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Epilepsy & Behavior : E&B Aug 2023Zellweger spectrum disorders (ZSD) are rare autosomal recessive disorders caused by defects in peroxisome biogenesis factor (PEX; peroxin) genes leading to impaired...
Zellweger spectrum disorders (ZSD) are rare autosomal recessive disorders caused by defects in peroxisome biogenesis factor (PEX; peroxin) genes leading to impaired transport of peroxisomal proteins with peroxisomal targeting signals (PTS). Four patients, including a pair of homozygotic twins, diagnosed as ZSD by genetic study with different clinical presentations and outcomes as well as various novel mutations are described here. A total of 3 novel mutations, including a nonsense, a frameshift, and a splicing mutation, in PEX1 from ZSD patients were identified and unequivocally confirmed that the p.Ile989Thr mutant PEX1 exhibited temperature-sensitive characteristics and is associated with milder ZSD. The nature of the p.Ile989Thr mutant exhibited different characteristics from that of the other previously identified temperature-sensitive p.Gly843Asp PEX1 mutant. Transcriptome profiles under nonpermissive vs. permissive conditions were explored to facilitate the understanding of p.Ile989Thr mutant PEX1. Further investigation of molecular mechanisms may help to clarify potential genetic causes that could modify the clinical presentation of ZSD.
Topics: Humans; Child; Zellweger Syndrome; Temperature; ATPases Associated with Diverse Cellular Activities; Membrane Proteins; Fibroblasts; Mutation
PubMed: 37385119
DOI: 10.1016/j.yebeh.2023.109266 -
Orphanet Journal of Rare Diseases Jun 2023
Correction: Multivariate analysis and model building for classifying patients in the peroxisomal disorders X-linked adrenoleukodystrophy and Zellweger syndrome in Chinese pediatric patients.
PubMed: 37322480
DOI: 10.1186/s13023-023-02752-z -
Indian Dermatology Online Journal 2023Zellweger syndrome (ZS) is a rare autosomal recessive, peroxisomal biogenesis disorder (PBD) that occurs due to a mutation in any of the thirteen peroxin ) genes. It is...
Zellweger syndrome (ZS) is a rare autosomal recessive, peroxisomal biogenesis disorder (PBD) that occurs due to a mutation in any of the thirteen peroxin ) genes. It is reported to manifest with varying degrees of severity, ranging from non-specific gastrointestinal abnormalities, nail and enamel defects to multisystem involvement (cerebro-hepato-renal syndrome, eye, ear, and neurological abnormalities). Uncombable hair syndrome (UHS) is a rare hair shaft disorder characterized by dry, frizzy, unmanageable hair. Diagnosis of UHS can be confirmed by scanning electron microscopy (SEM), which reveals a triangular cross-section of the hair. We report a case of UHS with a hitherto unreported association of ZS (due to a homozygous mutation of 12).
PubMed: 37266105
DOI: 10.4103/idoj.idoj_467_22 -
Indian Journal of Nephrology 2023Exploration into the causes of hereditary renal cystic diseases demonstrates a deep-rooted connection with the proteomic components of the cellular organelle cilia.... (Review)
Review
Exploration into the causes of hereditary renal cystic diseases demonstrates a deep-rooted connection with the proteomic components of the cellular organelle cilia. Cilia are essential to the signaling cascades, and their dysfunction has been tied to a range of renal cystic diseases initiating with studies on the oak ridge polycystic kidney (ORPK) mouse model. Here, we delve into renal cystic pathologies that have been tied with ciliary proteosome and highlight the genetics associated with each. The pathologies are grouped based on the mode of inheritance, where inherited causes that result in cystic kidney disease phenotypes include autosomal dominant and autosomal recessive polycystic kidney disease, nephronophthisis (Bardet-Biedl syndrome and Joubert Syndrome), and autosomal dominant tubulointerstitial kidney disease. Alternatively, phakomatoses-, also known as neurocutaneous syndromes, associated cystic kidney diseases include tuberous sclerosis (TS) and Von Hippel-Lindau (VHL) disease. Additionally, we group the pathologies by the mode of inheritance to discuss variations in recommendations for genetic testing for biological relatives of a diagnosed individual.
PubMed: 37234435
DOI: 10.4103/ijn.ijn_318_21 -
Indian Journal of Otolaryngology and... Apr 2023Zellweger Syndrome (ZS) is a genetic mutation disorders with associated craniofacial and developmental anomalies in new-born babies. It also manifest with hearing and...
Zellweger Syndrome (ZS) is a genetic mutation disorders with associated craniofacial and developmental anomalies in new-born babies. It also manifest with hearing and vision disorders. This case report discuss on a 2 year old male child diagnosed as ZS with hypotonia and the important milestones in the audiological diagnostic evaluation.
