Lysosomal Disorder Research Articles

Recent Therapeutic Advancements for Gaucher Disease

AbstractGaucher Disease (GD) is a well‐known lysosomal storage disease resulting from mutations in the GBA1 gene. GD exhibits a range of clinical manifestations, each with unique symptoms and severity levels. This review explores the genetic foundations of GD, highlighting the significance of Glucocerebrosidase (GCase) deficiency, resulting in the skeletal complications associated with GD, such as osteonecrosis, fractures, and bone pain, all of which significantly negatively influence the quality of life for patients. Over 700 mutations in the GBA1 gene are found to cause variations in gene expression in GD, indicating the disease's complexity and the need for continued research. Early diagnosis and prognosis evaluation depend heavily on diagnostic approaches integrating laboratory assessments, genetic testing, and clinical symptoms. Treatment strategies like enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) have advanced, but issues like high costs and invasiveness still exist. This review focuses on novel therapeutic approaches that show promise in treating GD, including gene and cell‐based therapies, pharmacological chaperone therapy (PCT), and drug delivery via nanoparticles. Finally, discussions on current clinical trials, limitations of the advanced therapies, and future scope are summarized.

Fabry Disease - literature review

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

Complement System and Adhesion Molecule Skirmishes in Fabry Disease: Insights into Pathogenesis and Disease Mechanisms

Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene, resulting in the accumulation of globotriaosylceramide (Gb3) and its deacetylated form, globotriaosylsphingosine (Lyso-Gb3) in various tissues and fluids throughout the body. This pathological accumulation triggers a cascade of processes involving immune dysregulation and complement system activation. Elevated levels of complement 3a (C3a), C5a, and their precursor C3 are observed in the plasma, serum, and tissues of patients with Fabry disease, correlating with significant endothelial cell abnormalities and vascular dysfunction. This review elucidates how the complement system, particularly through the activation of C3a and C5a, exacerbates disease pathology. The activation of these pathways leads to the upregulation of adhesion molecules, including vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1), platelet and endothelial cell adhesion molecule 1 (PECAM1), and complement receptor 3 (CR3) on leukocytes and endothelial cells. This upregulation promotes the excessive recruitment of leukocytes, which in turn exacerbates disease pathology. Targeting complement components C3a, C5a, or their respective receptors, C3aR (C3a receptor) and C5aR1 (C5a receptor 1), could potentially reduce inflammation, mitigate tissue damage, and improve clinical outcomes for individuals with Fabry disease.

Phenotype-Genotype Correlation in Morquio A Syndrome: Protocol for a Meta-Analysis.

Mucopolysaccharidosis type IVA (MPS IVA), also known as Morquio A syndrome, is a rare lysosomal storage disease characterized by autosomal recessive inheritance of mutations in the N-acetylgalactosamine-6-sulfatase (GALNS) gene. This leads to a deficiency of the GALNS enzyme, causing the accumulation of glycosaminoglycans in tissues. Morquio A syndrome primarily affects the skeletal system and joints but can also impact various organs, resulting in symptoms such as hearing and vision loss, respiratory issues, spinal cord compression, heart diseases, and hepatomegaly. The genotype-phenotype relationship is diverse, with studies highlighting variants associated with classic, nonclassic, or intermediate phenotypes. Understanding these genetic factors is crucial for predicting disease prognosis and tailoring effective treatment strategies for individuals with Morquio A syndrome. The aim of this meta-analysis is to comprehend the relationship between the severity of the phenotype and the genotype of patients with MPS IVA, considering factors such as the type of variant and its location in the different domains of the protein. This meta-analysis will include articles featuring participants of all genders and age groups who have a molecular diagnosis of MPS IVA and a description of the phenotype. Literature published in English, Spanish, and Portuguese will be considered. Exclusion criteria will encompass studies lacking full-text availability and those involving patients with an MPS IVA diagnosis but without phenotype information. The databases to be searched include PubMed, MEDLINE, ScienceDirect, and Scopus. The screening of literature, paper selection, and data extraction will involve 2 independent reviewers, who will conduct the process blindly. In the event of disagreements between the 2 reviewers at any stage, resolution will be sought through discussion or with the involvement of an additional reviewer. The final selection of manuscripts will be based on consensus. The results of the review will be presented using descriptive statistics, and the information will be organized in either diagrammatic or tabular formats, following the guidelines provided by the Joanna Briggs Institute. Genotype-phenotype relationships will be analyzed using IBM SPSS Statistics, using chi-square tests, Fisher exact tests, and regression analysis to interpret the data. A literature search conducted in January 2024 produced 760 results. The review is expected to be completed by the end of 2024. This meta-analysis will gather and analyze information on the phenotype-genotype relationship in patients diagnosed with MPS IVA. The data collection and resulting analyses will make a substantial contribution to understanding the underlying mechanism of the disease, enabling the prediction of the syndrome's progression and severity. DERR1-10.2196/56649.

