TY - JOUR T1 - Lysosome biogenesis : Regulation and functions A1 - Yang, Chonglin A1 - Wang, Xiaochen Y1 - 2021/// VL - 220 IS - 6 SP - 1 EP - 15 L1 - file:///C:/Users/juan/Downloads/lisosoma regulacion y funciones.pdf ER - TY - JOUR T1 - Characterization of Classical and Nonclassical Fabry Disease: A Multicenter Study A1 - Arends, Maarten A1 - Wanner, Christoph A1 - Hughes, Derralynn A1 - Mehta, Atul A1 - Oder, Daniel A1 - Watkinson, Oliver T A1 - Elliott, Perry M A1 - Linthorst, Gabor E A1 - Wijburg, Frits A A1 - Biegstraaten, Marieke A1 - Hollak, Carla E Y1 - 2017/// JF - J Am Soc Nephrol VL - 28 SP - 1631 EP - 1641 DO - 10.1681/ASN.2016090964 UR - www.jasn.org L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Arends et al. - 2017 - Characterization of Classical and Nonclassical Fabry Disease A Multicenter Study.pdf N2 - Fabry disease leads to renal, cardiac, and cerebrovascular manifestations. Phenotypic differences between classically and nonclassically affected patients are evident, but there are few data on the natural course of classical and nonclassical disease in men and women. To describe the natural course of Fabry disease stratified by sex and phenotype, we retrospectively assessed event-free survival from birth to the first clinical visit (before enzyme replacement therapy) in 499 adult patients (mean age 43 years old; 41% men; 57% with the classical phenotype) from three international centers of excellence. We classified patients by phenotype on the basis of characteristic symptoms and enzyme activity. Men and women with classical Fabry disease had higher event rate than did those with nonclassical disease (hazard ratio for men, 5.63, 95% confidence interval, 3.17 to 10.00; P,0.001; hazard ratio for women, 2.88, 95% confidence interval, 1.54 to 5.40; P,0.001). Furthermore, men with classical Fabry disease had lower eGFR, higher left ventricular mass, and higher plasma globotriaosylsphingosine concentrations than men with nonclassical Fabry disease or women with either phenotype (P,0.001). In conclusion, before treatment with enzyme replacement therapy, men with classical Fabry disease had a history of more events than men with nonclassical disease or women with either phenotype; women with classical Fabry disease were more likely to develop complications than women with nonclassical disease. These data may support the development of new guidelines for the monitoring and treatment of Fabry disease and studies on the effects of intervention in subgroups of patients. ER - TY - JOUR T1 - Lysosomal storage disorders: The cellular impact of lysosomal dysfunction A1 - Platt, Frances M A1 - Boland, Barry A1 - van der Spoel, Aarnoud C. Y1 - 2012/// JF - Journal of Cell Biology VL - 199 IS - 5 SP - 723 EP - 734 DO - 10.1083/jcb.201208152 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Platt, Boland, Spoel - 2012 - Lysosomal storage disorders The cellular impact of lysosomal dysfunction.pdf N2 - Lysosomal storage diseases (LSDs) are a family of disorders that result from inherited gene mutations that perturb lysosomal homeostasis. LSDs mainly stem from deficiencies in lysosomal enzymes, but also in some nonenzymatic lysosomal proteins, which lead to abnormal storage of macromolecular substrates. Valuable insights into lysosome functions have emerged from research into these diseases. In addition to primary lysosomal dysfunction, cellular pathways associated with other membrane-bound organelles are perturbed in these disorders. Through selective examples, we illustrate why the term "cellular storage disorders" may be a more appropriate description of these diseases and discuss therapies that can alleviate storage and restore normal cellular function. © 2012 Platt et al. ER - TY - JOUR T1 - Adult onset Sandhoff disease: a rare mimicker of amyotrophic lateral sclerosis A1 - Khoueiry, Maria A1 - Malek, Elia A1 - Salameh, Johnny S. Y1 - 2020/// KW - Sandhoff disease KW - hexosaminidase KW - motor neuron disease PB - Taylor & Francis JF - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration VL - 21 IS - 1-2 SP - 144 EP - 146 DO - 10.1080/21678421.2019.1663214 UR - https://doi.org/10.1080/21678421.2019.1663214 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Khoueiry, Malek, Salameh - 2020 - Adult onset Sandhoff disease a rare mimicker of amyotrophic lateral sclerosis.pdf N2 - Sandhoff disease is an under-recognized disease that may present as a lower motor neuron disorder in adulthood. We report the case of siblings presenting in their late 40s with a motor neuron disease phenotype and were misdiagnosed as amyotrophic lateral sclerosis and later found to have Sandhoff disease. Sandhoff disease should be considered in patients presenting with a slowly progressive predominately lower motor neuron disorder. A simple low-cost blood test can confirm the diagnosis. ER - TY - GEN T1 - The rapidly evolving view of lysosomal storage diseases A1 - Parenti, Giancarlo A1 - Medina, Diego L A1 - Ballabio, Andrea Y1 - 2021/// JF - EMBO Molecular Medicine VL - 13 IS - 2 DO - 10.15252/emmm.202012836 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Parenti, Medina, Ballabio - 2021 - The rapidly evolving view of lysosomal storage diseases.pdf N2 - Abstract Lysosomal storage diseases are a group of metabolic disorders caused by deficiencies of several components of lysosomal function. Most commonly affected are lysosomal hydrolases, which are involved in the breakdown and recycling of a variety of complex molecules and cellular structures. The understanding of lysosomal biology has progressively improved over time. Lysosomes are no longer viewed as organelles exclusively involved in catabolic pathways, but rather as highly dynamic elements of the autophagic-lysosomal pathway, involved in multiple cellular functions, including signaling, and able to adapt to environmental stimuli. This refined vision of lysosomes has substantially impacted on our understanding of the pathophysiology of lysosomal disorders. It is now clear that substrate accumulation triggers complex pathogenetic cascades that are responsible for disease pathology, such as aberrant vesicle trafficking, impairment of autophagy, dysregulation of signaling pathways, abnormalities of calcium homeostasis, and mitochondrial dysfunction. Novel technologies, in most cases based on high-throughput approaches, have significantly contributed to the characterization of lysosomal biology or lysosomal dysfunction and have the potential to facilitate diagnostic processes, and to enable the identification of new therapeutic targets. ER - TY - JOUR T1 - Identification of 83 novel alpha-mannosidosis-associated sequence variants: Functional analysis of MAN2B1 missense mutations A1 - Riise Stensland, Hilde Monica Frostad A1 - Klenow, Helle Bagterp A1 - Nguyen, Lam Van A1 - Hansen, Gaute Martin A1 - Malm, Dag A1 - Nilssen, Øivind Y1 - 2012/// KW - Alpha-mannosidosis KW - Functional studies KW - Lysosomal enzyme KW - Lysosomal storage disorder KW - MAN2B1 KW - Mutation spectrum JF - Human Mutation VL - 33 IS - 3 SP - 511 EP - 520 DO - 10.1002/humu.22005 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Riise Stensland et al. - 2012 - Identification of 83 novel alpha-mannosidosis-associated sequence variants Functional analysis of MAN2B1.pdf N2 - The lysosomal storage disorder alpha-mannosidosis is caused by deficiency of the enzyme lysosomal alpha-mannosidase (MAN2B1). In this study, 96 disease-associated sequence variants were identified in 130 unrelated alpha-mannosidosis patients