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Molecular Genetics and Metabolism Jul 2021In Zellweger syndrome (ZS), lack of peroxisome function causes physiological and developmental abnormalities in many organs such as the brain, liver, muscles, and...
In Zellweger syndrome (ZS), lack of peroxisome function causes physiological and developmental abnormalities in many organs such as the brain, liver, muscles, and kidneys, but little is known about the exact pathogenic mechanism. By disrupting the zebrafish pex2 gene, we established a disease model for ZS and found that it exhibits pathological features and metabolic changes similar to those observed in human patients. By comprehensive analysis of the fatty acid profile, we found organ-specific accumulation and reduction of distinct fatty acid species, such as an accumulation of ultra-very-long-chain polyunsaturated fatty acids (ultra-VLC-PUFAs) in the brains of pex2 mutant fish. Transcriptome analysis using microarray also revealed mutant-specific gene expression changes that might lead to the symptoms, including reduction of crystallin, troponin, parvalbumin, and fatty acid metabolic genes. Our data indicated that the loss of peroxisomes results in widespread metabolic and gene expression changes beyond the causative peroxisomal function. These results suggest the genetic and metabolic basis of the pathology of this devastating human disease.
Topics: Animals; Disease Models, Animal; Fatty Acids; Female; Gene Expression; Gene Expression Profiling; Humans; Liver; Male; Peroxins; Peroxisomes; Zebrafish; Zellweger Syndrome
PubMed: 34016526
DOI: 10.1016/j.ymgme.2021.05.002 -
The Southeast Asian Journal of Tropical... 1995We describe an infant boy with facial dysmorphism, profound hypotonia, psychomotor retardation, seizure and hepatomegaly. Biochemical study revealed elevation of very... (Review)
Review
We describe an infant boy with facial dysmorphism, profound hypotonia, psychomotor retardation, seizure and hepatomegaly. Biochemical study revealed elevation of very long chain fatty acids and pipecolic acid, consistent with peroxisomal disorder. He died at the age of 4 months. Electron microscopic study demonstrated decreased amounts of peroxisomes in liver and kidneys. The clinical characteristic, accompanied the biochemical and microscopic findings led to the diagnosis of Zellweger syndrome. The recognition of this syndrome is important since it is a fatal disease. The pattern of inheritance is autosomal recessive, hence genetic counseling is necessary. We emphasize that peroxisomal disorder should be included in the differential diagnosis in patients with infantile hypotonia. This patient is the first reported case of Zellweger syndrome in Thailand.
Topics: Fatal Outcome; Female; Genes, Recessive; Humans; Infant; Kidney; Liver; Male; Microbodies; Pedigree; Thailand; Zellweger Syndrome
PubMed: 8629140
DOI: No ID Found -
Microscopy Research and Technique Jun 2003In the era of application of molecular biological gene-targeting technology for the generation of knockout mouse models to study human genetic diseases, the availability... (Review)
Review
A review of morphological techniques for detection of peroxisomal (and mitochondrial) proteins and their corresponding mRNAs during ontogenesis in mice: application to the PEX5-knockout mouse with Zellweger syndrome.
In the era of application of molecular biological gene-targeting technology for the generation of knockout mouse models to study human genetic diseases, the availability of highly sensitive and reliable methods for the morphological characterization of the specific phenotypes of these mice is of great importance. In the first part of this report, the role of morphological techniques for studying the biology and pathology of peroxisomes is reviewed, and the techniques established in our laboratories for the localization of peroxisomal proteins and corresponding mRNAs in fetal and newborn mice are presented and discussed in the context of the international literature. In the second part, the literature on the ontogenetic development of the peroxisomal compartment in mice, with special emphasis on liver and intestine is reviewed and compared with our own data reported recently. In addition, some recent data on the pathological alterations in the liver of the PEX5(-/-) mouse with a peroxisomal biogenesis defect are briefly discussed. Finally, the methods developed during these studies for the localization of mitochondrial proteins (respiratory chain complexes and MnSOD) are presented and their advantages and pitfalls discussed. With the help of these techniques, it is now possible to identify and distinguish unequivocally peroxisomes from mitochondria, two classes of cell organelles giving by light microscopy a punctate staining pattern in microscopical immunohistochemical preparations of paraffin-embedded mouse tissues.
Topics: Animals; Disease Models, Animal; Humans; Immunohistochemistry; In Situ Hybridization; Intestinal Mucosa; Intestines; Liver; Mice; Mice, Knockout; Mitochondria; Peroxisome-Targeting Signal 1 Receptor; Peroxisomes; RNA, Messenger; Receptors, Cytoplasmic and Nuclear; Zellweger Syndrome
PubMed: 12740819
DOI: 10.1002/jemt.10322 -
Neurology India 2022
Topics: ATPases Associated with Diverse Cellular Activities; Humans; Neuroimaging; Phenotype; Zellweger Syndrome
PubMed: 35263876
DOI: 10.4103/0028-3886.338656 -
Nature Genetics Sep 1997The cerebro-hepato-renal syndrome of Zellweger is a fatal inherited disease caused by deficient import of peroxisomal matrix proteins. The pathogenic mechanisms leading...
