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Gaucher disease is one of the most common lysosomal storage disorders. Osteonecrosis is a principal clinical manifestation of Gaucher disease and often leads to joint collapse and fractures. T1-weighted (T1w) modality in MRI is widely used to monitor bone involvement in Gaucher disease and to diagnose osteonecrosis. However, objective and quantitative methods for characterizing osteonecrosis are still limited. In this work, we present a deep learning-based quantification approach for the segmentation of osteonecrosis and the extraction of characteristic parameters. We first constructed two independent U-net models to segment the osteonecrosis and bone marrow unaffected by osteonecrosis (UBM) in spine and femur respectively, based on T1w images from patients in the UK national Gaucherite study database. We manually delineated parcellation maps including osteonecrosis and UBM from 364 T1w images (176 for spine, 188 for femur) as the training datasets, and the trained models were subsequently applied to all the 917 T1w images in the database. To quantify the segmentation, we calculated morphological parameters including the volume of osteonecrosis, the volume of UBM, and the fraction of total marrow occupied by osteonecrosis. Then, we examined the correlation between calculated features and the bone marrow burden score for marrow infiltration of the corresponding image, and no strong correlation was found. In addition, we analyzed the influence of splenectomy and the interval between the age at first symptom and the age of onset of treatment on the quantitative measurements of osteonecrosis. The results are consistent with previous studies, showing that prior splenectomy is closely associated with the fractional volume of osteonecrosis, and there is a positive relationship between the duration of untreated disease and the quantifications of osteonecrosis. We propose this technique as an efficient and reliable tool for assessing the extent of osteonecrosis in MR images of patients and improving prediction of clinically important adverse events., Competing Interests: Declaration of competing interest PD and TMC received institutional research support from Aventis Sanofi for this study., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Gaucher disease (GD) is an autosomal recessively inherited lysosomal storage disorder caused by biallelic pathological variants in the GBA1 gene. Patients present along a broad clinical spectrum, and phenotypes are often difficult to predict based on genotype alone. The variant R463C (p.Arg502Cys) exemplifies this challenge. To better characterize its different clinical presentations, we examined the records of 25 current and historical patients evaluated at the National Institutes of Health. Nine patients were classified as GD1, 14 were classified as GD3, and two had an ambiguous diagnosis between GD1 and GD3. In addition, we reviewed the published literature in PubMed and Web of Science through December 2023, identifying 62 cases with an R463C variant from 18 countries. Within the NIH cohort, the most common second variants were N370S (p.N409S) and L444P (p.L483P). R463C/L444P was encountered in patients with GD1 and GD3 in both the NIH cohort and worldwide. In the literature, R463C/R463C was also reported in both GD1 and GD3, although sparse phenotypic information was shared. Often the phenotype reflected what might be predicted for the second mutant allele. This diversity of phenotypes emphasizes the need for longitudinal follow-up to assess symptom development and neurological involvement., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Gaucher Disease (GD) is an inherited metabolic disorder caused by mutations in the GBA1 gene. It can manifest with severe neurodegeneration and visceral pathology. The most acute neuronopathic form (nGD), for which there are no curative therapeutic options, is characterised by devastating neuropathology and death during infancy. In this study, we investigated the therapeutic benefit of systemically delivered AAV9 vectors expressing the human GBA1 gene at two different doses comparing a neuronal-selective promoter with ubiquitous promoters. Our results highlight the importance of a careful evaluation of the promoter sequence used in gene delivery vectors, suggesting a neuron-targeted therapy leading to high levels of enzymatic activity in the brain but lower GCase expression in the viscera, might be the optimal therapeutic strategy for nGD., (© The Author(s) 2024. Published by Oxford University Press.)

Nutrient avidity is one of the most distinctive features of tumours. However, nutrient deprivation has yielded limited clinical benefits. In Gaucher disease, an inherited metabolic disorder, cells produce cholesteryl-glucoside which accumulates in lysosomes and causes cell damage. Here we develop a nanoparticle (AbCholB) to emulate natural-lipoprotein-carried cholesterol and initiate Gaucher disease-like damage in cancer cells. AbCholB is composed of a phenylboronic-acid-modified cholesterol (CholB) and albumin. Cancer cells uptake the nanoparticles into lysosomes, where CholB reacts with glucose and generates a cholesteryl-glucoside-like structure that resists degradation and aggregates into microscale crystals, causing Gaucher disease-like damage in a glucose-dependent manner. In addition, the nutrient-sensing function of mTOR is suppressed. It is observed that normal cells escape severe damage due to their inferior ability to compete for nutrients compared with cancer cells. This work provides a bioinspired strategy to selectively impede the metabolic action of cancer cells by taking advantage of their nutrient avidity., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Gaucher disease (GD) is a lysosomal storage disorder caused by a mutation in the GBA1 gene, responsible for encoding the enzyme Glucocerebrosidase (GCase). Although neuronal death and neuroinflammation have been observed in the brains of individuals with neuronopathic Gaucher disease (nGD), the exact mechanism underlying neurodegeneration in nGD remains unclear. In this study, we used two induced pluripotent stem cells (iPSCs)-derived neuronal cell lines acquired from two type-3 GD patients (GD3-1 and GD3-2) to investigate the mechanisms underlying nGD by biochemical analyses. These iPSCs-derived neuronal cells from GD3-1 and GD3-2 exhibit an impairment in endoplasmic reticulum (ER) calcium homeostasis and an increase in unfolded protein response markers (BiP and CHOP), indicating the presence of ER stress in nGD. A significant increase in the BAX/BCL-2 ratio and an increase in Annexin V-positive cells demonstrate a notable increase in apoptotic cell death in GD iPSCs-derived neurons, suggesting downstream signaling after an increase in the unfolded protein response. Our study involves the establishment of iPSCs-derived neuronal models for GD and proposes a possible mechanism underlying nGD. This mechanism involves the activation of ER stress and the unfolded protein response, ultimately leading to apoptotic cell death in neurons., (© 2024. The Author(s).)

Gaucher disease (GD) is a lysosomal storage disorder caused by a deficiency in the GBA1-encoded enzyme, β-glucocerebrosidase. Enzyme replacement therapy is ineffective for neuronopathic Gaucher disease (nGD). High-dose ambroxol has been administered as an alternative treatment for a group of patients with nGD. However, little is known about the clinical indication and the long-term outcome of patients after ambroxol therapy. We herein report a case of a female patient who presented with a progressive disease of GD type 2 from 11 months of age and had the pathogenic variants of p.L483P (formerly defined as p.L444P) and p.R502H (p.R463H) in GBA1. A combined treatment of imiglucerase with ambroxol started improving the patient's motor activity in 1 week, while it kept the long-lasting effect of preventing the deteriorating phenotype for 30 months. A literature review identified 40 patients with nGD, who had received high-dose ambroxol therapy. More than 65% of these patients favorably responded to the molecular chaperone therapy, irrespective of p.L483P homozygous, heterozygous or the other genotypes. These results highlight the long-lasting effect of ambroxol-based chaperone therapy for patients with an expanding spectrum of mutations in GBA1., (© 2024 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GCase) are responsible for Gaucher disease (GD) and are considered the strongest genetic risk factor for Parkinson's disease (PD) and Lewy body dementia (LBD). GCase deficiency leads to extensive accumulation of glucosylceramides (GCs) in cells and contributes to the neuropathology of GD, PD, and LBD by triggering chronic neuroinflammation. Here, we investigated the mechanisms by which GC accumulation induces neuroinflammation. We found that GC accumulation within microglia induced by pharmacological inhibition of GCase triggered STING-dependent inflammation, which contributed to neuronal loss both in vitro and in vivo. GC accumulation in microglia induced mitochondrial DNA (mtDNA) leakage to the cytosol to trigger STING-dependent inflammation. Rapamycin, a compound that promotes lysosomal activity, improved mitochondrial function, thereby decreasing STING signaling. Furthermore, lysosomal damage caused by GC accumulation led to defects in the degradation of activated STING, further exacerbating inflammation mediated by microglia. Thus, limiting STING activity may be a strategy to suppress neuroinflammation caused by GCase deficiency.

Gaucher disease (GD) is a lysosomal storage disorder stemming from biallelic mutations in GBA1 , characterized by glucocerebrosidase dysfunction and glucocerebroside and glucosylsphingosine accumulation. Since phenotypes of murine models of GD often differ from those in patients, the careful characterization of Gba1 mutant mice is necessary to establish their ability to model GD. We performed side-by-side comparative biochemical and pathologic analyses of four murine Gba1 models with genotypes L444P/L444P (p.L483P/p.L483P), L444P/null, D409H/D409H (p.D448H/p.D448H) and D409H/null, along with matched wildtype mice, all with the same genetic background and cage conditions. All mutant mice exhibited significantly lower glucocerebrosidase activity ( p < 0.0001) and higher glucosylsphingosine levels than wildtype, with the lowest glucocerebrosidase and the highest glucosylsphingosine levels in mice carrying a null allele. Although glucocerebrosidase activity in L444P and D409H mice was similar, D409H mice showed more lipid accumulation. No Gaucher or storage-like cells were detected in any of the Gba1 mutant mice. Quantification of neuroinflammation, dopaminergic neuronal loss, alpha-synuclein levels and motor behavior revealed no significant findings, even in aged animals. Thus, while the models may have utility for testing the effect of different therapies on enzymatic activity, they did not recapitulate the pathological phenotype of patients with GD, and better models are needed.

