Journal of Clinical Medicine

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13 pages, 427 KiB

Open AccessArticle

A Cross-Sectional Retrospective Study of Non-Splenectomized and Never-Treated Patients with Type 1 Gaucher Disease

by Christine Serratrice, Jérôme Stirnemann, Amina Berrahal, Nadia Belmatoug, Fabrice Camou, Catherine Caillaud, Thierry Billette de Villemeur, Florence Dalbies, Bérengère Cador, Roseline Froissart, Agathe Masseau, Anaïs Brassier, Bénédicte Hivert, Laure Swiader, Ivan Bertchansky, Claire de Moreuil, Brigitte Chabrol, Isabelle Durieu, Vanessa Leguy Seguin, Leonardo Astudillo, Sébastien Humbert, Samia Pichard, Catherine Marcel, Isabelle Hau Rainsard, Monia Bengherbia, Karima Yousfi and Marc G. Berger Show full author list Hide full author list

J. Clin. Med. 2020, 9(8), 2343; https://doi.org/10.3390/jcm9082343 - 22 Jul 2020

Cited by 4 | Viewed by 3011

Abstract

Patients with type 1 Gaucher disease (GD1) present thrombocytopenia, anemia, organomegaly, and bone complications. Most experts consider that the less aggressive forms do not require specific treatment. However, little is known about the disease course of these forms. The objective of this cross-sectional [...] Read more.

Patients with type 1 Gaucher disease (GD1) present thrombocytopenia, anemia, organomegaly, and bone complications. Most experts consider that the less aggressive forms do not require specific treatment. However, little is known about the disease course of these forms. The objective of this cross-sectional retrospective study was to compare the clinical, radiological, and laboratory characteristics of patients with less severe GD1 at diagnosis and at the last evaluation to identify features that might lead to potential complications. Non-splenectomized and never-treated patients (19 women and 17 men) were identified in the French Gaucher Disease Registry (FGDR). Their median age was 36.6 years (2.4–75.1), and their median follow-up was 7.8 years (0.4–32.4). Moreover, 38.7% were heterozygous for the GBA1 N370S variant, and 22.6% for the GBA1 L444P variant. From diagnosis to the last evaluation, GD1 did not worsen in 75% of these patients. Some parameters improved (fatigue and hemoglobin concentration), whereas platelet count and chitotriosidase level remained stable. In one patient (2.7%), Lewy body dementia was diagnosed at 46 years of age. Bone lesion onset was late and usually a single event in most patients. This analysis highlights the genotypic heterogeneity of this subgroup, in which disease could remain stable and even improve spontaneously. It also draws attention to the possible risk of Lewy body disease and late onset of bone complications, even if isolated, to be confirmed in larger series and with longer follow-up. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Causes, Symptoms, Diagnosis, and Treatment)

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15 pages, 2471 KiB

Open AccessArticle

Beneficial Effects of Acetyl-DL-Leucine (ADLL) in a Mouse Model of Sandhoff Disease

by Ecem Kaya, David A. Smith, Claire Smith, Barry Boland, Michael Strupp and Frances M. Platt

J. Clin. Med. 2020, 9(4), 1050; https://doi.org/10.3390/jcm9041050 - 8 Apr 2020

Cited by 23 | Viewed by 6408

Abstract

Sandhoff disease is a rare neurodegenerative lysosomal storage disease associated with the storage of GM2 ganglioside in late endosomes/lysosomes. Here, we explored the efficacy of acetyl-DL-leucine (ADLL), which has been shown to improve ataxia in observational studies in patients with Niemann–Pick Type C1 [...] Read more.

Sandhoff disease is a rare neurodegenerative lysosomal storage disease associated with the storage of GM2 ganglioside in late endosomes/lysosomes. Here, we explored the efficacy of acetyl-DL-leucine (ADLL), which has been shown to improve ataxia in observational studies in patients with Niemann–Pick Type C1 and other cerebellar ataxias. We treated a mouse model of Sandhoff disease (Hexb^-/-) (0.1 g/kg/day) from 3 weeks of age with this orally available drug. ADLL produced a modest but significant increase in life span, accompanied by improved motor function and reduced glycosphingolipid (GSL) storage in the forebrain and cerebellum, in particular GA2. ADLL was also found to normalize altered glucose and glutamate metabolism, as well as increasing autophagy and the reactive oxygen species (ROS) scavenger, superoxide dismutase (SOD1). Our findings provide new insights into metabolic abnormalities in Sandhoff disease, which could be targeted with new therapeutic approaches, including ADLL. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Causes, Symptoms, Diagnosis, and Treatment)