The cerebro-hepato-renal syndrome of Zellweger is a fatal inherited disease caused by deficient import of peroxisomal matrix proteins. The pathogenic mechanisms leading to extreme hypotonia, severe mental retardation and early death are unknown. We generated a Zellweger animal model through inactivation of the murine Pxr1 gene (formally known as Pex5) that encodes the import receptor for most peroxisomal matrix proteins. Pxr1-/- mice lacked morphologically identifiable peroxisomes and exhibited the typical biochemical abnormalities of Zellweger patients. They displayed intrauterine growth retardation, were severely hypotonic at birth and died within 72 hours. Analysis of the neocortex revealed impaired neuronal migration and maturation and extensive apoptotic death of neurons.
Topics: Animals; Animals, Newborn; Apoptosis; Base Sequence; Brain; Cerebral Cortex; DNA; DNA Primers; Death; Disease Models, Animal; Female; Fetal Growth Retardation; Fibroblasts; Humans; Liver; Mice; Mice, Knockout; Molecular Sequence Data; Neurons; Peroxisome-Targeting Signal 1 Receptor; Polymerase Chain Reaction; Pregnancy; Receptors, Cytoplasmic and Nuclear; Recombination, Genetic; Zellweger Syndrome
PubMed: 9288097
DOI: 10.1038/ng0997-49 -
Orphanet Journal of Rare Diseases Sep 2021Zellweger spectrum disorders (ZSDs) are a rare, heterogenous group of autosomal recessively inherited disorders characterized by reduced peroxisomes numbers, impaired... (Review)
Review
BACKGROUND
Zellweger spectrum disorders (ZSDs) are a rare, heterogenous group of autosomal recessively inherited disorders characterized by reduced peroxisomes numbers, impaired peroxisomal formation, and/or defective peroxisomal functioning. In the absence of functional peroxisomes, bile acid synthesis is disrupted, and multisystem disease ensues with abnormalities in the brain, liver, kidneys, muscle, eyes, ears, and nervous system.
MAIN BODY
Liver disease may play an important role in morbidity and mortality, with hepatic fibrosis that can develop as early as the postnatal period and often progressing to cirrhosis within the first year of life. Because hepatic dysfunction can have numerous secondary effects on other organ systems, thereby impacting the overall disease severity, the treatment of liver disease in patients with ZSD is an important focus of disease management. CholbamĀ® (cholic acid), approved by the U.S. Food and Drug Administration in March 2015, is currently the only therapy approved as adjunctive treatment for patients with ZSDs and single enzyme bile acid synthesis disorders. This review will focus on the use of CA therapy in the treatment of liver disease associated with ZSDs, including recommendations for initiating and maintaining CA therapy and the limitations of available clinical data supporting its use in this patient population.
CONCLUSIONS
Cholbam is a safe and well-tolerated treatment for patients with ZSDs that has been shown to improve liver chemistries and reduce toxic bile acid intermediates in the majority of patients with ZSD. Due to the systemic impacts of hepatic damage, Cholbam should be initiated in patients without signs of advanced liver disease.
Topics: Bile Acids and Salts; Cholic Acid; Humans; Liver Diseases; United States; Zellweger Syndrome
PubMed: 34521419
DOI: 10.1186/s13023-021-01940-z -
Georgian Medical News Sep 2021The incidence of rare diseases is approximately two cases per 10,000 people. Today, in most cases, orphan diseases are caused by genetic disorders, less often - some...
The incidence of rare diseases is approximately two cases per 10,000 people. Today, in most cases, orphan diseases are caused by genetic disorders, less often - some forms of oncological, oncohematological, infectious disorders. These conditions have a severe and chronic course, accompanied by a decrease in quality and a reduction in the life expectancy of patients. Aim - describe a clinical case of an rare disease that is referred to as Zellweger spectrum disorders. Literature review and analysis of clinical-anamnestic and laboratory-instrumental methods of research of a 6.5 years old girl. The given clinical case, namely Zellweger spectrum disorders (ZSD), is a hereditary autosomal recessive disease characterized by nonspecific clinical manifestations and phenotype, which complicates timely diagnosis and delays symptomatic, and in some cases prognostically favorable treatment. Molecular genetic research makes it possible to finally confirm this disease. Therefore, at the slightest suspicion of this pathology, it is worth investigating the level of long-chain fatty acids, plasmalogen of erythrocytes, intermediate metabolites of bile acid synthesis, or carrying out genetic sequencing. Further studies of this condition are carried out in the world in order to obtain new methods of treatment and improve the quality of life of patients. The presented clinical case of a rare disease, which belongs to ZSD, confirms the need for alertness of family doctors and pediatricians in order to timely diagnose and correct rare diseases in children.
