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Introduction: Fabry disease (FD) is a rare lysosomal type 3 disorder with an X‐linked inheritance pattern caused by pathogenic variants in the GLA gene. This study aimed to describe the genotype and phenotype of 52 Mexican patients with FD. Methods: We included 12 patients with clinical and molecular diagnosis of FD treated at our institution and 40 FD Mexican patients already reported in the literature. Results: The most frequent manifestations were acroparesthesias (71.2%), hypohidrosis or anhidrosis (48.1%), heat intolerance (46.2%), and proteinuria (42.3%). Renal and neurological manifestations were more prevalent in males than females. Cardiac involvement included hypertrophic cardiomyopathy and Wolf–Parkinson–White arrhythmia. Cornea verticillata was seen in 14 patients (26.9%) and angiokeratomas in 15 (28.8%). We identified 14 variants in the GLA gene in Mexican patients with FD. We found a novel variant GLA c.122C>G that causes an atypical FD phenotype with predominantly neurological involvement in two unrelated patients, one of them with a forthright clinical and radiological overlap of Multiple Sclerosis and normal biological biomarkers, thus requiring a renal biopsy that helped confirm the diagnosis of FD. Conclusions: The genotype and phenotype of Mexican patients with FD are similar to other populations. Atypical phenotype of FD, such as the one associated with the novel variant c.122C>G, can be a diagnostic challenge, as it can be mixed up with MS. Our findings confirm the limitations of noninvasive diagnostic methods and the necessity of the renal biopsy when the clinical suspicion of FD is high. [ABSTRACT FROM AUTHOR]

Background: The clinical diagnosis of Fabry Disease (FD) can be challenging due to the clinical heterogeneity, especially in females. Patients with FD often experience a prolonged interval between the onset of symptoms and receiving a diagnosis. Genetic testing is the gold standard for precise diagnosis of FD, however conventional genetic testing could miss deep intronic variants and large deletions or duplications. Although next-generation sequencing, which analyzes numerous genes, has been successfully used for FD diagnosis and can detect complex variants, an effective and rapid tool for identifying a wide range of variants is imminent, contributing to decrease the diagnostic delay. Methods: The comprehensive Analysis of FD (CAFD) assay was developed for FD genetic diagnosis, employing long-range PCR coupled with long-read sequencing to target the full-length GLA gene and its flanking regions. Its clinical performance was assessed through a comparative analysis with Sanger sequencing. Results: Genetic testing was performed on 82 individuals, including 48 probands and 34 relatives. The CAFD assay additionally identified variants in two probands: one had a novel and de novo pathogenic variant with a 1715 bp insertion in intron 4, and the other carried two deep intronic VUS variants in cis-configuration also in intron 4. In total, CAFD identified 47 different variants among 48 probands. Of these, 42 (89.36%, 42/47) were pathogenic, while 5 (10.64%, 5/47) were VUS. Sixteen (34.04%, 16/47) of the variants were novel, including 15 SNV/Indels and one large intronic insertion. Pedigree analysis of 21 probands identified four de novo disease-causing variants. Hence, FD exhibits not only variable clinical presentations but also a wide spectrum of variants. Utilizing a comprehensive testing algorithm for diagnosing FD, which includes enzyme activity, clinical features, and genetic testing, the diagnostic yield of CAFD is 97.92% (47/48), which is higher than that of conventional Sanger sequencing, at 95.83% (46/48). Conclusion: The duration between initial clinical presentation and diagnosis remains long and winding. CAFD provides precise diagnosis for a wide spectrum of GLA variants, promoting timely diagnosis and appropriate treatment for FD patients. [ABSTRACT FROM AUTHOR]

Abstract Background The clinical diagnosis of Fabry Disease (FD) can be challenging due to the clinical heterogeneity, especially in females. Patients with FD often experience a prolonged interval between the onset of symptoms and receiving a diagnosis. Genetic testing is the gold standard for precise diagnosis of FD, however conventional genetic testing could miss deep intronic variants and large deletions or duplications. Although next-generation sequencing, which analyzes numerous genes, has been successfully used for FD diagnosis and can detect complex variants, an effective and rapid tool for identifying a wide range of variants is imminent, contributing to decrease the diagnostic delay. Methods The comprehensive Analysis of FD (CAFD) assay was developed for FD genetic diagnosis, employing long-range PCR coupled with long-read sequencing to target the full-length GLA gene and its flanking regions. Its clinical performance was assessed through a comparative analysis with Sanger sequencing. Results Genetic testing was performed on 82 individuals, including 48 probands and 34 relatives. The CAFD assay additionally identified variants in two probands: one had a novel and de novo pathogenic variant with a 1715 bp insertion in intron 4, and the other carried two deep intronic VUS variants in cis-configuration also in intron 4. In total, CAFD identified 47 different variants among 48 probands. Of these, 42 (89.36%, 42/47) were pathogenic, while 5 (10.64%, 5/47) were VUS. Sixteen (34.04%, 16/47) of the variants were novel, including 15 SNV/Indels and one large intronic insertion. Pedigree analysis of 21 probands identified four de novo disease-causing variants. Hence, FD exhibits not only variable clinical presentations but also a wide spectrum of variants. Utilizing a comprehensive testing algorithm for diagnosing FD, which includes enzyme activity, clinical features, and genetic testing, the diagnostic yield of CAFD is 97.92% (47/48), which is higher than that of conventional Sanger sequencing, at 95.83% (46/48). Conclusion The duration between initial clinical presentation and diagnosis remains long and winding. CAFD provides precise diagnosis for a wide spectrum of GLA variants, promoting timely diagnosis and appropriate treatment for FD patients.

ABSTRACT Introduction Fabry disease (FD) is a rare lysosomal type 3 disorder with an X‐linked inheritance pattern caused by pathogenic variants in the GLA gene. This study aimed to describe the genotype and phenotype of 52 Mexican patients with FD. Methods We included 12 patients with clinical and molecular diagnosis of FD treated at our institution and 40 FD Mexican patients already reported in the literature. Results The most frequent manifestations were acroparesthesias (71.2%), hypohidrosis or anhidrosis (48.1%), heat intolerance (46.2%), and proteinuria (42.3%). Renal and neurological manifestations were more prevalent in males than females. Cardiac involvement included hypertrophic cardiomyopathy and Wolf–Parkinson–White arrhythmia. Cornea verticillata was seen in 14 patients (26.9%) and angiokeratomas in 15 (28.8%). We identified 14 variants in the GLA gene in Mexican patients with FD. We found a novel variant GLA c.122C>G that causes an atypical FD phenotype with predominantly neurological involvement in two unrelated patients, one of them with a forthright clinical and radiological overlap of Multiple Sclerosis and normal biological biomarkers, thus requiring a renal biopsy that helped confirm the diagnosis of FD. Conclusions The genotype and phenotype of Mexican patients with FD are similar to other populations. Atypical phenotype of FD, such as the one associated with the novel variant c.122C>G, can be a diagnostic challenge, as it can be mixed up with MS. Our findings confirm the limitations of noninvasive diagnostic methods and the necessity of the renal biopsy when the clinical suspicion of FD is high.

Introduction and objective: Fabry disease (FD) is a rare lysosomal storage disorder that can manifest in classical and atypical forms, with the latter being more common. It results from deficient alpha-galactosidase activity, leading to the accumulation of globotriaosylceramide (Gb3), causing inflammation, cellular damage, and mitochondrial dysfunction. The aim of this publication is to discuss various aspects of Fabry disease based on the latest literature. Review Methods: The PubMed database was searched for scientific articles where the terms "Fabry disease" or "FD" appear in the title, abstract, or keywords. The focus was on articles published between 2017 and 2024, although in some cases, older sources were consulted when more recent data was lacking. Brief Description of the State of Knowledge: The Fabry disease occurs with a frequency between 1:40,000 and 1:117,000 live male births. Symptoms include proteinuria, kidney failure, hypertrophic cardiomyopathy, valve defects, peripheral neuropathy, and gastrointestinal issues. The disease affects life expectancy, primarily due to cardiovascular complications. Early diagnosis is often delayed due to non-specific symptoms, and prognosis tends to be worse in males. Current treatments include enzyme replacement therapy (ERT), chaperone therapy with migalastat, and second-generation ERT. Summary: Given the rarity of Fabry disease, research is limited, and there is a need for more studies to explore novel therapeutic options that could improve patient quality of life and mitigate the disease's complications.