from 30 countries. Eighty-three novel variants were detected, extending the mutation spectrum from 42 to 125. In total, 256 of the 260 mutant alleles (98.5%) were identified. Most of the variants were unique to each family, however, c.2248C>T (p.Arg750Trp) was detected in 50 patients from 16 countries, and accounted for 27.3% of the disease alleles. Haplotype analysis revealed that the c.2248T variant was present on four MAN2B1 haplotype backgrounds, where one major haplotype accounted for 95% of the alleles. The distribution of the c.2248T-associated haplotypes differed remarkably from those of the control populations, suggesting that c.2248C>T has occurred on a few ancestral haplotypes where the major haplotype subsequently has spread by founder effects. The disease-associated missense mutations were introduced into the human MAN2B1 cDNA, expressed in cell culture and assayed for MAN2B1 activity. The majority of the variants were inactive, however, ten showed MAN2B1 activity above background, and more detailed studies are necessary to further evaluate the pathogenicity of these variants. © 2011 Wiley Periodicals, Inc. ER - TY - JOUR T1 - Assessment of a targeted resequencing assay as a support tool in the diagnosis of lysosomal storage disorders A1 - Fernández-Marmiesse, Ana A1 - Morey, Marcos A1 - Pineda, Merce A1 - Eiris, Jesús A1 - Couce, Maria Luz A1 - Castro-Gago, Manuel A1 - Fraga, Jose Maria A1 - Lacerda, Lucia A1 - Gouveia, Sofia A1 - Pérez-Poyato, Maria Socorro A1 - Armstrong, Judith A1 - Castiñeiras, Daisy A1 - Cocho, Jose A. Y1 - 2014/// KW - Diagnostic odysseys KW - In-solution enrichment KW - Lysosomal storage disorders KW - Targeted resequencing JF - Orphanet Journal of Rare Diseases VL - 9 IS - 1 DO - 10.1186/1750-1172-9-59 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Fernández-Marmiesse et al. - 2014 - Assessment of a targeted resequencing assay as a support tool in the diagnosis of lysosomal stora(2).pdf N2 - With over 50 different disorders and a combined incidence of up to 1/3000 births, lysosomal storage diseases (LSDs) constitute a major public health problem and place an enormous burden on affected individuals and their families. Many factors make LSD diagnosis difficult, including phenotype and penetrance variability, shared signs and symptoms, and problems inherent to biochemical diagnosis. Developing a powerful diagnostic tool could mitigate the protracted diagnostic process for these families, lead to better outcomes for current and proposed therapies, and provide the basis for more appropriate genetic counseling. Methods. We have designed a targeted resequencing assay for the simultaneous testing of 57 lysosomal genes, using in-solution capture as the enrichment method and two different sequencing platforms. A total of 84 patients with high to moderate-or low suspicion index for LSD were enrolled in different centers in Spain and Portugal, including 18 positive controls. Results: We correctly diagnosed 18 positive blinded controls, provided genetic diagnosis to 25 potential LSD patients, and ended with 18 diagnostic odysseys. Conclusion: We report the assessment of a next-generation-sequencing-based approach as an accessory tool in the diagnosis of LSDs, a group of disorders which have overlapping clinical profiles and genetic heterogeneity. We have also identified and quantified the strengths and limitations of next generation sequencing (NGS) technology applied to diagnosis. © 2014 Fernández-Marmiesse et al.; licensee BioMed Central Ltd. ER - TY - JOUR T1 - Major Organic Involvement in Women with Fabry Disease in Argentina A1 - Perretta, Fernando A1 - Antongiovanni, Norberto A1 - Jaurretche, Sebastián Y1 - 2018/// JF - Scientific World Journal VL - 2018 DO - 10.1155/2018/6515613 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Perretta, Antongiovanni, Jaurretche - 2018 - Major Organic Involvement in Women with Fabry Disease in Argentina.pdf N2 - Fabry disease (FD) is an X-linked lysosomal storage disorder resulting from the deficiency or absence of the alpha galactosidase A enzyme. Organic involvement in men is well known, but in women it is controversial, partly due to the random X-chromosomes inactivation (Lyon hypothesis). The aim of this study was to describe the organic involvement in women at the time of FD diagnosis. A descriptive, cross-sectional and multicenter study was carried out. Thirty-five women with FD from three reference centers in Argentina were evaluated. The mean age of the whole group (n=35) was 26.6±16.9 years; 22 were adult (over 18) and 13 were paediatric patients. Enzymatic activity was performed in 29/35 patients, which was normal in 24/29 (82.8%). Seven different mutations of the GLA gene were found. The results showed urinary protein loss (45.7%) and decreased glomerular filtration rate (31.4%), mainly in adults. And also, cornea verticillata (56.5%), peripheral neuropathy (51.4%), cardiovascular manifestations (31.4%), hearing loss (20%), angiokeratomas (20%), central nervous system (17.1%), and gastrointestinal involvement (14.3%). Organic compromise in females with FD may be as severe as in men. This analysis has demonstrated a significant proportion of women with signs, symptoms, and major organic involvement at FD diagnosis. ER - TY - JOUR T1 - Identification of novel mutations among Iranian NPC1 patients: a bioinformatics approach to predict pathogenic mutations A1 - Abtahi, Rezvan A1 - Karimzadeh, Parvaneh A1 - Aryani, Omid A1 - Akbarzadeh, Diba A1 - Salehpour, Shadab A1 - Rezayi, Alireza A1 - Tonekaboni, Seyed Hassan A1 - Emameh, Reza Zolfaghari A1 - Houshmand, Massoud Y1 - 2022/// KW - Molecular Study KW - New Mutation KW - Niemann-Pick C PB - BioMed Central JF - Hereditas VL - 159 IS - 1 SP - 1 EP - 11 SN - 4106502200224 DO - 10.1186/s41065-022-00224-1 UR - https://doi.org/10.1186/s41065-022-00224-1 L1 - file:///C:/Users/juan/Downloads/REF 7.pdf N2 - Background: Niemann-Pick disease type C (NPC) is a rare lysosomal neurovisceral storage disease caused by mutations in the NPC 1 (95%) or NPC2 (5%) genes. The products of NPC1 and NPC2 genes play considerable roles in glycolipid and cholesterol trafficking, which could consequently lead to NPC disease with variable phenotypes displaying a broad spectrum of symptoms. Materials: In the present study 35 Iranian NPC unrelated patients were enrolled. These patients were first analysed by the Filipin Staining test of cholesterol deposits in cells for NPC diagnostics. Genomic DNA was extracted from the samples of peripheral blood leukocytes in EDTA following the manufacturer's protocol. All exon–intron boundaries and coding exons of the NPC1gene were amplified by polymerase chain reaction (PCR) using appropriate sets of primers. Thereafter, the products of PCR were sequenced and analysed using the NCBI database (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The variants were reviewed by some databases including the Human Gene Mutation Database (HGMD) (http://www.hgmd.cf.ac.uk/ac/index.php) and ClinVar (https://www.ncbi.nlm.nih.gov/clinvar (. Moreover, all the variants were manually classified in terms of the American College of Medical Genetics and Genomics (ACMG) guideline. Results: The sequence analysis revealed 20 different variations, 10 of which are new, including one nonsense mutation (c.406C > T); three small deletions, (c.3126delC, c.2920_2923delCCTG, and c.2037delG); and six likely pathogenic missense mutations, (c.542C > A, c.1970G > A, c.1993C > G, c.2821 T > C, c.2872C > G, and c.3632 T > A). Finally, the