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Investigative Ophthalmology & Visual... Feb 2024To investigate the molecular effect of the variant PHYH:c.678+5G>T. This variant has conflicting interpretations in the ClinVar database and a maximum allele frequency...
PURPOSE
To investigate the molecular effect of the variant PHYH:c.678+5G>T. This variant has conflicting interpretations in the ClinVar database and a maximum allele frequency of 0.0045 in the South Asian population in gnomAD.
METHODS
We recruited patients from Moorfields Eye Hospital (London, UK) and Buenos Aires, Argentina, who were diagnosed with retinitis pigmentosa and found to have biallelic variants in PHYH, with at least one being c.678+5G>T. Total RNA was purified from PaxGene RNA-stabilized whole-blood samples, followed by reverse transcription to cDNA, PCR amplification of the canonical PHYH transcript, Oxford Nanopore Technologies library preparation, and single-molecule amplicon sequencing.
RESULTS
Four patients provided a blood sample. One patient had isolated retinitis pigmentosa and three had mild extraocular findings. Blood phytanic acid levels were normal in two patients, mildly elevated in one, and markedly high in the fourth. Retinal evaluation showed an intact ellipsoid zone as well as preserved autofluorescence in the macular region in three of the four patients. In all patients, we observed in-frame skipping of exons 5 and 6 in 31.1% to 88.4% of the amplicons and a smaller proportion (0% to 11.3% of amplicons) skipping exon 6 only.
CONCLUSIONS
We demonstrate a significant effect of PHYH:c.678+5G>T on splicing of the canonical transcript. The in-frame nature of this may be in keeping with a mild presentation and higher prevalence in the general population. These data support the classification of the variant as pathogenic, and patients harboring a biallelic genotype should undergo phytanic acid testing.
Topics: Humans; Refsum Disease; Phytanic Acid; Retinitis Pigmentosa; Exons; RNA; Mixed Function Oxygenases
PubMed: 38411969
DOI: 10.1167/iovs.65.2.38 -
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 -
Analytica Chimica Acta Apr 2024Correct identification and quantification of different sterol biomarkers can be used as a first-line diagnostic approach for inherited metabolic disorders (IMD). The...
Correct identification and quantification of different sterol biomarkers can be used as a first-line diagnostic approach for inherited metabolic disorders (IMD). The main drawbacks of current methodologies are related to lack of selectivity and sensitivity for some of these compounds. To address this, we developed and validated two sensitive and selective assays for quantification of six cholesterol biosynthesis pathway intermediates (total amount (free and esterified form) of 7-dehydrocholesterol (7-DHC), 8-dehydrocholesterol (8-DHC), desmosterol, lathosterol, lanosterol and cholestanol), two phytosterols (total amount (free and esterified form) of campesterol and sitosterol) and free form of two oxysterols (7-ketocholesterol (7-KC) and 3β,5α,6β-cholestane-triol (C-triol). For quantification of four cholesterol intermediates we based our analytical approach on sterol derivatization with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD). Quantification of all analytes is performed using UPLC coupled to an Orbitrap high resolution mass spectrometry (HRMS) system, with detection of target ions through full scan acquisition using positive atmospheric pressure chemical ionization (APCI) mode. UPLC and MS parameters were optimized to achieve high sensitivity and selectivity. Analog stable isotope labeled for each compound was used for proper quantification and correction for recovery, matrix effects and process efficiency. Precision (2.4%-12.3% inter-assay variation), lower limit of quantification (0.027 nM-50.5 nM) and linearity (5.5 μM (R 0.999) - 72.3 μM (R 0.997)) for phyto- and oxysterols were determined. The diagnostic potential of these two assays in a cohort of patients (n = 31, 50 samples) diagnosed with IMD affecting cholesterol and lysosomal/peroxisomal homeostasis is demonstrated.
