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Human Heredity 1992The Zellweger syndrome is characterized by a defect which results in the abnormal biogenesis of peroxisomes. As a consequence, metabolic activities associated with...
The Zellweger syndrome is characterized by a defect which results in the abnormal biogenesis of peroxisomes. As a consequence, metabolic activities associated with peroxisomes such as the oxidation of very long chain fatty acids, the synthesis of plasmalogens, and the catabolism of phytanic and pipecolic acids are impaired. Since this disorder is genetically heterogeneous and several complementation groups are known, we were able to study the normalization of peroxisomal activity during the process of complementation. The restoration of catalase and dihydroxyacetone phosphate acyltransferase activities peaked within 3-4 days postfusion while the oxidation of lignoceric acid was much delayed (7-8 days). Electron microscopy indicated that by 6 days following hybridization, peroxisome structure and density in heterokaryons was comparable to normal control cells. The heterogenous biochemical response during peroxisome normalization could be due to several factors including a possible requirement for restoration of peroxisomal structural integrity for maximum activation of certain metabolic pathways.
Topics: Acyltransferases; Cell Line; Fatty Acids; Genetic Complementation Test; Humans; Microbodies; Oxidation-Reduction; Zellweger Syndrome
PubMed: 1511996
DOI: 10.1159/000154062 -
The Journal of Pediatrics Jan 2018
Topics: Abnormalities, Multiple; Brachydactyly; Calcinosis; Facies; Hepatomegaly; Humans; Infant, Newborn; Intensive Care, Neonatal; Male; Membrane Proteins; Patella; Polymorphism, Single Nucleotide; Zellweger Syndrome
PubMed: 29246349
DOI: 10.1016/j.jpeds.2017.09.064 -
Cells Jun 2022Zellweger spectrum disorder (ZSD) is a rare, debilitating genetic disorder of peroxisome biogenesis that affects multiple organ systems and presents with broad clinical... (Meta-Analysis)
Meta-Analysis Review
Zellweger spectrum disorder (ZSD) is a rare, debilitating genetic disorder of peroxisome biogenesis that affects multiple organ systems and presents with broad clinical heterogeneity. Although severe, intermediate, and mild forms of ZSD have been described, these designations are often arbitrary, presenting difficulty in understanding individual prognosis and treatment effectiveness. The purpose of this study is to conduct a scoping review and meta-analysis of existing literature and a medical chart review to determine if characterization of clinical findings can predict severity in ZSD. Our PubMed search for articles describing severity, clinical findings, and survival in ZSD resulted in 107 studies (representing 307 patients) that were included in the review and meta-analysis. We also collected and analyzed these same parameters from medical records of 136 ZSD individuals from our natural history study. Common clinical findings that were significantly different across severity categories included seizures, hypotonia, reduced mobility, feeding difficulties, renal cysts, adrenal insufficiency, hearing and vision loss, and a shortened lifespan. Our primary data analysis also revealed significant differences across severity categories in failure to thrive, gastroesophageal reflux, bone fractures, global developmental delay, verbal communication difficulties, and cardiac abnormalities. Univariable multinomial logistic modeling analysis of clinical findings and very long chain fatty acid (VLCFA) hexacosanoic acid (C26:0) levels showed that the number of clinical findings present among seizures, abnormal EEG, renal cysts, and cardiac abnormalities, as well as plasma C26:0 fatty acid levels could differentiate severity categories. We report the largest characterization of clinical findings in relation to overall disease severity in ZSD. This information will be useful in determining appropriate outcomes for specific subjects in clinical trials for ZSD.
Topics: Fatty Acids; Humans; Kidney Diseases, Cystic; Membrane Proteins; Seizures; Zellweger Syndrome
PubMed: 35741019
DOI: 10.3390/cells11121891 -
The Journal of Obstetrics and... Jun 2014Increased echogenicity of fetal bowel in the second trimester obstetrical ultrasound has been described in association with several pathologic conditions, such as growth...
Increased echogenicity of fetal bowel in the second trimester obstetrical ultrasound has been described in association with several pathologic conditions, such as growth restriction, aneuploidy, cystic fibrosis, congenital infections, and gastrointestinal malformations. Zellweger syndrome (ZS) is the prototype of peroxisomal disorders characterized by craniofacial dysmorphism and severe neurologic abnormalities. We report two cases with fetal echogenic bowel (FEB) but no associated anomalies and normal fetal growth. After birth, clinical and laboratory findings led to diagnosis of ZS. Association of FEB with neurometabolic disorders is limited to a few case reports in the medical literature. To the best of our knowledge, this is the first report of ZS associated with FEB.