pathogenicity of these new variants was determined using the ACMG guidelines. Conclusion: The present study aimed to facilitate the prenatal diagnosis of NPC patients in the future. In this regard, we identified 10 novel mutations, and verified that the majority of them occurred in six NPC1 exons (5, 8, 9, 13, 19, and 21), that should be considered with a high priority for Iranian patients' cost-effective evaluation. ER - TY - JOUR T1 - Functional and Clinical Consequences of Novel α-Galactosidase A Mutations in Fabry Disease A1 - Lukas, Jan A1 - Scalia, Simone A1 - Eichler, Sabrina A1 - Pockrandt, Anne Marie A1 - Dehn, Nicole A1 - Cozma, Claudia A1 - Giese, Anne Katrin A1 - Rolfs, Arndt Y1 - 2016/// KW - Fabry disease KW - GLA KW - GVUS KW - Pharmacological chaperone therapy KW - Variants of unknown significance JF - Human Mutation VL - 37 IS - 1 SP - 43 EP - 51 DO - 10.1002/humu.22910 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Lukas et al. - 2016 - Functional and Clinical Consequences of Novel α-Galactosidase A Mutations in Fabry Disease.pdf N2 - Fabry disease (FD) is a rare metabolic disorder of glycosphingolipid storage caused by mutations in the GLA gene encoding lysosomal hydrolase α-galactosidase A (α-gal A). Recently, the diagnostic procedure for FD has advanced in several ways, through the development of a specific biomarker (lyso-Gb3) and the implementation of newborn screenings, which acted as a catalyst to augment general awareness of the disease. Heterologous over-expression of α-gal A variants and subsequent in vitro measurement of enzyme activity provided molecular data to elucidate the relationship between mutation, enzyme damage, lyso-Gb3 biomarker levels, and clinical phenotype. This knowledge is the foundation for improved counseling with regard to prognosis and therapeutic decisions. Herein, we resume the approach of in vitro characterization, with a further 73 mainly novel GLA gene mutations. Patient lyso-Gb3 data were available for most of the mutations. All mutations were tested for responsiveness to pharmacological chaperone treatment and phenotypic data for 61 hemizygous male and 116 heterozygous female patients carrying a mutation associated with ≥20% residual activity, formerly classified as "mild" variant, were collected in order to evaluate the pathogenicity. We conclude that a mild GLA variant is typically characterized by high residual enzyme activity and normal biomarker levels. We found evidence that these variants can still be classified as a distinctive, but milder, sub-type of FD. Mutations within the GLA gene cause Fabry disease (FD). Number of individuals with atypical disease outnumbers the classically affected (indicated by circle/oval size in the picture). The conventional classification "mutation vs. SNP" seems to be inappropriate in FD. We conclude that all, or at least the overall majority of gene variants can be risk factors for one or more FD symptoms. ER - TY - BOOK T1 - Laboratory diagnosis of Niemann-Pick disease type C: The filipin staining test A1 - Vanier, Marie T. A1 - Latour, Philippe Y1 - 2015/// KW - Cholesterol homeostasis KW - Filipin KW - Intracellular cholesterol KW - Intracellular trafficking KW - Laboratory diagnosis KW - Late endosome KW - Lysosome KW - NPC1 KW - NPC2 KW - Niemann-Pick C disease PB - Elsevier Ltd JF - Methods in Cell Biology VL - 126 SP - 357 EP - 375 DO - 10.1016/bs.mcb.2014.10.028 UR - http://dx.doi.org/10.1016/bs.mcb.2014.10.028 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Vanier, Latour - 2015 - Laboratory diagnosis of Niemann-Pick disease type C The filipin staining test.pdf N2 - Niemann-Pick disease type C (NPC) is an atypical neurovisceral lysosomal storage disorder resulting from mutations in either the NPC1 or the NPC2 gene. , currently conceived as a lipid trafficking disorder. Impaired egress of cholesterol from the late endosomal/lysosomal (LE/L) compartment is a key element of the pathogenesis. The resulting accumulation of unesterified cholesterol in the LE/L compartment can be visualized by fluorescence microscopy after staining with filipin. The "filipin test," performed on cultured fibroblasts, is the historical gold standard method to establish the diagnosis in patients. The authors provide methodological details of the protocol developed and used in their laboratory since 1988, in which two sources of low-density lipoproteins (LDL) (total serum and pure LDL) are used in parallel to facilitate the final interpretation. Methodological caveats and variability of patterns encountered in patients with proven Niemann-Pick C disease (typical "classic" or "intermediate," atypical "variant") are described. An overview of the past 5. years referrals (533 subjects tested, 57 NPC cases, but also 74 mildly/weakly positive tests not due to NPC) is discussed, leading to a proposed algorithm for interpretation of results in the filipin test. This tool takes into account the limits of the method. In up to 15% of all referrals, the filipin test was inconclusive in absence of molecular analysis. Patients diagnosed in the adult age preferentially showed an "intermediate" or "variant" pattern. Well conducted, the filipin test remains an efficient approach for diagnosing NPC, and it is a good functional test to study the pathogenicity of novel mutations. ER - TY - JOUR T1 - Predicting Splicing from Primary Sequence with Deep Learning A1 - Jaganathan, Kishore A1 - Kyriazopoulou Panagiotopoulou, Sofia A1 - McRae, Jeremy F. A1 - Darbandi, Siavash Fazel A1 - Knowles, David A1 - Li, Yang I. A1 - Kosmicki, Jack A. A1 - Arbelaez, Juan A1 - Cui, Wenwu A1 - Schwartz, Grace B. A1 - Chow, Eric D. A1 - Kanterakis, Efstathios A1 - Gao, Hong A1 - Kia, Amirali A1 - Batzoglou, Serafim A1 - Sanders, Stephan J. A1 - Farh, Kyle Kai How Y1 - 2019/// KW - artificial intelligence KW - deep learning KW - genetics KW - splicing PB - Elsevier JF - Cell VL - 176 IS - 3 SP - 535 EP - 548.e24 DO - 10.1016/j.cell.2018.12.015 UR - http://dx.doi.org/10.1016/j.cell.2018.12.015 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Jaganathan et al. - 2019 - Predicting Splicing from Primary Sequence with Deep Learning.pdf N2 - The splicing of pre-mRNAs into mature transcripts is remarkable for its precision, but the mechanisms by which the cellular machinery achieves such specificity are incompletely understood. Here, we describe a deep neural network that accurately predicts splice junctions from an arbitrary pre-mRNA transcript sequence, enabling precise prediction of noncoding genetic variants that cause cryptic splicing. Synonymous and intronic mutations with predicted splice-altering consequence validate at a high rate on RNA-seq and are strongly deleterious in the human population. De novo mutations with predicted splice-altering consequence are significantly enriched in patients with autism and intellectual disability compared to healthy controls and validate against RNA-seq in 21 out of 28 of these patients. We estimate that 9%–11% of pathogenic mutations in patients with rare genetic disorders are caused by this previously underappreciated class of disease variation. ER - TY - JOUR T1 - The lysosome turns fifty. A1 - de Duve, Christian Y1 - 2005/09// KW - Acid Phosphatase KW - Animals KW - Biochemistry KW - History, 20th Century KW - Humans KW - Liver KW - Lysosomes KW - Rats KW - enzymology KW - history KW - isolation & purification KW - metabolism KW - ultrastructure JF - Nature cell biology VL - 7 LA - eng IS - 9 SP - 847 EP - 849 DO - 10.1038/ncb0905-847 