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30 pages, 5730 KiB

Open AccessArticle

Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human G_M1-Gangliosidosis

by Deborah Eikelberg, Annika Lehmbecker, Graham Brogden, Witchaya Tongtako, Kerstin Hahn, Andre Habierski, Julia B. Hennermann, Hassan Y. Naim, Felix Felmy, Wolfgang Baumgärtner and Ingo Gerhauser

J. Clin. Med. 2020, 9(4), 1004; https://doi.org/10.3390/jcm9041004 - 2 Apr 2020

Cited by 10 | Viewed by 3851

Abstract

G_M1-gangliosidosis is caused by a reduced activity of β-galactosidase (Glb1), resulting in intralysosomal accumulations of G_M1. The aim of this study was to reveal the pathogenic mechanisms of G_M1-gangliosidosis in a new Glb1 knockout mouse [...] Read more.

G_M1-gangliosidosis is caused by a reduced activity of β-galactosidase (Glb1), resulting in intralysosomal accumulations of G_M1. The aim of this study was to reveal the pathogenic mechanisms of G_M1-gangliosidosis in a new Glb1 knockout mouse model. Glb1^−/− mice were analyzed clinically, histologically, immunohistochemically, electrophysiologically and biochemically. Morphological lesions in the central nervous system were already observed in two-month-old mice, whereas functional deficits, including ataxia and tremor, did not start before 3.5-months of age. This was most likely due to a reduced membrane resistance as a compensatory mechanism. Swollen neurons exhibited intralysosomal storage of lipids extending into axons and amyloid precursor protein positive spheroids. Additionally, axons showed a higher kinesin and lower dynein immunoreactivity compared to wildtype controls. Glb1^−/− mice also demonstrated loss of phosphorylated neurofilament positive axons and a mild increase in non-phosphorylated neurofilament positive axons. Moreover, marked astrogliosis and microgliosis were found, but no demyelination. In addition to the main storage material G_M1, G_A1, sphingomyelin, phosphatidylcholine and phosphatidylserine were elevated in the brain. In summary, the current Glb1^−/− mice exhibit a so far undescribed axonopathy and a reduced membrane resistance to compensate the functional effects of structural changes. They can be used for detailed examinations of axon–glial interactions and therapy trials of lysosomal storage diseases. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Causes, Symptoms, Diagnosis, and Treatment)

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14 pages, 2739 KiB

Open AccessArticle

Hip Morphology in Mucolipidosis Type II

by Luise Sophie Ammer, Esmeralda Oussoren, Nicole Maria Muschol, Sandra Pohl, Maria Estela Rubio-Gozalbo, René Santer, Ralf Stuecker, Eik Vettorazzi and Sandra Rafaela Breyer

J. Clin. Med. 2020, 9(3), 728; https://doi.org/10.3390/jcm9030728 - 8 Mar 2020

Cited by 8 | Viewed by 4050

Abstract

Mucolipidosis type II (MLII) is a rare lysosomal storage disorder caused by defective trafficking of lysosomal enzymes. Severe skeletal manifestations are a hallmark of the disease including hip dysplasia. This study aims to describe hip morphology and the natural course of hip pathologies [...] Read more.

Mucolipidosis type II (MLII) is a rare lysosomal storage disorder caused by defective trafficking of lysosomal enzymes. Severe skeletal manifestations are a hallmark of the disease including hip dysplasia. This study aims to describe hip morphology and the natural course of hip pathologies in MLII by systematic evaluation of plain radiographs, ultrasounds and magnetic resonance imaging (MRI). An international two-centered study was performed by retrospective chart review. All MLII patients with at least one pelvic radiograph were included. A total of 16 patients were followed over a mean of 3.5 years (range 0.2–10.7 years). Typical age-dependent radiographic signs identified were femoral cloaking (7/16), rickets/hyperparathyroidism-like changes (6/16) and constrictions of the supra-acetabular part of the os ilium (16/16) and the femoral neck (7/16). The course of acetabular and migration indexes (AI, MI) significantly increased in female patients. However, in the overall group, there was no relevant progression of acetabular dysplasia with a mean AI of 23.0 (range 5°–41°) and 23.7° (range 5°–40°) at the first and last assessments, respectively. Better knowledge on hip morphology in MLII could lead to earlier diagnosis, improved clinical management and enables assessment of effects of upcoming therapies on the skeletal system. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Causes, Symptoms, Diagnosis, and Treatment)