Here, we report the identification and functional characterization of a novel GLA variant, not detectable by routine molecular tests, in a family with FD suspicion. [ABSTRACT FROM AUTHOR]

Molecular diagnosis has undergone rapid and significant advancements in recent years. But because molecular diagnosis can be conducted independently of phenotype, it can engender ambiguity and potential misinterpretations in disease diagnosis. Fabry disease, an X-linked lysosomal storage disorder, arises from a deficiency in α-galactosidase A. In 2002, Ishii and colleagues uncovered a variant (IVS4+919G > A) deep within intron 4 of the GLA gene that could lead to aberrant splicing of the GLA mRNA. This variant is present in 1:875 males in Taiwan, and many patients with hypertrophic cardiomyopathy and the IVS4+919G > A variant are currently treated by enzyme replacement therapy, an expensive treatment. Unfortunately, till now only one article published in 2013 described the outcome of treatment. This review summarized the conflicting evidence about the clinical relevance of the IVS4+919G > A variant, and suggest a multifactorial model, rather than a monogenic model, for the involvement of the IVS4+919G > A variant in hypertrophic cardiomyopathy. The diagnostic dilemma for this Taiwanese cardiac variant in Fabry disease clearly emphasizes the need for precise interpretation and application of molecular diagnostic results.

Molecular diagnosis has undergone rapid and significant advancements in recent years. But because molecular diagnosis can be conducted independently of phenotype, it can engender ambiguity and potential misinterpretations in disease diagnosis. Fabry disease, an X-linked lysosomal storage disorder, arises from a deficiency in α-galactosidase A. In 2002, Ishii and colleagues uncovered a variant (IVS4+919G > A) deep within intron 4 of the GLA gene that could lead to aberrant splicing of the GLA mRNA. This variant is present in 1:875 males in Taiwan, and many patients with hypertrophic cardiomyopathy and the IVS4+919G > A variant are currently treated by enzyme replacement therapy, an expensive treatment. Unfortunately, till now only one article published in 2013 described the outcome of treatment. This review summarized the conflicting evidence about the clinical relevance of the IVS4+919G > A variant, and suggest a multifactorial model, rather than a monogenic model, for the involvement of the IVS4+919G > A variant in hypertrophic cardiomyopathy. The diagnostic dilemma for this Taiwanese cardiac variant in Fabry disease clearly emphasizes the need for precise interpretation and application of molecular diagnostic results. [ABSTRACT FROM AUTHOR]

Background: The detailed clinical phenotype of patients carrying the α-galactosidase gene (GLA) c.548 G > A/p.Gly183Asp (p.G183D) variant in Fabry disease (FD) has not been thoroughly documented in the existing literature. Methods: This paper offers a meticulous overview of the clinical phenotype and relevant auxiliary examination results of nine confirmed FD patients with the p.G183D gene variant from two families. Pedigree analysis was conducted on two male patients with the gene variant, followed by biochemical and genetic screening of all high-risk relatives. Subsequently, evaluation of multiple organ systems and comprehensive instrument assessment were performed on heterozygotes of the p.G183D gene variant. Results: The study revealed that all patients exhibited varying degrees of cardiac involvement, with two demonstrating left ventricular wall thickness exceeding 15 mm on echocardiography, and the remaining six exceeding 11 mm. Impaired renal function was evident in all six patients with available blood test data, two of whom underwent kidney transplantation. Eight cases reported neuropathic pain, and five experienced varying degrees of stroke or transient ischemic attack (TIA). Conclusion: This study indicates that the GLA p.G183D gene variant can induce premature organ damage, particularly affecting the heart, kidneys, and nervous system.

Fabry disease (FD) is an X-linked recessive inheritance lysosomal storage disorder caused by pathogenic mutations in the GLA gene leading to a deficiency of the enzyme alpha-galactosidase A (α-Gal A). Multiple organ systems are implicated in FD, most notably the kidney, heart, and central nervous system. In our previous study, we identified four GLA mutations from four independent Fabry disease families with kidney disease or neuropathic pain: c.119C>A (p.P40H), c.280T>C (C94R), c.680G>C (p.R227P) and c.801+1G>A (p.L268fsX3). To reveal the molecular mechanism underlying the predisposition to Fabry disease caused by GLA mutations, we analyzed the effects of these four GLA mutations on the protein structure of α-galactosidase A using bioinformatics methods. The results showed that these mutations have a significant impact on the internal dynamics and structures of GLA, and all these altered amino acids are close to the enzyme activity center and lead to significantly reduced enzyme activity. Furthermore, these mutations led to the accumulation of autophagosomes and impairment of autophagy in the cells, which may in turn negatively regulate autophagy by slightly increasing the phosphorylation of mTOR. Moreover, the overexpression of these GLA mutants promoted the expression of lysosome-associated membrane protein 2 (LAMP2), resulting in an increased number of lysosomes. Our study reveals the pathogenesis of these four GLA mutations in FD and provides a scientific foundation for accurate diagnosis and precise medical intervention for FD. [ABSTRACT FROM AUTHOR]

Anderson–Fabry disease (AFD) results from decreased enzyme activity of lysosomal enzymes and intralysosomal storage of nonhydrolyzed forms. Cardiovascular complications, mainly in the form of HCM, contribute substantially to AFD patient mortality. Here, we report three new cases of obstructive HCM (HOCM) in nonclassical presentations of AFD and isolated cardiac involvement. In all three cases, the diagnosis of AFD was made postoperatively by routine genetic and morphological testing. Together with previously published cases, this report illustrates the potential safety and beneficial effect of septal surgical myectomy in patients with AFD-HOCM, as well as underlines the need for more thorough screening for clinical signs of AFD-associated cardiomyopathy and GLA variants among patients with HOCM.

Background: Fabry disease (FD) is a rare hereditary multisystem disease caused by variants of the GLA gene. Determination of GLA gene variants and identification of genotype–phenotype correlations allow us to explain the features of FD associated with predominant damage of one or another system, both in the classical and atypical forms of FD, as well as in cases with late manifestation and involvement of one of the systems. Methods: The study included 293 Russian patients with pathogenic variants of the GLA gene, which were identified as a result of various selective screening programs. Screening was carried out for 48,428 high-risk patients using a two-step diagnostic algorithm, including the determination of the concentration of the biomarker lyso-Gb3 as a first-tier test. Screening of atypical FD among patients with HCM was carried out via high-throughput sequencing in another 2427 patients. Results: 102 (0.20%) cases of FD were identified among unrelated patients as a result of the study of 50,855 patients. Molecular genetic testing allowed us to reveal the spectrum and frequencies of 104 different pathogenic variants of the GLA gene in 293 examined patients from 133 families. The spectrum and frequencies of clinical manifestations in patients with FD, including 20 pediatric patients, were described. Correlations between the concentration of the lyso-Gb3 biomarker and the type of pathogenic variants of the GLA gene have been established. Variants identified in patients with early stroke were described, and the association of certain variants with the development of stroke was established. Conclusions: The results of a large-scale selective FD screening, as well as clinical and molecular genetic features, in a cohort of 293 Russian patients with FD are described. [ABSTRACT FROM AUTHOR]