A 44-year-old female presented with a distended abdomen and fatigue. On physical examination, prominent splenomegaly was found. The laboratory investigations revealed pancytopenia and decreased albumin-globulin ratio. The abdominal ultrasonography revealed splenomegaly, cholelithiasis, and cystitis, and the bone survey showed osteopenia. Differential diagnoses included leukemia, multiple myeloma, and myelofibrosis therefore bone marrow puncture was performed. However, histopathologic examination found Gaucher-like cells in the bone marrow aspiration. The finding of CD68 positivity in Gaucher-like cells by using the immunohistochemistry staining supporting Gaucher disease. To confirm the diagnosis, an examination of glucocerebroside substrate from the patient's blood plasma was performed. Glucosylsphingosine, a deacylated form of glucosylceramide, was markedly elevated. Therefore, the diagnosis of Gaucher disease was confirmed. This is the first reported adult Gaucher case diagnosed in Indonesia.

The beta-glucocerebrosidase (GBA1) gene encodes the lysosomal beta-glucocerebrosidase (GCase) that metabolizes the lipids glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Biallelic loss-of-function mutations in GBA1 such as L444P cause Gaucher disease (GD), which is the most prevalent lysosomal storage disease and is histopathologically characterized by abnormal accumulation of the GCase substrates GlcCer and GlcSph. GD with neurological symptoms is associated with severe mutations in the GBA1 gene, most of which cause impairment in the process of GCase trafficking to lysosomes. Given that recombinant GCase protein cannot cross the blood-brain barrier due to its high molecular weight, it is invaluable to develop a brain-penetrant small-molecule pharmacological chaperone as a viable therapeutic strategy to boost GCase activity in the central nervous system. Despite considerable efforts to screen potent GCase activators/chaperones, cell-free assays using recombinant GCase protein have yielded compounds with only marginal efficacy and micromolar EC 50 that would not have sufficient clinical efficacy or an acceptable safety margin. Therefore, we utilized a fluorescence-labeled GCase suicide inhibitor, MDW933, to directly monitor lysosomal GCase activity and performed a cell-based screening in fibroblasts from a GD patient with homozygotic L444P mutations. Here, we identified novel compounds that increase the fluorescence signal from labeled GCase with L444P mutations in a dose-dependent manner. Secondary assays using an artificial cell-permeable lysosomal GCase substrate also demonstrated that the identified compounds augment lysosomal GCase L444P in the fibroblast. Moreover, those compounds increased the total GCase L444P protein levels, suggesting the pharmacological chaperone-like mechanism of action. To further elucidate the effect of the compounds on the endogenous GCase substrate GlcSph, we generated iPSC-derived dopaminergic neurons with a GBA1 L444P mutation that exhibit GlcSph accumulation in vitro. Importantly, the identified compounds reduce GlcSph in iPSC-derived dopaminergic neurons with a GBA1 L444P mutation, indicating that the increase in lysosomal GCase resulting from application of the compounds leads to the clearance of pathologically-accumulated GlcSph. Together, our findings pave the way for developing potent and efficacious GCase chaperone compounds as a potential therapeutic approach for neurological GD., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hideki Matsui reports a relationship with Takeda Pharmaceutical Company Limited that includes: employment and non-financial support. Yusuke Naito, Sou Sakamoto, Takuto Kojima, Misaki Homma, Maiko Tanaka reports a relationship with Takeda Pharmaceutical Company Limited that includes: employment and non-financial support., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Gaucher disease is a rare genetic disorder caused by a deficiency in the enzyme glucocerebrosidase, which impairs the body's ability to break down certain fats. This leads to the accumulation of glucosyl sphingosine and glucosyl ceramide in the liver, spleen, and bone marrow. Gaucher disease has two major types: nonneuropathic (Type 1) and neuropathic (Type 2 and Type 3). Gaucher disease can have various ophthalmologic manifestations, particularly in Type 3, including posterior segment abnormalities, such as vitreous opacities, condensations, and/or preretinal white dots. We present a case of a patient with Gaucher disease Type 3 who had severe bilateral vitreous and extensive retinal deposits, leading to challenges during surgery., Purpose: This video reports surgical outcomes for an uncommon ophthalmologic manifestation in a patient with Gaucher disease Type 3. We focus on the challenges and results of surgery for severe bilateral vitreous and extensive retinal deposits., Synopsis: A 16-year-old female patient with a history of Gaucher's disease since birth presented with a one-year history of blurred vision in both eyes. Her best-corrected visual acuity was 20/200 in the right eye and 20/100 in the left eye, as measured by Snellen's chart. Intraocular pressure was normal in both eyes, and anterior segment examinations were unremarkable. However, fundus evaluation revealed extensive vitreous deposits that obscured the details of the fundus. Additionally, an epiretinal membrane was observed over the macula in both eyes. Optical coherence tomography (OCT) confirmed the presence of deposits in the vitreous cavity and on the surface of the retina. The patient underwent pars plana vitrectomy with epiretinal membrane removal. A transconjunctival 23-G pars plana vitrectomy was performed to the extent possible. Multiple instruments were used to remove the fluffy vitreous deposits, as they were extremely adherent to the underlying surface of the retina, and brilliant blue dye was used to stain the internal limiting membrane. The epiretinal membrane and internal limiting membrane were removed from the macular area, and the entire cassette fluid was sent for histopathological examination to identify Gaucher cells. At one week postoperative, the patient's visual acuity improved to 20/125 in the right eye, and the fundus picture showed a cleared macular area. OCT showed a reduction in deposits over the retina. The histopathological examination revealed crumpled, barrel-like cytoplasm with an oval nucleus in a hemorrhagic background, suggestive of Gaucher cells., Highlights: Early detection and treatment of ocular manifestations of Gaucher's disease are important to prevent permanent damage to vision. An ophthalmological assessment involving a dilated fundus examination and optical coherence tomography can facilitate early diagnosis and follow-up of ocular manifestations. Timely surgery may be required to preserve functional vision in patients with severe ocular disease., Video Link: https://youtu.be/KR-kfgfDoqM., Competing Interests: None

Gaucher disease (GD) is caused by biallelic pathogenic variants in the acid β-glucosidase gene ( GBA1 ), leading to a deficiency in the β-glucocerebrosidase (GCase) enzyme activity resulting in the intracellular accumulation of sphingolipids. Skeletal alterations are one of the most disabling features in GD patients. Although both defective bone formation and increased bone resorption due to osteoblast and osteoclast dysfunction contribute to GD bone pathology, the molecular bases are not fully understood, and bone disease is not completely resolved with currently available specific therapies. For this reason, using editing technology, our group has developed a reliable, isogenic, and easy-to-handle cellular model of GD monocytes (GBAKO-THP1) to facilitate GD pathophysiology studies and high-throughput drug screenings. In this work, we further characterized the model showing an increase in proinflammatory cytokines (Interleukin-1β and Tumor Necrosis Factor-α) release and activation of osteoclastogenesis. Furthermore, our data suggest that GD monocytes would display an increased osteoclastogenic potential, independent of their interaction with the GD microenvironment or other GD cells. Both proinflammatory cytokine production and osteoclastogenesis were restored at least, in part, by treating cells with the recombinant human GCase, a substrate synthase inhibitor, a pharmacological chaperone, and an anti-inflammatory compound. Besides confirming that this model would be suitable to perform high-throughput screening of therapeutic molecules that act via different mechanisms and on different phenotypic features, our data provided insights into the pathogenic cascade, leading to osteoclastogenesis exacerbation and its contribution to bone pathology in GD.