N2 - In the course of an investigation aimed at characterizing hepatic glucose 6-phosphatase, the unrelated acid phosphatase of rat liver was serendipitously observed to be latent and particle-bound in freshly prepared homogenates. Experiments designed to elucidate this intriguing finding led, 50 years ago, to the discovery of lysosomes. This could not have happened if strict adherence to a previously set programme had been mandatory. ER - TY - GEN T1 - Assessment of a targeted resequencing assay as a support tool in the diagnosis of lysosomal storage disorders A1 - Fernández-Marmiesse, Ana A1 - Morey, Marcos A1 - Pineda, Merce A1 - Eiris, Jesús A1 - Couce, Maria Luz A1 - Castro-Gago, Manuel A1 - Fraga, Jose Maria A1 - Lacerda, Lucia A1 - Gouveia, Sofia A1 - Pérez-Poyato, Maria Socorro A1 - Armstrong, Judith A1 - Castiñeiras, Daisy A1 - Cocho, Jose A. Y1 - 2014/// KW - Diagnostic odysseys KW - In-solution enrichment KW - Lysosomal storage disorders KW - Targeted resequencing JF - Orphanet Journal of Rare Diseases VL - 9 IS - 1 DO - 10.1186/1750-1172-9-59 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Fernández-Marmiesse et al. - 2014 - Assessment of a targeted resequencing assay as a support tool in the diagnosis of lysosomal storage.pdf N2 - With over 50 different disorders and a combined incidence of up to 1/3000 births, lysosomal storage diseases (LSDs) constitute a major public health problem and place an enormous burden on affected individuals and their families. Many factors make LSD diagnosis difficult, including phenotype and penetrance variability, shared signs and symptoms, and problems inherent to biochemical diagnosis. Developing a powerful diagnostic tool could mitigate the protracted diagnostic process for these families, lead to better outcomes for current and proposed therapies, and provide the basis for more appropriate genetic counseling. Methods. We have designed a targeted resequencing assay for the simultaneous testing of 57 lysosomal genes, using in-solution capture as the enrichment method and two different sequencing platforms. A total of 84 patients with high to moderate-or low suspicion index for LSD were enrolled in different centers in Spain and Portugal, including 18 positive controls. Results: We correctly diagnosed 18 positive blinded controls, provided genetic diagnosis to 25 potential LSD patients, and ended with 18 diagnostic odysseys. Conclusion: We report the assessment of a next-generation-sequencing-based approach as an accessory tool in the diagnosis of LSDs, a group of disorders which have overlapping clinical profiles and genetic heterogeneity. We have also identified and quantified the strengths and limitations of next generation sequencing (NGS) technology applied to diagnosis. © 2014 Fernández-Marmiesse et al.; licensee BioMed Central Ltd. ER - TY - JOUR T1 - Case of late-onset Sandhoff disease due to a novel mutation in the HEXB gene A1 - Sung, Angela R. A1 - Moretti, Paolo A1 - Shaibani, Aziz Y1 - 2018/// JF - Neurology: Genetics VL - 4 IS - 4 SP - 1 EP - 3 SN - 0000000000000 DO - 10.1212/NXG.0000000000000260 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sung, Moretti, Shaibani - 2018 - Case of late-onset Sandhoff disease due to a novel mutation in the HEXB gene.pdf N2 - Sandhoff disease is one of a group of autosomal recessive conditions known as the GM2 gangliosidoses. Normal breakdown of GM2 gangliosides is performed by the enzyme β-hexosaminidase A. This enzyme consists of 2 subunits (α and β), which are encoded by the HEXA and HEXB genes, respectively. Mutations in either of these genes result in buildup of the GM2 gangliosides, with HEXA mutations producing a phenotype of Tay-Sachs disease and HEXB mutations causing Sandhoff disease. ER - TY - BOOK T1 - MÉDICOS CIRCULAR NÚMERO 013 DE 2022 CIRCULAR NÚMERO xx DE A1 - Vitales, Medicamentos A1 - Disponibles, No A1 - Comisi, L A A1 - Medicamentos, Nacional D E Precios D E A1 - En, Dicos A1 - Que, Considerando A1 - Vitales, Medicamentos A1 - Disponibles, No Y1 - 2022/// VL - 2022 SN - 2004964014 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Vitales et al. - 2022 - MÉDICOS CIRCULAR NÚMERO 013 DE 2022 CIRCULAR NÚMERO xx DE.pdf ER - TY - JOUR T1 - Therapeutic potential of αs evolvability for neuropathic gaucher disease A1 - Wei, Jianshe A1 - Takamatsu, Yoshiki A1 - Wada, Ryoko A1 - Fujita, Masayo A1 - Ho, Gilbert A1 - Masliah, Eliezer A1 - Hashimoto, Makoto Y1 - 2021/// KW - Autosomal recessive KW - Evolvability KW - Gaucher disease (GD) KW - Parkinson’s disease (PD) KW - antagonistic pleiotropy KW - α-synuclein (αS) KW - β-synuclein (βS) JF - Biomolecules VL - 11 IS - 2 SP - 1 EP - 11 DO - 10.3390/biom11020289 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wei et al. - 2021 - Therapeutic Potential of α S Evolvability for Neuropathic Gaucher Disease.pdf N2 - Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by autosomal recessive mutations of the glucocerebrosidase gene, GBA1. In the majority of cases, GD has a non-neuropathic chronic form with adult onset (GD1), while other cases are more acute and severer neuropathic forms with early onset (GD2/3). Currently, no radical therapies are established for GD2/3. Notably, GD1, but not GD2/3, is associated with increased risk of Parkinson’s disease (PD), the elucidation of which might provide a clue for novel therapeutic strategies. In this context, the objective of the present study is to discuss that the evolvability of α-synuclein (αS) might be differentially involved in GD subtypes. Hypothetically, aging-associated PD features with accumulation of αS, and the autophagy-lysosomal dysfunction might be an antagonistic pleiotropy phenomenon derived from αS evolvability in the development in GD1, without which neuropathies like GD2/3 might be manifested due to the autophagy-lysosomal dysfunction. Supposing that the increased severity of GD2/3 might be attributed to the decreased activity of αS evolvability, suppressing the expression of β-synuclein (βS), a potential buffer against αS evolvability, might be therapeutically efficient. Of interest, a similar view might be applicable to Niemann-Pick type C (NPC), another LSD, given that the adult type of NPC, which is comorbid with Alzheimer’s disease, exhibits milder medical symptoms compared with those of infantile NPC. Thus, it is predicted that the evolvability of amyloid β and tau, might be beneficial for the adult type of NPC. Collectively, a better understanding of amyloidogenic evolvability in the pathogenesis of LSD may inform rational therapy development. ER - TY - JOUR T1 - Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life A1 - Wang, Raymond Y. A1 - Lelis, Alicia A1 - Mirocha, James A1 - Wilcox, William R. Y1 - 2007/// KW - Fabry disease KW - Female KW - Heterozygote KW - Natural history KW - Outcome KW - Quality of life KW - SF-36 KW - Symptom JF - Genetics in Medicine VL - 9 IS - 1 SP - 34 EP - 45 DO - 10.1097/GIM.0b013e31802d8321 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wang et al. - 2007 - Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of li.pdf N2 - PURPOSE: To determine if there is significant symptomatology in women with heterozygous α-galactosidase mutations. METHODS: Data from medical records of the 44 heterozygous females followed at Cedars-Sinai Medical Center were compiled and analyzed for symptoms of Fabry disease. Quality of life data were also analyzed. RESULTS: Seventy-six percent were referred due to an affected male relative; 76% reported acroparesthesias as their first