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Special Issue "Lysosomal Storage Disorders: Novel Concepts, Therapeutic Aspects and Beyond"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (28 February 2017)

Special Issue Editor

Guest Editor
Prof. Dr. Ritva Tikkanen

Institute of Biochemistry, Medical Faculty, Justus-Liebig University of Giessen, Friedrichstrasse 24, D-35392, Giessen, Germany
Website 1 | Website 2 | E-Mail
Interests: lysosomes; matabolic pathways; lysosomal storage disorders; signaling; cell adhesion; endosomal trafficking

Special Issue Information

Dear Colleagues,

Lysosomal storage disorders (LSDs) are a heterogeneous group of rare monogenic diseases that are characterized by aberrant lysosomes with storage material. These diseases frequently manifest as severe defects of the central nervous system, mental retardation and reduced life span. Most LSDs result from a deficiency of a single enzyme, whereas others are caused by mutations in non-enzymatic proteins. In the past couple of years, our knowledge about the pathogenesis and the molecular details of the genes involved has substantially increased. These findings have forced us to rethink some old central dogmas about these diseases and revealed novel aspects about the pathomechanisms. Importantly, novel therapy options have become available, or are under development, for some LSDs that were previously considered fatal.

The purpose of this Special Issue is to summarize our current understanding of LSDs and the involvement of various cellular pathways such as autophagy, neuroinflammation, microgliosis and signaling in their pathogenesis. We also highly welcome papers addressing all current and prospective therapies for LSDs, as well as novel concepts and hypotheses about these disorders, including their connections to more common diseases such as Alzheimer’s or Parkinson’s. We encourage the submission of review articles and original research papers of any length. Our aim is to provide a comprehensive update on LSDs, their pathomechanisms and therapy options.

Prof. Dr. Ritva Tikkanen
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • lysosomes
  • lysosomal storage disorders
  • neurodegeneration
  • nanoparticles
  • enzyme replacement
  • gene therapy
  • substrate reduction
  • pharmacological chaperones

Related Special Issue

Published Papers (17 papers)

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Research

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Open AccessArticle Brain RNA-Seq Profiling of the Mucopolysaccharidosis Type II Mouse Model
Int. J. Mol. Sci. 2017, 18(5), 1072; https://doi.org/10.3390/ijms18051072
Received: 14 March 2017 / Revised: 5 May 2017 / Accepted: 8 May 2017 / Published: 17 May 2017
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Abstract
Lysosomal storage disorders (LSDs) are a group of about 50 genetic metabolic disorders, mainly affecting children, sharing the inability to degrade specific endolysosomal substrates. This results in failure of cellular functions in many organs, including brain that in most patients may go through
[...] Read more.
Lysosomal storage disorders (LSDs) are a group of about 50 genetic metabolic disorders, mainly affecting children, sharing the inability to degrade specific endolysosomal substrates. This results in failure of cellular functions in many organs, including brain that in most patients may go through progressive neurodegeneration. In this study, we analyzed the brain of the mouse model for Hunter syndrome, a LSD mostly presenting with neurological involvement. Whole transcriptome analysis of the cerebral cortex and midbrain/diencephalon/hippocampus areas was performed through RNA-seq. Genes known to be involved in several neurological functions showed a significant differential expression in the animal model for the disease compared to wild type. Among the pathways altered in both areas, axon guidance, calcium homeostasis, synapse and neuroactive ligand–receptor interaction, circadian rhythm, neuroinflammation and Wnt signaling were the most significant. Application of RNA sequencing to dissect pathogenic alterations of complex syndromes allows to photograph perturbations, both determining and determined by these disorders, which could simultaneously occur in several metabolic and biochemical pathways. Results also emphasize the common, altered pathways between neurodegenerative disorders affecting elderly and those associated with pediatric diseases of genetic origin, perhaps pointing out a general common course for neurodegeneration, independent from the primary triggering cause. Full article
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Open AccessArticle Induced Pluripotent Stem Cells Derived from a CLN5 Patient Manifest Phenotypic Characteristics of Neuronal Ceroid Lipofuscinoses
Int. J. Mol. Sci. 2017, 18(5), 955; https://doi.org/10.3390/ijms18050955
Received: 17 February 2017 / Revised: 12 April 2017 / Accepted: 26 April 2017 / Published: 1 May 2017
Cited by 8 | PDF Full-text (3804 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Neuronal ceroid lipofuscinoses (NCLs) are autosomal recessive progressive encephalopathies caused by mutations in at least 14 different genes. Despite extensive studies performed in different NCL animal models, the molecular mechanisms underlying neurodegeneration in NCLs remain poorly understood. To model NCL in human cells,
[...] Read more.
