Gaucher-like crystal-storing histiocytosis associated with kappa chain myeloma: A case report with next generation sequencing study.

Crystal-storing histiocytosis is a rare entity due to tumorous deposits of histiocytes containing crystalline inclusions, which in a majority of cases are made of immunoglobulins associated with lymphoproliferative disorders, although association with non-neoplastic disorders has also been reported. The histiocytes may be so abundant to obscure the underlying lymphoplasmacytic neoplasm. On the other hand, the Gaucher-like histiocytes might lead to a misinterpretation of granulomatous inflammation or storage disease. Herein, this case study reported clinical, pathological and next generation sequencing (NGS) features of a case of kappa chain myeloma with Gaucher-like crystal-storing histiocytosis in the bone marrow (BM). The methodology included BM aspiration and biopsy, immunohistochemistry, electron microscopy and NGS study by TruSight Oncology 500. Morphologically, the BM smear showed dense infiltration of sea blue histiocytes and atypical plasma cells with rhomboid crystals in cytoplasm. The BM biopsy showed excessive plasmacytic aggregates and dense histiocytic infiltrates with wrinkled paper-like or needle shaped cytoplasm. These plasma cells were positive for CD138 and showed lambda chain restriction. Electron microscopy highlighted the long rhomboid crystals with distinct periodicity consistent with crystalline immunoglobulins in the histiocytes. In addition, the NGS study from the BM aspiration specimen revealed PARP1, MSH6, KDR, CCND3 and STK11 mutations, which might be associated with inferior survival of myeloma patients. Accordingly, this case died of pneumonia with septic shock during treatment. Our findings suggest that the presence of rhomboid crystals in bone marrow smears may alert pathologists to look for the possibility of crystal-storing histiocytosis and the prognosis of patients with multiple myeloma may depend on the genetic features of tumor cells rather than the association with crystal-storing histiocytosis.

Different diseases, different needs: Patient preferences for gene therapy in lysosomal storage disorders, a probabilistic threshold technique survey.

BACKGROUND: Gene therapy is currently in development for several monogenetic diseases including lysosomal storage disorders. Limited evidence is available on patient preferences for gene therapy in this population. In this study, we compare gene therapy-related risk tolerance between people affected by three lysosomal storage diseases currently faced with different therapeutic options and prognoses. METHODS: A survey including the probabilistic threshold technique was developed in which respondents were asked to choose between gene therapy and the current standard of care. The attributes included to establish participants' risk tolerance were previously identified in focus groups of affected people or their representatives, namely: risk of mild side effects, severe side effects, the need for additional medication, and the likelihood of long-term effectiveness. The survey was distributed among people receiving outpatient care for type 1 Gaucher disease (good prognosis with current treatment options), Fabry disease (varying prognosis with current treatment options, XY-genotype on average more severely affected than XX), and parents representing people with severe forms of mucopolysaccharidosis type III A/B (poor prognosis, no disease-specific therapy available). RESULTS: A total of 85 surveys were completed (15 Gaucher disease respondents, 62 Fabry disease respondents (17 self-identifying male), eight parents of ten people with mucopolysaccharidosis type III). Disease groups with higher disease severity trended towards higher risk tolerance: Gaucher disease respondents were most cautious and predominantly preferred the current standard of care as opposed to MPS III representatives who were more risk tolerant. Respondents with Fabry disease were most heterogeneous in their risk tolerance, with male participants being more risk tolerant than female participants. Long-term effectiveness was the attribute in which respondents tolerated the least risk. CONCLUSIONS: People affected by a lysosomal storage disease associated with a poorer prognosis and less effective current treatment options trended towards more risk tolerance when choosing between gene therapy and the current standard of care. This study shows the importance of involvement of patient preferences before and during the development process of new treatment modalities such as gene therapy for rare diseases, to ensure that innovative therapies align with the wishes and needs of people affected by these diseases.

Therapeutic delivery of recombinant glucocerebrosidase enzyme-containing extracellular vesicles to human cells from Gaucher disease patients.