Bone biomineralization is a complex process in which type I collagen and associated non-collagenous proteins (NCPs), including glycoproteins and proteoglycans, interact closely with inorganic calcium and phosphate ions to control the precipitation of nanosized, non-stoichiometric hydroxyapatite (HAP, idealized stoichiometry Ca10(PO4)6(OH)2) within the organic matrix of a tissue. The ability of certain vertebrate tissues to mineralize is critically related to several aspects of their function. The goal of this study was to identify specific NCPs in mineralizing and non-mineralizing tissues of two animal models, rat and turkey, and to determine whether some NCPs are unique to each type of tissue. The tissues investigated were rat femur (mineralizing) and tail tendon (non-mineralizing) and turkey leg tendon (having both mineralizing and non-mineralizing regions in the same individual specimen). An experimental approach ex vivo was designed for this investigation by combining sequential protein extraction with comprehensive protein mapping using proteomics and Western blotting. The extraction method enabled separation of various NCPs based on their association with either the extracellular organic collagenous matrix phases or the inorganic mineral phases of the tissues. The proteomics work generated a complete picture of NCPs in different tissues and animal species. Subsequently, Western blotting provided validation for some of the proteomics findings. The survey then yielded generalized results relevant to various protein families, rather than only individual NCPs. This study focused primarily on the NCPs belonging to the small leucine-rich proteoglycan (SLRP) family and the small integrin-binding ligand N-linked glycoproteins (SIBLINGs). SLRPs were found to be associated only with the collagenous matrix, a result suggesting that they are mainly involved in structural matrix organization and not in mineralization. SIBLINGs as well as matrix Gla (γ-carboxyglutamate) protein were strictly localized within the inorganic mineral phase of mineralizing tissues, a finding suggesting that their roles are limited to mineralization. The results from this study indicated that osteocalcin was closely involved in mineralization but did not preclude possible additional roles as a hormone. This report provides for the first time a spatial survey and comparison of NCPs from mineralizing and non-mineralizing tissues ex vivo and defines the proteome of turkey leg tendons as a model for vertebrate mineralization.

The link between gut and lung starts as early as during organogenesis. Even though they are anatomically distinct, essential bidirectional crosstalk via complex mechanisms supports GLA. Emerging studies have demonstrated the association of gut and lung diseases via multifaceted mechanisms. Advancements in omics and metagenomics technologies revealed a potential link between gut and lung microbiota, adding further complexity to GLA. Despite substantial studies on GLA in various disease models, mechanisms beyond microbial dysbiosis regulating the interplay between gut and lung tissues during disease conditions are not thoroughly reviewed. This review outlines disease specific GLA mechanisms, emphasizing research gaps with a focus on gut-to-lung direction based on current GLA literature. Moreover, the review discusses potential gut microbiota and their products like metabolites, immune modulators, and non-bacterial contributions as a basis for developing treatment strategies for lung diseases. Advanced experimental methods, modern diagnostic tools, and technological advancements are also highlighted as crucial areas for improvement in developing novel therapeutic approaches for GLA-related diseases. In conclusion, this review underscores the importance of exploring additional mechanisms within the GLA to gain a deeper understanding that could aid in preventing and treating a wide spectrum of lung diseases.

Background: Fabry disease is an X-linked lysosomal storage disorder caused by insufficient α-galactosidase A (GLA) activity resulting from variants in the GLA gene, which leads to glycosphingolipid accumulation and life-threatening, multi-organ complications. Approximately 50 variants have been reported that cause splicing abnormalities in GLA. Most were found within canonical splice sites, which are highly conserved GT and AG splice acceptor and donor dinucleotides, whereas one-third were located outside canonical splice sites, making it difficult to interpret their pathogenicity. In this study, we aimed to investigate the genetic pathogenicity of variants located in non-canonical splice sites within the GLA gene. Methods: 13 variants, including four deep intronic variants, were selected from the Human Gene Variant Database Professional. We performed an in vitro splicing assay to identify splicing abnormalities in the variants. Results: All candidate non-canonical splice site variants in GLA caused aberrant splicing. Additionally, all but one variant was protein-truncating. The four deep intronic variants generated abnormal transcripts, including a cryptic exon, as well as normal transcripts, with the proportion of each differing in a cell-specific manner. Conclusions: Validation of splicing effects using an in vitro splicing assay is useful for confirming pathogenicity and determining associations with clinical phenotypes. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate whether CRISPR/Cas9-mediated suppression of A4GALT could rescue phenotype of Fabry disease nephropathy (FDN) using human induced pluripotent stem cells (hiPSCs) derived kidney organoid system. We generated FDN patient-derived hiPSC (CMC-Fb-002) and FD-specific hiPSCs (GLA -KO) by knock-out (KO) of GLA in wild-type (WT) hiPSCs using CRISPR/Cas9. We then performed A4GALT KO in both CMC-Fb-002 and GLA -KO to make Fb-002- A4GALT -KO and GLA/A4GALT -KO, respectively. Using these hiPSCs, we generated kidney organoids and compared alpha-galactosidase-A enzyme (α-GalA) activity, globotriaosylceramide (Gb-3) deposition, and zebra body formation under electron microscopy (EM). We also compared mRNA expression levels using RNA-seq and qPCR. Generated hiPSCs showed typical pluripotency markers without chromosomal disruption. Expression levels of GLA in CMC-Fb-002 and GLA-KO and expression levels of A4GALT in Fb-002- A4GALT -KO and GLA/A4GALT -KO were successfully decreased compared to those in WT-hiPSCs, respectively. Generated kidney organoids using these hiPSCs expressed typical nephron markers. In CMC-Fb-002 and GLA -KO organoids, α-GalA activity was significantly decreased along with increased deposition of Gb-3 in comparison with WT organoids. Intralysosomal inclusion body was also detected under EM. However, these disease phenotypes were rescued by KO of A4GALT in both GLA/A4GALT -KO and Fb-002- A4GALT -KO kidney organoids. RNA-seq showed increased expression levels of genes related to FDN progression in both GLA -mutant organoids compared to those in WT. Such increases were rescued in GLA/A4GALT -KO or Fb-002- A4GALT -KO organoids. CRISPR/Cas9 mediated suppression of A4GALT could rescue FDN phenotype. Hence, it can be proposed as a therapeutic approach to treat FDN. [ABSTRACT FROM AUTHOR]

From 2020 onwards, several specimens of the Neotropical fungus gnat Sciophila fractinervis (Edwards, 1940) have been intercepted by Fera Science Ltd. on or near plant material in the United Kingdom originating from nurseries and glasshouses at four separate locations: Preston, Lancashire; Chichester, West Sussex; East Riding of Yorkshire; and Middlesbrough, North Yorkshire, as well as a single interception from the Netherlands. Gnat interceptions were associated with a wide range of plant species: Ficus benjamina, Ficus elastica, Dracaena reflexa var. angustifolia, Origanum vulgare, Rosmarinus officinalis, Thymus vulgaris, Impatiens hawkeri (Impatiens New Guinea hybrids), Chrysanthemum, as well as Fragaria vesca (var. Lusa). The species does not appear to be doing any damage to affected plants with growing conditions likely promoting multiplication under protection. The larvae likely feed on spores (generally saprophytic) adhering to webs they erect on the soil and around the base of plants with spores likely originating from the growing medium and plants. Their spread is likely facilitated by movement of the growing medium or plant material where pupae are suspended in the lower stem or leaf axils.An account of the various interceptions is provided, as well as images of the different life-stages with a brief discussion of Sciophila cincticornis Edwards, 1940, its relationship with Sciophila fractinervis and further evidence of instability in vein R2+3 in the Sciophila genus.