Investigating p.Ala1035Val in NPC1: New Cellular Models for Niemann–Pick Type C Disease

Niemann–Pick type C (NPC) is a lysosomal storage disorder (LSD) caused by pathogenic variants in either the NPC1 or NPC2 genes, which encode proteins involved in the lysosomal export of unesterified cholesterol. In patients of Western European descent, the p.Ile1061Thr variant in NPC1 is especially prevalent. However, mounting evidence has positioned p.Ala1035Val as the most common variant in Portugal and the second most prevalent variant worldwide. By analyzing 10 Portuguese NPC patients homozygous for p.Ala1035Val, we found an SNP in cis on position 858 (p.Ile858Val), which we hypothesize could have a disease-modifying effect. To address this query, we created variant-specific in vitro models of NPC by stably transducing NPC1−/− ARPE-19 cells with constructs encoding different fluorescently-tagged variants of NPC1, which we used, alongside patient-derived skin fibroblasts, to investigate lysosomal positioning and the trafficking routes elicited by p.Ile1061Thr and p.Ala1035Val (with and without the p.Ile858Val SNP in cis). Our results corroborate the previously described decrease in p.Ile1061Thr-NPC1 trafficking to the lysosome and suggest a similar, if not worse, scenario for the p.Ala1035Val variant, especially when in cis with p.Ile858Val. This is the first reported functional study addressing the impact of the p.Ala1035Val variant at the cellular level, paving the way for novel therapeutic options.

Genetic and Cellular Basis of Impaired Phagocytosis and Photoreceptor Degeneration in CLN3 Disease.

CLN3 Batten disease (also known as juvenile neuronal ceroid lipofuscinosis) is a lysosomal storage disorder that typically initiates with retinal degeneration but is followed by seizure onset, motor decline and premature death. Patient-derived CLN3 disease induced pluripotent stem cell-RPE cells show defective phagocytosis of photoreceptor outer segment (POS). Because modifier genes are implicated in CLN3 disease, our goal here was to investigate a direct link between CLN3 mutation and POS phagocytosis defect. Isogenic control and CLN3 mutant stem cell lines were generated by CRISPR-Cas9-mediated biallelic deletion of exons 7 and 8. A transgenic CLN3Δ7-8/Δ7-8 (CLN3) Yucatan miniswine was also used to study the impact of CLN3Δ7-8/Δ7-8 mutation on POS phagocytosis. POS phagocytosis by cultured RPE cells was analyzed by Western blotting and immunohistochemistry. Electroretinogram, optical coherence tomography and histological analysis of CLN3Δ7-8/Δ7-8 and wild-type miniswine eyes were carried out at 6, 36, or 48 months of age. CLN3Δ7-8/Δ7-8 RPE (CLN3 RPE) displayed decreased POS binding and consequently decreased uptake of POS compared with isogenic control RPE cells. Furthermore, wild-type miniswine RPE cells phagocytosed CLN3Δ7-8/Δ7-8 POS less efficiently than wild-type POS. Consistent with decreased POS phagocytosis, lipofuscin/autofluorescence was decreased in CLN3 miniswine RPE at 36months of age and was followed by almost complete loss of photoreceptors at 48months of age. CLN3Δ7-8/Δ7-8 mutation (which affects ≤85% of patients) affects both RPE and POS and leads to photoreceptor cell loss in CLN3 disease. Furthermore, both primary RPE dysfunction and mutant POS independently contribute to impaired POS phagocytosis in CLN3 disease.