BACKGROUND: Gaucher disease (GD) is one of the most common types of lysosomal storage diseases (LSDs) caused by pathogenic variants of lysosomal ß-glucocerebrosidase gene (GBA1), resulting in the impairment of Glucocerebrosidase (GCase) enzyme function and the accumulation of a glycolipid substrate, glucosylceramide (GlcCer) within lysosomes. Current therapeutic approaches such as enzyme replacement therapy and substrate reduction therapy cannot fully rescue GD pathologies, especially neurological symptoms. Meanwhile, delivery of lysosomal enzymes to the endocytic compartment of affected human cells is a promising strategy for treating neuropathic LSDs. RESULT: Here, we describe a novel approach to restore GCase enzyme in cells from neuropathic GD patients by producing extracellular vesicle (EVs)-containing GCase from cells overexpressing GBA1 gene. Lentiviral vectors containing modified GBA1 were introduced into HEK293T cells to produce a stable cell line that provides a sustainable source of functional GCase enzyme. The GBA1-overexpressing cells released EV-containing GCase enzyme, that is capable of entering into and localizing in the endocytic compartment of recipient cells, including THP-1 macrophage, SH-SY5Y neuroblastoma, and macrophages and neurons derived from induced pluripotent stem cells (iPSCs) of neuropathic GD patients. Importantly, the recipient cells exhibit higher GCase enzyme activity. CONCLUSION: This study presents a promising therapeutic strategy to treat severe types of LSDs. It involves delivering lysosomal enzymes to the endocytic compartment of human cells affected by conditions such as GDs with neurological symptoms, as well as potentially other neurological disorders impacting lysosomes.

High-throughput screening for small-molecule stabilizers of misfolded glucocerebrosidase in Gaucher disease and Parkinson's disease.

Glucocerebrosidase (GCase) is implicated in both a rare, monogenic disorder (Gaucher disease, GD) and a common, multifactorial condition (Parkinson's disease, PD); hence, it is an urgent therapeutic target. To identify correctors of severe protein misfolding and trafficking obstruction manifested by the pathogenic L444P-variant of GCase, we developed a suite of quantitative, high-throughput, cell-based assays. First, we labeled GCase with a small proluminescent HiBiT peptide reporter tag, enabling quantitation of protein stabilization in cells while faithfully maintaining target biology. TALEN-based gene editing allowed for stable integration of a single HiBiT-GBA1 transgene into an intragenic safe-harbor locus in GBA1-knockout H4 (neuroglioma) cells. This GD cell model was amenable to lead discovery via titration-based quantitative high-throughput screening and lead optimization via structure-activity relationships. A primary screen of 10,779 compounds from the NCATS bioactive collections identified 140 stabilizers of HiBiT-GCase-L444P, including both pharmacological chaperones (ambroxol and noninhibitory chaperone NCGC326) and proteostasis regulators (panobinostat, trans-ISRIB, and pladienolide B). Two complementary high-content imaging-based assays were deployed to triage hits: The fluorescence-quenched substrate LysoFix-GBA captured functional lysosomal GCase activity, while an immunofluorescence assay featuring antibody hGCase-1/23 directly visualized GCase lysosomal translocation. NCGC326 was active in both secondary assays and completely reversed pathological glucosylsphingosine accumulation. Finally, we tested the concept of combination therapy by demonstrating synergistic actions of NCGC326 with proteostasis regulators in enhancing GCase-L444P levels. Looking forward, these physiologically relevant assays can facilitate the identification, pharmacological validation, and medicinal chemistry optimization of small molecules targeting GCase, ultimately leading to a viable therapeutic for GD and PD.

Unexplained splenomegaly as a diagnostic marker for a rare but severe disease with an innovative and highly effective new treatment option: A case report.

Acid Sphingomyelinase Deficiency (ASMD) is a lysosomal storage disorder that can lead to severe complications if not promptly treated. This case aims to highlight the critical importance of early awareness of ASMD and to introduce, for the first time in the literature, a new and highly effective treatment option for children.

Enzyme replacement therapy improves erythropoiesis and iron dysregulation in Gaucher disease.