We describe the case of a 44-year-old male patient with a longstanding history of microhematuria and mildly impaired kidney function (CKD G2A1). The family history disclosed three females who also had microhematuria. Genetic testing by whole exome sequencing revealed two novel variants in COL4A4 (NM_ 000092.5: c.1181G>T, NP_000083.3: p.Gly394Val, heterozygous, likely pathogenic; Alport syndrome, OMIM# 141200, 203780) and GLA (NM_ 000169.3: c.460A>G, NP_000160.1: p.Ile154Val, hemizygous, variant of uncertain significance; Fabry disease, OMIM# 301500), respectively. Extensive phenotyping revealed no biochemical or clinical evidence for the presence of Fabry disease. Thus, the GLA c.460A>G, p.Ile154Val, is to be classified as a benign variant, whereas the COL4A4 c.1181G>T, p.Gly394Val confirms the diagnosis of autosomal dominant Alport syndrome in this patient. [ABSTRACT FROM AUTHOR]

Background: Fabry cardiomyopathy is characterized by left ventricular hypertrophy, myocardial fibrosis, arrhythmia, and premature death. Treatment with migalastat, an oral pharmacological chaperone, was associated with a stabilization of cardiac biomarkers and a reduction in left ventricular mass index, as measured by echocardiography. A recent study, using cardiac magnetic resonance (CMR) as the gold standard, found a stable course of myocardial involvement after 18 months of treatment with migalastat. Our study aimed to provide long-term CMR data for the treatment with migalastat. Methods: A total of 11 females and four males with pathogenic amenable GLA mutations were treated with migalastat and underwent 1.5T CMR imaging for routine treatment effect monitoring. The main outcome was a long-term myocardial structural change, reflected by CMR. Results: After migalastat treatment initiation, left ventricular mass index, end diastolic volume, interventricular septal thickness, posterior wall thickness, estimated glomerular filtration rate, and plasma lyso-Gb3 remained stable during the median follow-up time of 34 months (min.: 25; max.: 47). The T1 relaxation times, reflecting glycosphingolipid accumulation and subsequent processes up to fibrosis, fluctuated over the time without a clear trend. No new onset of late gadolinium enhancement (LGE) areas, reflecting local fibrosis or scar formation of the myocardium, could be detected. However, patients with initially present LGE showed an increase in LGE as a percentage of left ventricular mass. The median α-galactosidase A enzymatic activity increased from 37.3% (IQR 5.88–89.3) to 105% (IQR 37.2–177) of the lower limit of the respective reference level (p = 0.005). Conclusion: Our study confirms an overall stable course of LVMi in patients with FD, treated with migalastat. However, individual patients may experience disease progression, especially those who present with fibrosis of the myocardium already at the time of therapy initiation. Thus, a regular treatment re-evaluation including CMR is needed to provide the optimal management for each patient. [ABSTRACT FROM AUTHOR]

Introduction: Variants in the galactosidase alpha (GLA) gene cause Fabry disease (FD), an X-linked lysosomal storage disorder caused by α-galactosidase A (α-GAL) deficiency. Recently, disease-modifying therapies have been developed, and simple diagnostic biomarkers for FD are required to initiate these therapies in the early stages of the disease. Detection of urinary mulberry bodies and cells (MBs/MCs) is beneficial for diagnosing FD. However, few studies have evaluated the diagnostic accuracy of urinary MBs/MCs in FD. Herein, we retrospectively evaluated the diagnostic ability of urinary MBs/MCs for FD. Methods: We analyzed the medical records of 189 consecutive patients (125 males and 64 females) who underwent MBs/MCs testing. Out of these, two female patients had already been diagnosed with FD at the time of testing, and the remaining 187 patients were suspected of having FD and underwent both GLA gene sequencing and/or α-GalA enzymatic testing. Results: Genetic testing did not confirm the diagnosis in 50 females (26.5%); hence, they were excluded from the evaluation. Two patients were previously diagnosed with FD, and sixteen were newly diagnosed. Among these 18 patients, 15, including two who had already developed HCM at diagnosis, remained undiagnosed until targeted genetic screening of at-risk family members of patients with FD was performed. The accuracy of urinary MBs/MCs testing exhibited a sensitivity of 0.944, specificity of 1, positive predictive value of 1, and negative predictive value of 0.992. Conclusions: MBs/MCs testing is highly accurate in diagnosing FD and should be considered during the initial evaluation prior to genetic testing, particularly in female patients.

Fabry disease (FD) is an X-linked recessive inheritance lysosomal storage disorder caused by pathogenic mutations in the GLA gene leading to a deficiency of the enzyme alpha-galactosidase A (α-Gal A). Multiple organ systems are implicated in FD, most notably the kidney, heart, and central nervous system. In our previous study, we identified four GLA mutations from four independent Fabry disease families with kidney disease or neuropathic pain: c.119C>A (p.P40H), c.280T>C (C94R), c.680G>C (p.R227P) and c.801+1G>A (p.L268fsX3). To reveal the molecular mechanism underlying the predisposition to Fabry disease caused by GLA mutations, we analyzed the effects of these four GLA mutations on the protein structure of α-galactosidase A using bioinformatics methods. The results showed that these mutations have a significant impact on the internal dynamics and structures of GLA, and all these altered amino acids are close to the enzyme activity center and lead to significantly reduced enzyme activity. Furthermore, these mutations led to the accumulation of autophagosomes and impairment of autophagy in the cells, which may in turn negatively regulate autophagy by slightly increasing the phosphorylation of mTOR. Moreover, the overexpression of these GLA mutants promoted the expression of lysosome-associated membrane protein 2 (LAMP2), resulting in an increased number of lysosomes. Our study reveals the pathogenesis of these four GLA mutations in FD and provides a scientific foundation for accurate diagnosis and precise medical intervention for FD.

Fabry disease (FD) is a multi-organ disorder caused by a deficiency of alpha-galactosidase (α-GLA) or reduced activity of the enzyme due to mutations in the GLA gene on the X chromosome, making it an X-linked hereditary disease. A 37-year-old man previously diagnosed with sudden deafness and cardiac hypertrophy was referred to our department after an abnormal urine finding during a public health checkup. A renal biopsy revealed characteristic findings, and he was diagnosed with FD with a novel GLA abnormality (c.714dupT (p.I239Yfs*11)). We are currently administering enzyme replacement therapy (ERT) with agalsidase α. This case shows that a novel genetic abnormality in FD can be overlooked for 37 years, even in the presence of typical symptoms. The significance of a renal biopsy in diagnosing FD is emphasized, highlighting the crucial role of nephrologists. [ABSTRACT FROM AUTHOR]

We describe the case of a 44-year-old male patient with a longstanding history of microhematuria and mildly impaired kidney function (CKD G2A1). The family history disclosed three females who also had microhematuria. Genetic testing by whole exome sequencing revealed two novel variants in COL4A4 (NM_000092.5: c.1181G>T, NP_000083.3: p.Gly394Val, heterozygous, likely pathogenic; Alport syndrome, OMIM# 141200, 203780) and GLA (NM_000169.3: c.460A>G, NP_000160.1: p.Ile154Val, hemizygous, variant of uncertain significance; Fabry disease, OMIM# 301500), respectively. Extensive phenotyping revealed no biochemical or clinical evidence for the presence of Fabry disease. Thus, the GLA c.460A>G, p.Ile154Val, is to be classified as a benign variant, whereas the COL4A4 c.1181G>T, p.Gly394Val confirms the diagnosis of autosomal dominant Alport syndrome in this patient.

Enzyme replacement therapy is the only therapeutic option for Fabry patients with completely absent AGAL activity. However, the treatment has side effects, is costly, and requires conspicuous amounts of recombinant human protein (rh-AGAL). Thus, its optimization would benefit patients and welfare/health services (i.e., society at large). In this brief report, we describe preliminary results paving the way for two possible approaches: i. the combination of enzyme replacement therapy with pharmacological chaperones; and ii. the identification of AGAL interactors as possible therapeutic targets on which to act. We first showed that galactose, a low-affinity pharmacological chaperone, can prolong AGAL half-life in patient-derived cells treated with rh-AGAL. Then, we analyzed the interactomes of intracellular AGAL on patient-derived AGAL-defective fibroblasts treated with the two rh-AGALs approved for therapeutic purposes and compared the obtained interactomes to the one associated with endogenously produced AGAL (data available as PXD039168 on ProteomeXchange). Common interactors were aggregated and screened for sensitivity to known drugs. Such an interactor-drug list represents a starting point to deeply screen approved drugs and identify those that can affect (positively or negatively) enzyme replacement therapy. [ABSTRACT FROM AUTHOR]