Gaucher disease (GD) is the most frequent lysosomal storage disorder due to biallelic pathogenic variants in GBA gene. Only homozygous D409H variant has been associated with the cardiovascular phenotype which is also known as Gaucher disease type 3c. In this descriptive study, we presented phenotypic heterogeneity and a novel clinical finding among 13 patients with GD type 3c. Patients presented with varying degrees of cardiac valve and/or aortic calcifications (84,6%) and corneal opacities (76,9%) in addition to visceral (100%), hematological (92,3%), neurological (92,3%), and skeletal (30%) manifestations. Also, cervical dystonia (38,4%) and psychiatric disorders (46,1%) were not infrequent entities with respect to neurological involvement in GD type 3c. In this report, we highlight transient neonatal cholestasis (38,4%) as a novel finding in GD type 3c. Neonatal cholestasis is a finding associated with Gaucher type 2, but transient neonatal cholestasis has not been reported in GD patients, so far. The clinical features of GD type 3c are highly heterogeneous, from disease severity or age of onset to disease progression. Also, we concluded that phenotypic spectrum may be associated with age at onset of clinical symptoms. As, patients presenting in infancy or childhood had mainly visceral and hematological involvement and patients presenting in adolescence and adulthood had mainly cardiac, neurological involvement, and psychiatric behavioral disorders. Identifying the heterogeneous clinical course of these patients in this fatal disease, may lead a sufficient understanding of the pathophysiology which will enable targeted therapeutic interventions., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Gaucher disease (GD) is the most frequent sphingolipidosis, caused by biallelic pathogenic variants in the GBA1 gene encoding for β-glucocerebrosidase (GCase, E.C. 3.2.1.45). The condition is characterized by hepatosplenomegaly, hematological abnormalities, and bone disease in both non-neuronopathic type 1 (GD1) and neuronopathic type 3 (GD3). Interestingly, GBA1 variants were found to be one of the most important risk factors for the development of Parkinson's disease (PD) in GD1 patients. We performed a comprehensive study regarding the two most disease-specific biomarkers, glucosylsphingosine (Lyso-Gb1) and α-synuclein for GD and PD, respectively. A total of 65 patients with GD treated with ERT (47 GD1 patients and 18 GD3 patients), 19 GBA1 pathogenic variant carriers (including 10 L444P carriers), and 16 healthy subjects were involved in the study. Lyso-Gb1 was assessed by dried blood spot testing. The level of α-synuclein as an mRNA transcript, total, and oligomer protein concentration were measured with real-time PCR and ELISA, respectively. α-synuclein mRNA level was found significantly elevated in GD3 patients and L444P carriers. GD1 patients, along with GBA1 carriers of an unknown or unconfirmed variant, as well as healthy controls, have the same low level of α-synuclein mRNA. There was no correlation found between the level of α-synuclein mRNA and age in GD patients treated with ERT, whereas there was a positive correlation in L444P carriers.

Acute neuronopathic (type II) Gaucher disease (GD) is a devastating, untreatable neurological disorder resulting from mutations in the glucocerebrosidase gene (GBA1), with subsequent accumulation of glucosylceramide and glucosylsphingosine. Patients experience progressive decline in neurological function, with onset typically within the first three-to-six months of life and premature death before two years. Mice and drosophila with GD have been described, however little is known about the brain pathology observed in the naturally occurring ovine model of GD. We have characterised pathological changes in GD lamb brain and compared the histological findings to those in GD patient post-mortem tissue, to determine the validity of the sheep as a model of this disease. Five GD and five age-matched unaffected lamb brains were examined. We observed significant expansion of the endo/lysosomal system in GD lamb cingulate gyrus however TPP1 and cathepsin D levels were unchanged or reduced. H&E staining revealed neurons with shrunken, hypereosinophilic cytoplasm and hyperchromatic or pyknotic nuclei (red neurons) that were also shrunken and deeply Nissl stain positive. Amoeboid microglia were noted throughout GD brain. Spheroidal inclusions reactive for TOMM20, ubiquitin and most strikingly, p-Tau were observed in many brain regions in GD lamb brain, potentially indicating disturbed axonal trafficking. Our findings suggest that the ovine model of GD exhibits similar pathological changes to human, mouse, and drosophila type II GD brain, and represents a model suitable for evaluating therapeutic intervention, particularly in utero-targeted approaches., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Gaucher disease (GD) is one of the most common lysosomal storage diseases. It is characterized by the accumulation of glucocerebroside lipids in the macrophages, with liver, spleen and bone marrow frequently affected. The affected organs can develop tumor-like lesions (Gaucheromas), which are difficult to diagnose. We present the Gaucheromas and their ultrasonographic characteristics., Methods: We selected Gaucheromas and their ultrasonographic characteristics found in the last 5 years during the periodical evaluation of 74 adult GD patients in Romania. All the patients had magnetic resonance imaging examination for comparison. A systematic review of all the Gaucheroma-related articles was performed to compare our results with the literature., Results: Gaucheromas were found in 7 adult patients: 4 in the spleen, 2 in the liver and one affecting the bone. No malignancy ultrasound characteristics were found and neither on MRI exams. In the literature, 10 articles reported Gaucheromas, most of them in the liver and spleen in type 1 GD patients. All our patients were also type 1 GD, and the ultrasound aspect did not change during the 5 years follow-up., Conclusions: Gaucheromas can be found in any patient with GD. Malignancies have to be considered unless proven otherwise. Imaging characterization (ultrasound and MRI) are useful as histopathologic examination is difficult to obtain in all cases.

Background and Objectives : Gaucher disease (GD) is a lysosomal storage disorder with the genetic autosomal recessive transmission. Bone involvement is a prevalent finding in Gaucher disease. It causes deformity and limits daily activities and the quality of life. In 75% of patients, there is bone involvement. This review aims to evaluate the principal findings in the jaw by a Cone-beam computed tomography (CBTC) and X-ray orthopantomography; Materials and Methods : PubMed, Web of Science, Lilacs and Scopus were systematically searched until 31 December 2022. In addition, a manual search was performed using the bibliography of selected articles and a Google Scholar search. Clinical studies were selected that considered principal radiographic findings in radiography in a group of patients affected by GD. Results : Out of 5079 papers, four studies were included. The main findings are generalized rarefaction and enlarged narrow space, anodontia. Conclusions : The exact mechanism of bone manifestation is probably due to the infiltration of Gaucher cells in the bone marrow and, consequently, the destruction of bone architecture. All long bones are a potential means of skeletal manifestation. The jaw is more affected than the maxilla, and the principal features are cortical thinning, osteosclerosis, pseudocystic lesions, mental demineralization, flattening in the head of the condyle, effacement of anatomical structures, thickening of maxillary sinus mucosa. The dentist plays a crucial role in diagnosing and treating these patients. Sometimes the diagnosis can be made by a simple panoramic radiograph. All long bones are affected, and the mandible is particularly involved.

Gaucher disease (GD) is the most common lysosomal storage disease caused by recessive mutations in the degrading enzyme of β-glucosylceramide (β-GlcCer). However, it remains unclear how β-GlcCer causes severe neuronopathic symptoms, which are not fully treated by current therapies. We herein found that β-GlcCer accumulating in GD activated microglia through macrophage-inducible C-type lectin (Mincle) to induce phagocytosis of living neurons, which exacerbated Gaucher symptoms. This process was augmented by tumor necrosis factor (TNF) secreted from activated microglia that sensitized neurons for phagocytosis. This characteristic pathology was also observed in human neuronopathic GD. Blockade of these pathways in mice with a combination of FDA-approved drugs, minocycline (microglia activation inhibitor) and etanercept (TNF blocker), effectively protected neurons and ameliorated neuronopathic symptoms. In this study, we propose that limiting unrestrained microglia activation using drug repurposing provides a quickly applicable therapeutic option for fatal neuronopathic GD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Lysosomal storage disorders (LSDs) are rare disorders and pose a diagnostic challenge for clinicians owing to their generalized symptomatology. In this study, we aim to classify LSDs into two broad categories, namely, Gaucher disease (GD) and Niemann-Pick/Niemann-Pick-like diseases (NP/NP-like diseases) based on the morphology of the storage cells in the bone marrow (BM) aspiration smears and trephine biopsy sections., Materials and Method: This retrospective study includes 32 BM specimens morphologically diagnosed as LSDs at our institute, in the last 10 years. Subsequently, they were subclassified into GD and NP/NP-like diseases. Further, we have compared and analyzed the clinical, hematological, and biochemical parameters for the two groups of LSDs., Results: Based on BM morphology, 59.4% (n = 19) cases were diagnosed as NP/NP-like diseases and 40.6% (n = 13) cases as GD. Abdominal distension and failure to thrive were the most common clinical manifestations in both groups of LSDs. Anemia and thrombocytopenia were frequently seen in either of the LSDs. On the assessment of metabolic profile, elevated total/direct bilirubin and liver enzymes were more commonly seen in NP/NP-like diseases when compared with GD., Conclusion: We have classified LSDs into GD and NP/NP-like diseases based on the morphology of the storage cells in the BM specimen. The hallmark findings on BM biopsy annexed with the comparative features of the two proposed categories can aid the clinician in clinching the diagnosis. Formulation of such a methodology will prove instrumental for patient care in an underresourced setting., Competing Interests: None

