Zellweger syndrome
Encyclopedia
Zellweger syndrome, also called cerebrohepatorenal syndrome is a rare, congenital disorder
, characterized by the reduction or absence of functional peroxisome
s in the cells of an individual. It is one of a family of disorders called leukodystrophies. Zellweger syndrome is named after Hans Zellweger, a former professor of Pediatrics
and Genetics
at the University of Iowa
who researched this disorder
.
, 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.
(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.
. 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.
and respiratory distress. Other treatment is symptomatic and supportive. Patients usually do not survive beyond one year of age.
Congenital disorder
A congenital disorder, or congenital disease, is a condition existing at birth and often before birth, or that develops during the first month of life , regardless of causation...
, characterized by the reduction or absence of functional peroxisome
Peroxisome
Peroxisomes are organelles found in virtually all eukaryotic cells. They are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, polyamines, and biosynthesis of plasmalogens, etherphospholipids critical for the normal function of mammalian brains...
s in the cells of an individual. It is one of a family of disorders called leukodystrophies. Zellweger syndrome is named after Hans Zellweger, a former professor of Pediatrics
Pediatrics
Pediatrics or paediatrics is the branch of medicine that deals with the medical care of infants, children, and adolescents. A medical practitioner who specializes in this area is known as a pediatrician or paediatrician...
and Genetics
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
at the University of Iowa
University of Iowa
The University of Iowa is a public state-supported research university located in Iowa City, Iowa, United States. It is the oldest public university in the state. The university is organized into eleven colleges granting undergraduate, graduate, and professional degrees...
who researched this disorder
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
.
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 PEX1PEX1
Peroxisome biogenesis factor 1, also known as PEX1, is a protein which in humans is encoded by the PEX1 gene.This gene encodes a member of the AAA protein family, a large group of ATPases associated with diverse cellular activities...
, PEX2, PEX3
PEX3
Peroxisomal biogenesis factor 3 is a protein that in humans is encoded by the PEX3 gene.-External Links:* *...
, PEX5
PEX5
Peroxisomal targeting signal 1 receptor is a protein that in humans is encoded by the PEX5 gene.-Interactions:PEX5 has been shown to interact with PEX12, PEX13 and PEX14.-External Links:* *...
, PEX6
PEX6
Peroxisome assembly factor 2 is a protein that in humans is encoded by the PEX6 gene.-Interactions:PEX6 has been shown to interact with PEX1 and PEX26.-External Links:* *...
, PEX10
PEX10
Peroxisome biogenesis factor 10 is a protein that in humans is encoded by the PEX10 gene.- Function :Peroxisome biogenesis factor 10 os involved in import of peroxisomal matrix proteins. This protein localizes to the peroxisomal membrane...
, PEX12
PEX12
Peroxisome assembly protein 12 is a protein that in humans is encoded by the PEX12 gene.- Function :The peroxisome biogenesis disorders are a group of genetically heterogeneous diseases that are usually lethal in early infancy...
, PEX13
PEX13
Peroxisomal membrane protein PEX13 is a protein that in humans is encoded by the PEX13 gene.. It located on chromosome 2 next to KIAA1841-Interactions:PEX13 has been shown to interact with PEX14, PEX5 and PEX19.-External Links:* *...
, PEX14
PEX14
Peroxisomal membrane protein PEX14 is a protein that in humans is encoded by the PEX14 gene.-Interactions:PEX14 has been shown to interact with* PEX5* PEX7* PEX13-External Links:* *...
, PEX16
PEX16
Peroxisomal membrane protein PEX16 is a protein that in humans is encoded by the PEX16 gene.- Function :The protein encoded by this gene is an integral peroxisomal membrane protein. An inactivating nonsense mutation localized to this gene was observed in a patient with Zellweger syndrome of the...
, PEX19
PEX19
Peroxisomal biogenesis factor 19 is a protein that in humans is encoded by the PEX19 gene.-Interactions:PEX19 has been shown to interact with PEX10, PEX12, PEX13, ABCD3, ABCD1, PEX3, ABCD2, PEX11B and PEX16.-External Links:* *...
, and PEX26
PEX26
Peroxisome assembly protein 26 is a protein that in humans is encoded by the PEX26 gene.-Interactions:PEX26 has been shown to interact with PEX1, PEX6 and SUFU.-External Links:* *...
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
Peroxisome
Peroxisomes are organelles found in virtually all eukaryotic cells. They are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, polyamines, and biosynthesis of plasmalogens, etherphospholipids critical for the normal function of mammalian brains...
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 diseaseInfantile Refsum disease
Infantile Refsum disease , also called infantile phytanic acid storage disease, is a rare autosomal recessive congenital peroxisomal biogenesis disorder within the Zellweger spectrum. These are disorders of the peroxisomes that are clinically similar to Zellweger syndrome and associated with...
(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
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS) myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
(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
Hepatomegaly
Hepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...
(enlarged liver), chondrodysplasia punctata
Chondrodysplasia punctata
Chondrodysplasia punctata is a clinically and genetically diverse group of rare diseases, first described by Conradi, that share the features of stippled epiphyses and skeletal changes.Types include:* Rhizomelic chondrodysplasia punctata , ,...
(punctate calcification of the cartilage in specific regions of the body), eye abnormalities, and renal cysts. Newborns may present with profound hypotonia
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
(low muscle tone), seizures, apnea, and an inability to eat.
Molecular diagnostics
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 plasmaBlood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
. Cultured primarily skin fibroblasts obtained from patients show elevated very long chain fatty acids, impaired very long chain fatty acid
Very long chain fatty acid
A very long chain fatty acid is a fatty acid with aliphatic tails longer than 22 carbons.Unlike most fatty acids, VLCFAs are too long to be metabolized in the mitochondria, and must be metabolized in peroxisomes....
beta-oxidation, phytanic acid
Phytanic acid
Phytanic acid is a branched chain fatty acid that humans can obtain through the consumption of dairy products, ruminant animal fats, and certain fish. Western diets are estimated to provide 50-100 mg of phytanic acid per day...
alpha-oxidation, pristanic acid
Pristanic acid
Pristanic acid is a terpenoid acid present at micromolar concentrations in the blood plasma of healthy individuals. It is also found in the lipids from many sources such as freshwater sponges, krill, earthworms, whales, human milk fat, bovine depot fat, butterfat or Californian petroleum. It is...
alpha-oxidation, and plasmalogen
Plasmalogen
Plasmalogens are a type of ether phospholipid characterized by the presence of a vinyl ether linkage at the sn-1 position and an ester linkage at the sn-2 position . In mammals, the sn-1 position is typically derived from C16:0, C18:0, or C18:1 fatty alcohols while the sn-2 position is most...
biosynthesis.
Prognosis
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 pneumoniaPneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
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
External links
- Health Link at Medical College of WisconsinMedical College of WisconsinMedical College of Wisconsin is a private, freestanding medical school and graduate school located in Milwaukee, Wisconsin, United States. It was formerly affiliated with Marquette University....