PubMed: 37206790
DOI: 10.1007/s12070-023-03485-y -
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 -
American Journal of Medical Genetics.... Aug 2023Zellweger spectrum disorder (ZSD) is a group of autosomal recessive disorders caused by biallelic pathogenic variants in any one of the 13 PEX genes essential for...
Zellweger spectrum disorder (ZSD) is a group of autosomal recessive disorders caused by biallelic pathogenic variants in any one of the 13 PEX genes essential for peroxisomal biogenesis. We report a cohort of nine infants who presented at birth with severe neonatal features suggestive of ZSD and found to be homozygous for a variant in PEX6 (NM_000287.4:c.1409G > C[p.Gly470Ala]). All were of Mixtec ancestry and identified by the California Newborn Screening (NBS) Program to have elevated C26:0-lysophosphatidylcholine but no reportable variants in ABCD1. The clinical and biochemical features of this cohort are described within. Gly470Ala may represent a founder variant in the Mixtec population of Central California. ZSD should be considered in patients who present at birth with severe hypotonia and enlarged fontanelles, especially in the setting of an abnormal NBS, Mixtec ancestry, or family history of infant death. There is a need to further characterize the natural history of ZSD, the Gly470Ala variant, and expand upon possible genotype-phenotype correlations.
Topics: Humans; Infant, Newborn; Zellweger Syndrome; ATPases Associated with Diverse Cellular Activities; Genetic Association Studies; Neonatal Screening; Lysophosphatidylcholines
PubMed: 37144748
DOI: 10.1002/ajmg.a.63234 -
European Heart Journal. Cardiovascular... May 2023
Topics: Humans; Pheochromocytoma; Takotsubo Cardiomyopathy; Syndrome; Adrenal Gland Neoplasms
PubMed: 37014047
DOI: 10.1093/ehjci/jead053 -
Journal of Lipid Research May 2023Peroxisomes are single-membrane bounded organelles that in humans play a dual role in lipid metabolism, including the degradation of very long-chain fatty acids and the...
Peroxisomes are single-membrane bounded organelles that in humans play a dual role in lipid metabolism, including the degradation of very long-chain fatty acids and the synthesis of ether lipids/plasmalogens. The first step in de novo ether lipid synthesis is mediated by the peroxisomal enzyme glyceronephosphate O-acyltransferase, which has a strict substrate specificity reacting only with the long-chain acyl-CoAs. The aim of this study was to determine the origin of these long-chain acyl-CoAs. To this end, we developed a sensitive method for the measurement of de novo ether phospholipid synthesis in cells and, by CRISPR-Cas9 genome editing, generated a series of HeLa cell lines with deficiencies of proteins involved in peroxisomal biogenesis, beta-oxidation, ether lipid synthesis, or metabolite transport. Our results show that the long-chain acyl-CoAs required for the first step of ether lipid synthesis can be imported from the cytosol by the peroxisomal ABCD proteins, in particular ABCD3. Furthermore, we show that these acyl-CoAs can be produced intraperoxisomally by chain shortening of CoA esters of very long-chain fatty acids via beta-oxidation. Our results demonstrate that peroxisomal beta-oxidation and ether lipid synthesis are intimately connected and that the peroxisomal ABC transporters play a crucial role in de novo ether lipid synthesis.
Topics: Humans; Plasmalogens; HeLa Cells; Fatty Acids; Peroxisomes; Oxidation-Reduction; Acyl Coenzyme A; Ethers
PubMed: 36990386
DOI: 10.1016/j.jlr.2023.100364 -
BMJ Case Reports Mar 2023Genetic conditions have varied presentations, and one of them is the association with multiple malformation syndrome (MMS), which has a high mortality rate in the...
Genetic conditions have varied presentations, and one of them is the association with multiple malformation syndrome (MMS), which has a high mortality rate in the immediate postnatal period. Here, we describe a neonate born with multiple anomalies-wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes equinovarus, hypoplastic inferior cerebellar vermis, poor reflexes, hypotonia and ventricular septal defect. There was a history of sibling death with similar malformations, pointing towards a genetic aetiology. Clinical exome sequencing yielded the diagnosis of Zellweger syndrome with a rare mutation in gene. Inherited metabolic syndromes frequently masquerade as malformations, but family history of an affected sibling and clinical suspicion aided diagnosis of the infant.
Topics: Infant; Infant, Newborn; Male; Humans; Zellweger Syndrome; Heart Septal Defects, Ventricular; Abnormalities, Multiple; Mutation; Clubfoot
PubMed: 36931687
DOI: 10.1136/bcr-2022-252014