Topics: Adult; Echogenic Bowel; Female; Humans; Infant, Newborn; Male; Pregnancy; Ultrasonography, Prenatal; Zellweger Syndrome
PubMed: 24888952
DOI: 10.1111/jog.12379 -
Journal of Molecular Neuroscience : MN 2001Zellweger syndrome is the prototypic human peroxisomal biogenesis disorder that results in abnormal neuronal migration in the central nervous system and severe... (Review)
Review
Zellweger syndrome is the prototypic human peroxisomal biogenesis disorder that results in abnormal neuronal migration in the central nervous system and severe neurologic dysfunction. A murine model for this disorder was previously developed by targeted deletion of the PEX2 peroxisomal gene. By labeling neuronal precursor cells in vivo with a mitotic marker, we can demonstrate a delay in neuronal migration in the cerebral cortex of homozygous PEX2 mutant mice. Postnatal PEX2 Zellweger mice develop severe cerebellar defects with abnormal Purkinje cell development and an altered folial pattern. When the PEX2 mutation is placed on an inbred murine genetic background, there is significant embryonic lethality and widespread neuronal lipidosis throughout the brain. Biochemical analysis of PEX2 mutant mice shows the characteristic accumulation of very long chain fatty acids and deficient plasmalogens in a wide variety of tissues. Docosahexaenoic acid levels (DHA; 22:6n-3) were found to be reduced in the brain of mutant mice but were normal in visceral organs at birth. All tissues examined in postnatal mutant mice had reduced DHA. The combined use of morphologic and biochemical analyses in these mice will be essential to elucidate the pathogenesis of this complex peroxisomal disease.
Topics: Animals; Cell Movement; Cerebellum; Cerebral Cortex; Crosses, Genetic; Dendrites; Dietary Fats; Disease Models, Animal; Docosahexaenoic Acids; Fatty Acids; Female; Gene Targeting; Genes, Lethal; Genotype; Humans; Inclusion Bodies; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Organ Specificity; Peroxisomal Biogenesis Factor 2; Peroxisomes; Plasmalogens; Purkinje Cells; Zellweger Syndrome
PubMed: 11478384
DOI: 10.1385/JMN:16:2-3:289 -
Journal of Applied Genetics Nov 2017Zellweger syndrome (ZS) is a consequence of a peroxisome biogenesis disorder (PBD) caused by the presence of a pathogenic mutation in one of the 13 genes from the PEX...
Zellweger syndrome (ZS) is a consequence of a peroxisome biogenesis disorder (PBD) caused by the presence of a pathogenic mutation in one of the 13 genes from the PEX family. ZS is a severe multisystem condition characterized by neonatal appearance of symptoms and a shorter life. Here, we report a case of ZS with a mild phenotype, due to a novel PEX6 gene mutation. The patient presented subtle craniofacial dysmorphic features and slightly slower psychomotor development. At the age of 2 years, he was diagnosed with adrenal insufficiency, hypoacusis, and general deterioration. Magnetic resonance imaging showed a symmetrical hyperintense signal in the frontal and parietal white matter. Biochemical tests showed elevated liver transaminases, elevated serum very long chain fatty acids, and phytanic acid. After the death of the child at the age of 6 years, molecular diagnostics were continued in order to provide genetic counseling for his parents. Next generation sequencing (NGS) analysis with the TruSight One™ Sequencing Panel revealed a novel homozygous PEX6 p.Ala94Pro mutation. In silico prediction of variant severity suggested its possible benign effect. To conclude, in the milder phenotypes, adrenal insufficiency, hypoacusis, and leukodystrophy together seem to be pathognomonic for ZS.
Topics: ATPases Associated with Diverse Cellular Activities; Child; Humans; Male; Mutation; Phenotype; Zellweger Syndrome
PubMed: 29047053
DOI: 10.1007/s13353-017-0414-5 -
Clinical EEG (electroencephalography) Jan 2001Differential diagnosis in a newborn with dysmorphic features and profound neurologic dysfunction should include the cerebro-hepato-renal syndrome of Zellweger. Its...