Neuronal ceroid lipofuscinoses (NCLs) are autosomal recessive progressive encephalopathies caused by mutations in at least 14 different genes. Despite extensive studies performed in different NCL animal models, the molecular mechanisms underlying neurodegeneration in NCLs remain poorly understood. To model NCL in human cells, we generated induced pluripotent stem cells (iPSCs) by reprogramming skin fibroblasts from a patient with CLN5 (ceroid lipofuscinosis, neuronal, 5) disease, the late infantile variant form of NCL. These CLN5 patient-derived iPSCs (CLN5Y392X iPSCs) harbouring the most common CLN5 mutation, c.1175_1176delAT (p.Tyr392X), were further differentiated into neural lineage cells, the most affected cell type in NCLs. The CLN5Y392X iPSC-derived neural lineage cells showed accumulation of autofluorescent storage material and subunit C of the mitochondrial ATP synthase, both representing the hallmarks of many forms of NCLs, including CLN5 disease. In addition, we detected abnormalities in the intracellular organelles and aberrations in neuronal sphingolipid transportation, verifying the previous findings obtained from Cln5-deficient mouse macrophages. Therefore, patient-derived iPSCs provide a suitable model to study the mechanisms of NCL diseases. Full article
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Open AccessArticle Increased Regenerative Capacity of the Olfactory Epithelium in Niemann–Pick Disease Type C1
Int. J. Mol. Sci. 2017, 18(4), 777; https://doi.org/10.3390/ijms18040777
Received: 2 February 2017 / Revised: 19 March 2017 / Accepted: 20 March 2017 / Published: 6 April 2017
Cited by 5 | PDF Full-text (7804 KB) | HTML Full-text | XML Full-text
Abstract
Niemann–Pick disease type C1 (NPC1) is a fatal neurovisceral lysosomal lipid storage disorder. The mutation of the NPC1 protein affects the homeostasis and transport of cholesterol and glycosphingolipids from late endosomes/lysosomes to the endoplasmic reticulum resulting in progressive neurodegeneration. Since olfactory impairment is
[...] Read more.
Niemann–Pick disease type C1 (NPC1) is a fatal neurovisceral lysosomal lipid storage disorder. The mutation of the NPC1 protein affects the homeostasis and transport of cholesterol and glycosphingolipids from late endosomes/lysosomes to the endoplasmic reticulum resulting in progressive neurodegeneration. Since olfactory impairment is one of the earliest symptoms in many neurodegenerative disorders, we focused on alterations of the olfactory epithelium in an NPC1 mouse model. Previous findings revealed severe morphological and immunohistochemical alterations in the olfactory system of NPC1−/− mutant mice compared with healthy controls (NPC1+/+). Based on immunohistochemical evaluation of the olfactory epithelium, we analyzed the impact of neurodegeneration in the olfactory epithelium of NPC1−/− mice and observed considerable loss of mature olfactory receptor neurons as well as an increased number of proliferating and apoptotic cells. Additionally, after administration of two different therapy approaches using either a combination of miglustat, 2-hydroxypropyl-β-cyclodextrin (HPβCD) and allopregnanolone or a monotherapy with HPβCD, we recorded a remarkable reduction of morphological damages in NPC1−/− mice and an up to four-fold increase of proliferating cells within the olfactory epithelium. Numbers of mature olfactory receptor neurons doubled after both therapy approaches. Interestingly, we also observed therapy-induced alterations in treated NPC1+/+ controls. Thus, olfactory testing may provide useful information to monitor pharmacologic treatment approaches in human NPC1. Full article
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Open AccessArticle Functional Analysis of the Ser149/Thr149 Variants of Human Aspartylglucosaminidase and Optimization of the Coding Sequence for Protein Production
Int. J. Mol. Sci. 2017, 18(4), 706; https://doi.org/10.3390/ijms18040706
Received: 16 December 2016 / Revised: 17 March 2017 / Accepted: 22 March 2017 / Published: 26 March 2017
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Abstract
Aspartylglucosaminidase (AGA) is a lysosomal hydrolase that participates in the breakdown of glycoproteins. Defects in the AGA gene result in a lysosomal storage disorder, aspartylglucosaminuria (AGU), that manifests mainly as progressive mental retardation. A number of AGU missense mutations have been identified that
[...] Read more.