Topics: Humans; Sterols; Chromatography, High Pressure Liquid; Mass Spectrometry; Phytosterols; Oxysterols
PubMed: 38401937
DOI: 10.1016/j.aca.2024.342347 -
Medical Sciences (Basel, Switzerland) Jan 2024Leukodystrophies, a group of rare demyelinating disorders, mainly affect the CNS. Clinical presentation of different types of leukodystrophies can be nonspecific, and... (Review)
Review
Leukodystrophies, a group of rare demyelinating disorders, mainly affect the CNS. Clinical presentation of different types of leukodystrophies can be nonspecific, and thus, imaging techniques like MRI can be used for a more definitive diagnosis. These diseases are characterized as cerebral lesions with characteristic demyelinating patterns which can be used as differentiating tools. In this review, we talk about these MRI study findings for each leukodystrophy, associated genetics, blood work that can help in differentiation, emerging diagnostics, and a follow-up imaging strategy. The leukodystrophies discussed in this paper include X-linked adrenoleukodystrophy, metachromatic leukodystrophy, Krabbe's disease, Pelizaeus-Merzbacher disease, Alexander's disease, Canavan disease, and Aicardi-Goutières Syndrome.
Topics: Humans; Leukodystrophy, Metachromatic; Leukodystrophy, Globoid Cell; Adrenoleukodystrophy; Neurodegenerative Diseases; Pelizaeus-Merzbacher Disease
PubMed: 38390857
DOI: 10.3390/medsci12010007 -
Cureus Jan 2024Adrenoleukodystrophy, a rare genetic disease associated with the X chromosome (X-ALD - X-linked adrenoleukodystrophy), predominantly affects males and stems from...
Adrenoleukodystrophy, a rare genetic disease associated with the X chromosome (X-ALD - X-linked adrenoleukodystrophy), predominantly affects males and stems from mutations in the gene, responsible for transporting very long chain fatty acids (VLCFA) into peroxisomes. It leads to adrenal insufficiency (AI) and axonal demyelination. In males, the phenotype varies from isolated adrenocortical insufficiency and progressive myelopathy to cerebral adrenoleukodystrophy (CALD). The aim of this case series is to characterize patients with different clinical presentations of X-ALD with follow-up at a tertiary Portuguese hospital. All four patients were males, and the median age at the diagnosis was 5 years. Three patients were diagnosed through family screening, with the oldest already displaying hyperpigmentation. Two distinct forms were identified: adolescent CALD (25%) and isolated primary adrenal insufficiency (75%). Analytical studies revealed elevated plasma VLCFA levels in all cases, and genetic analysis demonstrated two different mutations in the gene. This disorder requires early diagnosis for improved prognosis. Screening male children with primary AIfor X-ALD using a VLCFA panel should be considered, particularly after ruling out the most common causes or when learning difficulties are evident. Genetic confirmation of the diagnosis is essential, enabling genetic counseling, family planning, and preimplantation genetic diagnosis.
PubMed: 38370996
DOI: 10.7759/cureus.52496 -
Pharmacological Research Mar 2024Chronic interstitial fibrosis presents a significant challenge to the long-term survival of transplanted kidneys. Our research has shown that reduced expression of...
Chronic interstitial fibrosis presents a significant challenge to the long-term survival of transplanted kidneys. Our research has shown that reduced expression of acyl-coenzyme A oxidase 1 (ACOX1), which is the rate-limiting enzyme in the peroxisomal fatty acid β-oxidation pathway, contributes to the development of fibrosis in renal allografts. ACOX1 deficiency leads to lipid accumulation and excessive oxidation of polyunsaturated fatty acids (PUFAs), which mediate epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) reorganization respectively, thus causing fibrosis in renal allografts. Furthermore, activation of Toll-like receptor 4 (TLR4)-nuclear factor kappa-B (NF-κB) signaling induced ACOX1 downregulation in a DNA methyltransferase 1 (DNMT1)-dependent manner. Overconsumption of PUFA resulted in endoplasmic reticulum (ER) stress, which played a vital role in facilitating ECM reorganization. Supplementation with PUFAs contributed to delayed fibrosis in a rat model of renal transplantation. The study provides a novel therapeutic approach that can delay chronic interstitial fibrosis in renal allografts by targeting the disorder of lipid metabolism.
