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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 -
Journal of Neurology, Neurosurgery, and... Jan 1986Nine cases of neonatal adrenoleukodystrophy are described. All patients had abnormal facial features, moderate to severe hypotonia, hepatomegaly, and retinitis...
Nine cases of neonatal adrenoleukodystrophy are described. All patients had abnormal facial features, moderate to severe hypotonia, hepatomegaly, and retinitis pigmentosa. The clinical course was rapidly progressive in six cases and more protracted in three others. Biological signs of adrenal insufficiency were present in five cases. CT scan showed a demyelinating process in four patients. Trilamellar inclusions were found in the liver of four cases and dark and complex lipidic inclusions in three other cases. In the three necropsied patients there was severe alteration of the white matter involving particularly the cerebellum in two cases. Gyral and cytoarchitectonic disturbances were absent in all three cases. Increased plasma levels of very long chain fatty acids (8/8), phytanic acid (7/8) and bile fluid trihydroxycoprostanic acid (2/4) confirmed the deficiency of multiple peroxisomal enzymes. Clinical, histopathological and biochemical findings of these nine cases are compared to those reported in other neonatal adrenoleukodystrophy cases and to those of other neonatal peroxisomal disorders, that is cerebro-hepato-renal syndrome of Zellweger and infantile Refsum's disease.
Topics: Adrenal Cortex; Adrenoleukodystrophy; Biopsy; Brain; Diagnosis, Differential; Diffuse Cerebral Sclerosis of Schilder; Female; Humans; Infant; Infant, Newborn; Liver; Male; Microbodies; Refsum Disease; Spinal Nerves
PubMed: 2420940
DOI: 10.1136/jnnp.49.1.77 -
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 -
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 -
Survey of Ophthalmology 1991Several childhood multisystem disorders with prominent ophthalmological manifestations have been ascribed to the malfunction of the peroxisome, a subcellular organelle.... (Review)
Review
Several childhood multisystem disorders with prominent ophthalmological manifestations have been ascribed to the malfunction of the peroxisome, a subcellular organelle. The peroxisomal disorders have been divided into three groups: 1) those that result from defective biogenesis of the peroxisome (Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum's disease); 2) those that result from multiple enzyme deficiencies (rhizomelic chondrodysplasia punctata); and 3) those that result from a single enzyme deficiency (X-linked adrenoleukodystrophy, primary hyperoxaluria type 1). Zellweger syndrome, the most lethal of the three peroxisomal biogenesis disorders, causes infantile hypotonia, seizures, and death within the first year. Ophthalmic manifestations include corneal opacification, cataract, glaucoma, pigmentary retinopathy and optic atrophy. Neonatal adrenoleukodystrophy and infantile Refsum's disease appear to be genetically distinct, but clinically, biochemically, and pathologically similar to Zellweger syndrome, although milder. Rhizomelic chondrodysplasia punctata, a peroxisomal disorder which results from at least two peroxisomal enzyme deficiencies, presents at birth with skeletal abnormalities and patients rarely survive past one year of age. The most prominent ocular manifestation consists of bilateral cataracts. X-linked (childhood) adrenoleukodystrophy, results from a deficiency of a single peroxisomal enzyme, presents in the latter part of the first decade with behavioral, cognitive and visual deterioration. The vision loss results from demyelination of the entire visual pathway, but the outer retina is spared. Primary hyperoxaluria type 1 manifests parafoveal subretinal pigment proliferation. Classical Refsum's disease may also be a peroxisomal disorder, but definitive evidence is lacking. Early identification of these disorders, which may depend on recognizing the ophthalmological findings, is critical for prenatal diagnosis, treatment, and genetic counselling.
Topics: Abnormalities, Multiple; Adrenoleukodystrophy; Animals; Fundus Oculi; Humans; Hyperoxaluria; Metabolism, Inborn Errors; Microbodies; Refsum Disease; Retinal Diseases; Zellweger Syndrome
PubMed: 1710072
DOI: 10.1016/0039-6257(91)90185-i -
Neurology May 2013Zellweger syndrome (ZS) is a severe manifestation of disease within the spectrum of peroxisome biogenesis disorders that includes neonatal adrenoleukodystrophy,... (Review)
Review
Zellweger syndrome (ZS) is a severe manifestation of disease within the spectrum of peroxisome biogenesis disorders that includes neonatal adrenoleukodystrophy, infantile Refsum disease, and rhizomelic chondroplasia punctata. Patients with ZS present in the neonatal period with a characteristic phenotype of distinctive facial stigmata, pronounced hypotonia, poor feeding, hepatic dysfunction, and often seizures and boney abnormalities. In patients with ZS, a mutation in one of the PEX genes coding for a peroxin (a peroxisome assembly protein) creates functionally incompetent organelles causing an accumulation of very long chain fatty acids (VLCFA), among other complications. Despite an absence of treatment options, prompt diagnosis of ZS is important for providing appropriate symptomatic care, definitive genetic testing, and counseling regarding family planning.
