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Frontiers in Pediatrics 2022Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive genetic disorder caused by mutations in the AGXT gene. The hepatic peroxisomal enzyme alanine glyoxylate... (Review)
Review
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive genetic disorder caused by mutations in the AGXT gene. The hepatic peroxisomal enzyme alanine glyoxylate aminotransferase (AGT) defects encoded by the AGXT gene increase oxalate production, resulting in nephrocalcinosis, nephrolithiasis, chronic kidney disease, and kidney failure. Traditional pharmacological treatments for PH1 are limited. At present, the treatment direction of PH1 is mainly targeted therapy which refer to a method that targeting the liver to block the pathway of the production of oxalate. Lumasiran (OxlumoTM, developed by Alnylam Pharmaceuticals), an investigational RNA interference (RNAi) therapeutic agent, is the first drug approved for the treatment of PH1, which was officially approved by the US Food and Drug Administration and the European Union in November 2020. It is also the only drug that has been shown to decrease harmful oxalate. Currently, there are 5 keys completed and ongoing clinical trials of lumasiran in PH1. Through the three phase III trials that completed the primary analysis period, lumasiran has been shown to be effective in reducing oxalate levels in urine and plasma in different age groups, such as children, adults, and patients with advanced kidney disease, including those on hemodialysis. In addition to clinical trials, cases of lumasiran treatment for PH1 have been reported in small infants, twin infants, and children diagnosed with PH1 after kidney transplantation. These reports confirm the effectiveness and safety of lumasiran. All adverse events were of mild to moderate severity, with the most common being mild, transient injection-site reactions. No deaths or severe adverse events were reported. This article reviews PH1 and lumasiran which is the only approved therapeutic drug, and provide new options and hope for the treatment of PH1.
PubMed: 36704142
DOI: 10.3389/fped.2022.1052625 -
Frontiers in Neurology 2022X-linked adrenoleukodystrophy (X-ALD) is the most common inherited peroxisomal disorder caused by variants in the gene. The main phenotypes observed in men with X-ALD...
INTRODUCTION
X-linked adrenoleukodystrophy (X-ALD) is the most common inherited peroxisomal disorder caused by variants in the gene. The main phenotypes observed in men with X-ALD are primary adrenal insufficiency, adrenomyeloneuropathy, and cerebral ALD (cALD). Cerebral ALD consists of a demyelinating progressive cerebral white matter (WM) disease associated with rapid clinical decline and is fatal if left untreated. Hematopoietic stem cell transplantation is the standard treatment for cALD as it stabilizes WM degeneration when performed early in the disease. For this reason, early diagnosis is crucial, and several countries have already implemented their newborn screening programs (NBS) with the assessment of C26:0-lysophosphatidylcholine (C26:0-LPC) values as screening for X-ALD.
METHODS
In June 2021, an Italian group in Lombardy launched a pilot study for the implementation of X-ALD in the Italian NBS program. A three-tiered approach was adopted, and it involved quantifying the values of C26:0-LPC and other metabolites in dried blood spots with FIA-MS/MS first, followed by the more specific ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) technique and, finally, the genetic confirmation focused NGS.
DISCUSSION
Genetically confirmed patients are set to undergo a follow-up protocol and are periodically evaluated to promptly start a specific treatment if and when the first signs of brain damage appear, as suggested by international guidelines. A specific disease monitoring protocol has been created based on literature data and personal direct experience.
CONCLUSION
The primary aim of this study was to develop a model able to improve the early diagnosis and subsequent follow-up and timely treatment of X-ALD.
ETHICS
The study was approved by the local ethics committee. The research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.
PubMed: 36698902
DOI: 10.3389/fneur.2022.1072256 -
Practical Laboratory Medicine Jan 2023Very long-chain fatty acyl-lysophosphatidylcholines (VLCFA-LysoPCs) are measured in dried blood spots (DBS) for identifying X-linked adrenoleukodystrophy (X-ALD) and...
BACKGROUND AND OBJECTIVES
Very long-chain fatty acyl-lysophosphatidylcholines (VLCFA-LysoPCs) are measured in dried blood spots (DBS) for identifying X-linked adrenoleukodystrophy (X-ALD) and other inherited peroxisomal disorders. Our study aimed to establish age- and gender-specific reference intervals for a panel of LysoPCs measured by tandem mass spectrometry in DBS.