symptom. A mean of 15.7 years elapsed from onset of first symptoms to the diagnosis. Quality of life, measured by the SF-36 survey, was globally reduced. Pain affected mood and enjoyment of life. Central/peripheral nervous, cardiopulmonary, and renal system manifestations of Fabry disease were present far above that predicted for random X-inactivation of the normal allele. Fatigue, present in 59%, was associated with reduced maximum oxygen consumption (P = 0.049); exercise intolerance, present in 83%, was associated with reduced maximal heart rate during exercise testing (P = 0.0089). Women diagnosed via family history experienced more angina (P = 0.035), decreased vibration sense (P = 0.026), and had a worse percentage predicted FEF25-75 (P = 0.037) compared to women diagnosed because of symptoms. CONCLUSIONS: This study indicates that the asymptomatic female carrier of Fabry disease is the exception, not the rule: heterozygotes suffer from significant multisystemic disease and reduced quality of life and must be monitored and treated accordingly. ©2007The American College of Medical Genetics. ER - TY - JOUR T1 - The awesome lysosome A1 - Ballabio, Andrea Y1 - 2016/// JF - EMBO Molecular Medicine VL - 8 IS - 2 SP - 73 EP - 76 DO - 10.15252/emmm.201505966 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Ballabio - 2016 - The awesome lysosome.pdf N2 - In the early 50s, Christian De Duve identified a new cellular structure, the lysosome, defined as the cell's "suicide bag" (de Duve,). Sixty years later, it is clear that the lysosome greatly exceeded the expectations of its discoverer. Over 50 different types of lysosomal storage diseases have been identified, each due to the deficiency or malfunction of a specific lysosomal protein. In addition, an important role of the lysosome has been unveiled in several common human diseases, such as cancer, obesity, neurodegenerative diseases, and infection. Recent studies have led to the identification of a lysosome-to-nucleus signaling pathway and a lysosomal gene network that regulate cellular clearance and energy metabolism. These observations have opened a completely new field of research and changed our traditional view of the lysosome from a dead-end organelle to a control center of cell metabolism. An important challenge for the future will be to exploit these discoveries to identify modulators of lysosomal function that may be used to treat human diseases. ER - TY - BOOK T1 - Niemann-Pick diseases A1 - Vanier, Marie T. Y1 - 2013/// PB - Elsevier B.V. JF - Handbook of Clinical Neurology VL - 113 ET - 1 SP - 1717 EP - 1721 DO - 10.1016/B978-0-444-59565-2.00041-1 UR - http://dx.doi.org/10.1016/B978-0-444-59565-2.00041-1 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Vanier - 2013 - Niemann-Pick diseases.pdf N2 - The Niemann-Pick disease group is now divided into two distinct entities: (1) acid sphingomyelinase-deficient Niemann-Pick disease (ASM-deficient NPD) resulting from mutations in the SMPD1 gene and encompassing type A and type B as well as intermediate forms; (2) Niemann-Pick disease type C (NP-C) including also type D, resulting from mutations in either the NPC1 or the NPC2 gene. Both Niemann-Pick diseases have an autosomal recessive inheritance and are lysosomal lipid storage disorders, with visceral (type B) or neurovisceral manifestations. The clinical knowledge is updated taking into account recent surveys in large cohort of patients, particularly for type B and type C. The diagnosis of NP-C is often delayed due to the wide spectrum of clinical phenotypes. Systemic manifestations, if present, always precede onset of neurological manifestations. Most common neurological signs are vertical supranuclear gaze palsy, cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures, and dystonia are other common features of NP-C. For both ASM-deficient NPD and NP-C, strategies for laboratory diagnosis of patients and prenatal diagnosis are discussed. Recent progress towards enzyme replacement therapy in type B patients and management of the neurological disease in type C patients are finally highlighted. © 2013 Elsevier B.V. ER - TY - GEN T1 - Neuropathophysiology of lysosomal storage diseases: Synaptic dysfunction as a starting point for disease progression A1 - Pará, Camila A1 - Bose, Poulomee A1 - Pshezhetsky, Alexey V Y1 - 2020/// KW - Batten disease KW - Gangliosidosis KW - Krabbe disease KW - Lysosomal storage diseases KW - Mucopolysaccharidosis KW - NCL KW - Niemann-Pick type C KW - Synaptic dysfunction KW - Synaptic spines JF - Journal of Clinical Medicine VL - 9 IS - 3 DO - 10.3390/jcm9030616 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Par, Bose, Pshezhetsky - 2020 - Neuropathophysiology of Lysosomal Storage Diseases Synaptic Dysfunction as a Starting Point for Disease.pdf N2 - 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. ER - TY - JOUR T1 - Snapshot : Lysosomal Storage Diseases A1 - Martina, José A A1 - Raben, Nina A1 - Puertollano, Rosa Y1 - 2021/// VL - 180 IS - 3 SP - 3 EP - 8 DO - 10.1016/j.cell.2020.01.017.Snapshot L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Martina, Raben, Puertollano - 2021 - Snapshot Lysosomal Storage Diseases.pdf ER - TY - JOUR T1 - Fabry disease A1 - Germain, Dominique P. Y1 - 2010/// JF - Orphanet Journal of Rare Diseases VL - 5 IS - 1 SP - 1 EP - 49 DO - 10.1186/1750-1172-5-30 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Germain - 2010 - Fabry disease.pdf N2 - Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A activity. FD is pan-ethnic and the reported annual incidence of 1 in 100,000 may underestimate the true prevalence of the disease. Classically affected hemizygous males, with no residual α-galactosidase A activity may display all the characteristic neurological (pain), cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular and cerebrovascular (transient ischemic attacks, strokes) signs of the disease while heterozygous females have symptoms ranging from very mild to severe. Deficient activity of lysosomal α-galactosidase A results in progressive accumulation of globotriaosylceramide within lysosomes, believed to trigger a cascade of cellular events. Demonstration of marked α-galactosidase A deficiency is the definitive method for the diagnosis of hemizygous males. Enzyme analysis may occasionnally help to detect heterozygotes but is often inconclusive due to random X-chromosomal inactivation so that molecular testing (genotyping) of females is mandatory. In childhood, other possible causes of pain such as rheumatoid arthritis and 'growing pains' must be ruled out. In adulthood, multiple sclerosis is sometimes considered. Prenatal diagnosis, available by determination of enzyme activity or DNA testing in chorionic villi or cultured amniotic cells is, for ethical reasons, only considered in male fetuses. Pre-implantation diagnosis is possible. The existence of atypical variants and the availability of a specific therapy singularly complicate genetic counseling. A disease-specific therapeutic option - enzyme replacement therapy using recombinant human α-galactosidase A - has been recently introduced and its long term outcome is currently still being investigated. Conventional management consists of pain relief with analgesic drugs, nephroprotection (angiotensin converting enzyme inhibitors and angiotensin receptors blockers) and antiarrhythmic agents, whereas dialysis or renal transplantation are available for patients experiencing end-stage renal failure. With age, progressive damage to vital