Anemia and hyperferritinemia are frequent findings at diagnosis of Gaucher disease (GD). Macrophage-independent dyserythropoiesis and abnormal iron metabolism have been shown. We evaluated hematological and iron status at diagnosis (T0) and the effect of enzyme replacement therapy (ERT) on erythropoiesis and iron utilization over 5-year follow-up in type 1 GD patients and in an ex vivo model of erythropoiesis from CD34 + peripheral blood cells. At T0, 41% of patients had anemia and 51% hyperferritinemia. Hemoglobin increased from 12.6 (T0) to 13.9 g/dL (T6), GFD15, a marker of ineffective erythropoiesis, decreased from 5401 to 710 pg/ml, and serum ferritin decreased from 614 to 140 mcg/L (p < 0.001). In parallel, transferrin saturation (TSAT) increased. Hepcidin, although in the normal range, decreased from T0 to T6. Ex vivo studies showed that ERT restores the erythroid cells derived from CD34 + impaired ability to differentiate. During ERT, an increase in TFRC expression, consistent with the ability of erythroid precursors to uptake iron, and a reduction in HAMP and concomitant increase in SLC40A1 were observed. This is the largest study with a longitudinal follow-up evaluating erythropoiesis and iron metabolism, combining clinical and ex vivo data in GD. Iron dysregulation likely contributes to anemia, and ERT, by improving iron distribution, improves erythropoiesis.

Striking and widespread microglial activation in the brains of Southdown lambs with type II glucocerebrosidosis (neuronopathic Gaucher disease).

Glucocerebrosidosis (termed Gaucher disease in humans) is a lysosomal storage disease, caused by a deficiency of the enzyme glucocerebrosidase, which results in accumulation of the glycolipid substrate glucocerebroside in the macrophage-monocyte system. Three principal forms are recognized in humans, two being neuronopathic and resulting in neurodegeneration. Only two spontaneously arising cases have been described in domestic animals, one in a dog and the other in a flock of Southdown sheep. Since microglial activation is increasingly being recognized as having an important role in the pathogenesis of Gaucher disease and archival brains were available from lambs with type II glucocerebrosidosis, we wanted to determine whether microglia were activated in these brains. Ionized calcium binding adaptor molecule 1 (Iba1), a specific and the most widely expressed immunohistochemical marker of microglial activation, was used. Striking and widely distributed activation of microglia was demonstrated, suggesting that microglia actively participate in the development of neuropathological changes in ovine Gaucher disease. This aspect of Gaucher disease requires further study in any future cases detected in domestic animal species, including the mechanism by which this markedly increased Iba1 expression is related to disease progression.

Perinatal lethal form Gaucher disease with compound heterozygosity of single nucleotide variants and copy number variations presenting as nonimmune hydrops fetalis and cerebellar hypoplasia: A case report.

OBJECTIVE: To present the ultrasound imaging and genetic diagnosis of a fetus with prenatal lethal form of Gaucher disease. CASE REPORT: A 37-year-old primiparous woman was pregnant at her 23 weeks of gestation and the prenatal fetal ultrasound revealed hydrops fetalis, cerebellum hypoplasia, and fetal immobility. The pregnancy was terminated due to major fetal anomaly, and whole exome sequencing (WES) analysis of fetal tissue and parental blood unveiled a pathogenic variant in exon 10 of the GBA gene (NM_001005741.3: c.1265T > G: p.L422R) originating from the mother. Additionally, a novel CNV (chr1: 155204785-155205635 deletion, 0.85 kb) spanning exon 10-12 in the GBA gene was identified from the father. This compound heterozygosity confirmed the diagnosis of prenatal lethal form of Gaucher disease and was informative for genetic counseling. CONCLUSION: WES is a powerful tool to detect pathogenic variants among fetuses with nonimmune hydrops fetalis and complex abnormality from prenatal ultrasound. Compound heterozygosity consisted of single nucleotide variants (SNV) and copy number variations (CNVs) may lead rare inherited metabolic disorders including prenatal lethal form of Gaucher disease.