METHODS
LysoPCs (26:0-, 24:0-, 22:0- and 20:0-LysoPCs) were estimated by flow injection analysis-tandem mass spectrometry (FIA-MS/MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods in 3.2 mm blood spots of 2689 anonymized, putative normal subjects (1375 males, and 1314 females) aged between 2 days and 65 years. Samples were divided into groups: Neonates (0-1month), Infants (>1m-1year), Children and Adolescents (>1-18years), and Adults (>18years). Reference intervals were determined using the percentile approach and represented as the median with the 1 and 99 percentile lower and upper limits.
RESULTS
The percentage coefficient of variation (CV) for repeatability assays of internal and external quality control samples were within acceptable limits. Significant differences (P <0.0001, P <0.01) were observed in the concentrations of 26:0-, 24:0-, 22:0- and 20:0-LysoPCs and their ratios, 26:0/22:0-, 24:0/22:0-, 26:0/20:0-and 24:0/20:0-LysoPC in neonates and infants when compared to children, adolescents, and adults. Levels of 26:0-, 24:0- and 22:0-LysoPCs decreased, whereas 20:0-LysoPC increased with age. There were no significant gender-based differences in the concentration of LysoPCs.
CONCLUSION
We established age- and gender-specific reference intervals for a panel of LysoPCs in DBS. These reference values would be helpful when interpreting LysoPC values in DBS during screening for X-ALD and other peroxisomal disorders.
PubMed: 36618341
DOI: 10.1016/j.plabm.2022.e00305 -
Cureus Nov 2022Rhizomelic chondrodysplasia punctata (RCDP) is a rare, multisystem, autosomal recessive, peroxisomal disorder of a family of congenital disorders known as...
Rhizomelic chondrodysplasia punctata (RCDP) is a rare, multisystem, autosomal recessive, peroxisomal disorder of a family of congenital disorders known as chondrodysplasia calcificans punctate (CCP). RCDP is characterized by disproportionately short extremities (rhizomelia), congenital cataracts, and joint contractures. Dysmorphic facial features include a broad nasal bridge, epicanthus, high-arched palate, dysplastic external ears, and micrognathia. Severe mental retardation with spasticity and seizures may also be present. X-ray of the limbs showed punctate calcifications in cartilage (chondrodysplasia punctata). Genetic testing reveals the severity of phenotype. Treatment is limited to supportive symptomatic relief and prevention of complications. To the best of our knowledge, after searching through PubMed, our case is the first reported case of RCDP in the Middle East.
PubMed: 36561594
DOI: 10.7759/cureus.31702 -
Cells Dec 2022Peroxisome Biogenesis Disorders (PBD) and Zellweger syndrome spectrum disorders (ZSD) are rare genetic multisystem disorders that include hearing impairment and are...
Peroxisome Biogenesis Disorders (PBD) and Zellweger syndrome spectrum disorders (ZSD) are rare genetic multisystem disorders that include hearing impairment and are associated with defects in peroxisome assembly, function, or both. Mutations in 13 peroxin () genes have been found to cause PBD-ZSD with ~70% of patients harboring mutations in . Limited research has focused on the impact of peroxisomal disorders on auditory function. As sensory hair cells are particularly vulnerable to metabolic changes, we hypothesize that mutations in lead to oxidative stress affecting hair cells of the inner ear, subsequently resulting in hair cell degeneration and hearing loss. Global deletion of the gene is neonatal lethal in mice, impairing any postnatal studies. To overcome this limitation, we created conditional knockout mice (cKO) using or expressing mice crossed to floxed mice to allow for selective deletion of in the hair cells of the inner ear. We find that excision in inner hair cells (IHCs) leads to progressive hearing loss associated with significant decrease in auditory brainstem responses (ABR), specifically ABR wave I amplitude, indicative of synaptic defects. Analysis of IHC synapses in cKO mice reveals a decrease in ribbon synapse volume and functional alterations in exocytosis. Concomitantly, we observe a decrease in peroxisomal number, indicative of oxidative stress imbalance. Taken together, these results suggest a critical function of in development and maturation of IHC-spiral ganglion synapses and auditory function.
Topics: Animals; Mice; ATPases Associated with Diverse Cellular Activities; Cochlea; Deafness; Hair Cells, Auditory, Inner; Hearing; Hearing Loss; Mice, Knockout; Synapses
PubMed: 36552747
DOI: 10.3390/cells11243982 -
Autophagy Jun 2023Peroxisomes are rapidly degraded during amino acid and oxygen deprivation by a type of selective autophagy called pexophagy. However, how damaged peroxisomes are...