organ systems develops and at some point, organs may start to fail in functioning. End-stage renal disease and life-threatening cardiovascular or cerebrovascular complications limit life-expectancy of untreated males and females with reductions of 20 and 10 years, respectively, as compared to the general population. While there is increasing evidence that long-term enzyme therapy can halt disease progression, the importance of adjunctive therapies should be emphasized and the possibility of developing an oral therapy drives research forward into active site specific chaperones. © 2010 Germain; licensee BioMed Central Ltd. ER - TY - JOUR T1 - Synergistic heterozygosity: Disease resulting from multiple partial defects in one or more metabolic pathways A1 - Vockley, Jerry A1 - Rinaldo, Piero A1 - Bennett, Michael J. A1 - Matern, Dietrich A1 - Vladutiu, Georgirene D. Y1 - 2000/// JF - Molecular Genetics and Metabolism VL - 71 IS - 1-2 SP - 10 EP - 18 DO - 10.1006/mgme.2000.3066 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Vockley et al. - 2000 - Synergistic heterozygosity Disease resulting from multiple partial defects in one or more metabolic pathways.pdf N2 - Inborn errors of metabolism show considerable variation in the severity of symptoms. This is often ascribed to the differential effects of specific mutations on gene/enzyme function; however, such genotype/phenotype correlations are usually imprecise. In addition, in some patients with clinical and biochemical findings consistent with a defect in a particular metabolic pathway, it is ultimately impossible to arrive at a precise enzymatic diagnosis. In this situation, we have increasingly been identifying concurrent partial defects in more than one pathway, or at multiple steps in one pathway. In this study, we present the clinical, biochemical, and molecular findings from several patients showing multiple partial defects in energy metabolism. These patients show clinical symptoms consistent with a defect in the affected pathways even though they do not have a complete deficiency in any one enzyme. We hypothesize that such patients are exhibiting clinically significant reductions in energy metabolism related to the compound effects of these partial defects, a phenomenon we term 'synergistic heterozygosity.' Based on the frequencies of known disorders of energy metabolism, we propose that this may represent a previously unrecognized, relatively common mechanism of disease of potentially great clinical relevance. (C) 2000 Academic Press. ER - TY - JOUR T1 - Alpha-mannosidosis: Correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation Inherited metabolic diseases A1 - Borgwardt, Line A1 - Stensland, Hilde Monica Frostad Riise A1 - Olsen, Klaus Juul A1 - Wibrand, Flemming A1 - Klenow, Helle Bagterp A1 - Beck, Michael A1 - Amraoui, Yasmina A1 - Arash, Laila A1 - Fogh, Jens A1 - Nilssen, Øivind A1 - Dali, Christine I. A1 - Lund, Allan Meldgaard Y1 - 2015/// KW - Alpha-mannosidosis KW - CNS involvement KW - Genotype-phenotype correlation KW - MAN2B1 PB - Orphanet Journal of Rare Diseases JF - Orphanet Journal of Rare Diseases VL - 10 IS - 1 SN - 2010022084 DO - 10.1186/s13023-015-0286-x UR - http://dx.doi.org/10.1186/s13023-015-0286-x L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Borgwardt et al. - 2015 - Alpha-mannosidosis Correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation Inherite.pdf N2 - Background: Alpha-mannosidosis is caused by mutations in MAN2B1, leading to loss of lysosomal alpha-mannosidase activity. Symptoms include intellectual disabilities, hearing impairment, motor function disturbances, facial coarsening and musculoskeletal abnormalities. Methods: To study the genotype-phenotype relationship for alpha-mannosidosis 66 patients were included. Based on the predicted effect of the mutations and the subcellular localisation of mutant MAN2B1 in cultured cells, the patients were divided into three subgroups. Clinical and biochemical data were collected. Correlation analyses between each of the three subgroups of genotype/subcellular localisation and the clinical and biochemical data were done to investigate the potential relationship between genotype and phenotype in alpha-mannosidosis. Statistical analyses were performed using the SPSS software. Analyses of covariance were performed to describe the genotype-phenotype correlations. The phenotype parameters were modelled by the mutation group and age as a covariate. P values of <0.05 were considered as statistically significant. Results: Complete MAN2B1 genotypes were established for all patients. We found significantly higher scores in the Leiter-R test, lower concentrations of CSF-oligosaccharides, higher point scores in the Bruininks-Oseretsky Test of Motor Proficiency subtests (BOT-2); Upper limb coordination and Balance, and a higher FVC% in patients in subgroup 3, harbouring at least one variant that allows localisation of the mutant MAN2B1 protein to the lysosomes compared to subgrou 2 and/or subgroup 1 with no lysosomal localization of the mutant MAN2B1 protein. Conclusion: Our results indicate a correlation between the MAN2B1 genotypes and the cognitive function, upper limb coordination, balance, FVC% and the storage of oligosaccharides in CSF. This correlation depends on the subcellular localisation of the mutant MAN2B1 protein. ER - TY - GEN T1 - Miglustat in Niemann-Pick disease type C patients: A review A1 - Pineda, Mercè A1 - Walterfang, Mark A1 - Patterson, Marc C Y1 - 2018/// KW - Biomarker KW - Efficacy KW - Miglustat KW - Niemann-Pick disease type C PB - Orphanet Journal of Rare Diseases JF - Orphanet Journal of Rare Diseases VL - 13 IS - 1 SP - 1 EP - 21 DO - 10.1186/s13023-018-0844-0 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Pineda, Walterfang, Patterson - 2018 - Miglustat in Niemann-Pick disease type C patients a review.pdf N2 - Objective: Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive, neurodegenerative disease associated with a wide variety of progressive neurological manifestations. Miglustat is indicated for the treatment of progressive neurological manifestations in both adults and children. Since approval in 2009 there has been a vast growth in clinical experience with miglustat. The effectiveness of miglustat has been assessed using a range of measures. Methods: Comprehensive review of published data from studies of cellular neuropathological markers and structural neurological indices in the brain, clinical impairment/disability, specific clinical neurological manifestations, and patient survival. Results: Cranial diffusion tensor imaging and magnetic resonance spectroscopy studies have shown reduced levels of choline (a neurodegeneration marker), and choline/N-acetyl aspartate ratio (indicating increased neuronal viability) in the brain during up to 5 years of miglustat therapy, as well as a slowing of reductions in fractional anisotropy (an axonal/myelin integrity marker). A 2-year immunoassay study showed significant reductions in CSF-calbindin during treatment, indicating reduced cerebellar Purkinje cell loss. Magnetic resonance imaging studies have demonstrated a protective effect of miglustat on cerebellar and subcortical structure that correlated with clinical symptom severity. Numerous cohort studies assessing core neurological manifestations (impaired ambulation, manipulation, speech, swallowing, other) using NP-C disability scales indicate neurological stabilization over 2-8 years, with a trend for greater benefits in patients with older (non-infantile) age at neurological onset. A randomized controlled trial and several cohort studies have reported improvements or stabilization of saccadic eye movements during 1-5 years of therapy. Swallowing was also shown to improve/remain stable during the randomized trial (up to 2 years), as well as in long-term observational cohorts (up to 6 years). A meta-analysis of dysphagia - a potent risk factor for aspiration pneumonia and premature death in NP-C - demonstrated a survival benefit with miglustat due to improved/stabilized swallowing function. Conclusions: The effects of miglustat on neurological NP-C manifestations has been assessed using a range of approaches, with benefits ranging from cellular changes in the brain through to visible clinical improvements and improved survival. ER - TY - JOUR T1 - Characterization of classical and nonclassical fabry disease: A multicenter study A1 - Arends, Maarten A1 - Wanner, Christoph A1 - Hughes, Derralynn A1 - Mehta, Atul A1 - Oder, Daniel A1 - Watkinson, Oliver T. A1 - Elliott, Perry M. A1 - Linthorst, Gabor E. A1 - Wijburg, Frits A. A1 - Biegstraaten, Marieke A1 - Hollak, Carla E. Y1 - 2017/// JF - Journal of the American Society of Nephrology VL - 28 IS - 5 SP - 1631 EP - 1641 DO - 10.1681/ASN.2016090964 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Arends et al. - 2017 - Characterization of classical and nonclassical fabry disease A multicenter study(3).pdf N2 - Fabry disease leads to renal, cardiac, and cerebrovascular manifestations. Phenotypic differences between classically and nonclassically affected patients are evident, but there are few data on the natural course of classical and nonclassical disease in men and women. To describe the natural course of Fabry disease stratified by sex and phenotype, we retrospectively assessed event-free survival from birth to the first clinical visit (before enzyme replacement therapy) in 499 adult patients (mean age 43 years old; 41% men; 57% with the classical phenotype) from three international centers of excellence. We classified patients by phenotype on the basis of characteristic symptoms and enzyme activity. Men and women with classical Fabry disease had higher event rate than did those with nonclassical disease (hazard ratio for men, 5.63, 95%confidence interval, 3.17 to 10.00; P<0.001; hazard ratio for women, 2.88, 95%confidence interval, 1.54 to 5.40; P<0.001). Furthermore,men with classical Fabry disease had lower eGFR, higher left ventricular mass, andhigher plasma globotriaosylsphingosine concentrations thanmenwith nonclassical Fabry disease or womenwith either phenotype (P<0.001). In conclusion, before treatment with enzyme replacement therapy, men with classical Fabry disease had a history of more events than men with nonclassical disease or women with either phenotype; women with classical Fabry disease were more likely to develop complications than women with nonclassical disease. These data may support the development of new guidelines for the monitoring and treatment of Fabry disease and studies on the effects of intervention in subgroups of patients. ER - TY - GEN T1 - Lysosomal storage disorders – challenges, concepts and avenues for therapy: Beyond rare diseases A1 - Marques, André R.A. A1 - Saftig, Paul Y1 - 2019/// KW - Lysophagy KW - Lysosomal exocytosis KW - Lysosomal positioning KW - Lysosomal storage disease KW - Motility of lysosomes KW - Therapy JF - Journal of Cell Science VL - 132 IS - 2 SN - 0000000326377 DO - 10.1242/jcs.221739 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Marques, Saftig - 2019 - Lysosomal storage disorders – challenges, concepts and avenues for therapy Beyond rare diseases.pdf N2 - The pivotal role of lysosomes in cellular processes is increasingly appreciated. An understanding of the balanced interplay between the activity of acidic hydrolases, lysosomal membrane proteins and cytosolic proteins is required. Lysosomal storage diseases (LSDs) are characterized by disturbances in this network and by intralysosomal accumulation of substrates, often only in certain cell types. Even though our knowledge of these diseases has increased and therapies have been established, many aspects of the molecular pathology of LSDs remain obscure. This Review aims to discuss how lysosomal storage affects functions linked to lysosomes, such as membrane repair, autophagy, exocytosis, lipid homeostasis, signalling cascades and cell viability. Therapies must aim to correct lysosomal storage not only morphologically, but reverse its (patho)biochemical consequences. As different LSDs have different molecular causes, this requires custom tailoring of therapies. We will discuss the major advantages and drawbacks of current and possible future therapies for LSDs. Study of the pathological molecular mechanisms underlying these ‘experiments of nature’ often yields information that is relevant for other conditions found in the general population. Therefore, more common diseases may profit from a correction of impaired lysosomal function. ER - TY - JOUR T1 - Lysosomal storage disease A1 - Okada, S. Y1 - 1995/// KW - 1 KW - cystinosis KW - disease KW - fabry KW - farber disease KW - free sialic acid storage KW - gaucher disease KW - gm1 gangliosidosis KW - krabbe disease KW - lysosomal storage diseases KW - lysosomal structure and function KW - metachromatic leukodystrophy KW - mucolipidosis iv KW - newborn screening KW - niemann-pick disease KW - sandhoff disease KW - schindler disease KW - tay-sachs disease JF - Nippon rinsho. Japanese journal of clinical medicine VL - 53 IS - 12 SP - 2911 EP - 2914 DO - 10.3233/trd-160005 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Okada - 1995 - Lysosomal storage disease.pdf N2 - Lysosomes are the principal sites of intracellular digestion. In Lysosomes approximately 40 hydrolytic enzymes are contained. Lysosomal storage diseases are mainly caused by genetic defects that affect one or more of the lysosomal hydrolases, and result in accumulation of their undigested substrates in lysosomes, with profound pathological consequences. In this paper clinical features, diagnostic methods, and trend of the present research for lysosomal storage diseases are reviewed. ER - TY - JOUR T1 - Lysosomal storage diseases A1 - Platt, Frances M. A1 - d’Azzo, Alessandra A1 - Davidson, Beverly L. A1 - Neufeld, Elizabeth F. A1 - Tifft, Cynthia J. Y1 - 2018/// JF - Nature Reviews Disease Primers VL - 4 IS - 1 DO - 10.1038/s41572-018-0025-4 L1 - file:///C:/Users/juan/Downloads/platt2018.pdf N2 - Lysosomal storage diseases (LSDs) are a group of over 70 diseases that are characterized by lysosomal dysfunction, most of which are inherited as autosomal recessive traits. These disorders are individually rare but collectively affect 1 in 5,000 live births. LSDs typically present in infancy and childhood, although adult-onset forms also occur. Most LSDs have a progressive neurodegenerative clinical course, although symptoms in other organ systems are frequent. LSD-associated genes encode different lysosomal proteins, including lysosomal enzymes and lysosomal membrane proteins. The lysosome is the key cellular hub for macromolecule catabolism, recycling and signalling, and defects that impair any of these functions cause the accumulation of undigested or partially digested macromolecules in lysosomes (that is, ‘storage’) or impair the transport of molecules, which can result in cellular damage. Consequently, the cellular pathogenesis of these diseases is complex and is currently incompletely