The prevalence of non-alcoholic fatty liver disease (NAFLD) has soared globally. As our understanding of the disease grows, the role of the gut-liver axis (GLA) in NAFLD pathophysiology becomes more apparent. Hence, we focused mainly on the small intestinal area to explore the role of GLA. We looked at how multi-strain probiotics (MCP® BCMC® strains) containing six different Lactobacillus and Bifidobacterium species affected the small intestinal gut microbiota, inflammatory cytokines, and permeability in NAFLD patients. After six months of supplementation, biochemical blood analysis did not show any discernible alterations in either group. Five predominant phyla known as Actinobacteria, Proteobacteria, Firmicutes, Bacteroidota and Fusobacteria were found in NAFLD patients. The probiotics group demonstrated a significant cluster formation of microbiota composition through beta-diversity analysis (p < 0.05). This group significantly reduced three unclassifiable species: unclassified_Proteobacteria, unclassified_Streptococcus, and unclassified_Stenotrophomonas. In contrast, the placebo group showed a significant increase in Prevotella_melaninogenica and Rothia_mucilaginosa, which were classified as pathogens. Real-time quantitative PCR analysis of small intestinal mucosal inflammatory cytokines revealed a significant decrease in IFN-γ (−7.9 ± 0.44, p < 0.0001) and TNF-α (−0.96 ± 0.25, p < 0.0033) in the probiotics group but an increase in IL-6 (12.79 ± 2.24, p < 0.0001). In terms of small intestinal permeability analysis, the probiotics group, unfortunately, did not show any positive changes through ELISA analysis. Both probiotics and placebo groups exhibited a significant increase in the level of circulating zonulin (probiotics: 107.6 ng/mL ± 124.7, p = 0.005 vs. placebo: 106.9 ng/mL ± 101.3, p = 0.0002) and a significant decrease in circulating zonula occluden-1 (ZO-1) (probiotics: −34.51 ng/mL ± 18.38, p < 0.0001 vs. placebo: −33.34 ng/mL ± 16.62, p = 0.0001). The consumption of Lactobacillus and Bifidobacterium suggested the presence of a well-balanced gut microbiota composition. Probiotic supplementation improves dysbiosis in NAFLD patients. This eventually stabilised the expression of inflammatory cytokines and mucosal immune function. To summarise, more research on probiotic supplementation as a supplement to a healthy diet and lifestyle is required to address NAFLD and its underlying causes. [ABSTRACT FROM AUTHOR]

Atractylodin (ATL) has been reported to exert anti‐inflammatory effects. Osteogenic changes induced by inflammation in valve interstitial cells (VICs) play a key role in the development of calcified aortic valve disease (CAVD). This study aimed to investigate the anti‐calcification effects of ATL on aortic valves. Human VICs (hVICs) were exposed to osteogenic induction medium (OM) containing ATL to investigate cell viability, osteogenic gene and protein expression, and anti‐calcification effects. Gas chromatography–mass spectroscopy (GC–MS) metabolomics analysis was used to detect changes in the metabolites of hVICs stimulated with OM before and after ATL administration. The compound‐reaction‐enzyme‐gene network was used to identify drug targets. Gene interference was used to verify the targets. ApoE−/− mice fed a high‐fat (HF) diet were used to evaluate the inhibition of aortic valve calcification by ATL. Treatment with 20 μM ATL in OM prevented calcified nodule accumulation and decreases in the gene and protein expression levels of ALP, RUNX2, and IL‐1β. Differential metabolite analysis showed that D‐mannose was highly associated with the anti‐calcification effect of ATL. The addition of D‐mannose prevented calcified nodule accumulation and inhibited succinate‐mediated HIF‐1α activation and IL‐1β production. The target of ATL was identified as GLA. Silencing of the GLA gene (si‐GLA) reversed the anti‐osteogenic differentiation of ATL. In vivo, ATL ameliorated aortic valve calcification by preventing decreases in GLA expression and the up‐regulation of IL‐1β expression synchronously. In conclusion, ATL is a potential drug for the treatment of CAVD by targeting GLA to regulate D‐mannose metabolism, thereby inhibiting succinate‐mediated HIF‐1α activation and IL‐1β production. [ABSTRACT FROM AUTHOR]

This study examines fatty acid variations within Echium plantagineum L. populations in northwestern Türkiye. Significant differences in fatty acid ratios between locations suggest their potential for population segregation using chemometric data as a conceptual approach. Seed oil content ranged from 17 % to 29 %, with PUFAs being the most abundant group (60–75 %). SFA and MUFA concentrations ranged from 10 % to 15 % and 11–19 %, respectively. Total n3 and n6 fatty acids were 35–50.5 % and 22–32 % individually. USFA levels varied from 76 % to 87 %. GLA (9.26 %) and SDA (10.09 %) were notable. While overall fatty acid profiles showed no location-based differences, significant variations were observed in individual major fatty acids, unusual fatty acids, and certain ratios (e.g., SDA/GLA, USFA/SFA, PUFA/MUFA, n3/n6). These variations may aid in taxonomical delineation and population discrimination. Given the species' broad distribution and rich gene pool, high-yielding genotypes with desirable fatty acid profiles could be identified for agricultural purposes and biotechnological crop improvement. [Display omitted] • Echium plantagineum L. is an industrial crop plant. • The largest intraspecific study on E. plantagineum in Turkey. • SDA and GLA are found in high amounts in E. plantagineum. • Nutraceutical potential as a source of terrestrial omega-3 and omega-6. • Fatty acid ratios are reliable tool for chemotaxonomy. [ABSTRACT FROM AUTHOR]

The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease. To expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events. In p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25-34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55-64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31%, females 8%) while renal and cerebrovascular events were rare. Renal impairment occurred in 17% of p.N215S males (mostly in patients aged 65-74 years), and rarely in females (3%). p.N215S is a disease-causing mutation with severe clinical manifestations found primarily in the heart. Cardiac involvement may become as severe as in classic Fabry patients, especially in males.

Fabry disease (FD) is an X-linked inborn metabolic disorder due to partial or complete lysosomal α-galactosidase A deficiency. FD is characterized by progressive renal insufficiency and cardio- and cerebrovascular involvement. Restricted access on Gb3-independent tissue injury experimental models has limited the understanding of FD pathophysiology and delayed the development of new therapies. Accumulating glycosphingolipids, mainly Gb3 and lysoGb3, are Fabry specific markers used in clinical follow up. However, recent studies suggest there is a need for additional markers to monitor FD clinical course or response to treatment. We used a gla-knockout zebrafish (ZF) to investigate alternative biomarkers in Gb3-free-conditions. RNA sequencing was used to identify transcriptomic signatures in kidney tissues discriminating gla-mutant (M) from wild type (WT) ZF. Gene Ontology (GO) and KEGG pathways analysis showed upregulation of immune system activation and downregulation of oxidative phosphorylation pathways in kidneys from M ZF. In addition, upregulation of the Ca2+ signaling pathway was also detectable in M ZF kidneys. Importantly, disruption of mitochondrial and lysosome-related pathways observed in M ZF was validated by immunohistochemistry. Thus, this ZF model expands the pathophysiological understanding of FD, the Gb3-independent effects of gla mutations could be used to explore new therapeutic targets for FD. [ABSTRACT FROM AUTHOR]

Background: Primary thoracic lymphangioma is a rare disease. Most of the previous studies are comprised of individual case reports, with a very limited number of patients included., Objective: This study aims to investigate the chest computed tomography (CT) imaging features and clinical manifestations of thoracic lymphangioma, thereby enhancing our understanding of the condition., Methods: A retrospective analysis was conducted on 62 patients diagnosed with thoracic lymphangioma, comprising 32 males and 30 females. The study focused on analyzing the chest CT imaging features and the clinical manifestations observed in these patients., Results: The incidence rates of thoracic lymphangioma did not differ significantly between males and females; however, it was more frequently observed in children and adolescents. The most common clinical symptoms included cough, fever, chylothorax, chylous pericardium, and lymphedema. The mediastinum (82.3%) emerged as the most frequent location for thoracic lymphangioma, followed by the chest wall (62.9%), bone (40.3%), and pleura (32.3%). Pulmonary lymphangioma, the least prevalent subtype (19.4%), exhibited a propensity to induce respiratory symptoms, frequently manifesting as a generalized lymphatic anomaly (GLA). Furthermore, elevated levels of D-dimer were detected in 34 patients (54.8%) with thoracic lymphangioma., Conclusions: Imaging examinations play a crucial role in assisting clinicians in making more accurate early diagnoses of thoracic lymphangioma. They are also helpful for assessing the extent of systemic infiltration and enhancing diagnostic precision. With radiological assessment, clinicians could more readily select appropriate therapeutic treatments and monitor the progression of follow-up care.