Aspartylglucosaminidase (AGA) is a lysosomal hydrolase that participates in the breakdown of glycoproteins. Defects in the AGA gene result in a lysosomal storage disorder, aspartylglucosaminuria (AGU), that manifests mainly as progressive mental retardation. A number of AGU missense mutations have been identified that result in reduced AGA activity. Human variants that contain either Ser or Thr in position 149 have been described, but it is unknown if this affects AGA processing or activity. Here, we have directly compared the Ser149/Thr149 variants of AGA and show that they do not differ in terms of relative specific activity or processing. Therefore, Thr149 AGA, which is the rare variant, can be considered as a neutral or benign variant. Furthermore, we have here produced codon-optimized versions of these two variants and show that they are expressed at significantly higher levels than AGA with the natural codon-usage. Since optimal AGA expression is of vital importance for both gene therapy and enzyme replacement, our data suggest that use of codon-optimized AGA may be beneficial for these therapy options. Full article
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Open AccessArticle The Carotid Intima-Media Thickness and Arterial Stiffness of Pediatric Mucopolysaccharidosis Patients Are Increased Compared to Both Pediatric and Adult Controls
Int. J. Mol. Sci. 2017, 18(3), 637; https://doi.org/10.3390/ijms18030637
Received: 30 January 2017 / Revised: 25 February 2017 / Accepted: 8 March 2017 / Published: 15 March 2017
Cited by 1 | PDF Full-text (837 KB) | HTML Full-text | XML Full-text
Abstract
Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but cardiovascular disease causes mortality in a significant percentage of survivors. Markers must be developed to predict MPS cardiac risk and monitor efficacy of investigational therapies.MPS patients underwent carotid artery ultrasonography from which carotid intima-media thickness
[...] Read more.
Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but cardiovascular disease causes mortality in a significant percentage of survivors. Markers must be developed to predict MPS cardiac risk and monitor efficacy of investigational therapies.MPS patients underwent carotid artery ultrasonography from which carotid intima-media thickness (cIMT) and three measures of arterial stiffness were calculated: carotid artery distensibility (cCSD), compliance (cCSC), and incremental elastic modulus (cIEM). MPS carotid measurements were compared to corresponding data from pediatric and adult healthy cohorts. 33 MPS patients (17 MPS I, 9 MPS II, 4 MPS IIIA, and 3 MPS VI; mean age 12.5 ± 4.7 years), 560 pediatric controls (age 13.1 ± 4.0 years), and 554 adult controls (age 39.2 ± 2.2 years) were studied. Age and sex-adjusted aggregate MPS cIMT (0.56 ± 0.05 mm) was significantly greater than both pediatric (+0.12 mm; 95% CI +0.10 to +0.14 mm) and adult (+0.10 mm; 95% CI +0.06 to +0.14 mm) control cohorts; similar findings were observed for all MPS subtypes. Mean MPS cIMT approximated the 80th percentile of the adult cohort cIMT. MPS patients also demonstrated significantly increased adjusted arterial stiffness measurements, evidenced by reduced cCSD, cCSC, and increased cIEM, compared to pediatric and adult control cohorts. Regardless of treatment, MPS patients demonstrate increased cIMT and arterial stiffness compared to healthy pediatric and adult controls. These data suggest that relatively young MPS patients demonstrate a “structural vascular age” of at least 40 years old. Full article
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Open AccessArticle Osteocyte Alterations Induce Osteoclastogenesis in an In Vitro Model of Gaucher Disease
Int. J. Mol. Sci. 2017, 18(1), 112; https://doi.org/10.3390/ijms18010112
Received: 17 October 2016 / Revised: 30 December 2016 / Accepted: 2 January 2017 / Published: 13 January 2017
Cited by 1 | PDF Full-text (3267 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Gaucher disease (GD) is caused by mutations in the glucosylceramidase β (GBA 1) gene that confer a deficient level of activity of glucocerebrosidase (GCase). This deficiency leads to the accumulation of the glycolipid glucocerebroside in the lysosomes of cells, mainly in
[...] Read more.