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder due to the deficient activity of the acid beta-glucosidase (GCase) enzyme, resulting in the progressive lysosomal accumulation of glucosylceramide (GlcCer) and its deacylated derivate, glucosylsphingosine (GlcSph). GCase is encoded by the GBA1 gene, located on chromosome 1q21 16 kb upstream from a highly homologous pseudogene. To date, more than 400 GBA1 pathogenic variants have been reported, many of them derived from recombination events between the gene and the pseudogene. In the last years, the increased access to new technologies has led to an exponential growth in the number of diagnostic laboratories offering GD testing. However, both biochemical and genetic diagnosis of GD are challenging and to date no specific evidence-based guidelines for the laboratory diagnosis of GD have been published. The objective of the guidelines presented here is to provide evidence-based recommendations for the technical implementation and interpretation of biochemical and genetic testing for the diagnosis of GD to ensure a timely and accurate diagnosis for patients with GD worldwide. The guidelines have been developed by members of the Diagnostic Working group of the International Working Group of Gaucher Disease (IWGGD), a non-profit network established to promote clinical and basic research into GD for the ultimate purpose of improving the lives of patients with this disease. One of the goals of the IWGGD is to support equitable access to diagnosis of GD and to standardize procedures to ensure an accurate diagnosis. Therefore, a guideline development group consisting of biochemists and geneticists working in the field of GD diagnosis was established and a list of topics to be discussed was selected. In these guidelines, twenty recommendations are provided based on information gathered through a systematic review of the literature and two different diagnostic algorithms are presented, considering the geographical differences in the access to diagnostic services. Besides, several gaps in the current diagnostic workflow were identified and actions to fulfill them were taken within the IWGGD. We believe that the implementation of recommendations provided in these guidelines will promote an equitable, timely and accurate diagnosis for patients with GD worldwide., (© 2022. The Author(s).)

There are numerous reports of cancers in Gaucher disease (GD) from mostly small single-center studies; however, precise risk estimates and cancer types involved have not been delineated. We conducted a study involving 2123 patients with GD type 1 (GD1) to assess the incidence of hematological malignancies, gammopathies, and solid tumors in an international observational study, the International Cooperative Gaucher Group Gaucher Registry (Clinicaltrials.gov: NCT00358943). Risk for cancer overall and for each type of malignancy was compared to the United States (US) population using the Surveillance, Epidemiology, and End Results database. Natural history of gammopathy was determined through assessing the progression from a diagnosis of monoclonal gammopathy of unknown significance (MGUS) to multiple myeloma (MM). Risk for hematological malignancies was more than four times higher than expected compared to the general population: non-Hodgkin lymphoma was approximately three times higher; MM was approximately nine times higher. Age-specific incidence rates of MGUS were unexpectedly high among younger patients. The 10-year cumulative incidence of MM after diagnosis of MGUS was 7.9%, comparable to the general population. Compared to the general US population, GD1 patients were at higher risk for solid malignancies of liver (2.9 times), kidney (2.8 times), melanoma (2.5 times), and breast (1.4 times). Colorectal, prostate, and lung cancer risks were lower than expected. These findings help advance care of patients with GD1 by supporting recommendations for individualized monitoring for malignancies and antecedents such as MGUS for MM and provoke important questions of the role of glucosylceramide and related sphingolipids in cancer biology., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Lysosomes have a critical role in maintaining normal cellular homeostasis mediated by their involvement in secretion, plasma membrane repair, cell signaling and energy metabolism. Lysosomal storage disorders (LSDs) are a group of approximately 50 rare disorders caused by lysosomal dysfunction that occur due to mutations in a gene of a lysosomal protein. Gaucher disease (GD), an autosomal recessive disorder and one of the most common LSDs, is caused by the deficiency of the lysosomal enzyme acid-β-glucocerebrosidase (GCase), due to biallelic mutations in the GBA1 gene. Reduced GCase activity leads to the accumulation of glucosylceramide (GlcCer), which is deacylated by lysosomal acid ceramidase to a toxic metabolite, glucosylshpingosine (GlcSph). Most GBA1 variants are recognized as misfolded in the ER, where the retention for refolding attempts initiates stress and activates the stress response known as the Unfolded Protein Response (UPR). The distinct clinical subtypes of GD are based on whether there is primary involvement of the central nervous system. Type 1 GD (GD1) is the nonneuropathic type, however, the recent recognition of the association of GD with the development of parkinsonism defies this classification. Patients with GD1 and carriers of GBA1 mutations are at risk for the development of parkinsonian manifestations. Parkinson disease (PD), the second most prevalent neurodegenerative disease, culminates in a movement disorder with the premature death of the patients. In PD and related disorders, collectively called synucleinopathies, the hallmark pathology is α-synuclein positive aggregates referred to as Lewy bodies or Lewy neurites and the death of dopaminergic neurons. While PD is mostly sporadic, in ∼5-10% of cases, the disease results from pathogenic variants in a growing number of genes. The most common genetic cause of PD is mutations in GBA1. Two mechanisms have been proposed for this link: (A) a "gain of function" mechanism, in which mutant GCase (protein) contributes to aggregate formation and to the development of PD, and the (B) "haploinsufficiency" ("loss of function") model, suggesting that one normal GBA1 allele is insufficient to carry adequate GCase activity and functional deficiency of GCase impedes α-synuclein metabolism. Lysosomal dysfunction, compromised autophagy and mitophagy further enhance the accumulation of α-synuclein, which results in the development of PD pathology. The present review will elaborate on the biology of GD, its association with PD and related disorders, and discuss the possible mechanisms underlying this association., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MH received grants from SHIRE Pharmaceuticals (now Takeda) and from Pfizer Pharmaceuticals Ltd. HB has no competing interests. AZ receives honoraria from Takeda, Pfizer and BioEvents and consultancy from Takeda, NLC Pharma, Prevail Therapeutics and InsighTec. SRV receives grant/research support, honoraria, and advisory fee from Takeda, Pfizer, and Sanofi/Genzyme. The Gaucher Unit at Shaare Zedek Medical Center receives support from Sanofi/Genzyme for participation in the ICGG Registry, from Takeda for the GOS Registry and from Pfizer for TALIAS. The Unit also receives research grants from Takeda, Pfizer, Sanofi/Genzyme, and Centogene. OGA received a grant support from Sanofi for the clinical trial NCT02906020 and is a consultant for Prevail therapeutics., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Gaucher disease (GD) is caused by glucocerebrosidase deficiency leading to the accumulation of sphingolipids in macrophages named "Gaucher's Cells". These cells are characterized by deregulated expression of cell surface markers, abnormal secretion of inflammatory cytokines, and iron sequestration. These cells are known to infiltrate tissues resulting in hematological manifestations, splenomegaly, and bone diseases. We have already demonstrated that Gaucher red blood cells exhibit altered properties suggesting their key role in GD clinical manifestations. We hypothesized that Gaucher's erythrocytes could be prone to premature destruction by macrophages contributing to the formation of altered macrophages and Gaucher-like cells. We conducted in vitro experiments of erythrophagocytosis using erythrocytes from Gaucher's patients or healthy donors. Our results showed an enhanced erythrophagocytosis of Gaucher red blood cells compared to healthy red blood cells, which is related to erythrocyte sphingolipids overload and reduced deformability. Importantly, we showed elevated expression of the antigen-presenting molecules CD1d and MHC-II and of the iron-regulator hepcidin in macrophages, as well as enhanced secretion of the pro-inflammatory cytokine IL-1β after phagocytosis of GD erythrocytes. These results strongly suggested that erythrophagocytosis in GD contribute to phenotypic modifications in macrophages. This present study shows that erythrocytes-macrophages interactions may be crucial in GD pathophysiology and pathogenesis.

Objective: To analyze the clinical and genetical characteristics of children with Gaucher disease and to explore the relationship between genotype and phenotype. Methods: In this retrospective study, the clinical data of 14 children with Gaucher disease diagnosed in Children's Hospital of Nanjing Medical University from August 2016 to October 2021 were analyzed. Their general conditions, clinical manifestations, laboratory tests and gene variations were collected, followed by the analysis of the clinical phenotypes and genotypes. Results: Among 14 children diagnosed with Gaucher disease, 9 were males and 5 were females, with the age of diagnosis ranging from 0.7 to 15.8 years. There were 10 patients with type 1 Gaucher disease, 2 patients with type 2, and 2 patients with type 3. The most common clinical manifestations were splenomegaly, thrombocytopenia (14 cases), hepatomegaly (8 cases) and anemia (8 cases). There were 6 patients with growth retardation, and 5 patients lag in height compared with their peers. Bone abnormalities were revealed by magnetic resonance imaging in 7 type 1 Gaucher disease patients, but only 1 patient experienced bone pain. Patients with type 2 and type 3 Gaucher disease also presented with convulsions, nystagmus and hearing loss. Gaucher cells were found in bone marrow smears in 12 patients. The glucocerebrosidase gene variations identified in 13 patients were heterozygous and in 1 type 1 patient was homozygous of L483P. L483P variation accounted for 33%(10/30) of the variation alleles, followed by V414L, D448H and R159W. The variation alleles were L483P and L422R, F252I and L483P in 2 children with severe neurological manifestations of Gaucher disease. A novel variation c.22A>G was detected. Conclusions: Splenomegaly and thrombocytopenia are the main clinical presentations of Gaucher disease in children and bone lesions revealed by radiologic imaging appear prior to the occurrence of bone diseases, type 2 and type 3 Gaucher disease also present growth retardation and neurological manifestation. The most frequent variant allele is L483P, which are detected in all 3 subtypes of Gaucher disease. The L422R, F252I gene variants correlated with the neuronopathic phenotype.