Introduction: The focus in reverse shoulder arthroplasty (RSA) has been on the lateralization and distalization of prosthesis positioning, influenced by implant design and surgical technique. There's no consensus on the optimal amount of lateralization and distalization or the best radiographic parameters for evaluating placement. This study examines the correlation and the predictive value between previously described modified distalization shoulder angle (DSA) and lateralization shoulder angle (LSA) with postoperative outcomes, which aim to differentiate the contributions of the humeral and glenoid components in the global distalization and lateralization of the RSA. The LSA was divided into the glenoid lateralization angle (GLA) and the humeral lateralization angle (HLA); the modified distalization shoulder angle (mDSA) was divided into the glenoid distalization angle (GDA) and the humeral distalization angle (HDA). Our hypothesis was that these new angles play a marginal role in predicting clinical outcomes., Materials and Methods: Retrospective analysis of 83 RSA patients from 2017-2021 at San Pietro Fatebenefratelli Hospital, Rome. Angles were measured using true anteroposterior radiographs. Clinical outcomes were assessed using the Constant-Murley Score (CS), a visual analogue scale (VAS) for pain, and range of motion (ROM)., Results: A weak correlation was found between the modified angles and clinical outcomes. Modified DSA (mDSA) correlated positively with internal rotation and negatively with VAS score. Glenoid distalization angle (GDA) correlated positively with abduction, forward flexion, and CS. Humeral distalization angle (HDA) correlated positively with internal rotation and negatively with VAS. Glenoid lateralization angle (GLA) and humeral lateralization angle (HLA) showed negative correlation with internal rotation and positive correlation with VAS., Conclusion: Modified DSA and LSA show marginal correlation with postoperative outcomes and have limited predictive value. Further research with larger, diverse populations is needed to refine these metrics and their clinical utility., (Copyright © 2024. Published by Elsevier Inc.)

Background: The efficacy of enzyme replacement therapy (ERT) in mobilizing globotryaosylceramide (GB-3) from Fabry cardiomyocytes is limited. The mechanism involved is still obscure. Methods: Assessment of M6Pr, M6Pr-mRNA, and Ubiquitin has been obtained by Western blot analysis and real-time PCR of frozen endomyocardial biopsy samples, from 17 pts with FD, various degree of left ventricular hypertrophy, and maximal wall thickening (MWT) from 11.5 and 20 mm. The diagnosis and severity of FDCM followed definitions of GLA mutation, α-galactosidase A enzyme activity, cardiac magnetic resonance, and left ventricular endomyocardial biopsy with the quantification of myocyte hypertrophy and the extent of Gb-3 accumulation. All patients have received alpha or beta agalsidase for ≥3 years without a reduction in LV mass nor an increase in T1 mapping at CMR. Controls were surgical biopsies from 15 patients undergoing mitral valve replacement. Results: Protein analysis showed mean M6Pr in FDCM to be 5.4-fold lower than in a normal heart (4289 ± 6595 vs. 23,581 ± 4074, p = 0.0996) (p < 0.001): specifically, 9-fold lower in males, p = 0.009, (p < 0.001) and 3-fold lower in females, p = 0.5799, (p < 0.001) showing, at histology, a mosaic of normal and diseased cells. M6Pr-mRNA expression was normal, while ubiquitin showed an increase of 4.6 fold vs. controls (13,284 ± 1723 vs. 2870 ± 690, p = 0.001) suggesting that ubiquitin-dependent post-translational degradation is likely responsible for the reduction of M6Pr in FDCM. Conclusion: M6Pr expression is remarkably reduced in FDCM as a likely result of post-translational degradation. This may explain the reduced efficacy of ERT and be a therapeutic target for the enhancement of ERT activity. [ABSTRACT FROM AUTHOR]

Background: There is a vast number of screening studies described in the literature from the beginning of the twenty-first century to the present day. Many of these studies are related to the estimation of Fabry disease (FD) morbidity among patients from high-risk groups, including adult patients with hypertrophic cardiomyopathy (HCM) and left ventricular hypertrophy (LVH). These studies show diverse detection frequencies (0-12%) depending on the methodology. Our study is the only example of large-scale selective FD screening based on the implementation of next-generation sequencing technology (NGS) as a first-level test to estimate FD morbidity in the Russian population over 18 years of age burdened with HCM.Methods: The study included 1009 patients (578 males and 431 females), with a median age of 50 years, who were diagnosed with HCM according to current clinical guidelines. In the first stage of screening, all patients underwent molecular genetic testing (NGS method) of target regions. These regions included the coding sequences of 17 genes and mutations that can lead to the development of HCM. Lysosomal globotriaosylsphingosine (lyso-Gb3) concentrations and α-galactosidase A (α-gal A) enzyme activity were measured in the second stage of screening to reveal pathogenic or likely pathogenic variants in the GLA gene.Results: We revealed 8 (0.8%) patients (3 (37.5%) males and 5 (62.5%) females) with an average age of 59 ± 13.3 years who had pathogenic, likely pathogenic variants and variants of uncertain significance (VUS) in the GLA gene (NM_000169.2) as a result of selective screening of 1009 Russian patients with HCM. FD was confirmed via biochemical tests in a male with the pathogenic variant c.902G > A, p.R301Q as well as in two females with likely pathogenic variants c.897C > A, p.D299E and c.1287_1288dup, p.*430Fext*?. These tests showed reduced enzymatic activity and increased substrate concentration. However, a female with the pathogenic variant c.416A > G, p.N139S and with normal enzymatic activity only had increased substrate concentrations. The revealed nucleotide variants and high values of biochemical indicators (lyso-Gb3) in these 4 patients allowed us to estimate the FD diagnosis among 1009 Russian patients with HCM. Mild extracardiac manifestations were observed in these four patients; however, both biochemical values within the reference range in females with the c.971T > G, p.L324W (VUS) variant. α-gal A activity and lyso-Gb3 concentrations were also within the normal range in two males with hemizygous variants, c.546T > C, p.D182D and c.640-794_640-791del (we regarded them as VUS), and in one female with the c.427G > A, p.A143T variant (with conflicting interpretations of pathogenicity).Conclusion: The prevalence rate of FD among 1,009 adult Russian patients with HCM was 0.4%. We recommend FD screening among adult patients of both sexes with HCM and an undefined genetic cause via NGS method with subsequent analysis of α-gal A activity and lyso-Gb3 concentration in patients with pathogenic, likely pathogenic variants, and VUS. This strategy identifies patients with an atypical form of FD that is characterized by high residual activity of α-gal A, low concentrations of lyso-Gb3, and minor extracardiac manifestations. [ABSTRACT FROM AUTHOR]

Fabry disease (FD) is a rare genetic lysosomal storage disorder, resulting from partial or complete lack of alpha-galactosidase A (α-GAL) enzyme, leading to systemic accumulation of substrate glycosphingolipids with a broad range of tissue damage. Current in vivo models are laborious, expensive, and fail to adequately mirror the complex FD physiopathology. To address these issues, we developed an innovative FD model in zebrafish.Zebrafish GLA gene encoding α-GAL enzyme presents a high (>70%) homology with its human counterpart, and the corresponding protein has a similar tissue distribution, as evaluated by immunohistochemistry. Moreover, a similar enzymatic activity in different life stages could be demonstrated. By using CRISPR/Cas9 technology, we generated a mutant zebrafish with decreased GLA gene expression, and decreased expression of the specific gene product in the kidney. Mutant animals showed higher plasma creatinine levels and proteinuria. Transmission electron microscopy (TEM) studies documented an increased podocyte foot process width (FPW) in mutant, as compared to wild type zebrafish.This zebrafish model reliably mirrors distinct features of human FD and could be advantageously used for the identification of novel biomarkers and for an effective screening of innovative therapeutic approaches.