Topics: Animals; Rats; Acyl-CoA Oxidase; Allografts; Fibrosis; Kidney; Kidney Transplantation; Lipids; Metabolic Diseases
PubMed: 38367917
DOI: 10.1016/j.phrs.2024.107105 -
Biology Direct Feb 2024Peroxisomes are primarily studied in the brain, kidney, and liver due to the conspicuous tissue-specific pathology of peroxisomal biogenesis disorders. In contrast,... (Meta-Analysis)
Meta-Analysis
Peroxisomes are primarily studied in the brain, kidney, and liver due to the conspicuous tissue-specific pathology of peroxisomal biogenesis disorders. In contrast, little is known about the role of peroxisomes in other tissues such as the heart. In this meta-analysis, we explore mitochondrial and peroxisomal gene expression on RNA and protein levels in the brain, heart, kidney, and liver, focusing on lipid metabolism. Further, we evaluate a potential developmental and heart region-dependent specificity of our gene set. We find marginal expression of the enzymes for peroxisomal fatty acid oxidation in cardiac tissue in comparison to the liver or cardiac mitochondrial β-oxidation. However, the expression of peroxisome biogenesis proteins in the heart is similar to other tissues despite low levels of peroxisomal fatty acid oxidation. Strikingly, peroxisomal targeting signal type 2-containing factors and plasmalogen biosynthesis appear to play a fundamental role in explaining the essential protective and supporting functions of cardiac peroxisomes.
Topics: Humans; Peroxisomes; Fatty Acids; Peroxisomal Disorders; Mitochondria; Oxidation-Reduction
PubMed: 38365851
DOI: 10.1186/s13062-024-00458-1 -
RMD Open Feb 2024Interim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens...
OBJECTIVE
Interim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens and effectiveness of canakinumab in patients with cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumour-necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate-kinase deficiency (MKD)/hyperimmunoglobulin-D syndrome (HIDS).
METHODS
From September 2017 for patients with CAPS, and June 2018 for patients with FMF, TRAPS or MKD/HIDS, the registry enrolled paediatric (aged ≥2 years) and adult patients (aged ≥18 years) receiving canakinumab as part of their routine medical care. Safety, canakinumab dose, disease activity and quality of life outcome measures were evaluated at baseline and every 6 months until end of study visit.
RESULTS
At the analysis cut-off date (December 2020), 168 patients (91 CAPS, 54 FMF, 16 TRAPS and 7 MKD/HIDS) were enrolled. 85 (50.9%) patients were female and 72 (43.1%) were children (<18 years). The median patient age was 20.0 years (range 2.0-79.0 years). In the CAPS cohort, serious infections and serious adverse drug-reactions were more common in patients receiving higher than the recommended starting dose (SD) of canakinumab. A trend to receive >SD of canakinumab was observed in the pooled population. The majority of patients were reported as having either absent or mild/moderate disease activity (physician's global assessment) from baseline to Month 30, with a stable proportion of patients (~70%) in remission under canakinumab treatment. Patient-reported disease activity (Visual Analogue Scale (VAS), Autoinflammatory Disease Activity Index), fatigue (VAS); markers of inflammation (C-reactive protein, serum amyloid A and erythrocyte sedimentation rate) remained well-controlled throughout.
CONCLUSION
Data from this analysis confirm the long-term safety and effectiveness of canakinumab for the treatment of CAPS, FMF, TRAPS and MKD/HIDS.
Topics: Adult; Humans; Child; Female; Adolescent; Male; Prospective Studies; Quality of Life; Familial Mediterranean Fever; Cryopyrin-Associated Periodic Syndromes; Mevalonate Kinase Deficiency; Registries; Antibodies, Monoclonal, Humanized
PubMed: 38360038
DOI: 10.1136/rmdopen-2023-003890 -
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