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Indian Journal of Pediatrics May 2024Zellweger syndrome or cerebrohepatorenal syndrome is a rare, multisystem disorder occurring due to defect in metabolic pathway within the peroxisomes. Cirrhosis with...
Zellweger syndrome or cerebrohepatorenal syndrome is a rare, multisystem disorder occurring due to defect in metabolic pathway within the peroxisomes. Cirrhosis with portal hypertension is an important presentation of these patients. Given its progressive, multisystem nature, the role of liver transplantation (LT) in Zellweger syndrome remains undefined and controversial. An 11-y-old boy diagnosed with Zellweger syndrome presented to the authors with decompensated cirrhosis along with bilateral proptosis. After a meticulous evaluation, he was offered an ABO incompatible liver transplantation with his mother being the donor. He had an uneventful post operative period. After a follow up of 24 mo, he has normal graft function, normal cognition along with resolution of proptosis. Therefore, in a group of carefully selected patients with Zellweger syndrome, a liver transplantation can be offered successfully with an excellent prognosis.
Topics: Male; Humans; Zellweger Syndrome; Liver Transplantation; Liver Cirrhosis; Hypertension, Portal; Exophthalmos; Liver
PubMed: 38117438
DOI: 10.1007/s12098-023-04937-7 -
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 -
Frontiers in Cell and Developmental... 2022Peroxisomes are organelles containing different enzymes that catalyze various metabolic pathways such as β-oxidation of very long-chain fatty acids and synthesis of... (Review)
Review
Peroxisomes are organelles containing different enzymes that catalyze various metabolic pathways such as β-oxidation of very long-chain fatty acids and synthesis of plasmalogens. Peroxisome biogenesis is controlled by a family of proteins called peroxins, which are required for peroxisomal membrane formation, matrix protein transport, and division. Mutations of peroxins cause metabolic disorders called peroxisomal biogenesis disorders, among which Zellweger syndrome (ZS) is the most severe. Although patients with ZS exhibit severe pathology in multiple organs such as the liver, kidney, brain, muscle, and bone, the pathogenesis remains largely unknown. Recent findings indicate that peroxisomes regulate intrinsic apoptotic pathways and upstream fission-fusion processes, disruption of which causes multiple organ dysfunctions reminiscent of ZS. In this review, we summarize recent findings about peroxisome-mediated regulation of mitochondrial morphology and its possible relationship with the pathogenesis of ZS.
PubMed: 36158224
DOI: 10.3389/fcell.2022.938177 -
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 -
Children (Basel, Switzerland) Oct 2023The goal of this manuscript is to present and summarize several rare pediatric syndromes (Zellweger syndrome, Kartagener syndrome, Prader-Willi syndrome,... (Review)
Review
The goal of this manuscript is to present and summarize several rare pediatric syndromes (Zellweger syndrome, Kartagener syndrome, Prader-Willi syndrome, Schinzel-Giedion syndrome, Fanconi anemia, Joubert-Boltshauser syndrome, Poretti-Boltshauser syndrome, and Langer-Giedion syndrome) who have been named after luminary "Swiss" physicians (pediatricians, pediatric neurologists, or pediatric radiologists) who recognized, studied, and published these syndromes. In this manuscript, a brief historical summary of the physicians is combined with the key clinical symptoms at presentation and the typical imaging findings. This manuscript is not aiming to give a complete comprehensive summary of the syndromes, nor does it ignore the valuable contributions of many "Swiss" scientists who are not included here, but focuses on several rare syndromes that benefit from imaging data.
PubMed: 37892331
DOI: 10.3390/children10101668 -
JNMA; Journal of the Nepal Medical... Feb 2024Zellweger syndrome is an autosomal recessive disease within the spectrum of peroxisome biogenesis disorder manifesting in the neonatal period with profound dysfunction...
UNLABELLED
Zellweger syndrome is an autosomal recessive disease within the spectrum of peroxisome biogenesis disorder manifesting in the neonatal period with profound dysfunction of the central nervous system, liver and kidney. Common clinical presentations include hypotonia, seizure, hepatomegaly, craniofacial dysmorphism and early death. Mutation in one of the PEX genes coding for a peroxisome assembly protein creates a functionally incompetent organelle causing accumulation of very long chain fatty acids in various organs. Here we report the case of a 5-month-old male presented at birth with hypotonia, poor feeding, gross congenital anomalies and later during early infancy with failure to thrive, several episodes of seizures, aspiration due to feeding difficulties and recurrent severe pneumonia. A whole genomic sequencing brought us to the final diagnosis of Zellweger syndrome. Despite an absence of treatment options, prompt diagnosis of Zellweger syndrome is important for providing appropriate symptomatic care, definitive genetic testing and prenatal counselling.
KEYWORDS
case reports; mutation; neonate; Zellweger syndrome.
