004 (March 2, 2004). http://www.peroxisome.org/Layperson/layperson.html.
National Institute of Neurological Disorders and Stroke. NINDS Zellweger Syndrome Information Page January 3, 2004 (March 2, 2004). http://www.ninds.nih.gov/health_and_medical/disorders/zellwege_doc.htm.
ORGANIZATIONS
National Organization for Rare Disorders. P.O. Box 1968, Danbury, CT 06813-1968. (203) 744-0100. orphan@ rarediseases.org. http://www.rarediseases.org.
United Leukodystrophy Foundation, Inc. 2304 Highland Drive, Sycamore, IL 60178. (800) 728-5483; Fax: (815) 895-2432. ulf@tbcnet.com. http://www.ulf.org.
Bryan Richard Cobb, PhD