Aims: The aims of this study are (i) to develop a population pharmacokinetic model of enzyme activity in Gaucher-type 1 (GD1) patients after intravenous administration of enzyme replacement therapy (ERT), and (ii) to establish an exposure-efficacy relationship for bone marrow infiltration to propose dose adjustments according to patient covariate values., Methods: A prospective follow-up, semi-experimental multi-centre study was conducted in four hospitals to evaluate the pharmacokinetics, efficacy and safety of ERT in GD1 patients. Twenty-five individuals with 266 glucocerebrosidase (GCase) observations in plasma and leukocytes and 14 individuals with 68 Spanish magnetic resonance imaging (S-MRI) observations were enrolled., Results: A two concatenated compartment model with zero-order endogenous production and first-order distribution (CL 1  = 3.85 × 10 -1 L/d) and elimination (CL 2  = 1.25 L/d) allowed GCase observations in plasma and leukocytes to be described, respectively. An exponential time dependency (k T  = 6.14 × 10 -1 d -1 ) effect on CL 1 was incorporated. The final exposure-efficacy model was a longitudinal logistic regression model with a first-order Markov element. An E max function (EC 50  = 15.73 U/L and E max  = 2.33) linked steady-state concentrations of GCase in leukocytes to the probability of transition across the different S-MRI stages., Conclusion: A population pharmacokinetic model successfully characterized the leukocyte activity-time profiles of GCase following intravenous administration of ERT in GD1 patients together with an exposure-efficacy relationship in bone marrow using Markovian elements. The information obtained from this study could be of high clinical relevance in individualization of ERT in GD1 patients, as this could lead to anticipative decision-making regarding clinical response in bone and optimal dosing strategy., (© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Deficient acid β-glucocerebrosidase activity due to biallelic mutations in GBA1 results in Gaucher disease (GD). Patients with this lysosomal storage disorder exhibit a wide range of associated manifestations, spanning from virtually asymptomatic adults to infants with severe neurodegeneration. While type 1 GD (GD1) is considered non-neuronopathic, a small subset of patients develop parkinsonian features. Variants in GBA1 are also an important risk factor for several common Lewy body disorders (LBDs). Neuropathological examinations of patients with GD, including those who developed LBDs, are rare. GD primarily affects macrophages, and perivascular infiltration of Gaucher macrophages is the most common neuropathologic finding. However, the frequency of these clusters and the affected anatomical region varies. GD affects astrocytes, and, in neuronopathic GD, neurons in cerebral cortical layers 3 and 5, layer 4b of the calcarine cortex, and hippocampal regions CA2-4. In addition, several reports describe selective degeneration of the cerebellar dentate nucleus in chronic neuronopathic GD. GD1 is characterized by astrogliosis without prominent neuronal loss. In GD-LBD, widespread Lewy body pathology is seen, often involving hippocampal regions CA2-4. Additional neuropathological examinations in GD are sorely needed to clarify disease-specific patterns and elucidate causative mechanisms relevant to GD, and potentially to more common neurodegenerative diseases.

Lysosomal storage diseases (LSDs) are rare genetic disorders caused by a disruption in cellular clearance, resulting in pathological storage of undegraded lysosomal substrates. Recent clinical and genetic studies have uncovered links between multiple LSDs and common neurodegenerative diseases such as Parkinson's disease (PD). Here, we review recent literature describing the role of glia cells and neuroinflammation in PD and LSDs, including Gaucher disease (GD) and neuronal ceroid lipofuscinosis (NCL), and highlight converging inflammation pathways that lead to neuron loss. Recent data indicates that lysosomal dysfunction and accumulation of storage materials can initiate the activation of glial cells, through interaction with cell surface or cytosolic pattern recognition receptors that detect pathogenic aggregates of cellular debris. Activated glia cells could act to protect neurons through the elimination of toxic protein or lipid aggregates early in the disease process. However prolonged glial activation that occurs over several decades in chronic-age related neurodegeneration could induce the inappropriate elimination of synapses, leading to neuron loss. These studies provide mechanistic insight into the relationship between lysosomal dysfunction and glial activation, and offer novel therapeutic pathways for the treatment of PD and LSDs focused on reducing neuroinflammation and mitigating cell loss., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Neuronal loss in Parkinson's disease and related brain diseases has been firmly linked to the abundant neuronal protein α-synuclein (αS). However, we have gained surprisingly little insight into how exactly αS exerts toxicity in these diseases. Hypotheses of proteotoxicity, disturbed vesicle trafficking, mitochondrial dysfunction and other toxicity mechanisms have been proposed, and it seems possible that a combination of different mechanisms may drive pathology. A toxicity mechanism that has caught increased attention in the recent years is αS-related lipotoxicity. Lipotoxicity typically occurs in a cell when fatty acids exceed the metabolic needs, triggering a flux into harmful pathways of non-oxidative metabolism. Genetic and experimental approaches have revealed a significant overlap between lipid storage disorders, most notably Gaucher's disease, and synucleinopathies. There is accumulating evidence for lipid aberrations causing synuclein misfolding as well as for αS excess and misfolding causing lipid aberration. Does that mean the key problem in synucleinopathies is lipotoxicity, the accumulation of harmful lipid species or alteration in lipid equilibrium? Here, we review the existing literature in an attempt to get closer to an answer.

Background: Gaucher's disease is associated with a high variety of structural and functional abnormalities in the eye, which do not always affect visual acuity. The purpose of this study was to analyse ocular features in Spanish patients with Gaucher's disease type I, and to investigate their possible correlation with phenotypic and burden parameters of this entity., Methods: This cross-sectional observational study compared parameters belonging to 18 eyes from 9 Spanish patients with Gaucher's disease Type I with 80 eyes from 40 healthy controls. Complete ophthalmological examination included choroidal and retinal thickness maps with swept source optical coherence tomography. Systemic analysis included genotype, plasmatic biomarkers, [ferritin, chemokine ligand 18 (CCL18) and chitotriosidase (ChT)] and severity scoring systems results ["Gaucher Disease Severity Score Index Type I" (GauSSI-I) and "Gaucher disease severity scoring system" (GD-DS3)]., Results: Nine subjects (18 eyes) were cases (female: 55.5%, mean age 45 years; male: 44.5%, mean age 36 years) and 40 subjects (80 eyes) were controls (female: 49%, mean age 50 years; male: 51%, mean age 55 years). There were no statistically significant differences when comparing ocular parameters (visual acuity; axial length, refractive errors, corneal parameters, lens, retinal and choroidal thickness) between case and control subjects (p>0.05). A statistically significant moderate correlation was observed between lower retinal thickness and choroidal quadrants thickness and greater disease severity scores. A lower central retinal thickness also correlates with higher biological plasmatic levels, and has a statistically significant association with the most affected patient with genotype N370S/Del 55pb. Conversely, higher pachymetry involves a more severe plasmatic concentration of biomarkers., Conclusions: Our results suggest that pachymetry, and retinal and choroidal thickness, are associated with burden biomarkers and disease severity index scores in Spanish patients with Gaucher's disease Type I., Competing Interests: The authors have declared that no competing interests exist.

Gaucher disease (GD) caused by mutation in the GBA gene has a wide spectrum of phenotypes. Besides the storage disorder, secondary alteration of various pathways occurs with modification of the expression of many genes. In our work we analysed the expression profile of genes in adult patients with type 1 GD., Methods: This study was an observational, cross-sectional analysis of a group of twenty patients with type 1 GD and ten healthy volunteers as a control group. First, on the group of ten persons, microarray gene analysis was performed. Afterwards, significantly regulated genes were selected, and the microarray results were confirmed by real-time PCR on the whole study group., Results: Based on the microarray results in the pathway analysis, we focused on genes related to chemokines, inflammatory processes, endocytosis, autophagy, and apoptosis. Patients with GD demonstrated up-regulation of genes related to NFkB pathway (NFkB, NKkBR SQSTM1), inflammation (IL-1b), endocytosis and autophagy (BCN1, SMAD), genes coding proteins involved in apoptosis (CASP, NFkB, BCL2) as well as genes related to proteasome degradation (PSMD2, PSMB9) and SNARE complex (SNAP, STX). Simultaneously, we showed down-regulation of genes coding proteins of chemokines and their receptors (GNB4, CCL5). The qRT-PCR results confirmed changes in expression of selected genes. Parallel microarray results showed inhibition of genes related to neurones development and survival (NTRK1) and stimulation of gene expression related to neurodegeneration and apoptosis (BCN1, IL1B)., Conclusions: The work revealed different pathway activation, especially inflammatory processes followed by autophagy and apoptosis. Our results also pay attention to new pathways leading to disorders of the functioning of the nervous tissue in patients with type 1 GD, which may lead to the development of polyneuropathy and chronic pain. These are clinical symptoms that severely decrease the quality of life in GD patients., (Copyright © 2021. Published by Elsevier Inc.)

