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Oxford Medical Case Reports Jun 2024Pigmentary retinal dystrophy (PRD) is a group of inherited disorders involving the progressive degeneration of rod and cone photoreceptors and the retinal pigment...
Pigmentary retinal dystrophy (PRD) is a group of inherited disorders involving the progressive degeneration of rod and cone photoreceptors and the retinal pigment epithelium (RPE), which can progress to pigmentary retinopathy (PR). We present a case of PRD in a female pediatric patient who has pathogenic variants in the PRPH2 and PEX1 genes. The patient has associated macular edema and secondary visual impairment. Treatment has included serial dexamethasone intravitreal implant injections and topical dorzolamide. The PEX1 gene mutation is associated with peroxisome biogenesis disorder-Zellweger syndrome spectrum (PBD-ZSS) and resulting retinal dystrophies. The PRPH2 mutation may play a role in macular edema and PRD, as it is implicated in macular degeneration, choroid defects, and photoreceptor dysfunction. In this case, we review multiple gene mutations playing potential etiologic roles for PRD and discuss care management.
PubMed: 38860019
DOI: 10.1093/omcr/omae067 -
Frontiers in Neurology 2024[This corrects the article DOI: 10.3389/fneur.2022.1072256.].
[This corrects the article DOI: 10.3389/fneur.2022.1072256.].
PubMed: 38510379
DOI: 10.3389/fneur.2024.1376447 -
Epilepsy & Behavior Reports 2024Zellweger Syndrome is a peroxisomal disorder that can lead to elevation of long chain fatty acids and epilepsy, which can be drug resistant. The treatment of drug...
Zellweger Syndrome is a peroxisomal disorder that can lead to elevation of long chain fatty acids and epilepsy, which can be drug resistant. The treatment of drug resistant epilepsy can include the ketogenic diet in appropriately chosen patients. Typically, the ketogenic diet is contraindicated in individuals with defects in fatty acid metabolism because of the diet's reliance on medium and long chain fatty acids. To our knowledge this is the first publication outlining the use of the ketogenic diet in patients with defects in beta oxidation of very long chain fatty acids. We present two patients with Zellweger Syndrome who were placed on a ketogenic diet for drug resistant epilepsy. Safety and tolerance of the ketogenic diet in patients with Zellweger Syndrome.
PubMed: 38501062
DOI: 10.1016/j.ebr.2024.100655 -
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 -
Cell Communication and Signaling : CCS Feb 2024Calcium is a ubiquitous intracellular messenger that regulates the expression of various genes involved in cell proliferation, differentiation, and motility. The...
BACKGROUND
Calcium is a ubiquitous intracellular messenger that regulates the expression of various genes involved in cell proliferation, differentiation, and motility. The involvement of calcium in diverse metabolic pathways has been suggested. However, the effect of calcium in peroxisomes, which are involved in fatty acid oxidation and scavenges the result reactive oxygen species (ROS), remains elusive. In addition, impaired peroxisomal ROS inhibit the mammalian target of rapamycin complex 1 (mTORC1) and promote autophagy. Under stress, autophagy serves as a protective mechanism to avoid cell death. In response to oxidative stress, lysosomal calcium mediates transcription factor EB (TFEB) activation. However, the impact of calcium on peroxisome function and the mechanisms governing cellular homeostasis to prevent diseases caused by calcium deficiency are currently unknown.
METHODS
To investigate the significance of calcium in peroxisomes and their roles in preserving cellular homeostasis, we established an in-vitro scenario of calcium depletion.
RESULTS
This study demonstrated that calcium deficiency reduces catalase activity, resulting in increased ROS accumulation in peroxisomes. This, in turn, inhibits mTORC1 and induces pexophagy through TFEB activation. However, treatment with the antioxidant N-acetyl-l-cysteine (NAC) and the autophagy inhibitor chloroquine impeded the nuclear translocation of TFEB and attenuated peroxisome degradation.
