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European Journal of Human Genetics :... Aug 2015
Topics: ATPases Associated with Diverse Cellular Activities; Genetic Testing; Humans; Membrane Proteins; Mutation; Pathology, Molecular; Zellweger Syndrome
PubMed: 25407003
DOI: 10.1038/ejhg.2014.250 -
Current Opinion in Pediatrics Dec 1999Peroxisomes, subcellular organelles found in nearly all eukaryotic cells, are involved in numerous biochemical functions within the cell. There has been an increasing... (Review)
Review
Peroxisomes, subcellular organelles found in nearly all eukaryotic cells, are involved in numerous biochemical functions within the cell. There has been an increasing understanding of the genetic mechanism of the diseases of the single peroxisomal enzyme abnormalities as well as defects of peroxisome biogenesis. Peroxisome assembly disorders including Zellweger syndrome and rhizomelic chondrodysplasia punctata are caused by genetic defects in PEX genes and the altering of their proteins, peroxins, which are necessary for the importation of targeted proteins into the peroxisomes. Therapies for peroxisomal disorders have been unsatisfactory to date, but there has been interest in docosahexaenoic acid in assembly disorders and phenylbutyrate and lovastatin in adrenoleukodystrophy (ALD). Whether any of these therapies will result in clinical improvement awaits additional study.
Topics: Animals; Chondrodysplasia Punctata, Rhizomelic; Humans; Membrane Proteins; Mutation; Peroxisomal Disorders; Zellweger Syndrome
PubMed: 10590918
DOI: 10.1097/00008480-199912000-00017 -
Forensic Science International Oct 2015Peroxisomal diseases are rare (1:50,000), genetically determined disorders (autosomal recessive), systemic, multiorgan illnesses with prominent involvement of the...
Peroxisomal diseases are rare (1:50,000), genetically determined disorders (autosomal recessive), systemic, multiorgan illnesses with prominent involvement of the nervous system, caused either by the failure to form or to maintain the peroxisome, or by a defect in the function of a single or multiple peroxisomal enzymes. Peroxisomes contain approximately 50 enzymes which are responsible for many metabolic reactions, and play an important role in the oxidation of saturated very-long-chain fatty acids (VLCFA). The authors present the case of a Romanian boy, who died at the age of 1.6 of one of the peroxisomal diseases-Zellweger syndrome. Newborn infants with Zellweger syndrome have a typical dysmorphic facies, neonatal seizures, profound hypotonia, and eye abnormalities. Major abnormalities are present in the liver (fibrotic), kidney (cortical cysts), and brain (lipid-laden macrophages and histiocytes in cortical and periventricular areas, demyelination, centrosylvian polymicrogyria and pachygyria)-cerebro-hepato-renal syndrome (CHRS) (Zellweger). Infants with Zellweger syndrome rarely live more than a few months, but in this case the survival was longer, and the cause of death was not directly the peroxisomal disease but a violent cause of death-mechanical asphyxia with tracheo-bronchial food aspiration. The authors present the results of investigations carried out during the child's life, but also data collected at the autopsy and hystopathological postnecroptic investigations. By presenting this case, the authors wish to bring to your attention a rare pathology in forensic practice by the paradox of finding a common violent cause of death, asphyxia with food aspiration, in a rare metabolic-genetic disease, which is usually fatal by itself.
Topics: Asphyxia; Fatal Outcome; Forensic Pathology; Humans; Infant; Male; Respiratory Aspiration; Zellweger Syndrome
PubMed: 26235911
DOI: 10.1016/j.forsciint.2015.07.009 -
Advances in Neonatal Care : Official... Feb 2005At least 29 proteins are required for assembly of the peroxisome, a single-membrane organelle responsible for many metabolic processes. A defect in any of these proteins...
At least 29 proteins are required for assembly of the peroxisome, a single-membrane organelle responsible for many metabolic processes. A defect in any of these proteins affects the numerous biochemical functions of the cell. Many genetic disorders are associated with peroxisome defects. Zellweger syndrome, a rare autosomal recessive disorder, is one of the disorders that result from a deficiency in the assembly of the peroxisome. Impaired metabolism results in the accumulation of toxic metabolites and damages developing neural cells. This article provides an overview of peroxisome function and its effect on central nervous system development. It highlights the presentation, clinical features, and nursing care of infants with Zellweger syndrome. A meticulous systematic physical assessment enhances early recognition of the physical features of this disorder. Although magnetic resonance imaging detects polymicrogyria, a manifestation of abnormal neuronal migration that is often associated with Zellweger syndrome, the diagnosis is confirmed biochemically. An emphasis on family support through genetic counseling and the integration of palliative resources to enhance quality of life for infants and families with this lethal condition is provided.