Mutations in GBA which are causative of Gaucher disease in their biallelic form, are the most common genetic risk factor for Parkinson's disease (PD). The diagnosis of PD relies upon clinically defined motor features which appear after irreversible neurodegeneration. Prodromal symptoms of PD may provide a means to predict latent pathology, years before the onset of motor features. Previous work has reported prodromal features of PD in GBA mutation carriers, however this has been insufficiently sensitive to identify those that will develop PD. The Remote Assessment of Parkinsonism Supporting Ongoing Development of Interventions in Gaucher Disease (RAPSODI GD) study assesses a large cohort of GBA mutation carriers, to aid development of procedures for earlier diagnosis of PD.

Parkinson's Disease (PD) is the most common movement disorder, and the strongest genetic risk factor for PD is mutations in the glucocerebrosidase gene ( GBA ). Mutations in GBA also lead to the development of Gaucher Disease (GD), the most common type of lysosomal storage disorder. Current therapeutic approaches fail to address neurological GD symptoms. Therefore, identifying therapeutic strategies that improve the phenotypic traits associated with GD/PD in animal models may provide an opportunity for treating neurological manifestations of GD/PD. Thiazolidinediones (TZDs, also called glitazones) are a class of compounds targeted for the treatment of type 2 diabetes, and have also shown promise for the treatment of neurodegenerative disease, including PD. Here, we tested the efficacy of glitazone administration during development in a fly GD model with deletions in the GBA homolog, dGBA1b (GBA1 ΔTT/ΔTT ). We observed an optimal dose of pioglitazone (PGZ) at a concentration of 1 μM that reduced sleep deficits, locomotor impairments, climbing defects, and restoration of normal protein levels of Ref(2)P, a marker of autophagic flux, in GBA1 ΔTT/ΔTT mutant flies, compared to GBA1 +/+ control flies. These data suggest that PGZ may represent a potential compound with which to treat GD/PD by improving function of lysosomal-autophagy pathways, a cellular process that removes misfolded or aggregated proteins.

Gaucher disease is a lysosomal storage disease, which happens due to mutations in GBA1 / Gba1 that encodes the enzyme termed as lysosomal acid β-glucosidase. The major function of this enzyme is to catalyze glucosylceramide (GC) into glucose and ceramide. The deficiency of this enzyme and resultant abnormal accumulation of GC cause altered function of several of the innate and adaptive immune cells. For example, augmented infiltration of T cells contributes to the increased production of pro-inflammatory cytokines, (e.g., IFNγ, TNFα, IL6, IL12p40, IL12p70, IL23, and IL17A/F). This leads to tissue damage in a genetic mouse model ( Gba1 9V/- ) of Gaucher disease. The cellular mechanism(s) by which increased tissue infiltration of T cells occurs in this disease is not fully understood. Here, we delineate role of the CXCR3 receptor and its exogenous C-X-C motif chemokine ligand 9 (CXCL9) in induction of increased tissue recruitment of CD4 + T and CD8 + T cells in Gaucher disease. Intracellular FACS staining of macrophages (Mϕs) and dendritic cells (DCs) from Gba1 9V/- mice showed elevated production of CXCL9. Purified CD4 + T cells and the CD8 + T cells from Gba1 9V/- mice showed increased expression of CXCR3. Ex vivo and in vivo chemotaxis experiments showed CXCL9 involvement in the recruitment of Gba1 9V/- T cells. Furthermore, antibody blockade of the CXCL9 receptor (CXCR3) on T cells caused marked reduction in CXCL9- mediated chemotaxis of T cells in Gba1 9V/- mice. These data implicate abnormalities of the CXCL9-CXCR3 axis leading to enhanced tissue recruitment of T cells in Gaucher disease. Such results provide a rationale for blockade of the CXCL9/CXCR3 axis as potential new therapeutic targets for the treatment of inflammation in Gaucher disease.

Background: Gaucher disease (GD) is the most common lysosomal storage disease and requires long-term enzyme replacement therapy (ERT), which is costly and inconvenient for resource-limited countries such as Thailand. The authors present the case of a 1-year-old boy who was diagnosed with GD type 1 with a homozygous mutation at c.1448 T>C (L444P). He was treated with ERT and matched sibling hematopoietic stem cell transplantation (HSCT) was performed 6 months after the ERT was initiated. At a 3-year follow-up after the HSCT, he had full engraftment and the Lyso-GL1 levels were also at an acceptable level, which indicated disease remission. In conclusion, the authors suggest HSCT for long-term remission of GD in children., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Data from 38 children were retrospectively analyzed to determine the patient characteristics of Turkish children with Gaucher disease (GD) and evaluate the impact of enzyme replacement therapy (ERT) in a pediatric cohort consisting of two different sub-types of the disease, Gaucher disease type 1 (GD1) and type 3 (GD3). Both types were represented equally (GD1/GD3 = 20/18). L444P (35.5%) was the most common mutant allele while L444P/L444P (34.2%) was the most common genotype overall. Compound heterozygosity of N370S and L444P homozygosity were the dominant genotypes in Turkish children with GD1 and GD3, respectively. None of the patients had moderate to severe thrombocytopenia at last follow-up while the percent of patients with anemia decreased from 60% to 5.7% (p < 0.001). Significant improvements in mean liver (from 2.2 to 1.6 MN, p < 0.001) and spleen (from 15.5 to 7.6 MN, p < 0.001) volumes were observed in the first year of ERT. Linear growth was ameliorated as shown by the decrease in the percent of patients having short stature from 34.3% to 13.3% (p < 0.01) at year 5. Erlenmeyer flask deformity, osteopenia and scoliosis were common skeletal findings. Although none of the patients had lung disease at diagnosis, 20% developed radiological findings suggestive of pulmonary involvement. This single center experience is the first comprehensive study from Turkey not only reporting clinical and genetic characteristics of GD patients but also providing information on the outcomes of ERT in two different sub-types of GD. Genotypic background of Turkish children with GD is similar to western populations. Although visceral and hematological therapeutic goals are reached as early as one year of ERT in both sub-types, achieving normal growth takes several more years than suggested in significant number of children with GD., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Gaucher disease is a lysosomal storage disorder characterized by β-glucosidase enzyme deficiency and substrate accumulation, especially in cells of the reticuloendothelial system. Typical features of the disease are the unrestrained activation of inflammatory mechanisms, whose molecular pathways are still unclear. To investigate biological mechanisms underlying the macrophage activation in GD, we derived iPSCs from a healthy donor and a GD patient line and differentiated them into hematopoietic progenitors. While GD iPSCs are able to efficiently give rise to CD33+/CD45+ myeloid progenitors, the maturation towards the CD14+/CD163+ monocyte/macrophages fate resulted enhanced in the GD lines, that in addition displayed a decreased growth potential compared to control cells either in semisolid or in liquid culture. The GD lines growth impairment was associated with a significant upregulation of RIPK3 and MLKL, two key effectors of necroptosis, the inflammation related cell death pathway. The activation of necroptosis, which has already been linked to neuronopathic GD, may play a role in the disease proinflammatory condition and in the identified cell growth defects. Understanding the GD macrophage role in the alteration of mechanisms linked to cellular metabolism imbalance, cell death and inflammation are crucial in identifying new ways to approach the disease.

Introduction: Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of acid β-glucosidase encoded by the GBA gene. In patients with GD, childhood onset parkinsonian features have been rarely described., Methods: Twin siblings with GD are described, including clinical follow-up and treatment response. Bone marrow, enzyme activity studies and genotyping were performed., Results: By age 9 months, symptoms at onset were thrombocytopenia and splenomegaly. By age 2, hypokinesia, bradykinesia and oculomotor apraxia were observed. By age 5 a complete rigid hypokinetic syndrome was stablished in both patients, including bradykinesia, tremor and rigidity. Treatment with imiglucerase, miglustat, ambroxol and levodopa were performed. Levodopa showed a good response with improvement in motor and non-motor skills. Foamy cells were found in the bone marrow study. Glucocerebrosidase activity was 28% and 26%. Sanger sequencing analysis identified a missense mutation and a complex allele (NP&#95;000148: p.[(Asp448His)]; [(Leu422Profs*4)]) in compound heterozygosity in GBA gene., Conclusions: Two siblings with neuronopathic GD with an intermediate form between type 2 and 3, with a systemic and neurological phenotype are described. The complex neurological picture included a hypokinetic-rigid and tremor syndrome that improved with levodopa treatment. These conditions together have not been previously described in pediatric GD. We suggest that in children with parkinsonian features, lysosomal storage disorders must be considered, and a levodopa trial must be performed. Moreover, this report give support to the finding that GBA and parkinsonian features share biological pathways and highlight the importance of lysosomal mechanisms in parkinsonism pathogenesis, what might have therapeutic implications., (Copyright © 2021. Published by Elsevier Ltd.)