Topics: Child; Female; Humans; Peroxisomes; Phenotype; Quality of Life; Zellweger Syndrome
PubMed: 34628380
DOI: No ID Found -
Orphanet Journal of Rare Diseases Dec 2015Zellweger spectrum disorders (ZSDs) represent the major subgroup within the peroxisomal biogenesis disorders caused by defects in PEX genes. The Zellweger spectrum is a... (Review)
Review
Zellweger spectrum disorders (ZSDs) represent the major subgroup within the peroxisomal biogenesis disorders caused by defects in PEX genes. The Zellweger spectrum is a clinical and biochemical continuum which can roughly be divided into three clinical phenotypes. Patients can present in the neonatal period with severe symptoms or later in life during adolescence or adulthood with only minor features. A defect of functional peroxisomes results in several metabolic abnormalities, which in most cases can be detected in blood and urine. There is currently no curative therapy, but supportive care is available. This review focuses on the management of patients with a ZSD and provides recommendations for supportive therapeutic options for all those involved in the care for ZSD patients.
Topics: Disease Management; Humans; Mutation; Peroxisomes; Zellweger Syndrome
PubMed: 26627182
DOI: 10.1186/s13023-015-0368-9 -
Molecular and Cellular Biochemistry Mar 1997Alterations in the metabolism of arachidonic (20:4n-6), docosapentaenoic (22:5n-6), and docosahexaenoic (22:6n-3) acids and other polyunsaturated fatty acids in... (Review)
Review
On the molecular etiology of decreased arachidonic (20:4n-6), docosapentaenoic (22:5n-6) and docosahexaenoic (22:6n-3) acids in Zellweger syndrome and other peroxisomal disorders.
Alterations in the metabolism of arachidonic (20:4n-6), docosapentaenoic (22:5n-6), and docosahexaenoic (22:6n-3) acids and other polyunsaturated fatty acids in Zellweger syndrome and other peroxisomal disorders are reviewed. Previous proposals that peroxisomes are necessary for the synthesis of 22:6n-3 and 22:5n-6 are critically examined. The data suggest that 22:6n-3 is biosynthesized in mitochondria via a channelled carnitine-dependent pathway involving an n-3-specific delta-4 desaturase, while 20:4n-6, 20:5n-3 and 22:5n-6 are synthesized by both mitochondrial and microsomal systems; these pathways are postulated to be interregulated as compensatory-redundant systems. Present evidence suggests that 22:6n-3-containing phospholipids may be required for the biochemical events involved in successful neuronal migration and developmental morphogenesis, and as structural cofactors for the functional assembly and integration of a variety of membrane enzymes, receptors, and other proteins in peroxisomes and other subcellular organelles. A defect in the mitochondrial desaturation pathway is proposed to be a primary etiologic factor in the clinicopathology of Zellweger syndrome and other related disorders. Several implications of this proposal are examined relating to effects of pharmacological agents which appear to inhibit steps in this pathway, such as some hypolipidemics (fibrates), neuroleptics (phenothiazines and phenytoin) and prenatal alcohol exposure.
Topics: Arachidonic Acid; Docosahexaenoic Acids; Fatty Acids, Unsaturated; Humans; Peroxisomal Disorders; Zellweger Syndrome
PubMed: 9062899
DOI: 10.1023/a:1006895209833 -
American Journal of Medical Genetics.... Jun 2009Peroxisomal biogenesis disorders represent a group of genetically heterogeneous conditions that have in common failure of proper peroxisomal assembly. Clinically, they...
Peroxisomal biogenesis disorders represent a group of genetically heterogeneous conditions that have in common failure of proper peroxisomal assembly. Clinically, they are characterized by a spectrum of dysmorphia, neurological, liver, and other organ involvement. To date, mutations in 13 PEX genes encoding peroxins have been identified in patients with peroxisomal biogenesis disorders. Mutations in PEX13, which encodes peroxisomal membrane protein PEX13, are among the least common causes of peroxisomal biogenesis disorders with only three mutations reported so far. Here, we report on two infants whose clinical and biochemical profile was consistent with classical Zellweger syndrome and whose complementation analysis assigned them both to group H of peroxisomal biogenesis disorders. We show that they harbor two novel mutations in PEX13. One patient had a genomic rearrangement resulting in a 147 kb deletion that spans the whole of PEX13, while the other had an out-of-frame deletion of 14 bp. This represents the first report of a PEX13 deletion and suggests that further work is needed to examine the frequency of PEX13 mutations among Arab patients with peroxisomal biogenesis disorders.
Topics: Base Sequence; Fibroblasts; Frameshift Mutation; Gene Rearrangement; Genetic Complementation Test; Humans; Infant; Membrane Proteins; Molecular Sequence Data; Sequence Deletion; Zellweger Syndrome
PubMed: 19449432
DOI: 10.1002/ajmg.a.32874