Prolonged catamnesis of a child with type I mucopolysaccharidosis, Gurler syndrome, receiving enzyme replacement therapy

Hereditary pathology makes up a significant part of the structure of childhood morbidity, disability and mortality. Mucopolysaccharidosis type I is a hereditary lysosomal accumulation disease, with an autosomal recessive type of inheritance. At birth, children with Gurler syndrome look normal, but in the future, they develop symptoms characteristic of mucopolysaccharidosis, and the first clinical manifestations of the disease are often hernias and hepatosplenomegaly. The presented clinical case demonstrates the difficulties of early diagnosis of mucopolysaccharidosis type I, which lead to a later prescription of enzyme replacement therapy and the inability to use a more effective method of therapy – hematopoietic stem cell transplantation, due to the development of serious manifestations of the cardiovascular system. While the positive effects of enzyme replacement therapy in the early stages of treatment may seem promising, it does not guarantee a favorable prognosis for the future.Conclusion. Currently, early diagnosis of mucopolysaccharidosis type I is difficult due to the lack of early manifestations. Often, the progression of clinical manifestations leads to disability, and in severe cases, to death. Therefore, it is important to have early diagnosis and appropriate treatment.

4-Phenylbutyric acid mitigates ER stress-induced neurodegeneration in the spinal cords of a GM2 gangliosidosis mouse model.

Sandhoff disease (SD), a fatal and rare lysosomal storage disorder (LSD), is caused by a deficiency of the enzyme β-hexosaminidase B and leads to severe accumulation of GM2 gangliosides in lysosomes, primarily within the central nervous system (CNS). This accumulation results in severe neurological impairment, lower motor neuron disease, and death. Currently, there are no effective therapies available for SD. Here, we explored the role of endoplasmic reticulum (ER) stress in the spinal cord during disease progression in an established mouse model of SD and revealed the beneficial outcome of off-label treatment with the FDA-approved drug, 4-phenylbutyric acid (4-PBA). We analyzed the expression and localization of ER stress and cellular apoptosis markers, which revealed significant upregulation of these factors within motor neurons. Additionally, we observed a > 50% reduction in neuronal numbers throughout all spinal cord regions. Our studies also tested the impact of the chemical chaperone 4-PBA on ER stress in mice, and following administration, we observed significant improvements in motor neuromuscular function and life span throughout disease progression. 4-PBA treatment significantly reduced apoptosis in spinal cord neurons and increased the number of choline acetyltransferase (ChAT)-positive neurons, with little effect on astrogliosis or sensory interneurons. Overall, this study provides strong evidence for the role of chronic ER stress in the pathophysiology of SD and highlights 4-PBA as a promising therapeutic treatment for SD and potentially other related LSDs.

Abstract 4136394: Elucidation of a novel genetic substrate responsible for genetically elusive ring-like arrhythmogenic cardiomyopathy

Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic heart disease characterized by fibrofatty replacement of ventricular myocardium. Arrhythmogenic left ventricular (LV) cardiomyopathy (ALVC) is a phenotypic variant of ACM predominantly involving the LV. Mutations in genes encoding for desmosome proteins and filamin C have been implicated in ALVC, especially in the setting of a ring-like late gadolinium enhancement (LGE) imaging pattern. Objective: To identify the underlying genetic substrate responsible for genetically elusive ring-like ALVC in a patient with seemingly sporadic/recessive disease. Methods: A 38-year-old male was referred for genetic investigation to determine the underlying genetic substrate responsible for his ALVC phenotype. The patient fulfilled both electrocardiographic (low voltage in the limb leads and anterolateral T-wave inversions) and imaging (>1 segment of subepicardial LGE) criteria for ALVC. Additionally, the patient experienced unexplained episodes of tachycardia, shakiness, sweating, and nausea prompting concern for an underlying neuromuscular disease. Genome sequencing (GS) was performed on DNA isolated from the affected patient and both of his unaffected parents. Variants were filtered assuming either a sporadic de novo occurrence or an autosomal recessive inheritance pattern. Results: GS identified compound heterozygous GNPTAB variants in the affected patient. A previously reported maternally derived p.Leu257Leu (c.771G>A) variant involving the last nucleotide of exon 7 of the GNPTAB gene and a novel paternally inherited Lys834fs*5 frame-shift variant were identified. The p.Leu257Leu variant has been reported to cause aberrant splicing and exon skipping of the GNPTAB mRNA transcript. Pathogenic variants in the GNPTAB encoded N-acetylglucosamine-1 (GlcNAc)-phosphotransferase subunits alpha/beta cause mucolipidosis type III, a rare recessive lysosomal storage disease characterized by coarse facial features, developmental delay, short stature, skeletal deformities, and cardiac involvement including valvular thickening and cardiomyopathy. Conclusions: Here, using a genome sequencing trio analysis we identified a compound heterozygous GNPTAB pathogenic variants as the underlying genetic substrate in a patient with ring-like ALVC and concomitant neuromuscular disease manifestation. Genome sequencing may identify the genetic etiology responsible for an otherwise undifferentiated diagnosis of cardiomyopathy.