Gaucher disease (GD) is an autosomal recessive disorder caused by bi-allelic GBA1 mutations that reduce the activity of the lysosomal enzyme β-glucocerebrosidase (GCase). GCase catalyzes the conversion of glucosylceramide (GluCer), a ubiquitous glycosphingolipid, to glucose and ceramide. GCase deficiency causes the accumulation of GluCer and its metabolite glucosylsphingosine (GluSph) in a number of tissues and organs. In the immune system, GCase deficiency deregulates signal transduction events, resulting in an inflammatory environment. It is known that the complement system promotes inflammation, and complement inhibitors are currently being considered as a novel therapy for GD; however, the mechanism by which complement drives systemic macrophage-mediated inflammation remains incompletely understood. To help understand the mechanisms involved, we used human GD-induced pluripotent stem cell (iPSC)-derived macrophages. We found that GD macrophages exhibit exacerbated production of inflammatory cytokines via an innate immune response mediated by receptor 1 for complement component C5a (C5aR1). Quantitative RT-PCR and ELISA assays showed that in the presence of recombinant C5a (rC5a), GD macrophages secreted 8-10-fold higher levels of TNF-α compared to rC5a-stimulated control macrophages. PMX53, a C5aR1 blocker, reversed the enhanced GD macrophage TNF-α production, indicating that the observed effect was predominantly C5aR1-mediated. To further analyze the extent of changes induced by rC5a stimulation, we performed gene array analysis of the rC5a-treated macrophage transcriptomes. We found that rC5a-stimulated GD macrophages exhibit increased expression of genes involved in TNF-α inflammatory responses compared to rC5a-stimulated controls. Our results suggest that rC5a-induced inflammation in GD macrophages activates a unique immune response, supporting the potential use of inhibitors of the C5a-C5aR1 receptor axis to mitigate the chronic inflammatory abnormalities associated with GD.

Substrate reduction therapy (SRT) in clinic adequately manages the visceral manifestations in Gaucher disease (GD) but has no direct effect on brain disease. To understand the molecular basis of SRT in GD treatment, we evaluated the efficacy and underlying mechanism of SRT in an immortalized neuronal cell line derived from a Gba knockout ( Gba -/- ) mouse model. Gba -/- neurons accumulated substrates, glucosylceramide, and glucosylsphingosine. Reduced cell proliferation was associated with altered lysosomes and autophagy, decreased mitochondrial function, and activation of the mTORC1 pathway. Treatment of the Gba -/- neurons with venglustat analogue GZ452, a central nervous system-accessible SRT, normalized glucosylceramide levels in these neurons and their isolated mitochondria. Enlarged lysosomes were reduced in the treated Gba -/- neurons, accompanied by decreased autophagic vacuoles. GZ452 treatment improved mitochondrial membrane potential and oxygen consumption rate. Furthermore, GZ452 diminished hyperactivity of selected proteins in the mTORC1 pathway and improved cell proliferation of Gba -/- neurons. These findings reinforce the detrimental effects of substrate accumulation on mitochondria, autophagy, and mTOR in neurons. A novel rescuing mechanism of SRT was revealed on the function of mitochondrial and autophagy-lysosomal pathways in GD. These results point to mitochondria and the mTORC1 complex as potential therapeutic targets for treatment of GD.

Eliglustat, an oral substrate reduction therapy, is approved for eligible adults with Gaucher disease type 1. In the Phase 3 ENGAGE trial of previously untreated adults with Gaucher disease type 1, eliglustat-treated patients had statistically significant improvements in organ volumes and hematologic parameters compared with placebo in the 9-month primary analysis. We report final outcomes by time on eliglustat among all patients who participated in the ENGAGE trial and extension. No patient deteriorated clinically or withdrew due to adverse events; 39/40 patients entered the open-label extension period and 34/40 (85%) remained in the trial until completion or switching to commercial eliglustat after its approval (2.3-6 years). Clinically meaningful improvements in Gaucher disease manifestations were seen in all patients concomitant with reductions in pathological lipid substrate levels (glucosylceramide and glucosylsphingosine). Among patients with 4.5 years of eliglustat exposure, mean spleen volume decreased by 66% (from 17.1 to 5.8 multiples of normal [MN], n = 13), mean liver volume decreased by 23% (from 1.5 to 1.1 MN, n = 13), mean hemoglobin increased 1.4 g/dl (from 11.9 to 13.4 g/dl, n = 12), mean platelet count increased by 87% (from 67.6 to 122.6 × 10 9 /L, n = 12), median chitotriosidase decreased by 82% (from 13 394 to 2312 nmol/h/ml, n = 11), median glucosylceramide decreased by 79% (from 11.5 to 2.4 μg/ml, n = 11), median glucosylsphingosine decreased by 84% (from 518.5 to 72.1 ng/ml, n = 10), and mean spine T-score increased from -1.07 (osteopenia) to -0.53 (normal) (n = 9). The magnitude of improvement in Gaucher disease manifestations and biomarkers over time was similar among the full trial cohort. Eliglustat was well-tolerated and led to clinically significant improvements in previously untreated patients with Gaucher disease type 1 during 4.5 years of treatment., (© 2021 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Background: There are minimal data on the frequencies of monocyte subsets and dendritic cells (DCs) in children with Gaucher disease (GD), as nearly all previous studies have involved adult patients. Consequently, we aimed to describe the changes in these cell subpopulations in children with GD type 1 who were on regular enzyme replacement therapy (ERT)., Methods: This case-control study included 25 children with GD1 and 20 healthy controls. All participants underwent investigations such as complete blood count and flow cytometric assessment of DC and monocyte frequencies and phenotype., Results: We found that GD1 children had significantly reduced percentages of both types of DCs, i.e., plasmacytoid DCs and myeloid DCs, compared to the control group. There was also a significant reduction in absolute monocyte numbers and percentage of classical monocyte. Moreover, the GD1 children had higher frequencies of non-classical and intermediate monocytes than the control group., Conclusions: Our results so far indicate that, when compared to the control group, the GD1 children had significantly reduced total and classical monocyte, with significantly decreased frequencies for both types of DCs. These changes can contribute to immunological abnormalities in pediatric patients with GD1., Impact: Children with Gaucher disease type 1 (GD1) have significantly reduced total and classical monocyte frequencies, with decreasing percentages for both types of dendritic cells. GD1 children had significantly reduced frequencies of myeloid and plasmacytoid dendritic cells as compared to the controls. The GD1 children also had significant changes in monocyte subsets when compared to the controls. Our results show that monocytes and dendritic cells' significant changes could contribute to immunological abnormalities in pediatric patients with GD1., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Homozygous mutations in the lysosomal glucocerebrosidase gene, GBA1, cause Gaucher's disease (GD), while heterozygous mutations in GBA1 are a strong risk factor for Parkinson's disease (PD), whose pathological hallmark is intraneuronal α-synuclein (asyn) aggregates. We previously reported that gba1 knockout (KO) medaka exhibited glucosylceramide accumulation and neuronopathic GD phenotypes, including short lifespan, the dopaminergic and noradrenergic neuronal cell loss, microglial activation, and swimming abnormality, with asyn accumulation in the brains. A recent study reported that deletion of GBA2, non-lysosomal glucocerebrosidase, in a non-neuronopathic GD mouse model rescued its phenotypes. In the present study, we generated gba2 KO medaka and examined the effect of Gba2 deletion on the phenotypes of gba1 KO medaka. The Gba2 deletion in gba1 KO medaka resulted in the exacerbation of glucosylceramide accumulation and no improvement in neuronopathic GD pathological changes, asyn accumulation, or swimming abnormalities. Meanwhile, though gba2 KO medaka did not show any apparent phenotypes, biochemical analysis revealed asyn accumulation in the brains. gba2 KO medaka showed a trend towards an increase in sphingolipids in the brains, which is one of the possible causes of asyn accumulation. In conclusion, this study demonstrated that the deletion of Gba2 does not rescue the pathological changes or behavioral abnormalities of gba1 KO medaka, and GBA2 represents a novel factor affecting asyn accumulation in the brains.