In this study, 18 standard amino acids were tested as a single nitrogen source on biomass, total lipid, total fatty acid (TFA) production, and yield of γ-linolenic acid (GLA) in Rhizomucor pusillus AUMC 11616.A and Mucor circinelloides AUMC 6696.A isolated from unusual habitats. Grown for 4 days at 28°C, shaking at 150 rpm, the maximum fungal biomass for AUMC 6696.A was 14.6 ± 0.2 g/L with arginine and 13.68 ± 0.1 g/L with asparagine, when these amino acids were used as single nitrogen sources, while AUMC 11616.A maximum biomass was 10.73 ± 0.8 g/L with glycine and 9.44 ± 0.6 g/L with valine. These were significantly higher than the ammonium nitrate control (p < 0.05). The highest levels of TFA were achieved with glycine for AUMC 11616.A, 26.2 ± 0.8% w/w of cell dry weight, and glutamic acid for AUMC 6696.A, 23.1 ± 1.3%. The highest GLA yield was seen with proline for AUMC 11616.A, 13.4 ± 0.6% w/w of TFA, and tryptophan for AUMC 6696.A, 12.8 ± 0.3%, which were 38% and 25% higher than the ammonium tartrate control. The effects of environmental factors such as temperature, pH, fermentation time, and agitation speed on biomass, total lipids, TFA, and GLA concentration of the target strains have also been investigated. Our results demonstrated that nitrogen assimilation through amino acid metabolism, as well as the use of glucose as a carbon source and abiotic factors, are integral to increasing the oleaginicity of tested strains. Few studies have addressed the role of amino acids in fermentation media, and this study sheds light on R. pusillus and M. circinelloides as promising candidates for the potential applications of amino acids as nitrogen sources in the production of lipids.

Bilateral Fibrocystic Breast is the most common form of benign breast disease and besides tender breasts is clinically associated with a relative risk for the subsequent development of cancer. We present a successful reversal of macrocytic anemia using iron bisglycinate, B-vitamins, and protein powder alongside symptomatic regression of bilateral fibrocystic breast with correction of concomitant mastodynia and dysmenorrhea using therapeutic iodine paired with estrogen metabolite support with GLA, DIM, I3C, and estrogen excretion with Calcium D-Glucarate. [ABSTRACT FROM AUTHOR]

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the alpha-galactosidase A (GLA) gene, which encodes the exogalactosyl hydrolase, alpha-galactosidase A (α-Gal A). Deficient α-Gal A activity results in the progressive, systemic accumulation of its substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3), leading to renal, cardiac, and/or cerebrovascular disease and early demise. The current standard treatment for Fabry disease is enzyme replacement therapy, which necessitates lifelong biweekly infusions of recombinant enzyme. A more long-lasting treatment would benefit Fabry patients. Here, a gene therapy approach using an episomal adeno-associated viral 2/6 (AAV2/6) vector that encodes the human GLA cDNA driven by a liver-specific expression cassette was evaluated in a Fabry mouse model that lacks α-Gal A activity and progressively accumulates Gb3 and Lyso-Gb3 in plasma and tissues. A detailed 3-month pharmacology and toxicology study showed that administration of a clinical-scale-manufactured AAV2/6 vector resulted in markedly increased plasma and tissue α-Gal A activities, and essentially normalized Gb3 and Lyso-Gb3 at key sites of pathology. Further optimization of vector design identified the clinical lead vector, ST-920, which produced several-fold higher plasma and tissue α-Gal A activity levels with a good safety profile. Together, these studies provide the basis for the clinical development of ST-920.

Anderson-Fabry disease (AFD) results from decreased enzyme activity of lysosomal enzymes and intralysosomal storage of nonhydrolyzed forms. Cardiovascular complications, mainly in the form of HCM, contribute substantially to AFD patient mortality. Here, we report three new cases of obstructive HCM (HOCM) in nonclassical presentations of AFD and isolated cardiac involvement. In all three cases, the diagnosis of AFD was made postoperatively by routine genetic and morphological testing. Together with previously published cases, this report illustrates the potential safety and beneficial effect of septal surgical myectomy in patients with AFD-HOCM, as well as underlines the need for more thorough screening for clinical signs of AFD-associated cardiomyopathy and GLA variants among patients with HOCM.

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Fabry disease (FD) is a rare hereditary disorder characterized by a wide range of symptoms caused by a variety of mutations in the galactosidase α (GLA) gene. The heterogeneous nuclear ribonucleoprotein (HNRNPH2) gene is divergently paired with GLA on chromosome X and is thought to be implicated in FD. However, insufficient information is available on the regulatory mechanisms associated with the expression of HNRNPH2 and the GLA loci. Therefore, the current study performed bioinformatics analyses to assess the GLA and HNRNPH2 loci and investigate the regulatory mechanisms involved in the expression of each gene. The regulatory mechanisms underlying GLA and HNRNPH2 were revealed. The expression of each gene was associated with a bidirectional promoter (BDP) characterized by the absence of TATA box motifs and the presence of specific transcription factor binding sites (TFBSs) and a CpG Island (CGI). The nuclear run-on transcription assay confirmed the activity of BDP GLA and HNRNPH2 transcription in 293T. Methylation-specific PCR analysis demonstrated a statistically significant variation in the DNA methylation pattern of BDP in several cell lines, including human adult epidermal keratinocytes (AEKs), human renal glomerular endothelial cells, human renal epithelial cells and 293T cells. The highest observed significance was demonstrated in AEKs (P<0.05). The results of the chromatin-immunoprecipitation assay using 293T cells identified specific TFBS motifs for Yin Yang 1 and nuclear respiratory factor 1 transcription factors in BDPs. The National Center for Biotechnology Information-single nucleotide polymorphism database revealed pathogenic variants in the BDP sequence. Additionally, a previously reported variant associated with a severe heterozygous female case of GLA FD was mapped in BDP. The results of the present study suggested that the expression of the divergent paired loci, GLA and HNRNPH2, were controlled by BDP. Mutations in BDP may also serve a role in FD and may explain clinical disease diversity. [ABSTRACT FROM AUTHOR]