Gaucher disease (GD) is caused by mutations in the glucosylceramidase β (GBA 1) gene that confer a deficient level of activity of glucocerebrosidase (GCase). This deficiency leads to the accumulation of the glycolipid glucocerebroside in the lysosomes of cells, mainly in the monocyte/macrophage lineage. Its mildest form is Type I GD, characterized by non-neuronopathic involvement. Bone compromise is the most disabling aspect of the Gaucher disease. However, the pathophysiological aspects of skeletal alterations are not yet fully understood. The bone tissue homeostasis is maintained by a balance between resorption of old bone by osteoclasts and new bone formation by osteoblasts. A central player in this balance is the osteocyte as it controls both processes. We studied the involvement of osteocytes in an in vitro chemical model of Gaucher disease. The osteocyte cell line MLO-Y4 was exposed to conduritol-β-epoxide (CBE), an inhibitor of GCase, for a period of 7, 14 and 21 days. Conditioned media from CBE-treated osteocytes was found to induce osteoclast differentiation. GCase inhibition caused alterations in Cx43 expression and distribution pattern and an increase in osteocyte apoptosis. Osteoclast differentiation involved osteocyte apoptotic bodies, receptor activator of nuclear factor κ-B ligand (RANKL) and soluble factors. Thus, our results indicate that osteocytes may have a role to play in the bone pathophysiology of GD. Full article
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Open AccessCommunication Correlations between Endomyocardial Biopsies and Cardiac Manifestations in Taiwanese Patients with the Chinese Hotspot IVS4+919G>A Mutation: Data from the Fabry Outcome Survey
Int. J. Mol. Sci. 2017, 18(1), 119; https://doi.org/10.3390/ijms18010119
Received: 1 November 2016 / Revised: 16 December 2016 / Accepted: 21 December 2016 / Published: 9 January 2017
Cited by 1 | PDF Full-text (3756 KB) | HTML Full-text | XML Full-text
Abstract
We retrospectively evaluated correlations between cardiac manifestations and globotriaosylceramide (Gb3) accumulation in cardiomyocytes from Taiwanese patients with Fabry disease and the IVS4+919G>A (IVS4) mutation who underwent endomyocardial biopsy (Shire; Fabry Outcome Survey data; extracted January 2015). Of 24 males and six females (median
[...] Read more.
We retrospectively evaluated correlations between cardiac manifestations and globotriaosylceramide (Gb3) accumulation in cardiomyocytes from Taiwanese patients with Fabry disease and the IVS4+919G>A (IVS4) mutation who underwent endomyocardial biopsy (Shire; Fabry Outcome Survey data; extracted January 2015). Of 24 males and six females (median age [Q1; Q3] at biopsy 60.4 [57.4; 64.1] and 61.3 [60.4; 65.1] years, respectively), 13 males (54.2%) and five females (83.3%) received agalsidase alfa enzyme replacement therapy (ERT) before biopsy. Median left ventricular mass indexed to height (LVMI) within ±6 months of biopsy was 65.3 (52.7; 93.1) in males and 53.2 (42.0; 55.0) g/m2.7 in females. A moderate, positive, statistically significant correlation was found between the percentage area Gb3 accumulation in cardiomyocytes and LVMI (Spearman’s ρ, 0.45; p = 0.014); a smaller, positive, non-statistically significant correlation was observed between cardiomyocyte diameter and LVMI (Spearman’s ρ 0.16, p = 0.394). Moderate, statistically significant, negative correlations were found between Gb3 accumulation and ERT duration (Spearman’s ρ, −0.49, p = 0.007) and between cardiomyocyte size and ERT duration (Spearman’s ρ, −0.37, p = 0.048). Longer ERT duration was associated with smaller amounts of Gb3 accumulation and smaller cardiomyocyte size. Further follow-up is recommended to confirm these trends in a larger sample size. Full article
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Open AccessArticle Using CRISPR/Cas9-Mediated GLA Gene Knockout as an In Vitro Drug Screening Model for Fabry Disease
Int. J. Mol. Sci. 2016, 17(12), 2089; https://doi.org/10.3390/ijms17122089
Received: 20 September 2016 / Revised: 30 November 2016 / Accepted: 5 December 2016 / Published: 13 December 2016
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Abstract
The CRISPR/Cas9 Genome-editing system has revealed promising potential for generating gene mutation, deletion, and correction in human cells. Application of this powerful tool in Fabry disease (FD), however, still needs to be explored. Enzyme replacement therapy (ERT), a regular administration of recombinant human
[...] Read more.