Analyzing immune cell infiltrates in skeletal muscle of infantile-onset Pompe disease using bioinformatics and machine learning

Pompe disease, a severe lysosomal storage disorder, is marked by heart problems, muscle weakness, and respiratory difficulties. This study aimed to identify novel markers for infantile-onset Pompe disease by analyzing key genes and immune cells infiltrating affected skeletal muscles, building on existing research linking its progression to the immune cell infiltration. The datasets GSE38680 and GSE159062 were downloaded and differential expression genes (DEGs) were identified. Potential markers were screened using support vector machine recursive feature elimination (SVM-RFE) analysis and least absolute shrinkage and selection operator (LASSO) regression models. To analyze DEGs and immune processes, 22 immune cell types in affected tissues were examined using CIBERSORT. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed significant enrichment in the calcium signaling pathway, phosphatidylinositol signaling system, ubiquitin-mediated proteolysis and JAK-STAT signaling pathway. Machine learning identified GPNMB, CALML6 and TRIM7 as key genes. Immune cell infiltration analysis showed that the expression levels of the above three genes were closely related to immune cells in our target population under study, including T cells regulatory (Tregs), monocytes, macrophages M0, resting and activated dendritic cells, naive and memory B cells. Overall, our study results may provide new clues for exploring markers related to Pompe disease by highlighting key genes and their relationship with immune infiltration, offering insights into the disease’s development. However, previous studies have shown limited evidence of significant immune cell infiltration in muscle biopsies from Pompe patients, and this lack of direct evidence necessitates further investigation and experimental validation in laboratory settings to confirm these associations.

Challenging clinical management of a patient with Gaucher disease type IIIC homozygous for the D409H mutation, aortic valve calcification and porcelain aorta

Background. Gaucher disease is a rare lysosomal storage disorder caused by glucocerebrosidase enzyme deficiency resulting in the cumulative deposition of glucocerebroside in macrophages, predominantly effecting bone marrow, liver and spleen. Gaucher disease type IIIC is a rare subtype that is characterized by cardiovascular involvement, eye-movement disorders, and late-onset neurological symptoms. Case presentation. We present a 14-year-old adolescent boy diagnosed with Gaucher disease type IIIC at age four with a homozygous D409H mutation who developed severe aortic valve stenosis, extensive aortic calcification and a porcelain aorta despite enzyme replacement treatment since the diagnosis. Despite the challenges during the cardiac surgery, we successfully performed transcatheter aortic valve implantation (TAVI). The patient developed a complete atrioventricular block and required a pacemaker after the TAVI. He experienced further complications during the follow-up. Conclusion. The case presents the challenges in the treatment of cardiovascular complications in patients with Gaucher disease and demonstrates the importance of individualized treatment approaches, as well as the potential advantages and complications of TAVI in difficult situations like this.