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15 pages, 2259 KiB

Open AccessArticle

Conventional and Unconventional Therapeutic Strategies for Sialidosis Type I

by Rosario Mosca, Diantha van de Vlekkert, Yvan Campos, Leigh E. Fremuth, Jaclyn Cadaoas, Vish Koppaka, Emil Kakkis, Cynthia Tifft, Camilo Toro, Simona Allievi, Cinzia Gellera, Laura Canafoglia, Gepke Visser, Ida Annunziata and Alessandra d’Azzo

J. Clin. Med. 2020, 9(3), 695; https://doi.org/10.3390/jcm9030695 - 4 Mar 2020

Cited by 18 | Viewed by 3730

Abstract

Congenital deficiency of the lysosomal sialidase neuraminidase 1 (NEU1) causes the lysosomal storage disease, sialidosis, characterized by impaired processing/degradation of sialo-glycoproteins and sialo-oligosaccharides, and accumulation of sialylated metabolites in tissues and body fluids. Sialidosis is considered an ultra-rare clinical condition and falls into [...] Read more.

Congenital deficiency of the lysosomal sialidase neuraminidase 1 (NEU1) causes the lysosomal storage disease, sialidosis, characterized by impaired processing/degradation of sialo-glycoproteins and sialo-oligosaccharides, and accumulation of sialylated metabolites in tissues and body fluids. Sialidosis is considered an ultra-rare clinical condition and falls into the category of the so-called orphan diseases, for which no therapy is currently available. In this study we aimed to identify potential therapeutic modalities, targeting primarily patients affected by type I sialidosis, the attenuated form of the disease. We tested the beneficial effects of a recombinant protective protein/cathepsin A (PPCA), the natural chaperone of NEU1, as well as pharmacological and dietary compounds on the residual activity of mutant NEU1 in a cohort of patients’ primary fibroblasts. We observed a small, but consistent increase in NEU1 activity, following administration of all therapeutic agents in most of the fibroblasts tested. Interestingly, dietary supplementation of betaine, a natural amino acid derivative, in mouse models with residual NEU1 activity mimicking type I sialidosis, increased the levels of mutant NEU1 and resolved the oligosacchariduria. Overall these findings suggest that carefully balanced, unconventional dietary compounds in combination with conventional therapeutic approaches may prove to be beneficial for the treatment of sialidosis type I. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Causes, Symptoms, Diagnosis, and Treatment)

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21 pages, 2435 KiB

Open AccessArticle

Molecular Genetics of Niemann–Pick Type C Disease in Italy: An Update on 105 Patients and Description of 18 NPC1 Novel Variants

by Andrea Dardis, Stefania Zampieri, Cinzia Gellera, Rosalba Carrozzo, Silvia Cattarossi, Paolo Peruzzo, Rosalia Dariol, Annalisa Sechi, Federica Deodato, Claudio Caccia, Daniela Verrigni, Serena Gasperini, Agata Fiumara, Simona Fecarotta, Miryam Carecchio, Massimiliano Filosto, Lucia Santoro, Barbara Borroni, Andrea Bordugo, Francesco Brancati, Cinzia V. Russo, Maja Di Rocco, Antonio Toscano, Maurizio Scarpa and Bruno Bembi Show full author list Hide full author list

J. Clin. Med. 2020, 9(3), 679; https://doi.org/10.3390/jcm9030679 - 3 Mar 2020

Cited by 21 | Viewed by 5481

Abstract

Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disorder caused by mutations in NPC1 or NPC2 genes. In 2009, the molecular characterization of 44 NPC Italian patients has been published. Here, we present an update of the genetic findings in [...] Read more.

Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disorder caused by mutations in NPC1 or NPC2 genes. In 2009, the molecular characterization of 44 NPC Italian patients has been published. Here, we present an update of the genetic findings in 105 Italian NPC patients belonging to 83 unrelated families (77 NPC1 and 6 NPC2). NPC1 and NPC2 genes were studied following an algorithm recently published. Eighty-four different NPC1 and five NPC2 alleles were identified. Only two NPC1 alleles remained non detected. Sixty-two percent of NPC1 alleles were due to missense variants. The most frequent NPC1 mutation was the p.F284Lfs*26 (5.8% of the alleles). All NPC2 mutations were found in the homozygous state, and all but one was severe. Among newly diagnosed patients, 18 novel NPC1 mutations were identified. The pathogenic nature of 7/9 missense alleles and 3/4 intronic variants was confirmed by filipin staining and NPC1 protein analysis or mRNA expression in patient’s fibroblasts. Taken together, our previous published data and new results provide an overall picture of the molecular characteristics of NPC patients diagnosed so far in Italy. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Causes, Symptoms, Diagnosis, and Treatment)

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15 pages, 2593 KiB

Open AccessArticle

Neuronal and Astrocytic Differentiation from Sanfilippo C Syndrome iPSCs for Disease Modeling and Drug Development

by Noelia Benetó, Monica Cozar, Laura Castilla-Vallmanya, Oskar G. Zetterdahl, Madalina Sacultanu, Eulalia Segur-Bailach, María García-Morant, Antonia Ribes, Henrik Ahlenius, Daniel Grinberg, Lluïsa Vilageliu and Isaac Canals

J. Clin. Med. 2020, 9(3), 644; https://doi.org/10.3390/jcm9030644 - 28 Feb 2020

Cited by 10 | Viewed by 4696

Abstract

Sanfilippo syndrome type C (mucopolysaccharidosis IIIC) is an early-onset neurodegenerative lysosomal storage disorder, which is currently untreatable. The vast majority of studies focusing on disease mechanisms of Sanfilippo syndrome were performed on non-neural cells or mouse models, which present obvious limitations. Induced pluripotent [...] Read more.

Sanfilippo syndrome type C (mucopolysaccharidosis IIIC) is an early-onset neurodegenerative lysosomal storage disorder, which is currently untreatable. The vast majority of studies focusing on disease mechanisms of Sanfilippo syndrome were performed on non-neural cells or mouse models, which present obvious limitations. Induced pluripotent stem cells (iPSCs) are an efficient way to model human diseases in vitro. Recently developed transcription factor-based differentiation protocols allow fast and efficient conversion of iPSCs into the cell type of interest. By applying these protocols, we have generated new neuronal and astrocytic models of Sanfilippo syndrome using our previously established disease iPSC lines. Moreover, our neuronal model exhibits disease-specific molecular phenotypes, such as increase in lysosomes and heparan sulfate. Lastly, we tested an experimental, siRNA-based treatment previously shown to be successful in patients’ fibroblasts and demonstrated its lack of efficacy in neurons. Our findings highlight the need to use relevant human cellular models to test therapeutic interventions and shows the applicability of our neuronal and astrocytic models of Sanfilippo syndrome for future studies on disease mechanisms and drug development. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Causes, Symptoms, Diagnosis, and Treatment)

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18 pages, 4740 KiB

Open AccessArticle

Brain Pathology in Mucopolysaccharidoses (MPS) Patients with Neurological Forms

by Gustavo M. Viana, David A. Priestman, Frances M. Platt, Shaukat Khan, Shunji Tomatsu and Alexey V. Pshezhetsky

J. Clin. Med. 2020, 9(2), 396; https://doi.org/10.3390/jcm9020396 - 1 Feb 2020

Cited by 38 | Viewed by 4060

Abstract

Mucopolysaccharidoses (MPS) are the group of lysosomal storage disorders caused by deficiencies of enzymes involved in the stepwise degradation of glycosaminoglycans. To identify brain pathology common for neurological MPS, we conducted a comprehensive analysis of brain cortex tissues from post-mortem autopsy materials of [...] Read more.