The CRISPR/Cas9 Genome-editing system has revealed promising potential for generating gene mutation, deletion, and correction in human cells. Application of this powerful tool in Fabry disease (FD), however, still needs to be explored. Enzyme replacement therapy (ERT), a regular administration of recombinant human α Gal A (rhα-GLA), is a currently available and effective treatment to clear the accumulated Gb3 in FD patients. However, the short half-life of rhα-GLA in human body limits its application. Moreover, lack of an appropriate in vitro disease model restricted the high-throughput screening of drugs for improving ERT efficacy. Therefore, it is worth establishing a large-expanded in vitro FD model for screening potential candidates, which can enhance and prolong ERT potency. Using CRISPR/Cas9-mediated gene knockout of GLA in HEK-293T cells, we generated GLA-null cells to investigate rhα-GLA cellular pharmacokinetics. The half-life of administrated rhα-GLA was around 24 h in GLA-null cells; co-administration of proteasome inhibitor MG132 and rhα-GLA significantly restored the GLA enzyme activity by two-fold compared with rhα-GLA alone. Furthermore, co-treatment of rhα-GLA/MG132 in patient-derived fibroblasts increased Gb3 clearance by 30%, compared with rhα-GLA treatment alone. Collectively, the CRISPR/Cas9-mediated GLA-knockout HEK-293T cells provide an in vitro FD model for evaluating the intracellular pharmacokinetics of the rhα-GLA as well as for screening candidates to prolong rhα-GLA potency. Using this model, we demonstrated that MG132 prolongs rhα-GLA half-life and enhanced Gb3 clearance, shedding light on the direction of enhancing ERT efficacy in FD treatment. Full article
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Open AccessArticle The Large Phenotypic Spectrum of Fabry Disease Requires Graduated Diagnosis and Personalized Therapy: A Meta-Analysis Can Help to Differentiate Missense Mutations
Int. J. Mol. Sci. 2016, 17(12), 2010; https://doi.org/10.3390/ijms17122010
Received: 9 October 2016 / Revised: 23 November 2016 / Accepted: 24 November 2016 / Published: 1 December 2016
Cited by 3 | PDF Full-text (933 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Fabry disease is caused by mutations in the GLA gene and is characterized by a large genotypic and phenotypic spectrum. Missense mutations pose a special problem for graduating diagnosis and choosing a cost-effective therapy. Some mutants retain enzymatic activity, but are less stable
[...] Read more.
Fabry disease is caused by mutations in the GLA gene and is characterized by a large genotypic and phenotypic spectrum. Missense mutations pose a special problem for graduating diagnosis and choosing a cost-effective therapy. Some mutants retain enzymatic activity, but are less stable than the wild type protein. These mutants can be stabilized by small molecules which are defined as pharmacological chaperones. The first chaperone to reach clinical trial is 1-deoxygalactonojirimycin, but others have been tested in vitro. Residual activity of GLA mutants has been measured in the presence or absence of pharmacological chaperones by several authors. Data obtained from transfected cells correlate with those obtained in cells derived from patients, regardless of whether 1-deoxygalactonojirimycin was present or not. The extent to which missense mutations respond to 1-deoxygalactonojirimycin is variable and a reference table of the results obtained by independent groups that is provided with this paper can facilitate the choice of eligible patients. A review of other pharmacological chaperones is provided as well. Frequent mutations can have residual activity as low as one-fourth of normal enzyme in vitro. The reference table with residual activity of the mutants facilitates the identification of non-pathological variants. Full article
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Open AccessArticle Aortic Root Dilatation in Mucopolysaccharidosis I–VII
Int. J. Mol. Sci. 2016, 17(12), 2004; https://doi.org/10.3390/ijms17122004
Received: 21 October 2016 / Revised: 22 November 2016 / Accepted: 22 November 2016 / Published: 29 November 2016
Cited by 3 | PDF Full-text (732 KB) | HTML Full-text | XML Full-text
Abstract
The prevalence of aortic root dilatation (ARD) in mucopolysaccharidosis (MPS) is not well documented. We investigated aortic root measurements in 34 MPS patients at the Children’s Hospital of Orange County (CHOC). The diagnosis, treatment status, age, gender, height, weight and aortic root parameters
[...] Read more.
The prevalence of aortic root dilatation (ARD) in mucopolysaccharidosis (MPS) is not well documented. We investigated aortic root measurements in 34 MPS patients at the Children’s Hospital of Orange County (CHOC). The diagnosis, treatment status, age, gender, height, weight and aortic root parameters (aortic valve annulus (AVA), sinuses of Valsalva (SoV), and sinotubular junction (STJ)) were extracted by retrospective chart review and echocardiographic measurements. Descriptive statistics, ANOVA, and paired post-hoc t-tests were used to summarize the aortic dimensions. Exact binomial 95% confidence intervals (CIs) were constructed for ARD, defined as a z-score greater than 2 at the SoV. The patient age ranged from 3.4–25.9 years (mean 13.3 ± 6.1), the height from 0.87–1.62 meters (mean 1.24 ± 0.21), and the weight from 14.1–84.5 kg (mean 34.4 ± 18.0). The prevalence of dilation at the AVA was 41% (14/34; 95% CI: 25%–59%); at the SoV was 35% (12/34; 95% CI: 20%–54%); and at the STJ was 30% (9/30; 95% CI: 15%–49%). The highest prevalence of ARD was in MPS IVa (87.5%). There was no significant difference between mean z-scores of MPS patients who received treatment with hematopoietic stem cell transplantation (HSCT) or enzyme replacement therapy (ERT) vs. untreated MPS patients at the AVA (z = 1.9 ± 2.5 vs. z = 1.5 ± 2.4; p = 0.62), SoV (z = 1.2 ± 1.6 vs. z = 1.3 ± 2.2; p = 0.79), or STJ (z = 1.0 ± 1.8 vs. z = 1.2 ± 1.6; p = 0.83). The prevalence of ARD was 35% in our cohort of MPS I–VII patients. Thus, we recommend screening for ARD on a routine basis in this patient population. Full article
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Open AccessArticle Gender Differences in the Application of Spanish Criteria for Initiation of Enzyme Replacement Therapy for Fabry Disease in the Fabry Outcome Survey
Int. J. Mol. Sci. 2016, 17(12), 1965; https://doi.org/10.3390/ijms17121965
Received: 2 August 2016 / Revised: 11 November 2016 / Accepted: 18 November 2016 / Published: 24 November 2016
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Abstract
Both male/female patients with Fabry disease (FD) may receive enzyme replacement therapy (ERT). Previously published analyses of the Fabry Outcome Survey (FOS; Shire-sponsored) database suggested gender differences in timing of ERT initiation. We assessed alignment of criteria for ERT initiation in the Spanish
[...] Read more.