Safety and Tolerability of a Shorter Agalsidase Beta Infusion Time in Patients with Classic or Later-Onset Fabry Disease

Background: The multisystem manifestations of Fabry disease can create major challenges in patient care. Although enzyme replacement therapy with recombinant agalsidase beta has demonstrated clinical benefits, the standard fortnightly, multi-hour infusion regimen imposes a substantial burden on patients. Methods: We assessed the safety and feasibility of shortening the agalsidase beta infusion time to 90 min in adult patients with classic or later-onset Fabry disease in the absence of premedication. A total of 39 consecutive adult patients (agalsidase-naïve: n = 7; with significant comorbidities: n = 15) with no recent infusion-associated reactions underwent a total of 85 agalsidase beta infusions in our tertiary reference centre for lysosomal diseases. Each infusion was administered at a constant rate (between 0.78 and 1.17 mg/min, depending on the total dose administered). Results: No adverse events of any type (including discomfort and infusion-associated reactions) were reported during or after infusions. The patients’ vital signs and physical examination remained stable, and patients’ satisfaction was high. Conclusions: Our results suggest that shortening the agalsidase beta infusion time to 90 min is safe and feasible in stably treated adult patients with Fabry disease and no recent infusion-associated reactions.

Cinemeducation improves early clinical exposure to inborn errors of metabolism.

Cinemeducation is an effective tool to help students develop humanistic skills. However, there was a need for more studies to find out if this can also be utilized to improve the interest and satisfaction of students learning about rare diseases such as the inborn errors of metabolism. The aim was to introduce cinemeducation as part of early clinical exposure and teach first-year MBBS students in the Department of Biochemistry about inborn errors of metabolism. This was a quasi-experimental, cross-over study involving 100 MBBS students. Movie clips prepared from Lorenzo's Oil (for Lipid metabolism) and Extraordinary Measures (for Lysosomal Storage Disease) and corresponding paper-based cases; questionnaires and feedback forms were validated by expert group review. Students' academic performance was improved in the groups where the Extraordinary Measures movie was used for cinemeducation. Still, this effect was not observed when the movie Lorenzo's Oil was used. Both learners and facilitators were satisfied with cinemeducation. Cinemeducation was effectively introduced to teach inborn errors of metabolism in the Department of Biochemistry topic-dependent manner.

Promises and challenges of genomic newborn screening (NBS) - lessons from public health NBS programs.

Newborn screening (NBS) in the United States began in the 1960s to detect inborn errors of metabolism that benefited from presymptomatic treatment compared with treatment after the development of symptoms and diagnosis. Over time, it expanded to include endocrinological disorders, hematological disorders, immunodeficiencies, and other treatable diseases such as lysosomal storage diseases (LSD), cystic fibrosis, X-linked adrenoleukodystrophy, and spinal muscular dystrophy. This expansion has been driven by new technologies (e.g., tandem mass spectrometry) and novel treatments (e.g., enzyme replacement therapy and stem cell transplant for LSDs). Advances in next-generation gene sequencing (NGS) enable rapid identification of many additional conditions that might benefit from early presymptomatic intervention. We review the NGS technologies that evolved as diagnostic testing and suggest issues to be resolved before their potential application to screening the asymptomatic population. We illustrate the importance of selecting diseases to be screened and propose recommendations to follow when variants of uncertain significance are found. We address ethical issues around achieving equity in the sensitivity of genomic NBS, access to follow-up and management, especially for people from diverse backgrounds, and other considerations. Finally, we discuss the potential benefits and harms of genomic NBS to the overall health of children with monogenic diseases. IMPACT: Genomic newborn screening programs are ongoing worldwide. Public discussion is needed as to whether genomic newborn screening should be offered as a public health program and, if so, what conditions should be screened for. Providers should understand that the sensitivity of genomic newborn screening is especially low for newborns from non-European populations. Methylation, large structural variants and repeat expansion variants are not amenable to next-generation sequencing-based genomic newborn screening. The article serves as a comprehensive guide to understanding issues that need to be solved before genomic newborn screening is implemented as a public health program.