La maladie de Fabry est la maladie de surcharge lysosomale la plus fréquente après la maladie de Gaucher. Il s'agit d'une maladie liée au chromosome X, secondaire au déficit enzymatique en alpha-galactosidase A. Les manifestations cliniques sont progressives et systémiques. Bien que liée à l'X, les femmes sont également atteintes au cours de la maladie de Fabry. Les symptômes et atteintes typiques sont les douleurs acrales (acroparesthésies), la cornée verticillée, la cardiopathie hypertrophique, les accidents vasculaires cérébraux et l'insuffisance rénale chronique avec protéinurie. Néanmoins, les atteintes d'organes peuvent être manquantes ou paucisymptomatiques et certaines manifestations sont méconnues. Au cours du phénotype classique de la maladie de Fabry, les symptômes débutent pendant l'enfance ou l'adolescence chez les garçons, mais plus tardivement chez les filles. Chez les patients atteints d'un phénotype dit "non classique" ou "tardif", les symptômes et atteintes d'organes apparaissent plus tardivement et peuvent même être limités à un seul organe. Des traitements spécifiques adaptés sont disponibles et des stratégies de prise en charge thérapeutique sont maintenant établies et font l'objet de recommandations. Ces traitements auront d'autant plus de chance d'être efficace que le diagnostic de la maladie sera précoce. Le diagnostic est aisé chez l'homme, par le dosage de l'activité leucocytaire de l'alpha-galactosidase A, mais est plus difficile chez la femme en raison de la possible normalité de l'activité enzymatique. Un autre marqueur plasmatique, le lyso-globotriaosylceramide (lyso-Gb3) est intéressant chez la femme, mais il doit impérativement être suivi d'une recherche de variants sur le gène GLA pour valider ou infirmer le diagnostic. L'enquête familiale est essentielle, permettant le diagnostic chez les apparentés. Dans cet article, nous décrivons les manifestations cliniques de la maladie de Fabry pour savoir quand la suspecter et proposons un algorithme pratique pour savoir comment diagnostiquer cette maladie complexe. Fabry disease is the second most frequent lysosomal storage disorder. It is a X-linked genetic disease secondary to alpha-galactosidase A enzyme deficiency. This is a progressive and systemic disease that affects both males and females. Classical symptoms and organ involvements are acral pain crisis, cornea verticillata, hypertrophic cardiomyopathy, stroke and chronic kidney disease with proteinuria. Nevertheless, organ damages can be missing or pauci-symptomatic and other common symptoms are poorly recognised, such as gastrointestinal or ear involvement. In classical Fabry disease, symptoms first appear during childhood or teenage in males, but later in females. Patients may have non-classical or late-onset Fabry disease with delayed manifestations or with single-organ involvement. Recognition of Fabry disease is important because treatments are available, but it may be challenging. Diagnosis is easy in males, with dosage of alpha-galactosidase A enzyme activity into leukocytes, but more difficult in females who can express normal residual activity. Other plasmatic biomarkers, such as lyso-globotriaosylceramide (lyso-Gb3), are interesting in females, but need to be associated with GLA gene analysis. In this review, we aimed at summarize the main clinical manifestations of Fabry disease and propose a practical algorithm to know how to diagnose this complex disease. [ABSTRACT FROM AUTHOR]

Background: The detailed clinical phenotype of patients carrying the α-galactosidase gene ( GLA ) c.548 G   >   A / p.Gly183Asp ( p.G183D ) variant in Fabry disease (FD) has not been thoroughly documented in the existing literature., Methods: This paper offers a meticulous overview of the clinical phenotype and relevant auxiliary examination results of nine confirmed FD patients with the p.G183D gene variant from two families. Pedigree analysis was conducted on two male patients with the gene variant, followed by biochemical and genetic screening of all high-risk relatives. Subsequently, evaluation of multiple organ systems and comprehensive instrument assessment were performed on heterozygotes of the p.G183D gene variant., Results: The study revealed that all patients exhibited varying degrees of cardiac involvement, with two demonstrating left ventricular wall thickness exceeding 15 mm on echocardiography, and the remaining six exceeding 11 mm. Impaired renal function was evident in all six patients with available blood test data, two of whom underwent kidney transplantation. Eight cases reported neuropathic pain, and five experienced varying degrees of stroke or transient ischemic attack (TIA)., Conclusion: This study indicates that the GLA p.G183D gene variant can induce premature organ damage, particularly affecting the heart, kidneys, and nervous system., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. Published by Elsevier Inc.)

Intratumoral (IT) injections of Glucopyranosyl lipid A (G100), a synthetic toll-like receptor 4 (TLR4) agonist formulated in a stable emulsion, resulted in T-cell inflammation of the tumor microenvironment (TME) and complete cure of 60% of mice with large established A20 lymphomas. Strong abscopal effects on un-injected lesions were observed in a bilateral tumor model and surviving mice resisted a secondary tumor challenge. Depletion of CD8 T-cells, but not CD4 or NK cells, abrogated the anti-tumor effect. Unexpectedly, TLR4 knock-out rendered A20 tumors completely non-responsive to G100. In vitro studies showed that GLA has direct effect on A20 cells, but not on A20 cells deficient for TLR4. As shown by genotyping and phenotyping analysis, G100 strongly activated antigen presentation functions in A20 cells in vitro and in vivo and induced their apoptosis in a dose dependent manner. Similarly, the TLR4 positive human mantle cell lymphoma line Mino showed in vitro activation with G100 that was blocked with an anti-TLR4 antibody. In the A20 model, direct activation of B-lymphoma cells with G100 is sufficient to induce protective CD8 T-cell responses and TLR4 expressing human B-cell lymphomas may be amenable to this therapy as well.

Background/Aims: Fabry disease (FD) is a lysosomal storage disorder characterized by pervasive renal involvement. However, this disease is underdiagnosed in patient with chronic kidney disease (CKD), including those with end stage renal disease (ESRD), so their investigation represents an unexploited opportunity for early diagnosis of the disease and for its identification in relatives of affected patients. Methods: We investigated Fabry disease in a clinical and biological database including ESRD patients of unknown cause in a geographical area with 2 million residents. The study was based on state of art GLA gene sequencing and was extended to relatives of affected ESRD patients. Results: Among ESRD patients qualified for enrollment into this study, a previously undiagnosed young man harboring the mutation p.I91T was identified. The study of the proband's family led to the identification of 8 additional cases. In another ESRD male patient, we identified the functional polymorphism p.D313Y. Furthermore, in 55 ESRD patients (24.2%) we found intronic polymorphisms of uncertain functional relevance in the non-coding regions of the GLA gene. Conclusion: A comprehensive survey of ESRD patients in a geographical area of 2 million residents identified one undiagnosed case of Fabry disease and led to the identification of 8 additional cases among his relatives. Screening protocols starting from the dialysis population and upstream extended to families of affected individuals may be an effective strategy to maximize the early identification of subjects with Fabry disease.

Recent research has suggested a possible link between Parkinson's disease (PD) and Fabry disease. To test this relationship, we administered a self-report and family history questionnaire to determine the prevalence of PD in Fabry disease patients and family members with likely pathogenic alpha-galactosidase A (GLA) mutations. A total of 90 Fabry patients (77 from the online survey and 13 from the Icahn School of Medicine at Mount Sinai (ISMMS)) were included in the analysis. Two of the Fabry disease patients who completed the online survey were diagnosed with PD (2/90, 2.2%). Among probands older than 60, 8.3% (2/24) were diagnosed with PD. Using Kaplan Meier survival analysis, the age-specific risk of PD by age 70 was 11.1%. Family history was available on 72 Fabry families from the online study and 9 Fabry families from ISMMS. Among these 81 families, 6 (7.4%) had one first degree relative who fit the criteria for a conservative diagnosis of PD. The results of this study suggest that there may be an increased risk of developing PD in individuals with GLA mutations, but these findings should be interpreted with caution given the limitations of the study design.

Pure carbon sources, especially carbohydrates which are raw materials deriving from agro‐industrial processes, are often used for small‐scale single‐cell oil production by fermentation. The aim of this study was to investigate the effects of different pure carbon sources on cell growth, lipid accumulation, and γ‐linolenic acid (GLA) production by the filamentous fungus Mortierella isabellina DSM 1414 (Deutsche Sammlung von Mikroorganismen). The sugars utilized in this study are found extensively and abundantly in nature, especially in food raw materials and, in consequence, in agro‐food industry wastes or surpluses. Thus, the potential of many waste materials containing these sugars to be used in the production of single‐cell oil by fermentation could also be evaluated. The effects of the sugars utilized on cell growth, biomass production, and lipid production were investigated. Fatty acids were also analysed in the lipids produced at the end of the fermentations. Results showed that the maximum biomass production was 10.80 g/L in lactose‐based media, while the maximum oil production was 5.44 g/L in maltose‐based media. Oleic (20.42%–42.94%), palmitic (14.96%–22.19%), and stearic (9.00%–26.92%) acids were the major fatty acids along with linoleic acid (11.35%–18.67%) and GLA (3.56%–8.04%). The production of GLA as the target fatty acid was remarkable. This study indicates that agro‐industrial waste including most of the sugars utilized (except for arabinose and sucrose with lipid production of 0.81 and 0.28 g/L, respectively) can be employed for production of single‐cell oil by M. isabellina DSM 1414 which contains a high amount of GLA. [ABSTRACT FROM AUTHOR]