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Clinical Pediatrics Feb 1999Clinical and laboratory findings of Zellweger syndrome (ZS) patients diagnosed at King Faisal Specialist Hospital and Research Center (KFSH & RC), Riyadh, Saudi Arabia...
Clinical and laboratory findings of Zellweger syndrome (ZS) patients diagnosed at King Faisal Specialist Hospital and Research Center (KFSH & RC), Riyadh, Saudi Arabia over a period of 10 years are presented in this report. Eleven patients (nine females and two males) from 2 to 4 months old were referred to KFSH & RC for evaluation of hypotonia, seizures, and dysmorphic features. The common clinical findings included high forehead, large fontanelle, shallow orbit ridges, micrognathia, upslanting palebral fissures, epicanthal folds, severe hypotonia, hyporeflexia, pigmentary retinopathy, optic nerve atrophy, complete or partial agenesis of corpus callusum, and failure to thrive. We did not observe any Brushfield spots, any renal and brain cysts, or adrenal insufficiency. Some unique clinical findings were the presence of gallstones, club feet, or bilateral knee or hip dislocation in some patients. All patients had markedly elevated plasma levels of very long chain fatty acids (VLCFA). Electron microscopy performed on liver biopsies of two patients revealed absence of peroxisomes. Biochemical studies of dermal fibroblasts from three patients showed deficient beta-oxidation of lignoceric acid and dihydroxyacetone phosphate acyltransferase (DHAPATase) activity. The tribal living in Saudi Arabia and our observation that 10 of the 11 parents in this study were first-degree relatives and, except for families 1 and 3, each family had at least another baby who died of the same disease. This suggests that the incidence of ZS in Saudi Arabia may actually be higher than our experience at KFSH & RC.
Topics: Abnormalities, Multiple; Agenesis of Corpus Callosum; Cholelithiasis; Female; Humans; Infant, Newborn; Liver; Magnetic Resonance Imaging; Male; Optic Atrophy; Patella; Radiography; Retinal Degeneration; Saudi Arabia; Ultrasonography; Zellweger Syndrome
PubMed: 10047940
DOI: 10.1177/000992289903800203 -
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 -
Biochimica Et Biophysica Acta Dec 2006Defects in PEX genes impair peroxisome assembly and multiple metabolic pathways confined to this organelle, thus providing the biochemical and molecular bases of the... (Review)
Review
Defects in PEX genes impair peroxisome assembly and multiple metabolic pathways confined to this organelle, thus providing the biochemical and molecular bases of the peroxisome biogenesis disorders (PBD). PBD are divided into two types--Zellweger syndrome spectrum (ZSS) and rhizomelic chondrodysplasia punctata (RCDP). Biochemical studies performed in blood and urine are used to screen for the PBD. DNA testing is possible for all of the disorders, but is more challenging for the ZSS since 12 PEX genes are known to be associated with this spectrum of PBD. In contrast, PBD-RCDP is associated with defects in the PEX7 gene alone. Studies of the cellular and molecular defects in PBD patients have contributed significantly to our understanding of the role of each PEX gene in peroxisome assembly.
Topics: Amino Acid Sequence; Chondrodysplasia Punctata, Rhizomelic; Humans; Membrane Proteins; Molecular Sequence Data; Peroxisomal Disorders; Peroxisomes; Pipecolic Acids; Plasmalogens; Refsum Disease, Infantile; Zellweger Syndrome
PubMed: 17055079
DOI: 10.1016/j.bbamcr.2006.09.010 -
Orphanet Journal of Rare Diseases May 2023The peroxisome is a ubiquitous single membrane-enclosed organelle with an important metabolic role. Peroxisomal disorders represent a class of medical conditions caused...
Multivariate analysis and model building for classifying patients in the peroxisomal disorders X-linked adrenoleukodystrophy and Zellweger syndrome in Chinese pediatric patients.
BACKGROUND
The peroxisome is a ubiquitous single membrane-enclosed organelle with an important metabolic role. Peroxisomal disorders represent a class of medical conditions caused by deficiencies in peroxisome function and are segmented into enzyme-and-transporter defects (defects in single peroxisomal proteins) and peroxisome biogenesis disorders (defects in the peroxin proteins, critical for normal peroxisome assembly and biogenesis). In this study, we employed multivariate supervised and non-supervised statistical methods and utilized mass spectrometry data of neurological patients, peroxisomal disorder patients (X-linked adrenoleukodystrophy and Zellweger syndrome), and healthy controls to analyze the role of common metabolites in peroxisomal disorders, to develop and refine a classification models of X-linked adrenoleukodystrophy and Zellweger syndrome, and to explore analytes with utility in rapid screening and diagnostics.
RESULTS
T-SNE, PCA, and (sparse) PLS-DA, operated on mass spectrometry data of patients and healthy controls were utilized in this study. The performance of exploratory PLS-DA models was assessed to determine a suitable number of latent components and variables to retain for sparse PLS-DA models. Reduced-features (sparse) PLS-DA models achieved excellent classification performance of X-linked adrenoleukodystrophy and Zellweger syndrome patients.
CONCLUSIONS
Our study demonstrated metabolic differences between healthy controls, neurological patients, and peroxisomal disorder (X-linked adrenoleukodystrophy and Zellweger syndrome) patients, refined classification models and showed the potential utility of hexacosanoylcarnitine (C26:0-carnitine) as a screening analyte for Chinese patients in the context of a multivariate discriminant model predictive of peroxisomal disorders.