Mucopolysaccharidoses (MPS) are the group of lysosomal storage disorders caused by deficiencies of enzymes involved in the stepwise degradation of glycosaminoglycans. To identify brain pathology common for neurological MPS, we conducted a comprehensive analysis of brain cortex tissues from post-mortem autopsy materials of eight patients affected with MPS I, II, IIIA, IIIC, and IIID, and age-matched controls. Frozen brain tissues were analyzed for the abundance of glycosaminoglycans (heparan, dermatan, and keratan sulfates) by LC-MS/MS, glycosphingolipids by normal phase HPLC, and presence of inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor superfamily member 10 (TNFSF10) by Western blotting. Fixed tissues were stained for the markers for microgliosis, astrogliosis, misfolded proteins, impaired autophagy, and GM2 ganglioside. Our results demonstrate that increase of heparan sulfate, decrease of keratan sulfate, and storage of simple monosialogangliosides 2 and 3 (GM2 and GM3) as well as the neutral glycosphingolipid, LacCer, together with neuroinflammation and neuronal accumulation of misfolded proteins are the hallmarks of brain pathology in MPS patients. These biomarkers are similar to those reported in the corresponding mouse models, suggesting that the pathological mechanism is common for all neurological MPS in humans and mice. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Causes, Symptoms, Diagnosis, and Treatment)

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13 pages, 1197 KiB

Open AccessArticle

NPC1 Deficiency in Mice is Associated with Fetal Growth Restriction, Neonatal Lethality and Abnormal Lung Pathology

by Jorge L. Rodriguez-Gil, Dawn E. Watkins-Chow, Laura L. Baxter, Tadafumi Yokoyama, Patricia M. Zerfas, Matthew F. Starost, William A. Gahl, May Christine V. Malicdan, Forbes D. Porter, Frances M. Platt and William J. Pavan

J. Clin. Med. 2020, 9(1), 12; https://doi.org/10.3390/jcm9010012 - 19 Dec 2019

Cited by 10 | Viewed by 3540

Abstract

The rare lysosomal storage disorder Niemann-Pick disease type C1 (NPC1) arises from mutation of NPC1, which encodes a lysosomal transmembrane protein essential for normal transport and trafficking of cholesterol and sphingolipids. NPC1 is highly heterogeneous in both clinical phenotypes and age of [...] Read more.

The rare lysosomal storage disorder Niemann-Pick disease type C1 (NPC1) arises from mutation of NPC1, which encodes a lysosomal transmembrane protein essential for normal transport and trafficking of cholesterol and sphingolipids. NPC1 is highly heterogeneous in both clinical phenotypes and age of onset. Previous studies have reported sub-Mendelian survival rates for mice homozygous for various Npc1 mutant alleles but have not studied the potential mechanisms underlying this phenotype. We performed the first developmental analysis of a Npc1 mouse model, Npc1^em1Pav, and discovered significant fetal growth restriction in homozygous mutants beginning at E16.5. Npc1^{em1Pav/em1Pav} mice also exhibited cyanosis, increased respiratory effort, and over 50% lethality at birth. Analysis of neonatal lung tissues revealed lipid accumulation, notable abnormalities in surfactant, and enlarged alveolar macrophages, suggesting that lung abnormalities may be associated with neonatal lethality in Npc1^{em1Pav/em1Pav} mice. The phenotypic severity of the Npc1^em1Pav model facilitated this first analysis of perinatal lethality and lung pathology in an NPC1 model organism, and this model may serve as a useful resource for developing treatments for respiratory complications seen in NPC1 patients. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Causes, Symptoms, Diagnosis, and Treatment)

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17 pages, 4464 KiB

Open AccessArticle

Toward Engineering the Mannose 6-Phosphate Elaboration Pathway in Plants for Enzyme Replacement Therapy of Lysosomal Storage Disorders

by Ying Zeng, Xu He, Tatyana Danyukova, Sandra Pohl and Allison R. Kermode

J. Clin. Med. 2019, 8(12), 2190; https://doi.org/10.3390/jcm8122190 - 12 Dec 2019

Cited by 4 | Viewed by 4182

Abstract

Mucopolysaccharidosis (MPS) I is a severe lysosomal storage disease caused by α-L-iduronidase (IDUA) deficiency, which results in accumulation of non-degraded glycosaminoglycans in lysosomes. Costly enzyme replacement therapy (ERT) is the conventional treatment for MPS I. Toward producing a more cost-effective and safe alternative [...] Read more.