Topics: Brain; Brain Diseases, Metabolic; Female; Humans; Infant; Male; Muscle Hypotonia; Muscles; Pedigree; Peroxisomes; Skin; Zellweger Syndrome
PubMed: 15685158
DOI: 10.1016/j.adnc.2004.10.007 -
Seminars in Neurology Feb 2012Peroxisomal leukoencephalopathies include diseases belonging to the Zellweger spectrum and the rhizomelic chondrodysplasia punctata spectrum, as well as some single... (Review)
Review
Peroxisomal leukoencephalopathies include diseases belonging to the Zellweger spectrum and the rhizomelic chondrodysplasia punctata spectrum, as well as some single enzyme defects of peroxisomal β-oxidation. The authors present information on the clinical and diagnostic approach, and the characteristics of brain magnetic resonance imaging (MRI) in these diseases. MRIs of patients belonging to the Zellweger spectrum may show developmental anomalies and regressive changes consisting of abnormal cerebral white matter. Involvement of the central white matter of the cerebellar hemispheres is frequently seen. The leukoencephalopathy is progressive, with or without peripheral nerve involvement, in patients with a prolonged course of the disease. MRI characteristics in the severe phenotype of rhizomelic chondrodysplasia punctata include supratentorial white matter abnormalities, with a parietooccipital predominance. Demyelinative lesions are the hallmark of the cerebral form of X-linked adrenoleukodystrophy and may appear in a similar way in patients with adrenomyeloneuropathy progressing to a cerebral form. The diagnosis of a peroxisomal disorder can be determined by a battery of biochemical assays in blood and/or urine, and should be confirmed in cultured fibroblasts and DNA analysis. Treatment of the peroxisomal leukoencephalopathies is largely symptomatic, except for boys affected by the cerebral form of X-linked adrenoleukodystrophy in whom a bone marrow/hematopoietic stem cell transplant can be lifesaving, at least in the early stages of the disease.
Topics: Adrenoleukodystrophy; Chondrodysplasia Punctata, Rhizomelic; Female; Humans; Leukoencephalopathies; Magnetic Resonance Imaging; Male; Peroxisomal Disorders; Zellweger Syndrome
PubMed: 22422205
DOI: 10.1055/s-0032-1306385 -
Pediatrics International : Official... Dec 2015Zellweger syndrome, one of the peroxisome biogenesis disorders, is an autosomal recessive disease caused by mutations in PEX genes. It is characterized by severe...
Zellweger syndrome, one of the peroxisome biogenesis disorders, is an autosomal recessive disease caused by mutations in PEX genes. It is characterized by severe hypotonia, failure to thrive, psychomotor retardation, liver dysfunction, and sensorineural hearing impairment. Most of the patients with this disease die before the age of 1 year. PEX14 is the 13th PEX gene responsible for peroxisome biogenesis disorders. Thus far, only two patients with PEX14 deficiency have been reported. Here, we report the first case of a Japanese patient with a PEX14 mutation who showed severe hypotonia, psychomotor retardation, demyelination, and developed rickets at the age of 5 months. An increased excretion of 3,6-epoxydicarboxylic acids leads to the diagnosis of Zellweger syndrome and a mutation analysis of PEX14 revealed a homozygous mutation of c.538C>T (p.Q180X). The patient survived for a prolonged period of time but died of liver failure at the age of 46 months.
Topics: DNA; DNA Mutational Analysis; Fatal Outcome; Humans; Infant, Newborn; Japan; Male; Membrane Proteins; Mutation; Repressor Proteins; Zellweger Syndrome
PubMed: 26627464
DOI: 10.1111/ped.12713 -
Scientific Reports May 2018Peroxisomes are ubiquitous cell organelles involved in many metabolic and signaling functions. Their assembly requires peroxins, encoded by PEX genes. Mutations in PEX...