Clinical, mechanistic, biomarker, and therapeutic advances in GBA1-associated Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease. The development of PD is closely linked to genetic and environmental factors, with GBA1 variants being the most common genetic risk. Mutations in the GBA1 gene lead to reduced activity of the coded enzyme, glucocerebrosidase, which mediates the development of PD by affecting lipid metabolism (especially sphingolipids), lysosomal autophagy, endoplasmic reticulum, as well as mitochondrial and other cellular functions. Clinically, PD with GBA1 mutations (GBA1-PD) is characterized by particular features regarding the progression of symptom severity. On the therapeutic side, the discovery of the relationship between GBA1 variants and PD offers an opportunity for targeted therapeutic interventions. In this review, we explore the genotypic and phenotypic correlations, etiologic mechanisms, biomarkers, and therapeutic approaches of GBA1-PD and summarize the current state of research and its challenges.

Upregulation of NFE2L1 reduces ROS levels and α-synuclein aggregation caused by GBA1 knockdown.

Biallelic mutations in the GBA1 gene result in Gaucher disease (GD), and both patients with GD and carriers of a single GBA1 mutation have an increased susceptibility to Parkinson's disease (PD), but the underlying mechanisms of this association are not yet clear. In previous studies, we established Gba1 F213I point mutation mice and found that homozygous Gba1 F213I mutant mice died shortly after birth, while heterozygous mice could survive normally. In this study, we investigated the transcriptomic changes in the brain tissue of Gba1 F213I heterozygous mice, identifying 138 differentially expressed genes. Among them, Nfe2l1 was the most significantly downregulated gene. Inhibition or knockdown of GBA1 in BE(2)-M17 cells resulted in decreased expression levels of NFE2L1. Knockdown of GBA1 or NFE2L1 could lead to an elevation in intracellular aggregation of α-synuclein (α-syn) and reactive oxygen species (ROS) levels, while upregulation of NFE2L1 effectively mitigated those cellular manifestations induced by GBA1 knockdown. In summary, our in vitro results showed that upregulation of NFE2L1 may provide a therapeutic benefit for cellular phenotypes resulting from GBA1 knockdown, providing new insights for future research on GD and GBA1-associated PD.

A machine learning model for early diagnosis of type 1 Gaucher disease using real-life data.

OBJECTIVE: The diagnosis of Gaucher disease (GD) presents a major challenge due to the high variability and low specificity of its clinical characteristics, along with limited physician awareness of the disease's early symptoms. Early and accurate diagnosis is important to enable effective treatment decisions, prevent unnecessary testing, and facilitate genetic counseling. This study aimed to develop a machine learning (ML) model for GD screening and GD early diagnosis based on real-world clinical data using the Maccabi Healthcare Services electronic database, which contains 20 years of longitudinal data on approximately 2.6 million patients. STUDY DESIGN AND SETTING: We screened the Maccabi Healthcare Services database for patients with GD between January 1998 and May 2022. Eligible controls were matched by year of birth, sex, and socioeconomic status in a 1:13 ratio. The data were partitioned into 75% training and 25% test sets and trained to predict GD using features obtained from medical and laboratory records. Model performances were evaluated using the area under the receiver operating characteristic curve and the area under the precision-recall curve. RESULTS: We detected 264 confirmed patients with GD to which we matched 3,429 controls. The best model performance (which included known GD signs and symptoms, previously unknown clinical features, and administrative codes) on the test set had an area under the receiver operating characteristic curve = 0.95 ± 0.03 and area under the precision-recall curve = 0.80 ± 0.08, which yielded a median GD identification of 2.78 years earlier than the clinical diagnosis (25th-75th percentile: 1.29-4.53). CONCLUSION: Using an ML approach on real-world data led to excellent discrimination between GD patients and controls, with the ability to detect GD significantly earlier than the time of actual diagnosis. Hence, this approach might be useful as a screening tool for GD and lead to earlier diagnosis and treatment. Furthermore, advanced ML analytics may highlight previously unrecognized features associated with GD, including clinical diagnoses and health-seeking behaviors. PLAIN LANGUAGE SUMMARY: Diagnosing Gaucher disease is difficult, which often leads to late or incorrect diagnoses. As a result, patients may undergo unnecessary tests and treatments and experience health deterioration despite medications availability for Gaucher disease. In this study, we used electronic health data to develop machine learning models for early diagnosis of Gaucher disease type 1. Our models, which included known Gaucher disease signs and symptoms, previously unknown clinical features, and administrative codes, were able to significantly outperform other models and expert opinions, detecting type 1 Gaucher disease 3 years on average before actual diagnosis. Our models also revealed new features linked to type 1 Gaucher disease, including specific diagnoses and patterns in patients' healthcare-seeking behaviors. We believe that the tool of machine learning can be valuable for patients with rare diseases.