Both male/female patients with Fabry disease (FD) may receive enzyme replacement therapy (ERT). Previously published analyses of the Fabry Outcome Survey (FOS; Shire-sponsored) database suggested gender differences in timing of ERT initiation. We assessed alignment of criteria for ERT initiation in the Spanish adult population included in FOS with recommendations of a Spanish national consensus. This retrospective analysis examined baseline clinical data of 88 adults (49 females) enrolled in the FOS database up to August 2014. Thirty-five (39.8%) patients were not receiving ERT: five (12.8%) males and 30 (61.2%) females. Baseline disease severity on the FOS-derived Mainz Severity Score Index was lower in untreated males (median (interquartile range), 0.0 (0.0–1.0)) than treated males (TM; 15.0 (7.5–26.5)), and was similar in untreated and treated females. The percentage of untreated females with at least one criterion for treatment initiation was 76.7% versus 100.0% of treated females (p = 0.0340) and 97.1% (p = 0.0210) of TM. In discordance with Spanish consensus recommendations, a substantial number of females with evidence of FD who might benefit from ERT have not yet initiated treatment. These results suggest unequal gender perceptions with respect to ERT initiation in Spain. Full article
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Open AccessArticle Pharmacologic Treatment Assigned for Niemann Pick Type C1 Disease Partly Changes Behavioral Traits in Wild-Type Mice
Int. J. Mol. Sci. 2016, 17(11), 1866; https://doi.org/10.3390/ijms17111866
Received: 26 September 2016 / Revised: 28 October 2016 / Accepted: 3 November 2016 / Published: 9 November 2016
Cited by 5 | PDF Full-text (2244 KB) | HTML Full-text | XML Full-text
Abstract
Niemann-Pick Type C1 (NPC1) is an autosomal recessive inherited disorder characterized by accumulation of cholesterol and glycosphingolipids. Previously, we demonstrated that BALB/c-npc1nihNpc1−/− mice treated with miglustat, cyclodextrin and allopregnanolone generally performed better than untreated Npc1−/− animals. Unexpectedly, they also
[...] Read more.
Niemann-Pick Type C1 (NPC1) is an autosomal recessive inherited disorder characterized by accumulation of cholesterol and glycosphingolipids. Previously, we demonstrated that BALB/c-npc1nihNpc1−/− mice treated with miglustat, cyclodextrin and allopregnanolone generally performed better than untreated Npc1−/− animals. Unexpectedly, they also seemed to accomplish motor tests better than their sham-treated wild-type littermates. However, combination-treated mutant mice displayed worse cognition performance compared to sham-treated ones. To evaluate effects of these drugs in healthy BALB/c mice, we here analyzed pharmacologic effects on motor and cognitive behavior of wild-type mice. For combination treatment mice were injected with allopregnanolone/cyclodextrin weekly, starting at P7. Miglustat injections were performed daily from P10 till P23. Starting at P23, miglustat was embedded in the chow. Other mice were treated with miglustat only, or sham-treated. The battery of behavioral tests consisted of accelerod, Morris water maze, elevated plus maze, open field and hot-plate tests. Motor capabilities and spontaneous motor behavior were unaltered in both drug-treated groups. Miglustat-treated wild-type mice displayed impaired spatial learning compared to sham- and combination-treated mice. Both combination- and miglustat-treated mice showed enhanced anxiety in the elevated plus maze compared to sham-treated mice. Additionally, combination treatment as well as miglustat alone significantly reduced brain weight, whereas only combination treatment reduced body weight significantly. Our results suggest that allopregnanolone/cyclodextrin ameliorate most side effects of miglustat in wild-type mice. Full article
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Open AccessCommunication Clinical and Molecular Characterization of Patients with Mucopolysaccharidosis Type I in an Algerian Series
Int. J. Mol. Sci. 2016, 17(5), 743; https://doi.org/10.3390/ijms17050743
Received: 1 April 2016 / Revised: 2 May 2016 / Accepted: 6 May 2016 / Published: 17 May 2016
Cited by 3 | PDF Full-text (196 KB) | HTML Full-text | XML Full-text
Abstract
Mucopolysaccharidoses (MPS’s) represent a subgroup of lysosomal storage diseases related to a deficiency of enzymes that catalyze glycosaminoglycans degradation. Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder caused by a deficiency of α-l-iduronidase encoded by the IDUA gene.