Effects of GBA1 Variants and Prenatal Exposition on the Glucosylsphingosine (Lyso-Gb1) Levels in Gaucher Disease Carriers

Gaucher disease (GD) is a lysosomal lipid storage disorder caused by β-glucocerebrosidase (encoded by GBA1 gene) activity deficiency, resulting in the accumulation of glucosylceramide (Gb1) and its deacylated metabolite glucosylsphingosine (lyso-Gb1). Lyso-Gb1 has been studied previously and proved to be a sensitive biomarker, distinguishing patients with GD from carriers and healthy subjects. It was shown that its level corresponds with β-glucocerebrosidase activity, thus it remains unknown as to why carriers have slightly higher lyso-Gb1 level than healthy population. This is the first report on lyso-Gb1 levels describing representative cohort of GD carriers. Our data of 48 GD carriers, including three newborns, indicated that there are significant differences in lyso-Gb1 levels between carriers having a GD-affected mother and a healthy mother (11.53 and 8.45, respectively, p = 0.00077), and between carriers of the L483P GBA1 variant and carriers of other GBA1 pathogenic variants (9.85 and 7.03, respectively, p = 0.07). Through analysing our unique data of three newborns whose mothers are patients with GD, we also found that lyso-Gb1 is most probably transferred to the foetus via placenta.

Abnormally accumulated GM2 ganglioside contributes to skeletal deformity in Tay-Sachs mice.

Tay-Sachs Disease is a rare lysosomal storage disorder caused by mutations in the HEXA gene, responsible for the degradation of ganglioside GM2. In addition to progressive neurodegeneration, Tay-Sachs patients display bone anomalies, including kyphosis. Tay-Sachs disease mouse model (Hexa-/-Neu3-/-) shows both neuropathological and clinical abnormalities of the infantile-onset disease phenotype. In this study, we investigated the effects of GM2 accumulation on bone remodeling activity. Here, we evaluated the bone phenotype of 5-month-old Hexa-/-Neu3-/- mice with age-matched control groups using gene expression analysis, bone plasma biomarker analysis, and micro-computed tomography. We demonstrated lower plasma alkaline phosphatase activity and calcium levels with increased tartrate-resistant acid phosphatase levels, indicating reduced bone remodeling activity in mice. Consistently, gene expression analysis confirmed osteoblast reduction and osteoclast induction in the femur of mice. Micro-computed tomography and analysis show reduced trabecular bone volume, mineral density, number, and thickness in Hexa-/-Neu3-/- mice. In conclusion, we demonstrated that abnormal GM2 ganglioside accumulation significantly triggers skeletal abnormality in Tay-Sachs mice. We suggest that further investigation of the molecular basis of bone structure anomalies is necessary to elucidate new therapeutic targets that preventthe progression ofbone symptoms and improve the life standards of Tay-Sachs patients. KEY MESSAGES: We detected the markers of bone loss-associated disorders such as osteopenia and osteoporosis in the Tay-Sachs disease mice model Hexa-/-Neu3-/-. We also demonstrated for the first time there is an increase in trabecular spacing and a reduction in trabecular thickness and number indicating skeletal abnormalities in mice model using micro-CT analysis.

Deletion of Gba in neurons, but not microglia, causes neurodegeneration in a Gaucher mouse model.

Gaucher disease, the most prevalent lysosomal storage disease, is caused by homozygous mutations at the GBA gene, which is responsible for encoding the enzyme glucocerebrosidase. Neuronopathic Gaucher disease is associated with microgliosis, astrogliosis, and neurodegeneration. However, the role that microglia, astrocytes, and neurons play in the disease remains to be determined. In the current study, we developed inducible, cell-type-specific Gba-KO mice to better understand the individual impacts of Gba deficiencies on microglia and neurons. Gba was conditionally knocked out either exclusively in microglia or neurons or throughout the body. These mouse models were developed using a tamoxifen-inducible Cre system, with tamoxifen administration commencing at weaning. Microglia-specific Gba-KO mice showed no signs of disease. However, the neuron-specific Gba KO resulted in a shortened lifespan, severe weight loss, and ataxia. These mice also had significant neurodegeneration, microgliosis, and astrogliosis accompanied by the accumulation of glucosylceramide and glucosylsphingosine, recapitulating Gaucher disease-like symptoms. These surprising findings reveal that, unlike the neuron-specific Gba deficiency, microglia-specific Gba deficiency alone does not induce disease. The neuronal Gaucher disease mouse model, with a median survival of 16 weeks, may be useful for future studies of pathogenesis and the evaluation of therapies.