Transition of patients with Gaucher disease type 1 from pediatric to adult care: results from two international surveys of patients and health care professionals.

Introduction: Gaucher disease (GD) is a rare, autosomal recessive lysosomal storage disorder caused by a deficiency in the enzyme glucocerebrosidase. The most common subtype in Europe and the USA, type 1 (GD1), is characterized by fatigue, cytopenia, splenomegaly, hepatomegaly, bone disease, and rarely pulmonary disease. Increased life expectancy brought about by improved treatments has led to new challenges for adolescents and their transition to adult care. Efficient healthcare transition to adult care is essential to manage the long-term age-related complications of the disease. Methods: This international study consisted of two online surveys: one survey for patients with GD1 and one survey for healthcare professionals (HCPs) involved in treatment of patients with GD1. The aims of this international, multi-center project were to evaluate the current transition process in various countries and to understand the challenges that both HCPs and patients experience. Results: A total of 45 patients and 26 HCPs took part in the survey, representing 26 countries. Our data showed that a third (11/33) of patients were aware of transition clinics and most stated that the clinic involved patients with metabolic diseases or with GD. Seven patients attended a transition clinic, where most patients (5/7) received an explanation of the transition process. Approximately half of HCPs (46%; 12/26) had a transition clinic coordinator in their healthcare center, and 10 of HCPs had a transition clinic for patients with metabolic diseases in their healthcare center. HCPs reported that transition clinics were comprised of multi-disciplinary teams, with most patients over the age of 18 years old managed by hematology specialists. The main challenges of the transition process reported by HCPs included limited funding, lack of expertise and difficulty coordinating care amongst different specialties. Discussion: Our study demonstrates the lack of a standardized process, the need to raise awareness of transition clinics amongst patients and the differences between the transition process in different countries. Both patients and HCPs expressed the need for a specialist individual responsible for transition, efficient coordination between pediatricians and adult specialists and for patient visits to the adult center prior to final transition of care.

A PIKfyve modulator combined with an integrated stress response inhibitor to treat lysosomal storage diseases.

Lysosomal degradation pathways coordinate the clearance of superfluous and damaged cellular components. Compromised lysosomal degradation is a hallmark of many degenerative diseases, including lysosomal storage diseases (LSDs), which are caused by loss-of-function mutations within both alleles of a lysosomal hydrolase, leading to lysosomal substrate accumulation. Gaucher's disease, characterized by <15% of normal glucocerebrosidase function, is the most common LSD and is a prominent risk factor for developing Parkinson's disease. Here, we show that either of two structurally distinct small molecules that modulate PIKfyve activity, identified in a high-throughput cellular lipid droplet clearance screen, can improve glucocerebrosidase function in Gaucher patient-derived fibroblasts through an MiT/TFE transcription factor that promotes lysosomal gene translation. An integrated stress response (ISR) antagonist used in combination with a PIKfyve modulator further improves cellular glucocerebrosidase activity, likely because ISR signaling appears to also be slightly activated by treatment by either small molecule at the higher doses employed. This strategy of combining a PIKfyve modulator with an ISR inhibitor improves mutant lysosomal hydrolase function in cellular models of additional LSD.

Machine Learning-Driven Biomarker Discovery for Skeletal Complications in Type 1 Gaucher Disease Patients.