Peroxisomes are rapidly degraded during amino acid and oxygen deprivation by a type of selective autophagy called pexophagy. However, how damaged peroxisomes are detected and removed from the cell is poorly understood. Recent studies suggest that the peroxisomal matrix protein import machinery may serve double duty as a quality control machinery, where they are directly involved in activating pexophagy. Here, we explored whether any matrix import factors are required to prevent pexophagy, such that their loss designates peroxisomes for degradation. Using gene editing and quantitative fluorescence microscopy on culture cells and a zebrafish model system, we found that PEX13, a component of the peroxisomal matrix import system, is required to prevent the degradation of otherwise healthy peroxisomes. The loss of PEX13 caused an accumulation of ubiquitinated PEX5 on peroxisomes and an increase in peroxisome-dependent reactive oxygen species that coalesce to induce pexophagy. We also found that PEX13 protein level is downregulated to aid in the induction of pexophagy during amino acid starvation. Together, our study points to PEX13 as a novel pexophagy regulator that is modulated to maintain peroxisome homeostasis. AAA ATPases: ATPases associated with diverse cellular activities; ABCD3: ATP binding cassette subfamily D member; 3ACOX1: acyl-CoA oxidase; 1ACTA1: actin alpha 1, skeletal muscle; ACTB: actin beta; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; ATG16L1: autophagy related 16 like 1; CAT: catalase; CQ: chloroquine; Dpf: days post fertilization: FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HO hydrogen peroxide; HA - human influenza hemagglutinin; HBSS: Hanks' Balanced Salt Solution; HCQ; hydroxychloroquine; KANL: lysine alanine asparagine leucine; KO: knockout; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; MYC: MYC proto-oncogene, bHLH transcription factor; MZ: maternal and zygotic; NAC: N-acetyl cysteine; NBR1 - NBR1 autophagy cargo receptor; PBD: peroxisome biogenesis disorder; PBS: phosphate-buffered saline; PEX: peroxisomal biogenesis factor; PTS1: peroxisome targeting sequence 1; RFP: red fluorescent protein; ROS: reactive oxygen speciess; iRNA: short interfering RNA; SKL: serine lysine leucine; SLC25A17/PMP34: solute carrier family 25 member 17; Ub: ubiquitin; USP30: ubiquitin specific peptidase 30.
Topics: Animals; Humans; Mice; Macroautophagy; Autophagy; Reactive Oxygen Species; Leucine; Lysine; Actins; Zebrafish; Fibroblasts; Ubiquitin; Peroxisomes; Amino Acids; Oxygen; Sirolimus; Membrane Proteins
PubMed: 36541703
DOI: 10.1080/15548627.2022.2160566 -
Biological Chemistry Feb 2023For the biogenesis and maintenance of peroxisomes several proteins, called peroxins, are essential. Malfunctions of these proteins lead to severe diseases summarized as...
For the biogenesis and maintenance of peroxisomes several proteins, called peroxins, are essential. Malfunctions of these proteins lead to severe diseases summarized as peroxisome biogenesis disorders. The different genetic background of patient-derived cell lines and the residual expression of mutated PEX genes impede analysis of the whole spectrum of cellular functions of affected peroxins. To overcome these difficulties, we have generated a selected PEX knockout resource of HEK T-REx293 cells using the CRISPR/Cas9 technique. Comparative analyses of whole cell lysates revealed PEX-KO specific alterations in the steady-state level of peroxins and variations in the import efficacy of matrix proteins with a Type 2 peroxisomal targeting signal. One of the observed differences concerned PEX1 as in the complete absence of the protein, the number of peroxisomal ghosts is significantly increased. Upon expression of PEX1, import competence and abundance of peroxisomes was adjusted to the level of normal HEK cells. In contrast, expression of an alternatively spliced PEX1 isoform lacking 321 amino acids of the N-terminal region failed to rescue the peroxisomal import defects but reduced the number of peroxisomal vesicles. All in all, the data suggest a novel 'moonlighting' function of human PEX1 in the regulation of pre-peroxisomal vesicles.
Topics: Humans; ATPases Associated with Diverse Cellular Activities; Cell Line; Membrane Proteins; Peroxins; Peroxisomal Disorders; Peroxisomes; Protein Isoforms; Organelle Biogenesis
PubMed: 36534601
DOI: 10.1515/hsz-2022-0223 -
Journal of Neuroinflammation Dec 2022Saturated very long-chain fatty acids (VLCFA, ≥ C22), enriched in brain myelin and innate immune cells, accumulate in X-linked adrenoleukodystrophy (X-ALD) due to...