[...] Read more.
Mucopolysaccharidoses (MPS’s) represent a subgroup of lysosomal storage diseases related to a deficiency of enzymes that catalyze glycosaminoglycans degradation. Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder caused by a deficiency of α-l-iduronidase encoded by the IDUA gene. Partially degraded heparan sulfate and dermatan sulfate accumulate progressively and lead to multiorgan dysfunction and damage. The aim of this study is to describe the clinical, biochemical, and molecular characteristics of 13 Algerian patients from 11 distinct families. MPS I diagnosis was confirmed by molecular study of the patients’ IDUA gene. Clinical features at the diagnosis and during the follow-up are reported. Eighty-four percent of the studied patients presented with a mild clinical phenotype. Molecular study of the IDUA gene allowed the characterization of four pathological variations at the homozygous or compound heterozygote status: IDUA NM_00203.4:c.1598C>G-p.(Pro533Arg) in 21/26 alleles, IDUA NM_00203.4:c.532G>A-p.(Glu178Lys) in 2/26 alleles, IDUA NM_00203.4:c.501C>G-p.(Tyr167*) in 2/26 alleles, and IDUA NM_00203. 4: c.1743C>G-p.(Tyr581*) in 1/26 alleles. This molecular study unveils the predominance of p.(Pro533Arg) variation in our MPS I patients. In this series, the occurrence of some clinical features linked to the Scheie syndrome is consistent with the literature, such as systematic valvulopathies, corneal opacity, and umbilical hernia; however, storage signs, facial dysmorphic features, and hepatomegaly were more frequent in our series. Screening measures for these debilitating diseases in highly consanguineous at-risk populations must be considered a priority health problem. Full article
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Review

Jump to: Research

Open AccessReview From Lysosomal Storage Diseases to NKT Cell Activation and Back
Int. J. Mol. Sci. 2017, 18(3), 502; https://doi.org/10.3390/ijms18030502
Received: 26 December 2016 / Revised: 17 February 2017 / Accepted: 20 February 2017 / Published: 25 February 2017
Cited by 6 | PDF Full-text (858 KB) | HTML Full-text | XML Full-text
Abstract
Lysosomal storage diseases (LSDs) are inherited metabolic disorders characterized by the accumulation of different types of substrates in the lysosome. With a multisystemic involvement, LSDs often present a very broad clinical spectrum. In many LSDs, alterations of the immune system were described. Special
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Lysosomal storage diseases (LSDs) are inherited metabolic disorders characterized by the accumulation of different types of substrates in the lysosome. With a multisystemic involvement, LSDs often present a very broad clinical spectrum. In many LSDs, alterations of the immune system were described. Special emphasis was given to Natural Killer T (NKT) cells, a population of lipid-specific T cells that is activated by lipid antigens bound to CD1d (cluster of differentiation 1 d) molecules at the surface of antigen-presenting cells. These cells have important functions in cancer, infection, and autoimmunity and were altered in a variety of LSDs’ mouse models. In some cases, the observed decrease was attributed to defects in either lipid antigen availability, trafficking, processing, or loading in CD1d. Here, we review the current knowledge about NKT cells in the context of LSDs, including the alterations detected, the proposed mechanisms to explain these defects, and the relevance of these findings for disease pathology. Furthermore, the effect of enzyme replacement therapy on NKT cells is also discussed. Full article
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Open AccessReview A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments
Int. J. Mol. Sci. 2017, 18(2), 441; https://doi.org/10.3390/ijms18020441
Received: 28 November 2016 / Revised: 9 February 2017 / Accepted: 10 February 2017 / Published: 17 February 2017
Cited by 36 | PDF Full-text (2214 KB) | HTML Full-text | XML Full-text
Abstract
Gaucher disease (GD, ORPHA355) is a rare, autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in macrophages. In the general population, its incidence is approximately 1/40,000 to