Mucopolysaccharidosis (MPS) I is a severe lysosomal storage disease caused by α-L-iduronidase (IDUA) deficiency, which results in accumulation of non-degraded glycosaminoglycans in lysosomes. Costly enzyme replacement therapy (ERT) is the conventional treatment for MPS I. Toward producing a more cost-effective and safe alternative to the commercial mammalian cell-based production systems, we have produced recombinant human IDUA in seeds of an Arabidopsis mutant to generate the enzyme in a biologically active and non-immunogenic form containing predominantly high mannose N-linked glycans. Recombinant enzyme in ERT is generally thought to require a mannose 6-phosphate (M6P) targeting signal for endocytosis into patient cells and for intracellular delivery to the lysosome. Toward effecting in planta phosphorylation, the human M6P elaboration machinery was successfully co-expressed along with the recombinant human IDUA using a single multi-gene construct. Uptake studies using purified putative M6P-IDUA generated in planta on cultured MPS I primary fibroblasts indicated that the endocytosed recombinant lysosomal enzyme led to substantial reduction of glycosaminoglycans. However, the efficiency of the putative M6P-IDUA in reducing glycosaminoglycan storage was comparable with the efficiency of the purified plant mannose-terminated IDUA, suggesting a poor in planta M6P-elaboration by the expressed machinery. Although the in planta M6P-tagging process efficiency would need to be improved, an exciting outcome of our work was that the plant-derived mannose-terminated IDUA yielded results comparable to those obtained with the commercial IDUA (Aldurazyme^® (Sanofi, Paris, France)), and a significant amount of the plant-IDUA is trafficked by a M6P receptor-independent pathway. Thus, a plant-based platform for generating lysosomal hydrolases may represent an alternative and cost-effective strategy to the conventional ERT, without the requirement for additional processing to create the M6P motif. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Causes, Symptoms, Diagnosis, and Treatment)

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7 pages, 1484 KiB

Open AccessArticle

Long Term Follow-Up of 103 Untreated Adult Patients with Type 1 Gaucher Disease

by Tama Dinur, Ari Zimran, Michal Becker-Cohen, David Arkadir, Claudia Cozma, Marina Hovakimyan, Sebastian Oppermann, Laura Demuth, Arndt Rolfs and Shoshana Revel-Vilk

J. Clin. Med. 2019, 8(10), 1662; https://doi.org/10.3390/jcm8101662 - 11 Oct 2019

Cited by 23 | Viewed by 3232

Abstract

The introduction of disease-specific therapy for patients with type I Gaucher disease (GD1) was a revolution in the management of patients, but not without cost. Thus, the management of mildly affected patients is still debated. We herein report a long-term follow-up (median (range) [...] Read more.

The introduction of disease-specific therapy for patients with type I Gaucher disease (GD1) was a revolution in the management of patients, but not without cost. Thus, the management of mildly affected patients is still debated. We herein report a long-term follow-up (median (range) of 20 (5–58) years) of 103 GD1 patients who have never received enzymatic or substrate reduction therapy. The median (range) platelet count and hemoglobin levels in last assessment of all but six patients who refused therapy (although recommended and approved) were 152 (56–408) × 10³/mL and 13.1 (7.6–16.8) g/dL, respectively. Most patients had mild hepatosplenomegaly. Nine patients were splenectomized. No patient developed clinical bone disease. The median (range) lyso-Gb1 levels at last visit was 108.5 (8.1–711) ng/mL; lowest for patients with R496H/other and highest for patients refusing therapy. This rather large cohort with long follow-up confirms that mildly affected patients may remain stable for many years without GD-specific therapy. The challenge for the future, when newborn screening may detect all patients, is to be able to predict which of the early diagnosed patients is at risk for disease-related complications and therefore for early treatment, and who may remain asymptomatic or minimally affected with no need for disease-specific therapy. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Causes, Symptoms, Diagnosis, and Treatment)

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23 pages, 3406 KiB

Open AccessArticle

Drosophila melanogaster Mutated in its GBA1b Ortholog Recapitulates Neuronopathic Gaucher Disease

by Or Cabasso, Sumit Paul, Orly Dorot, Gali Maor, Olga Krivoruk, Metsada Pasmanik-Chor, Mina Mirzaian, Maria Ferraz, Johannes Aerts and Mia Horowitz

J. Clin. Med. 2019, 8(9), 1420; https://doi.org/10.3390/jcm8091420 - 9 Sep 2019

Cited by 23 | Viewed by 4790

Abstract

Gaucher disease (GD) results from mutations in the GBA1 gene, which encodes lysosomal glucocerebrosidase (GCase). The large number of mutations known to date in the gene lead to a heterogeneous disorder, which is divided into a non-neuronopathic, type 1 GD, and two neurological, [...] Read more.