CONCLUSIONS
Collectively, our study revealed that ROS-mediated TFEB activation triggers pexophagy during calcium deficiency, primarily because of attenuated catalase activity. We posit that calcium plays a significant role in the proper functioning of peroxisomes, critical for fatty-acid oxidation and ROS scavenging in maintaining cellular homeostasis. These findings have important implications for signaling mechanisms in various pathologies, including Zellweger's syndrome and ageing.
Topics: Macroautophagy; Reactive Oxygen Species; Calcium; Catalase; Oxidative Stress; Autophagy; Mechanistic Target of Rapamycin Complex 1
PubMed: 38383392
DOI: 10.1186/s12964-024-01524-x -
Frontiers in Pediatrics 2024Mitchell syndrome is a rare, neurodegenerative disease caused by an ACOX1 gain-of-function mutation (c.710A>G; p.N237S), with fewer than 20 reported cases. Affected...
BACKGROUND
Mitchell syndrome is a rare, neurodegenerative disease caused by an ACOX1 gain-of-function mutation (c.710A>G; p.N237S), with fewer than 20 reported cases. Affected patients present with leukodystrophy, seizures, and hearing loss. ACOX1 serves as the rate-limiting enzyme in peroxisomal beta-oxidation of very long-chain fatty acids. The N237S substitution has been shown to stabilize the active ACOX1 dimer, resulting in dysregulated enzymatic activity, increased oxidative stress, and glial damage. Mitchell syndrome lacks a vertebrate model, limiting insights into the pathophysiology of ACOX1-driven white matter damage and neuroinflammatory insults.
METHODS
We report a patient presenting with rapidly progressive white matter damage and neurological decline, who was eventually diagnosed with an ACOX1 N237S mutation through whole genome sequencing. We developed a zebrafish model of Mitchell syndrome using transient ubiquitous overexpression of the human ACOX1 N237S variant tagged with GFP. We assayed zebrafish behavior, oligodendrocyte numbers, expression of white matter and inflammatory transcripts, and analysis of peroxisome counts.
RESULTS
The patient experienced progressive leukodystrophy and died 2 years after presentation. The transgenic zebrafish showed a decreased swimming ability, which was restored with the reactive microglia-targeted antioxidant dendrimer--acetyl-cysteine conjugate. The mutants showed no effect on oligodendrocyte counts but did display activation of the integrated stress response (ISR). Using a novel SKL-targeted mCherry reporter, we found that mutants had reduced density of peroxisomes.
CONCLUSIONS
We developed a vertebrate (zebrafish) model of Mitchell syndrome using transient ubiquitous overexpression of the human ACOX1 N237S variant. The transgenic mutants exhibited motor impairment and showed signs of activated ISR, but interestingly, there were no changes in oligodendrocyte counts. However, the mutants exhibited a deficiency in the number of peroxisomes, suggesting a possible shared mechanism with the Zellweger spectrum disorders.
PubMed: 38357503
DOI: 10.3389/fped.2024.1326886 -
Cell Reports Feb 2024Peroxisome biogenesis disorders (PBDs) represent a group of metabolic conditions that cause severe developmental defects. Peroxisomes are essential metabolic organelles,...
Peroxisome biogenesis disorders (PBDs) represent a group of metabolic conditions that cause severe developmental defects. Peroxisomes are essential metabolic organelles, present in virtually every eukaryotic cell and mediating key processes in immunometabolism. To date, the full spectrum of PBDs remains to be identified, and the impact PBDs have on immune function is unexplored. This study presents a characterization of the hepatic immune compartment of a neonatal PBD mouse model at single-cell resolution to establish the importance and function of peroxisomes in developmental hematopoiesis. We report that hematopoietic defects are a feature in a severe PBD murine model. Finally, we identify a role for peroxisomes in the regulation of the major histocompatibility class II expression and antigen presentation to CD4 T cells in dendritic cells. This study adds to our understanding of the mechanisms of PBDs and expands our knowledge of the role of peroxisomes in immunometabolism.
Topics: Animals; Mice; Zellweger Syndrome; Peroxisomes; Antigen Presentation; Peroxisomal Disorders
PubMed: 38329874
DOI: 10.1016/j.celrep.2024.113744 -
Translational Pediatrics Jan 2024The protein PEX26 is involved in the biogenesis and maintenance of peroxisomes, which are organelles within cells. Dysfunction of PEX26 results in peroxisome biogenesis...