Topics: Child; Fatal Outcome; Humans; Infant; Male; Neurology; Zellweger Syndrome
PubMed: 23671347
DOI: 10.1212/WNL.0b013e3182929f8e -
Frontiers in Physiology 2014To investigate peroxisome assembly and human peroxisome biogenesis disorders (PBDs) such as Zellweger syndrome, thirteen different complementation groups (CGs) of... (Review)
Review
To investigate peroxisome assembly and human peroxisome biogenesis disorders (PBDs) such as Zellweger syndrome, thirteen different complementation groups (CGs) of Chinese hamster ovary (CHO) cell mutants defective in peroxisome biogenesis have been isolated and established as a model research system. Successful gene-cloning studies by a forward genetic approach utilized a rapid functional complementation assay of CHO cell mutants led to isolation of human peroxin (PEX) genes. Search for pathogenic genes responsible for PBDs of all 14 CGs is now completed together with the homology search by screening the human expressed sequence tag database using yeast PEX genes. Peroxins are divided into three groups: (1) peroxins including Pex3p, Pex16p, and Pex19p, are responsible for peroxisome membrane biogenesis via classes I and II pathways; (2) peroxins that function in matrix protein import; (3) those such as three forms of Pex11p, Pex11pα, Pex11pβ, and Pex11pγ, are involved in peroxisome proliferation where DLP1, Mff, and Fis1 coordinately function. In membrane assembly, Pex19p forms complexes in the cytosol with newly synthesized PMPs including Pex16p and transports them to the receptor Pex3p, whereby peroxisomal membrane is formed (Class I pathway). Pex19p likewise forms a complex with newly made Pex3p and translocates it to the Pex3p receptor, Pex16p (Class II pathway). In matrix protein import, newly synthesized proteins harboring peroxisome targeting signal type 1 or 2 are recognized by Pex5p or Pex7p in the cytoplasm and are imported to peroxisomes via translocation machinery. In regard to peroxisome-cytoplasmic shuttling of Pex5p, Pex5p initially targets to an 800-kDa docking complex consisting of Pex14p and Pex13p and then translocates to a 500-kDa RING translocation complex. At the terminal step, Pex1p and Pex6p of the AAA family mediate the export of Pex5p, where Cys-ubiquitination of Pex5p is essential for the Pex5p exit.
PubMed: 25177298
DOI: 10.3389/fphys.2014.00307 -
Journal of Medical Genetics Oct 1996Until recently, the peroxisome was considered a "reactor chamber" for H2O2 producing oxidases, and it is now recognised as a versatile organelle performing complex... (Review)
Review
Until recently, the peroxisome was considered a "reactor chamber" for H2O2 producing oxidases, and it is now recognised as a versatile organelle performing complex catabolic and biosynthetic roles in the cell. Zellweger syndrome (ZS), the paradigm of human peroxisomal disorders, is characterised by neonatal hypotonia, severe neuro-developmental delay, hepatomegaly, renal cysts, senorineural deafness, retinal dysfunction, and facial dysmorphism. It is now clear that ZS is at the severe end of a phenotypic spectrum of Zellweger-like syndromes which may present for diagnosis later in childhood and even in adult life. It is important that clinical geneticists are aware of these milder clinical variants as the availability of sensitive and specific biochemical assays of peroxisomal function (for example, serum VLCFA ratios, platelet DHAP-AT activity) makes their diagnosis relatively straightforward.
Topics: Animals; Humans; Male; Microbodies; Phenotype; Zellweger Syndrome
PubMed: 8933342
DOI: 10.1136/jmg.33.10.863 -
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 -
Indian Pediatrics Jul 2003
Topics: Humans; Infant; Male; Zellweger Syndrome
PubMed: 12881630
DOI: No ID Found