Gaucher disease (GD) results from mutations in the GBA1 gene, which encodes lysosomal glucocerebrosidase (GCase). The large number of mutations known to date in the gene lead to a heterogeneous disorder, which is divided into a non-neuronopathic, type 1 GD, and two neurological, type 2 and type 3, forms. We studied the two fly GBA1 orthologs, GBA1a and GBA1b. Each contains a Minos element insertion, which truncates its coding sequence. In the GBA1a^m/m flies, which express a mutant protein, missing 33 C-terminal amino acids, there was no decrease in GCase activity or substrate accumulation. However, GBA1b^m/m mutant flies presented a significant decrease in GCase activity with concomitant substrate accumulation, which included C14:1 glucosylceramide and C14:0 glucosylsphingosine. GBA1b^m/m mutant flies showed activation of the Unfolded Protein Response (UPR) and presented inflammation and neuroinflammation that culminated in development of a neuronopathic disease. Treatment with ambroxol did not rescue GCase activity or reduce substrate accumulation; however, it ameliorated UPR, inflammation and neuroinflammation, and increased life span. Our results highlight the resemblance between the phenotype of the GBA1b^m/m mutant fly and neuronopathic GD and underlie its relevance in further GD studies as well as a model to test possible therapeutic modalities. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Causes, Symptoms, Diagnosis, and Treatment)

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Review

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30 pages, 1588 KiB

Open AccessReview

Glucocerebrosidase: Functions in and Beyond the Lysosome

by Daphne E.C. Boer, Jeroen van Smeden, Joke A. Bouwstra and Johannes M.F.G Aerts

J. Clin. Med. 2020, 9(3), 736; https://doi.org/10.3390/jcm9030736 - 9 Mar 2020

Cited by 35 | Viewed by 9083

Abstract

Glucocerebrosidase (GCase) is a retaining β-glucosidase with acid pH optimum metabolizing the glycosphingolipid glucosylceramide (GlcCer) to ceramide and glucose. Inherited deficiency of GCase causes the lysosomal storage disorder named Gaucher disease (GD). In GCase-deficient GD patients the accumulation of GlcCer in lysosomes of [...] Read more.

Glucocerebrosidase (GCase) is a retaining β-glucosidase with acid pH optimum metabolizing the glycosphingolipid glucosylceramide (GlcCer) to ceramide and glucose. Inherited deficiency of GCase causes the lysosomal storage disorder named Gaucher disease (GD). In GCase-deficient GD patients the accumulation of GlcCer in lysosomes of tissue macrophages is prominent. Based on the above, the key function of GCase as lysosomal hydrolase is well recognized, however it has become apparent that GCase fulfills in the human body at least one other key function beyond lysosomes. Crucially, GCase generates ceramides from GlcCer molecules in the outer part of the skin, a process essential for optimal skin barrier property and survival. This review covers the functions of GCase in and beyond lysosomes and also pays attention to the increasing insight in hitherto unexpected catalytic versatility of the enzyme. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Causes, Symptoms, Diagnosis, and Treatment)

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24 pages, 726 KiB

Open AccessReview

Neuropathophysiology of Lysosomal Storage Diseases: Synaptic Dysfunction as a Starting Point for Disease Progression

by Camila Pará, Poulomee Bose and Alexey V. Pshezhetsky

J. Clin. Med. 2020, 9(3), 616; https://doi.org/10.3390/jcm9030616 - 25 Feb 2020

Cited by 23 | Viewed by 6655

Abstract

About two thirds of the patients affected with lysosomal storage diseases (LSD) experience neurological manifestations, such as developmental delay, seizures, or psychiatric problems. In order to develop efficient therapies, it is crucial to understand the neuropathophysiology underlying these symptoms. How exactly lysosomal storage [...] Read more.