Peroxisomes are ubiquitous cell organelles involved in many metabolic and signaling functions. Their assembly requires peroxins, encoded by PEX genes. Mutations in PEX genes are the cause of Zellweger Syndrome spectrum (ZSS), a heterogeneous group of peroxisomal biogenesis disorders (PBD). The size and morphological features of peroxisomes are below the diffraction limit of light, which makes them attractive for super-resolution imaging. We applied Stimulated Emission Depletion (STED) microscopy to study the morphology of human peroxisomes and peroxisomal protein localization in human controls and ZSS patients. We defined the peroxisome morphology in healthy skin fibroblasts and the sub-diffraction phenotype of residual peroxisomal structures ('ghosts') in ZSS patients that revealed a relation between mutation severity and clinical phenotype. Further, we investigated the 70 kDa peroxisomal membrane protein (PMP70) abundance in relationship to the ZSS sub-diffraction phenotype. This work improves the morphological definition of peroxisomes. It expands current knowledge about peroxisome biogenesis and ZSS pathoethiology to the sub-diffraction phenotype including key peroxins and the characteristics of ghost peroxisomes.
Topics: ATP-Binding Cassette Transporters; Fibroblasts; Humans; PHEX Phosphate Regulating Neutral Endopeptidase; Peroxisomes; Zellweger Syndrome
PubMed: 29773809
DOI: 10.1038/s41598-018-24119-2 -
Neuroscience Aug 2014Zellweger syndrome (ZS) is a severe peroxisomal disorder caused by mutations in peroxisome biogenesis, or PEX, genes. A central hallmark of ZS is abnormal neuronal...
Zellweger syndrome (ZS) is a severe peroxisomal disorder caused by mutations in peroxisome biogenesis, or PEX, genes. A central hallmark of ZS is abnormal neuronal migration and neurodegeneration, which manifests as widespread neurological dysfunction. The molecular basis of ZS neuropathology is not well understood. Here we present findings using a mouse model of ZS neuropathology with conditional brain inactivation of the PEX13 gene. We demonstrate that PEX13 brain mutants display changes that reflect an abnormal serotonergic system - decreased levels of tryptophan hydroxylase-2, the rate-limiting enzyme of serotonin (5-hydroxytryptamine, 5-HT) synthesis, dysmorphic 5-HT-positive neurons, abnormal distribution of 5-HT neurons, and dystrophic serotonergic axons. The raphe nuclei region of PEX13 brain mutants also display increased levels of apoptotic cells and reactive, inflammatory gliosis. Given the role of the serotonergic system in brain development and motor control, dysfunction of this system would account in part for the observed neurological changes of PEX13 brain mutants.
Topics: Animals; Apoptosis; Axons; Brain; Cell Count; Disease Models, Animal; Fluorescent Antibody Technique; Gliosis; Membrane Proteins; Mice, Transgenic; Mutation; Neuroimmunomodulation; Peroxisomes; Serotonergic Neurons; Tryptophan Hydroxylase; Zellweger Syndrome
PubMed: 24881576
DOI: 10.1016/j.neuroscience.2014.05.034 -
Ryoikibetsu Shokogun Shirizu 1997
Review
Topics: Humans; Kidney Diseases; Peroxisomal Disorders; Zellweger Syndrome
PubMed: 9277917
DOI: No ID Found -
Human Mutation Jan 2010The autosomal recessive Zellweger syndrome spectrum (ZSS) disorders comprise a main subgroup of the peroxisome biogenesis disorders. The ZSS disorders can be caused by...
The autosomal recessive Zellweger syndrome spectrum (ZSS) disorders comprise a main subgroup of the peroxisome biogenesis disorders. The ZSS disorders can be caused by mutations in any of 12 different currently identified PEX genes resulting in severe, often lethal, multi-systemic disorders. Defects in the PEX6 gene are the second most common cause for ZSS disorders. The encoded protein PEX6 belongs to the AAA ATPase family and contains two AAA cassettes and an AAA protein family signature. The PEX6 gene consists of 17 exons and previously mutations in the PEX6 gene were found to be scattered over all exons. We developed a post-PCR high-resolution melting (HRM) curve assay to scan the PEX6 gene for potential sequence variations followed by selective sequencing to identify these. We analyzed the PEX6 genes of 75 patients assigned to the PEX6 complementation group. We identified a total of 77 different mutations of which 47 mutations have not been reported previously, and 14 polymorphic variants.
Topics: ATPases Associated with Diverse Cellular Activities; Adenosine Triphosphatases; Cell Line; Cells, Cultured; Exons; Fibroblasts; Humans; Mutation; Peroxisomes; Polymerase Chain Reaction; Polymorphism, Genetic; Sequence Analysis, DNA; Transfection; Transition Temperature; Zellweger Syndrome
PubMed: 19877282
DOI: 10.1002/humu.21153