Differential diagnosis in a newborn with dysmorphic features and profound neurologic dysfunction should include the cerebro-hepato-renal syndrome of Zellweger. Its distinct clinical features, markedly elevated plasma levels of very long chain fatty acids and characteristic radiological findings support the diagnosis, which can now be confirmed by genetic markers. Quite consistent abnormalities of the neurophysiological studies in this syndrome have also been reported. We report a case with typical clinical and biochemical findings in whom distinctive brain MRI abnormalities were found. The results of neurophysiological studies with an unusual EEG pattern of continuous negative vertex sharp waves and spikes are discussed. We believe that such a pattern could be considered as a pathognomonic EEG finding, especially in cases of Zellweger syndrome with extensive brain abnormalities and may even be closely associated with cortical dysplasias.
Topics: Diagnosis, Differential; Electroencephalography; Fatal Outcome; Humans; Infant, Newborn; Magnetic Resonance Imaging; Male; Zellweger Syndrome
PubMed: 11202139
DOI: 10.1177/155005940103200108 -
Developmental Disabilities Research... 2013The peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive disorders in which peroxisome assembly is impaired, leading to multiple... (Review)
Review
The peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive disorders in which peroxisome assembly is impaired, leading to multiple peroxisome enzyme deficiencies, complex developmental sequelae and progressive disabilities. Mammalian peroxisome assembly involves the protein products of 16 PEX genes; defects in 14 of these have been shown to cause PBD. Three broad phenotypic groups are described on a spectrum of severity: Zellweger syndrome is the most severe, neonatal adrenoleukodystrophy is intermediate and infantile Refsum disease is less severe. Another group is Rhizomelic chondrodysplasia punctata spectrum. Recently, atypical phenotypes have been described, indicating that the full spectrum of these disorders remains to be identified. For most patients, there is a correlation between clinical severity and effect of the mutation on PEX protein function. Diagnosis relies on biochemical measurements of peroxisome functions and PEX gene sequencing. There are no targeted therapies, although management protocols have been suggested and research endeavors continue. In this review we will discuss peroxisome biology and PBD, and research contributions to pathophysiology and treatment.
Topics: Age Factors; Age of Onset; Animals; Humans; Mutation; PHEX Phosphate Regulating Neutral Endopeptidase; Peroxisomal Disorders; Peroxisomes; Phenotype; Zellweger Syndrome
PubMed: 23798008
DOI: 10.1002/ddrr.1113 -
Proceedings of the National Academy of... Nov 1991By both histological and biochemical criteria, peroxisomes in patients with Zellweger syndrome appear to be absent or severely deficient. By using 15-30% (wt/vol)... (Comparative Study)
Comparative Study
By both histological and biochemical criteria, peroxisomes in patients with Zellweger syndrome appear to be absent or severely deficient. By using 15-30% (wt/vol) Nycodenz/sucrose gradients to study the subcellular localization of extraperoxisomal catalase activity, a commonly used marker for mature peroxisomes, we detected a single peak of activity in Zellweger syndrome fibroblasts at an equilibrium density of 1.13 g/cm3, lower than the expected 1.17 g/cm3 of mature peroxisomes. Upon recentrifugation in either the original gradient or one with a higher salt concentration, essentially all catalase activity was recovered in fractions of the original densities. The activity of the catalase peak was further analyzed by a digitonin titration and filtration assay in combination with Triton X-100 treatment. The catalase activity passed through 0.1-microns and 0.22-microns but was retained on 0.025-microns membrane filters (mean pore size). After treatment with Triton X-100 nearly all catalase activity passed through the filters. The results from fractionations data, digitonin latency measurement, and the detergent effect on the filtration behavior suggest that catalase is not free in the cytosol of Zellweger syndrome fibroblasts as commonly thought but in particles (W-particles). Similar low-density catalase-containing particles, distinct from peroxisomes, are also found in normal fibroblasts. We found that L-alpha-hydroxyacid oxidase, another peroxisomal matrix enzyme, is also present in W-particles derived from normal and Zellweger syndrome fibroblasts. We speculate that the low-density catalase-containing W-particle may represent an immature or incomplete form of peroxisome distinct from previously described "peroxisomal ghosts" in Zellweger syndrome fibroblasts.
Topics: Biomarkers; Catalase; Cell Fractionation; Cell Line; Centrifugation, Density Gradient; Digitonin; Fibroblasts; Humans; Microbodies; Organelles; Zellweger Syndrome
PubMed: 1946426
DOI: 10.1073/pnas.88.22.10084 -
Pediatric Neurology Oct 2017
Topics: DNA Mutational Analysis; Exome; Humans; Infant; Male; Membrane Proteins; Muscle Hypotonia; Mutation; Zellweger Syndrome
PubMed: 28823628
DOI: 10.1016/j.pediatrneurol.2017.06.012