BACKGROUND
The protein PEX26 is involved in the biogenesis and maintenance of peroxisomes, which are organelles within cells. Dysfunction of PEX26 results in peroxisome biogenesis disorders (PBDs) complementation group 8 (CG8), leading to Zellweger spectrum disorders (ZSDs). These disorders present as a syndrome with multiple congenital anomalies, varying in clinical severity.
CASE DESCRIPTION
We present the case of a 7-month-old boy who exhibited hepatic impairment with hepatomegaly, sensorineural hearing loss, developmental delay, abnormal ossification, and mild craniofacial dysmorphology. Tandem mass spectrometry analysis of plasma isolated from whole blood revealed a significant increase in the levels of very long chain fatty acids (VLCFAs) C26:0, C26:0/C22:0, and C24:0/C22:0, consistent with peroxisomal fatty acid oxidation disorder. Exome sequencing identified two variants in the gene (c.347T>C and c.616C>T), with the latter being a suspected pathogenic variation. The variant can lead to a defect in the gene, resulting in impaired peroxisome biogenesis, β-oxidation of VLCFAs, and disruption of other biochemical pathways. Ultimately, this cascade of events manifests as ZSDs. Currently, symptomatic supportive treatment is the main approach for managing this condition and regular follow-up is being conducted for the patient.
CONCLUSIONS
The present study introduces a novel heterozygous variant comprising two previously unidentified variants in the gene, thereby expanding the range of known genetic alterations and highlighting the effectiveness of highly efficient exome sequencing in patients with undetermined multiple system dysfunctions.
PubMed: 38323187
DOI: 10.21037/tp-23-454 -
Journal of Lipid Research Mar 2024The gold-standard diagnostic test for peroxisomal disorders (PDs) is plasma concentration analysis of very long-chain fatty acids (VLCFAs). However, this method's...
The gold-standard diagnostic test for peroxisomal disorders (PDs) is plasma concentration analysis of very long-chain fatty acids (VLCFAs). However, this method's time-consuming nature and limitations in cases which present normal VLCFA levels necessitates alternative approaches. The analysis of C26:0-lysophosphatydylcholine (C26:0-LPC) in dried blood spot samples by tandem-mass spectrometry (MS/MS) has successfully been implemented in certain newborn screening programs to diagnose X-linked adrenoleukodystrophy (ALD). However, the diagnostic potential of very long-chain LPCs concentrations in plasma remains poorly understood. This study sought to evaluate the diagnostic performance of C26:0-LPC and other very long-chain LPCs, comparing them to VLCFA analysis in plasma. The study, which included 330 individuals affected by a peroxisomal β-oxidation deficiency and 407 control individuals, revealed that C26:0- and C24:0-LPC concentrations demonstrated the highest diagnostic accuracy (98.8% and 98.4%, respectively), outperforming VLCFA when C26:0/C22:0 and C24:0/C22:0 ratios were combined (98.1%). Combining C24:0- and C26:0-LPC gave the highest sensitivity (99.7%), with ALD females exhibiting notably higher sensitivity compared with the VLCFA ratio combination (98.7% vs. 93.5%, respectively). In contrast, C22:0-LPC exhibited suboptimal performance, primarily due to its low sensitivity (75%), but we identified a potential use to help distinguish between ALD and Zellweger spectrum disorders. In summary, MS/MS analysis of plasma C24:0- and C26:0-LPC concentrations represents a rapid and straightforward approach to diagnose PDs, demonstrating superior diagnostic accuracy, particularly in ALD females, compared with conventional VLCFA biomarkers. We strongly recommend integrating very-long chain LPC plasma analysis in the diagnostic evaluation of individuals suspected of having a PD.
Topics: Infant, Newborn; Female; Humans; Lysophosphatidylcholines; Tandem Mass Spectrometry; Adrenoleukodystrophy; Neonatal Screening; Biomarkers; Fatty Acids, Nonesterified; Fatty Acids
PubMed: 38320654
DOI: 10.1016/j.jlr.2024.100516