Topics: Infant, Newborn; Humans; Male; Infant; Zellweger Syndrome; Muscle Hypotonia; Peroxisomal Disorders; Genetic Testing; Mutation
PubMed: 38409970
DOI: 10.31729/jnma.8467 -
International Journal of Molecular... Aug 2019Peroxisome biogenesis disorders (PBDs) are nontreatable hereditary diseases with a broad range of severity. Approximately 65% of patients are affected by mutations in... (Review)
Review
Peroxisome biogenesis disorders (PBDs) are nontreatable hereditary diseases with a broad range of severity. Approximately 65% of patients are affected by mutations in the peroxins Pex1 and Pex6. The proteins form the heteromeric Pex1/Pex6 complex, which is important for protein import into peroxisomes. To date, no structural data are available for this AAA+ ATPase complex. However, a wealth of information can be transferred from low-resolution structures of the yeast Pex1/Pex6 complex and homologous, well-characterized AAA+ ATPases. We review the abundant records of missense mutations described in PBD patients with the aim to classify and rationalize them by mapping them onto a homology model of the human Pex1/Pex6 complex. Several mutations concern functionally conserved residues that are implied in ATP hydrolysis and substrate processing. Contrary to fold destabilizing mutations, patients suffering from function-impairing mutations may not benefit from stabilizing agents, which have been reported as potential therapeutics for PBD patients.
Topics: ATPases Associated with Diverse Cellular Activities; Adenosine Triphosphate; Amino Acid Sequence; Animals; Humans; Membrane Proteins; Models, Molecular; Mutation, Missense; Peroxisomal Disorders; Protein Conformation; Protein Interaction Maps; Sequence Alignment
PubMed: 31374812
DOI: 10.3390/ijms20153756 -
Journal of Cell Science May 2020Peroxisomes are single-membrane organelles present in eukaryotes. The functional importance of peroxisomes in humans is represented by peroxisome-deficient peroxisome... (Review)
Review
Peroxisomes are single-membrane organelles present in eukaryotes. The functional importance of peroxisomes in humans is represented by peroxisome-deficient peroxisome biogenesis disorders (PBDs), including Zellweger syndrome. Defects in the genes that encode the 14 peroxins that are required for peroxisomal membrane assembly, matrix protein import and division have been identified in PBDs. A number of recent findings have advanced our understanding of the biology, physiology and consequences of functional defects in peroxisomes. In this Review, we discuss a cooperative cell defense mechanisms against oxidative stress that involves the localization of BAK (also known as BAK1) to peroxisomes, which alters peroxisomal membrane permeability, resulting in the export of catalase, a peroxisomal enzyme. Another important recent finding is the discovery of a nucleoside diphosphate kinase-like protein that has been shown to be essential for how the energy GTP is generated and provided for the fission of peroxisomes. With regard to PBDs, we newly identified a mild mutation, Pex26-F51L that causes only hearing loss. We will also discuss findings from a new PBD model mouse defective in Pex14, which manifested dysregulation of the BDNF-TrkB pathway, an essential signaling pathway in cerebellar morphogenesis. Here, we thus aim to provide a current view of peroxisome biogenesis and the molecular pathogenesis of PBDs.
Topics: Animals; Intracellular Membranes; Mice; Peroxins; Peroxisomal Disorders; Peroxisomes; Protein Transport
PubMed: 32393673
DOI: 10.1242/jcs.236943 -
Cells Jun 2022The AAA-ATPases Pex1 and Pex6 are required for the formation and maintenance of peroxisomes, membrane-bound organelles that harbor enzymes for specialized metabolism.... (Review)
Review
The AAA-ATPases Pex1 and Pex6 are required for the formation and maintenance of peroxisomes, membrane-bound organelles that harbor enzymes for specialized metabolism. Together, Pex1 and Pex6 form a heterohexameric AAA-ATPase capable of unfolding substrate proteins via processive threading through a central pore. Here, we review the proposed roles for Pex1/Pex6 in peroxisome biogenesis and degradation, discussing how the unfolding of potential substrates contributes to peroxisome homeostasis. We also consider how advances in cryo-EM, computational structure prediction, and mechanisms of related ATPases are improving our understanding of how Pex1/Pex6 converts ATP hydrolysis into mechanical force. Since mutations in and cause the majority of known cases of peroxisome biogenesis disorders such as Zellweger syndrome, insights into Pex1/Pex6 structure and function are important for understanding peroxisomes in human health and disease.
Topics: ATPases Associated with Diverse Cellular Activities; Adenosine Triphosphatases; Homeostasis; Humans; Membrane Proteins; Peroxisomes
PubMed: 35805150
DOI: 10.3390/cells11132067 -
Frontiers in Cell and Developmental... 2023
PubMed: 36711036
DOI: 10.3389/fcell.2023.1136992