Gaucher disease (GD) is caused by homozygous mutations in the GBA1 gene, which encodes the lysosomal β-glucosidase (GBA) enzyme. GD affects several organs and tissues, including the brain in certain variants of the disease. Heterozygous GBA1 variants are a major genetic risk factor for developing Parkinson's disease. The RIPK3 kinase is relevant in GD and its deficiency improves the neurological and visceral symptoms in a murine GD model. RIPK3 mediates necroptotic-like cell death: it is unknown whether the role of RIPK3 in GD is the direct induction of necroptosis or if it has a more indirect function by mediating necrosis-independent. Also, the mechanisms that activate RIPK3 in GD are currently unknown. In this study, we show that c-Abl tyrosine kinase participates upstream of RIPK3 in GD. We found that the active, phosphorylated form of c-Abl is increased in several GD models, including patient's fibroblasts and GBA null mice. Furthermore, its pharmacological inhibition with the FDA-approved drug Imatinib decreased RIPK3 signaling. We found that c-Abl interacts with RIPK3, that RIPK3 is phosphorylated at a tyrosine site, and that this phosphorylation is reduced when c-Abl is inhibited. Genetic ablation of c-Abl in neuronal GD and GD mice models significantly reduced RIPK3 activation and MLKL downstream signaling. These results showed that c-Abl signaling is a new upstream pathway that activates RIPK3 and that its inhibition is an attractive therapeutic approach for the treatment of GD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Mutations in the GBA1 gene encoding glucocerebrosidase (GCase) are linked to Gaucher (GD) and Parkinson's Disease (PD). Since some GD and PD patients develop ocular phenotypes, we determined whether ocular phenotypes might result from impaired GCase activity and the corresponding accumulation of glucosylceramide (GluCer) and glucosylsphingosine (GluSph) in the Gba1 D409V/D409V knock-in (Gba KI/KI; "KI") mouse. Gba KI mice developed age-dependent pupil dilation deficits to an anti-muscarinic agent; histologically, the iris covered the anterior part of the lens with adhesions between the iris and the anterior surface of the lens (posterior synechia). This may prevent pupil dilation in general, beyond an un-responsiveness of the iris to anti-muscarinics. Gba KI mice displayed atrophy and pigment dispersion of the iris, and occlusion of the iridocorneal angle by pigment-laden cells, reminiscent of secondary open angle glaucoma. Gba KI mice showed progressive thinning of the retina consistent with retinal degeneration. GluSph levels were increased in the anterior and posterior segments of the eye, suggesting that accumulation of lipids in the eye may contribute to degeneration in this compartment. We conclude that the Gba KI model provides robust and reproducible eye phenotypes which may be used to test for efficacy and establish biomarkers for GBA1-related therapies.

Most lysosomal storage diseases (LSDs) have a significant neurological component, including types 2 and 3 Gaucher disease (neuronal forms of Gaucher disease; nGD). No therapies are currently available for nGD since the recombinant enzymes used in the systemic form of Gaucher disease do not cross the blood-brain barrier (BBB). However, a number of promising approaches are currently being tested, including substrate reduction therapy (SRT), in which partial inhibition of the synthesis of the glycosphingolipids (GSLs) that accumulate in nGD lowers their accumulation. We now induce nGD in mice by injection with conduritol B-epoxide (CBE), an irreversible inhibitor of acid beta-glucosidase (GCase), the enzyme defective in nGD, with or without co-injection with Genz-667161, a prototype for SRT which crosses the BBB. Significant neuropathology, and a reduction in lifespan, was observed upon CBE injection, and this was largely reversed by co-injection with Genz-667161, along with a reduction in glucosylceramide and glucosylsphingosine levels. Analysis of gene expression by RNAseq revealed that Genz-667161 largely reversed the changes in genes and pathways that were differentially expressed upon CBE injection, specifically pathways of GSL metabolism, lipoproteins and other lipid metabolic pathways, lipid droplets, astrocyte activation, neuronal function, and to some extent, neuroinflammation. Together, this demonstrates the efficacy of SRT to reverse the effects of substrate accumulation on pathological components and pathways in nGD brain., (© 2020 International Society for Neurochemistry.)

Objectives: Diagnosis of lysosomal storage disorders (LSDs) remains challenging due to wide clinical, biochemical and molecular heterogeneity. The study applies a combined biochemical and genetic approach to diagnose symptomatic Indian patients of Pompe, Fabry, Gaucher and Hurler disease to generate a comprehensive dataset of pathogenic variants for these disorders., Design & Methods: Symptomatic patients were biochemically diagnosed by fluorometric methods and molecular confirmation was carried out by gene sequencing. Genetic variants were analyzed according to the ACMG/AMP 2015 variant interpretation guidelines., Results: Amongst the 2181 suspected patients, 285 (13%) were biochemically diagnosed. Of these, 22.5% (64/285) diagnosed with Pompe disease harboured c.1933G>A, c.1A>G, c.1927G>A and c.2783G>C as common and 10 novel pathogenic variants while 7.4% (21/285) patients diagnosed with Fabry disease carried c.851T>C, c.902G>A, c.905A>C and c.1212&#95;1234del as frequent disease-causing variants along with 7 novel pathogenic variants. As many as 48.4% (138/285) patients were diagnosed with Gaucher disease and had c.1448T>C as the most common pathogenic variant followed by c.1342G>C and c.754T>C with 7 previously unreported disease-causing variants and in the 21.7% (62/285) diagnosed cases of Hurler disease, c.1469T>C, c.754delC c.568&#95;581del and c.1898C>T were identified as the most common causative variants along with 21 novel pathogenic variants., Conclusion: This comprehensive data set of disease-causing frequent and novel pathogenic variants reported for the first time in such a large patient cohort for each of these four LSDs from the Indian sub-continent, along with their biochemical and clinical spectrum will contribute towards providing definitive diagnosis and treatment, identifying carrier status, as well as in counselling prenatal cases to reduce the morbidity and mortality associated with these disorders., (Copyright © 2020 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Alglucerase enzyme replacement therapy was approved for Gaucher disease (GD) in the United States in 1991; imiglucerase in 1994. We report hematologic, visceral, bone pain, bone crisis, height, weight, and Body Mass Index (BMI) outcomes in patients treated for 20 (±3) years with subset analyses based on pre-treatment severity, genotype, and age at treatment initiation., Methods: GD type 1 (GD1) patients in the ICGG Gaucher Registry with complete sets of baseline, 10-year, and 20-year data are included (N = 475). Ten-year and 20-year data are compared to pre-treatment baseline, stratified by splenectomy status., Results: Non-splenectomized patients: Improvements observed at 10 years were maintained at 20 years for most outcomes. Mean changes from baseline at 10 and 20 years, respectively, were: spleen volume: 18.2 multiples of normal (MN) to 5.1 MN and 4.2 MN; liver volume: 1.8 MN to 1.0 MN and 1.0 MN; hemoglobin: 11.4 g/dL to 13.7 g/dL and 13.8 g/dL; platelet count: 91.6 × 10 9 /L to 168.0 × 10 9 /L and 169.1 × 10 9 /L; without bone crisis: 85.0% to 98.2% and 96.5%; without bone pain: 52.5% to 72.0% at 10 years, no significant change at 20 years (58.5%). Splenectomized patients: significant changes were observed in liver volume: 2.3 MN to 1.1 MN and 1.0 MN; hemoglobin: 11.7 g/dL to 13.3 g/dL and 13.4 g/dL; platelet count: 229.1 × 10 9 /L to 288.1 × 10 9 /L and 257.0 × 10 9 /L; without bone crisis: 52.2% to 91.3% and 100%; without bone pain: 16.3% to 30.6% (not significant) and 46.9%. Similar results were found in each of the subset analyses. Patients who start treatment during childhood have normal weight and height in young adulthood. Many treated adult patients are overweight or obese; however, this is consistent with BMI trends observed in the general population. After 1-2 years, the average biweekly imiglucerase dose is ~40 units/kg body weight., Conclusion: Imiglucerase is an effective, long-term treatment for GD1. In a long-term observational setting, improvements seen during early treatment years are sustained by continuing treatment for 20 years, except for bone pain in non-splenectomized patients. These results are consistent when analyzed by different patient subsets, including by disease severity., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Gaucher disease (GD) is caused by pathogenic mutations in GBA1, the gene that encodes the lysosomal enzyme β-glucocerebrosidase. Despite the existence of a variety of specific treatments for GD, they cannot completely reverse bone complications. Many studies have evidenced the impairment in bone tissue of GD, and molecular mechanisms of bone density alterations in GD are being studied during the last years and different reports emphasized its efforts trying to unravel why and how bone tissue is affected. The cause of skeletal density affection in GD is a matter of debates between research groups. and there are two opposing hypotheses trying to explain reduced bone mineral density in GD: increased bone resorption versus impaired bone formation. In this review, we discuss the diverse mechanisms of bone alterations implicated in GD revealed until the present, along with a presentation of normal bone physiology and its regulation. With this information in mind, we discuss effectiveness of specific therapies, introduce possible adjunctive therapies and present a novel model for GD-associated bone density pathogenesis. Under the exposed evidence, we may conclude that both sides of the balance of remodeling process are altered. In GD the observed osteopenia/osteoporosis may be the result of contribution of both reduced bone formation and increased bone resorption., (Copyright © 2020 Elsevier Inc. All rights reserved.)