Pain, quality of life, and integral management in a cohort of patients diagnosed with hypophosphatasia in Colombia

BackgroundHypophosphatasia (HPP; OMIM 241510, 241500, and 146300) is a progressive metabolic, genetic disease with wide clinical heterogeneity, ranging from perinatal lethality to mild or moderate localized symptoms. This study aims to analyze the perception of pain, quality of life, and access barriers to healthcare among patients diagnosed with hypophosphatasia in Colombia. In this document we present pain and quality of life results.MethodsThis study is an observational cohort of 18 HPP patients registered in the Colombian Association of Patients with Lysosomal Storage Diseases and Other Orphan Diseases (ACOPEL) database. We conducted a descriptive analysis using data from three questionnaires (SF-36, Brief Pain Questionnaire (BPQ), and Hypophosphatasia Impact Patient Survey (HIPS); the latter was translated into Spanish and validated for this study.ResultsThe most affected features, according to the SF-36 questionnaire, were overall health, vitality, and pain, with a median score above 67%. Patients' perception of their health status (HIPS questionnaire) was favorable, with 38.9% of cases reporting excellent health. On average, results from the BPQ indicated mild to moderate intensity of current pain experienced by patients. Consistency was observed in the reports of either the absence of pain or the presence of mild to moderate intensity when analyzing the results of the three questionnaires.ConclusionsColombian patients with HPP experience mild to moderate impairment in quality of life and pain that interfere with their daily activities. However, there is wide variability in the results obtained.

Lysosomal enzyme binding to the cation-independent mannose 6-phosphate receptor is regulated allosterically by insulin-like growth factor 2.

The cation-independent mannose 6-phosphate receptor (CI-MPR) is clinically significant in the treatment of patients with lysosomal storage diseases because it functions in the biogenesis of lysosomes by transporting mannose 6-phosphate (M6P)-containing lysosomal enzymes to endosomal compartments. CI-MPR is multifunctional and modulates embryonic growth and fetal size by downregulating circulating levels of the peptide hormone insulin-like growth factor 2 (IGF2). The extracellular region of CI-MPR comprises 15 homologous domains with binding sites for M6P-containing ligands located in domains 3, 5, 9, and 15, whereas IGF2 interacts with residues in domain 11. How a particular ligand affects the receptor's conformation or its ability to bind other ligands remains poorly understood. To address these questions, we purified a soluble form of the receptor from newborn calf serum, carried out glycoproteomics to define the N-glycans at its 19 potential glycosylation sites, probed its ability to bind lysosomal enzymes in the presence and absence of IGF2 using surface plasmon resonance, and assessed its conformation in the presence and absence of IGF2 by negative-staining electron microscopy and hydroxyl radical protein footprinting studies. Together, our findings support the hypothesis that IGF2 acts as an allosteric inhibitor of lysosomal enzyme binding by inducing global conformational changes of CI-MPR.

Neurological manifestations of lysosomal storage diseases.

Lysosomal storage diseases (LSDs) encompass a group of rare inherited metabolic disorders characterized by the accumulation of undegraded substrates within lysosomes, leading to multisystemic manifestations, including profound neurological involvement. This article provides a concise overview of the neurological manifestations of LSDs, with a focus on central nervous system (CNS) involvement and treatment strategies. While the paper intricacies of each LSD subtype and its associated CNS manifestations, it aims to provide a summary of the essential findings and implications. The neurological manifestations of LSDs encompass a spectrum of symptoms, including cognitive impairment, motor dysfunction, seizures, and sensory deficits, which significantly impact patients' quality of life and pose therapeutic challenges. Current treatment strategies primarily aim to alleviate symptoms and slow disease progression, with limited success in reversing established neurological damage. Enzyme replacement therapy, substrate reduction therapy, and emerging gene therapies hold promise for addressing CNS involvement in LSDs. However, challenges such as blood-brain barrier penetration and long-term efficacy remain. In addition to discussing treatment modalities, this article highlights the importance of early diagnosis, multidisciplinary care, and patient advocacy in optimizing outcomes for individuals affected by LSDs. Ethical considerations are also addressed, including equitable access to emerging treatments and integrating personalized medicine approaches. Overall, this article underscores the complex interplay between genetics, neuroscience, and clinical care in understanding and managing the neurological manifestations of LSDs while emphasizing the need for continued research and collaboration to advance therapeutic interventions and improve patient outcomes.