Type 1 Gaucher disease (GD1) is a rare, autosomal recessive disorder caused by glucocerebrosidase deficiency. Skeletal manifestations represent one of the most debilitating and potentially irreversible complications of GD1. Although imaging studies are the gold standard, early diagnostic/prognostic tools, such as molecular biomarkers, are needed for the rapid management of skeletal complications. This study aimed to identify potential protein biomarkers capable of predicting the early diagnosis of bone skeletal complications in GD1 patients using artificial intelligence. An in silico study was performed using the novel Therapeutic Performance Mapping System methodology to construct mathematical models of GD1-associated complications at the protein level. Pathophysiological characterization was performed before modeling, and a data science strategy was applied to the predicted protein activity for each protein in the models to identify classifiers. Statistical criteria were used to prioritize the most promising candidates, and 18 candidates were identified. Among them, PDGFB, IL1R2, PTH and CCL3 (MIP-1α) were highlighted due to their ease of measurement in blood. This study proposes a validated novel tool to discover new protein biomarkers to support clinician decision-making in an area where medical needs have not yet been met. However, confirming the results using in vitro and/or in vivo studies is necessary.

Intrinsic link between PGRN and Gba1 D409V mutation dosage in potentiating Gaucher disease.

Gaucher disease (GD) is caused by biallelic GBA1/Gba1 mutations that encode defective glucocerebrosidase (GCase). Progranulin (PGRN, encoded by GRN/Grn) is a modifier of GCase, but the interplay between PGRN and GCase, specifically GBA1/Gba1 mutations, contributing to GD severity is unclear. Mouse models were developed with various dosages of Gba1 D409V mutation against the PGRN deficiency (Grn-/-) [Grn-/-;Gba1D409V/WT (PG9Vwt), Grn-/-;Gba1D409V/D409V (PG9V), Grn-/-;Gba1D409V/Null (PG9VN)]. Disease progression in those mouse models was characterized by biochemical, pathological, transcriptomic, and neurobehavioral analyses. Compared to PG9Vwt, Grn-/-;Gba1WT/Null and Grn-/- mice that had a higher level of GCase activity and undetectable pathologies, homozygous or hemizygous D409V in PG9V or PG9VN, respectively, resulted in profound inflammation and neurodegeneration. PG9VN mice exhibited much earlier onset, shorter life span, tissue fibrosis, and more severe phenotypes than PG9V mice. Glycosphingolipid accumulation, inflammatory responses, lysosomal-autophagy dysfunction, microgliosis, retinal gliosis, as well as α-Synuclein increases were much more pronounced in PG9VN mice. Neurodegeneration in PG9VN was characterized by activated microglial phagocytosis of impaired neurons and programmed cell death due to necrosis and, possibly, pyroptosis. Brain transcriptomic analyses revealed the intrinsic relationship between D409V dosage, and the degree of altered gene expression related to lysosome dysfunction, microgliosis, and neurodegeneration in GD, suggesting the disease severity is dependent on a GCase activity threshold related to Gba1 D409V dosage and loss of PGRN. These findings contribute to a deeper understanding of GD pathogenesis by elucidating additional underlying mechanisms of interplay between PGRN and Gba1 mutation dosage in modulating GCase function and disease severity in GD and GBA1-associated neurodegenerative diseases.

The natural history of Gaucher disease type 1 in 31 patients over a median of 15 years: a retrospective study.

BACKGROUND AND AIMS: The natural history of untreated patients with type 1 Gaucher disease (GD1) is not well documented, and there is controversy over when and how to treat such patients, especially if they are only mildly symptomatic. Treatment of GD1 is inconvenient, very costly, and may result in undesirable side effects. We documented the clinical history of 31 untreated patients with GD1 followed in our clinic for 4-26 (median 15) years. METHODS: This was a retrospective, observational study of the progress of untreated adult patients with GD1 followed by blood tests (haemoglobin, platelet counts, ferritin and chitotriosidase), organ volumes (spleen and liver), bone manifestations (through magnetic resonance imaging and dual X-ray absorptiometry scans) and neurological and quality of life issues. Statistical analyses were performed with the use of the Student paired t test and the modified Wald test for 95% confidence intervals. RESULTS: We found that the above parameters remained stable in most patients over a period of 4-26 (median 15) years. Five patients progressed from normal bone density to osteopenia and two from osteopenia to osteofibrosis; six were peri- or post-menopausal females. The DS-3 was stable over time. Only four of the 31 patients were started on enzyme or substrate reduction therapy. CONCLUSIONS: Our results demonstrate that many patients with GD1, provided with close follow-up by a specialist centre, can be followed for many years without requiring treatment and with no or minimal worsening of their GD1 manifestations.