Saturated very long-chain fatty acids (VLCFA, ≥ C22), enriched in brain myelin and innate immune cells, accumulate in X-linked adrenoleukodystrophy (X-ALD) due to inherited dysfunction of the peroxisomal VLCFA transporter ABCD1. In its severest form, X-ALD causes cerebral myelin destruction with infiltration of pro-inflammatory skewed monocytes/macrophages. How VLCFA levels relate to macrophage activation is unclear. Here, whole transcriptome sequencing of X-ALD macrophages indicated that VLCFAs prime human macrophage membranes for inflammation and increased expression of factors involved in chemotaxis and invasion. When added externally to mimic lipid release in demyelinating X-ALD lesions, VLCFAs did not activate toll-like receptors in primary macrophages. In contrast, VLCFAs provoked pro-inflammatory responses through scavenger receptor CD36-mediated uptake, cumulating in JNK signalling and expression of matrix-degrading enzymes and chemokine release. Following pro-inflammatory LPS activation, VLCFA levels increased also in healthy macrophages. With the onset of the resolution, VLCFAs were rapidly cleared in control macrophages by increased peroxisomal VLCFA degradation through liver-X-receptor mediated upregulation of ABCD1. ABCD1 deficiency impaired VLCFA homeostasis and prolonged pro-inflammatory gene expression upon LPS treatment. Our study uncovers a pivotal role for ABCD1, a protein linked to neuroinflammation, and associated peroxisomal VLCFA degradation in regulating macrophage plasticity.
Topics: Humans; Adrenoleukodystrophy; Lipopolysaccharides; ATP-Binding Cassette Transporters; Fatty Acids; Macrophages
PubMed: 36528616
DOI: 10.1186/s12974-022-02664-y -
Journal of Inherited Metabolic Disease Mar 2023X-linked adrenoleukodystrophy (ALD) is a rare inherited neurological disorder that poses considerable challenges for clinical management throughout the lifespan.... (Review)
Review
X-linked adrenoleukodystrophy (ALD) is a rare inherited neurological disorder that poses considerable challenges for clinical management throughout the lifespan. Although males are generally more severely affected than females, the time course and presentation of clinical symptoms are otherwise difficult to predict. Opportunities to improve outcomes for individuals with ALD are rapidly expanding due to the introduction of newborn screening programs for this condition and an evolving treatment landscape. The aim of this comprehensive review is to synthesize current knowledge regarding the neurocognitive and mental health effects of ALD. This review provides investigators and clinicians with context to improve case conceptualization, inform prognostic counseling, and optimize neuropsychological and mental health care for patients and their families. Results highlight key predictive factors and brain-behavior relationships associated with the diverse manifestations of ALD. The review also discusses considerations for endpoints within clinical trials and identifies gaps to address in future research.
Topics: Male; Infant, Newborn; Female; Humans; Adrenoleukodystrophy; Neonatal Screening; Longevity; Mental Health; Brain
PubMed: 36527290
DOI: 10.1002/jimd.12581 -
Biochemical Society Transactions Dec 2022Peroxisomes are membrane-bounded organelles that exist in most eukaryotic cells and are involved in the oxidation of fatty acids and the destruction of reactive oxygen...
Peroxisomes are membrane-bounded organelles that exist in most eukaryotic cells and are involved in the oxidation of fatty acids and the destruction of reactive oxygen species. Depending on the organism, they house additional metabolic reactions that range from glycolysis in parasitic protozoa to the production of ether lipids in animals and antibiotics in fungi. The importance of peroxisomes for human health is revealed by various disorders - notably the Zellweger spectrum - that are caused by defects in peroxisome biogenesis and are often fatal. Most peroxisomal metabolic enzymes reside in the lumen, but are synthesized in the cytosol and imported into the organelle by mobile receptors. The receptors accompany cargo all the way into the lumen and must return to the cytosol to start a new import cycle. Recycling requires receptor monoubiquitination by a membrane-embedded ubiquitin ligase complex composed of three RING finger (RF) domain-containing proteins: PEX2, PEX10, and PEX12. A recent cryo-electron microscopy (cryo-EM) structure of the complex reveals its function as a retro-translocation channel for peroxisomal import receptors. Each subunit of the complex contributes five transmembrane segments that assemble into an open channel. The N terminus of a receptor likely inserts into the pore from the lumenal side, and is then monoubiquitinated by one of the RFs to enable extraction into the cytosol. If recycling is compromised, receptors are polyubiquitinated by the concerted action of the other two RFs and ultimately degraded. The new data provide mechanistic insight into a crucial step of peroxisomal protein import.
Topics: Animals; Humans; Peroxins; Peroxisome-Targeting Signal 1 Receptor; Cryoelectron Microscopy; Membrane Proteins; Receptors, Cytoplasmic and Nuclear; Peroxisomes; Protein Transport; Ubiquitins; Ligases
PubMed: 36421406
DOI: 10.1042/BST20221393