Topics: Child; Humans; Adrenoleukodystrophy; East Asian People; Multivariate Analysis; Peroxisomal Disorders; Zellweger Syndrome; China
PubMed: 37189159
DOI: 10.1186/s13023-023-02673-x -
[Zhonghua Yan Ke Za Zhi] Chinese... Oct 2022A 5-year-old female patient, presented with"night blindness and poor hearing for 1 year"whose first diagnosis was Usher syndrome due to retinitis pigmentosa accompanied...
A 5-year-old female patient, presented with"night blindness and poor hearing for 1 year"whose first diagnosis was Usher syndrome due to retinitis pigmentosa accompanied by sensorineural deafness. Compound heterozygous variants (c.5G>A, p.W2*/c.3022C>T, p.P1008S) of PEX1, the causative gene for Zellweger spectrum disorder was confirmed by targeted exome sequencing analysis. Permanent tooth enamel dysplasia, nail leukoplakia, and biochemical abnormalities of peroxisome which is consistent with mild Zellweger spectrum disorder were found when she followed up.
Topics: ATPases Associated with Diverse Cellular Activities; Child, Preschool; Female; Genetic Testing; Humans; Membrane Proteins; Mutation; Pedigree; Retinitis Pigmentosa; Usher Syndromes; Zellweger Syndrome
PubMed: 36220650
DOI: 10.3760/cma.j.cn112142-20211206-00580 -
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. Cholbam® (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 -
Genetics in Medicine : Official Journal... Nov 2023Zellweger spectrum disorders (ZSDs) are known as autosomal recessive disorders caused by defective peroxisome biogenesis due to bi-allelic pathogenic variants in any of...
PURPOSE
Zellweger spectrum disorders (ZSDs) are known as autosomal recessive disorders caused by defective peroxisome biogenesis due to bi-allelic pathogenic variants in any of at least 13 different PEX genes. Here, we report 2 unrelated patients who present with an autosomal dominant ZSD.
METHODS
We performed biochemical and genetic studies in blood and skin fibroblasts of the patients and demonstrated the pathogenicity of the identified PEX14 variants by functional cell studies.
RESULTS
We identified 2 different single heterozygous de novo variants in the PEX14 genes of 2 patients diagnosed with ZSD. Both variants cause messenger RNA mis-splicing, leading to stable expression of similar C-terminally truncated PEX14 proteins. Functional studies indicated that the truncated PEX14 proteins lost their function in peroxisomal matrix protein import and cause increased degradation of peroxisomes, ie, pexophagy, thus exerting a dominant-negative effect on peroxisome functioning. Inhibition of pexophagy by different autophagy inhibitors or genetic knockdown of the peroxisomal autophagy receptor NBR1 resulted in restoration of peroxisomal functions in the patients' fibroblasts.
CONCLUSION
Our finding of an autosomal dominant ZSD expands the genetic repertoire of ZSDs. Our study underscores that single heterozygous variants should not be ignored as possible genetic cause of diseases with an established autosomal recessive mode of inheritance.
Topics: Humans; Alleles; Peroxisomes; Protein Transport; Proteins; Zellweger Syndrome
PubMed: 37493040
DOI: 10.1016/j.gim.2023.100944 -
Clinical Dysmorphology Jul 2005The cerebro-hepato-renal syndrome of Zellweger is the most severe peroxisome biogenesis disorder. Zellweger syndrome is caused by a disturbance in the peroxisomal...
The cerebro-hepato-renal syndrome of Zellweger is the most severe peroxisome biogenesis disorder. Zellweger syndrome is caused by a disturbance in the peroxisomal protein import machinery and leads to multiple organ defects and death usually within the first year of life. Here we report a 3-month-old girl with Zellweger syndrome who was found to have cysts in the caudothalamic groove on cranial magnetic resonance imaging.
Topics: Caudate Nucleus; Cysts; Fatal Outcome; Female; Humans; Infant; Magnetic Resonance Imaging; Thalamic Diseases; Zellweger Syndrome
PubMed: 15930911
DOI: No ID Found -
Ugeskrift For Laeger Aug 2000Zellweger syndrome is a fatal recessively inherited disease with disturbed function of many organs. The disease is caused by a defect of peroxisomes, subcellular...
Zellweger syndrome is a fatal recessively inherited disease with disturbed function of many organs. The disease is caused by a defect of peroxisomes, subcellular organelles, which are absent in these patients. Several genes are necessary for the formation and function of the peroxisomes. The clinical picture of Zellweger syndrome can be caused by defects in a number of genes. On the other hand, clinically different diseases such as neonatal adrenoleucodystrophy and infantile Refsum disease have been shown to be allelic to Zellweger syndrome. We describe a typical Zellweger patient belonging to complementation group 1, which is by far the largest group containing more than half of the Zellweger patients.
Topics: Child, Preschool; Humans; Infant; Male; Zellweger Syndrome
PubMed: 10986890
DOI: No ID Found -
Scandinavian Journal of Clinical and... Feb 1989Bile acids are the end products of cholesterol metabolism, and represent the principal form in which cholesterol is eliminated from the body. Salts of bile acids are the... (Review)
Review
Bile acids are the end products of cholesterol metabolism, and represent the principal form in which cholesterol is eliminated from the body. Salts of bile acids are the major driving force to bile flow and are important to maintain insoluble constituents of bile in solution. The detergent properties of bile salts permit dispersion and absorption of lipophilic substances in the gut. This overview is intended to summarize the knowledge of the role of liver peroxisomes in bile acid formation.
Topics: Bile Acids and Salts; Chemical Phenomena; Chemistry; Humans; Liver; Microbodies; Zellweger Syndrome
PubMed: 2658011
DOI: 10.3109/00365518909089071