Clinical and preclinical insights into high-dose ambroxol therapy for Gaucher disease type 2 and 3: A comprehensive systematic review.

RATIONALE: Gaucher disease (GD), an autosomal recessive lysosomal storage disease, results from GBA1 variants causing glucocerebrosidase (GCase) deficiency. While enzyme replacement therapy (ERT) helps with systemic symptoms, neurological complications in GD2 and GD3 persist due to the blood-brain-barrier (BBB) limiting ERT efficacy. Ambroxol, a BBB-permeable chaperone, enhances GCase activity. Our review explores high-dose ambroxol's therapeutic potential, both preclinical and clinical, in GD2 and GD3. METHODS: PubMed was searched for studies published before March 2023, including clinical, animal, and in vitro studies focusing on the effect of high-dose ambroxol in GD2 and GD3. A narrative synthesis was performed. RESULTS: Nine in vitro, three animal, and eight clinical studies were included, demonstrating varied responses to ambroxol across diverse outcome measures. In vitro and animal studies demonstrated reduced endoplasmatic reticulum stress due to the relocation of GCase from the ER to the lysosomes. In vitro cell lines exhibited varying degrees of increased GCase activity. Clinical trials observed reduced lyso-GL1 levels in plasma (41-89%) and cerebrospinal fluid (CSF) (26-97%), alongside increased GCase activity in GD3 patients. Ambroxol exhibited varying effects on neurological outcomes and development. No severe adverse events were reported. CONCLUSION: High-dose ambroxol shows promise in managing neurological manifestations in GD3, albeit with uncertainties resulting from genetic heterogeneity and variable response. Further clinical trials, are essential for elucidating dosage-response relationships and refining treatment outcomes and strategies for neuronopathic GD.

A 6-month randomized controlled trial for vitamin E supplementation in pediatric patients with Gaucher disease: Effect on oxidative stress, disease severity and hepatic complications.

Enzymatic deficiency in Gaucher disease (GD) may induce oxidative stress. Vitamin E is the nature's most effective lipid-soluble antioxidant. This prospective clinical trial assessed the oxidant-antioxidant status in Egyptian patients with GD and the efficacy and safety and of vitamin E as an adjuvant antioxidant therapy. Forty children and adolescents with GD on stable doses of enzyme replacement therapy (ERT) were enrolled. Abdominal ultrasonography and transient elastography were performed. Malondialdehyde (MDA), vitamin E, and antioxidant enzymes (reduced glutathione [GSH], superoxide dismutase [SOD], glutathione peroxidase [GPx], and peroxiredoxin 2 [PRDX2]) were assessed. Patients were compared with 40 age- and sex-matched healthy controls. Patients with GD were randomized either to receive oral vitamin E for 6 months or not. All patients with GD had significantly higher MDA levels with lower levels of vitamin E and antioxidant enzymes compared with healthy controls (p < 0.001). Vitamin E and PRDX2 were negatively correlated to severity score index (SSI), lyso GL1, and MDA. After 6 months of vitamin E supplementation, SSI and liver and spleen volumes and liver stiffness were significantly lower. Lyso GL1 and MDA were significantly decreased post-vitamin E therapy while antioxidant enzymes were significantly higher compared with baseline levels and with patients without vitamin E therapy. Oxidative stress is related to disease severity in pediatric patients with GD. A 6-month vitamin E supplementation for those patients represents a safe therapeutic adjuvant agent increasing the efficacy of ERT, reducing oxidative stress, and improving outcomes.

Presentation of ichthyosis after substrate reduction therapy in Gaucher type 1.

We describe a case in which a type 1 Gaucher patient developed ichthyosis weeks after starting substrate reduction therapy (SRT) with eliglustat. There are no reports of ichthyosis in the literature in enzyme replacement or SRT for Gaucher disease. Ichthyosis is seen with type 2 and 3 Gaucher disease, but not type 1. This raises the question: Why would a patient develop ichthyosis after starting SRT?