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Gaucher disease (GD, ORPHA355) is a rare, autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in macrophages. In the general population, its incidence is approximately 1/40,000 to 1/60,000 births, rising to 1/800 in Ashkenazi Jews. The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells. Type-1 Gaucher disease, which affects the majority of patients (90% in Europe and USA, but less in other regions), is characterized by effects on the viscera, whereas types 2 and 3 are also associated with neurological impairment, either severe in type 2 or variable in type 3. A diagnosis of GD can be confirmed by demonstrating the deficiency of acid glucocerebrosidase activity in leukocytes. Mutations in the GBA1 gene should be identified as they may be of prognostic value in some cases. Patients with type-1 GD—but also carriers of GBA1 mutation—have been found to be predisposed to developing Parkinson’s disease, and the risk of neoplasia associated with the disease is still subject to discussion. Disease-specific treatment consists of intravenous enzyme replacement therapy (ERT) using one of the currently available molecules (imiglucerase, velaglucerase, or taliglucerase). Orally administered inhibitors of glucosylceramide biosynthesis can also be used (miglustat or eliglustat). Full article
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Open AccessReview Practical Recommendations for Diagnosis and Management of Respiratory Muscle Weakness in Late-Onset Pompe Disease
Int. J. Mol. Sci. 2016, 17(10), 1735; https://doi.org/10.3390/ijms17101735
Received: 28 August 2016 / Revised: 29 September 2016 / Accepted: 10 October 2016 / Published: 17 October 2016
Cited by 4 | PDF Full-text (1006 KB) | HTML Full-text | XML Full-text
Abstract
Pompe disease is an autosomal-recessive lysosomal storage disorder characterized by progressive myopathy with proximal muscle weakness, respiratory muscle dysfunction, and cardiomyopathy (in infants only). In patients with juvenile or adult disease onset, respiratory muscle weakness may decline more rapidly than overall neurological disability.
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Pompe disease is an autosomal-recessive lysosomal storage disorder characterized by progressive myopathy with proximal muscle weakness, respiratory muscle dysfunction, and cardiomyopathy (in infants only). In patients with juvenile or adult disease onset, respiratory muscle weakness may decline more rapidly than overall neurological disability. Sleep-disordered breathing, daytime hypercapnia, and the need for nocturnal ventilation eventually evolve in most patients. Additionally, respiratory muscle weakness leads to decreased cough and impaired airway clearance, increasing the risk of acute respiratory illness. Progressive respiratory muscle weakness is a major cause of morbidity and mortality in late-onset Pompe disease even if enzyme replacement therapy has been established. Practical knowledge of how to detect, monitor and manage respiratory muscle involvement is crucial for optimal patient care. A multidisciplinary approach combining the expertise of neurologists, pulmonologists, and intensive care specialists is needed. Based on the authors’ own experience in over 200 patients, this article conveys expert recommendations for the diagnosis and management of respiratory muscle weakness and its sequelae in late-onset Pompe disease. Full article
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Open AccessReview Less Is More: Substrate Reduction Therapy for Lysosomal Storage Disorders
Int. J. Mol. Sci. 2016, 17(7), 1065; https://doi.org/10.3390/ijms17071065
Received: 27 May 2016 / Revised: 24 June 2016 / Accepted: 27 June 2016 / Published: 4 July 2016
Cited by 15 | PDF Full-text (570 KB) | HTML Full-text | XML Full-text | Correction
Abstract
Lysosomal storage diseases (LSDs) are a group of rare, life-threatening genetic disorders, usually caused by a dysfunction in one of the many enzymes responsible for intralysosomal digestion. Even though no cure is available for any LSD, a few treatment strategies do exist. Traditionally,
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Lysosomal storage diseases (LSDs) are a group of rare, life-threatening genetic disorders, usually caused by a dysfunction in one of the many enzymes responsible for intralysosomal digestion. Even though no cure is available for any LSD, a few treatment strategies do exist. Traditionally, efforts have been mainly targeting the functional loss of the enzyme, by injection of a recombinant formulation, in a process called enzyme replacement therapy (ERT), with no impact on neuropathology. This ineffectiveness, together with its high cost and lifelong dependence is amongst the main reasons why additional therapeutic approaches are being (and have to be) investigated: chaperone therapy; gene enhancement; gene therapy; and, alternatively, substrate reduction therapy (SRT), whose aim is to prevent storage not by correcting the original enzymatic defect but, instead, by decreasing the levels of biosynthesis of the accumulating substrate(s). Here we review the concept of substrate reduction, highlighting the major breakthroughs in the field and discussing the future of SRT, not only as a monotherapy but also, especially, as complementary approach for LSDs. Full article
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