About two thirds of the patients affected with lysosomal storage diseases (LSD) experience neurological manifestations, such as developmental delay, seizures, or psychiatric problems. In order to develop efficient therapies, it is crucial to understand the neuropathophysiology underlying these symptoms. How exactly lysosomal storage affects biogenesis and function of neurons is still under investigation however recent research highlights a substantial role played by synaptic defects, such as alterations in synaptic spines, synaptic proteins, postsynaptic densities, and synaptic vesicles that might lead to functional impairments in synaptic transmission and neurodegeneration, finally culminating in massive neuronal death and manifestation of cognitive symptoms. Unveiling how the synaptic components are affected in neurological LSD will thus enable a better understanding of the complexity of disease progression as well as identify crucial targets of therapeutic relevance and optimal time windows for targeted intervention. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Causes, Symptoms, Diagnosis, and Treatment)

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20 pages, 1148 KiB

Open AccessReview

Lysosomal Ceramide Metabolism Disorders: Implications in Parkinson’s Disease

by Silvia Paciotti, Elisabetta Albi, Lucilla Parnetti and Tommaso Beccari

J. Clin. Med. 2020, 9(2), 594; https://doi.org/10.3390/jcm9020594 - 21 Feb 2020

Cited by 30 | Viewed by 5071

Abstract

Ceramides are a family of bioactive lipids belonging to the class of sphingolipids. Sphingolipidoses are a group of inherited genetic diseases characterized by the unmetabolized sphingolipids and the consequent reduction of ceramide pool in lysosomes. Sphingolipidoses include several disorders as Sandhoff disease, Fabry [...] Read more.

Ceramides are a family of bioactive lipids belonging to the class of sphingolipids. Sphingolipidoses are a group of inherited genetic diseases characterized by the unmetabolized sphingolipids and the consequent reduction of ceramide pool in lysosomes. Sphingolipidoses include several disorders as Sandhoff disease, Fabry disease, Gaucher disease, metachromatic leukodystrophy, Krabbe disease, Niemann Pick disease, Farber disease, and GM2 gangliosidosis. In sphingolipidosis, lysosomal lipid storage occurs in both the central nervous system and visceral tissues, and central nervous system pathology is a common hallmark for all of them. Parkinson’s disease, the most common neurodegenerative movement disorder, is characterized by the accumulation and aggregation of misfolded α-synuclein that seem associated to some lysosomal disorders, in particular Gaucher disease. This review provides evidence into the role of ceramide metabolism in the pathophysiology of lysosomes, highlighting the more recent findings on its involvement in Parkinson’s disease. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Causes, Symptoms, Diagnosis, and Treatment)

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Open AccessReview

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

by Rachel Heon-Roberts, Annie L. A. Nguyen and Alexey V. Pshezhetsky

J. Clin. Med. 2020, 9(2), 344; https://doi.org/10.3390/jcm9020344 - 27 Jan 2020

Cited by 43 | Viewed by 4782

Abstract

The mucopolysaccharidoses (MPS) are a group of diseases caused by the lysosomal accumulation of glycosaminoglycans, due to genetic deficiencies of enzymes involved in their degradation. MPS III or Sanfilippo disease, in particular, is characterized by early-onset severe, progressive neurodegeneration but mild somatic involvement, [...] Read more.

The mucopolysaccharidoses (MPS) are a group of diseases caused by the lysosomal accumulation of glycosaminoglycans, due to genetic deficiencies of enzymes involved in their degradation. MPS III or Sanfilippo disease, in particular, is characterized by early-onset severe, progressive neurodegeneration but mild somatic involvement, with patients losing milestones and previously acquired skills as the disease progresses. Despite being the focus of extensive research over the past years, the links between accumulation of the primary molecule, the glycosaminoglycan heparan sulfate, and the neurodegeneration seen in patients have yet to be fully elucidated. This review summarizes the current knowledge on the molecular bases of neurological decline in Sanfilippo disease. It emerges that this deterioration results from the dysregulation of multiple cellular pathways, leading to neuroinflammation, oxidative stress, impaired autophagy and defects in cellular signaling. However, many important questions about the neuropathological mechanisms of the disease remain unanswered, highlighting the need for further research in this area. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Causes, Symptoms, Diagnosis, and Treatment)

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