understood. Several LSDs can be treated with approved, disease-specific therapies that are mostly based on enzyme replacement. However, small-molecule therapies, including substrate reduction and chaperone therapies, have also been developed and are approved for some LSDs, whereas gene therapy and genome editing are at advanced preclinical stages and, for a few disorders, have already progressed to the clinic. ER - TY - JOUR T1 - Open Access REVIEW Niemann-Pick disease type C A1 - Vanier, Marie T Y1 - 2010/// JF - Vanier Orphanet Journal of Rare Diseases VL - 5 SP - 16 EP - 16 UR - http://www.ojrd.com/content/5/1/16 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Vanier - 2010 - Open Access REVIEW Niemann-Pick disease type C.pdf ER - TY - JOUR T1 - Disease manifestations and X inactivation in heterozygous females with Fabry disease A1 - Maier, Esther M. A1 - Osterrieder, Stephanie A1 - Whybra, Catharina A1 - Ries, Markus A1 - Gal, Andreas A1 - Beck, Michael A1 - Roscher, Adelbert A. A1 - Muntau, Ania C. Y1 - 2006/// KW - Fabry disease KW - HUMARA assay KW - Heterozygotes KW - Lysosomal storage disorder KW - X inactivation JF - Acta Paediatrica, International Journal of Paediatrics VL - 95 IS - SUPPL. 451 SP - 30 EP - 38 DO - 10.1080/08035320600618809 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Maier et al. - 2006 - Disease manifestations and X inactivation in heterozygous females with Fabry disease.pdf N2 - Aim: Fabry disease is an X-linked lysosomal storage disorder characterized by an accumulation of neutral glycosphingolipids in multiple organ systems caused by α-galactosidase A deficiency due to mutations in the GLA gene. The majority of heterozygous females show the characteristic signs and symptoms of the disease, and some of them are severely affected. The current hypothesis for the occurrence of disease manifestations in females is skewed X inactivation favouring the mutant GLA allele. Method: We analyzed the patterns of X inactivation in the leukocytes of 28 biochemically and genetically characterized symptomatic Fabry disease heterozygotes and their correlation with clinical and biochemical disease expression. Results: X inactivation patterns in symptomatic females who are heterozygous for Fabry disease did not differ from those of female controls of the same age (p = 0.669). Thirteen (46%) of the 28 females with Fabry disease showed random X inactivation, ten (36%) moderate skewing, and five (18%) highly skewed X inactivation. Segregation analysis was performed in the families of six females who had highly or moderately skewed X inactivation. In four of these females, skewing favoured the wild-type GLA allele and in the other two skewing favoured the mutant allele. Patterns of X inactivation or the extent of skewing were not related to the severity of clinical manifestations or to residual enzyme activity. Conclusion: In this study we provide evidence that heterozygous females with Fabry disease show random X inactivation. Our data do not support the hypothesis that the occurrence and severity of disease manifestations in the majority of Fabry heterozygotes are related to skewed X inactivation. © 2006 Taylor & Francis. ER - TY - JOUR T1 - Niemann-Pick type C disease: The atypical sphingolipidosis A1 - Newton, Jason A1 - Milstien, Sheldon A1 - Spiegel, Sarah Y1 - 2018/// JF - Advances in Biological Regulation VL - 70 SP - 82 EP - 88 DO - 10.1016/j.jbior.2018.08.001 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Newton, Milstien, Spiegel - 2018 - Niemann-Pick type C disease The atypical sphingolipidosis.pdf N2 - Niemann-Pick type C (NPC) disease is a lysosomal storage disorder resulting from mutations in either the NPC1 (95%) or NPC2 (5%) genes. NPC typically presents in childhood with visceral lipid accumulation and complex progressive neurodegeneration characterized by cerebellar ataxia, dysphagia, and dementia, resulting in a shortened lifespan. While cholesterol is widely acknowledged as the principal storage lipid in NPC, multiple species of sphingolipids accumulate as well. This accumulation of sphingolipids led to the initial assumption that NPC disease was caused by a deficiency in a sphingolipid catabolism enzyme, similar to sphingomyelinase deficiencies with which it shares a family name. It took about half a century to determine that NPC was in fact caused by a cholesterol trafficking defect, and still as we approach a century after the initial identification of the disease, the mechanisms by which sphingolipids accumulate remain poorly understood. Here we focus on the defects of sphingolipid catabolism in the endolysosomal compartment and how they contribute to the biology and pathology observed in NPC disease. This review highlights the need for further work on understanding and possibly developing treatments to correct the accumulation of sphingolipids in addition to cholesterol in this currently untreatable disease. ER - TY - JOUR T1 - Lysosomal glycosphingolipid storage diseases A1 - Kolter, Thomas A1 - Sandhoff, Konrad Y1 - 2009/// KW - Catabolism KW - Glycolipids KW - Glycosphingolipids KW - Lysosomal storage diseases KW - Sphingolipidoses JF - Neuroglycobiology: (Molecular and Cellular Neurobiology) SN - 9780191723872 DO - 10.1093/acprof:oso/9780198525387.003.0008 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Kolter, Sandhoff - 2009 - Lysosomal glycosphingolipid storage diseases.pdf N2 - This chapter focuses on the catabolism of glycolipids and diseases caused by anomalies in this process. Topics covered include lysosomal storage diseases, glycosphingolipids, mechanism of lysosomal glycosphingolipid degradation, defects of glycosphingolipid catabolism, and general aspects of sphingolipidoses. ER - TY - JOUR T1 - Treatable lysosomal storage diseases in the advent of disease-specific therapy A1 - Peters, Heidi A1 - Ellaway, Carolyn A1 - Nicholls, Kathleen A1 - Reardon, Katrina A1 - Szer, Jeff Y1 - 2020/// KW - Fabry KW - Gaucher KW - Pompe KW - lysosomal storage disease KW - mucopolysaccharidosis JF - Internal Medicine Journal VL - 50 IS - S4 SP - 5 EP - 27 DO - 10.1111/imj.15100 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Peters et al. - 2020 - Treatable lysosomal storage diseases in the advent of disease-specific therapy.pdf N2 - Lysosomal storage diseases (LSD) comprise a rare and heterogeneous group of nearly 50 heritable metabolic disorders caused by mutations in proteins critical for cellular lysosomal function. Defects in the activity of these proteins in multiple organs leads to progressive intra-lysosomal accumulation of specific substrates, resulting in disruption of cellular functions, extracellular inflammatory responses, tissue damage and organ dysfunction. The classification and clinical presentation of different LSD are dependent on the type of accumulated substrate. Some clinical signs and symptoms are common across multiple LSD, while others are more specific to a particular syndrome. Due to the rarity and wide clinical diversity of LSD, identification and diagnosis can be challenging, and in many cases diagnosis is delayed for months or years. Treatments, such as enzyme replacement therapy, haemopoietic stem cell transplantation and substrate reduction therapy, are now available for some of the LSD. For maximum effect, therapy must be initiated prior to the occurrence of irreversible tissue damage, highlighting the importance of prompt diagnosis. Herein, we discuss the clinical presentation, diagnosis and treatment of four of the treatable LSD: Gaucher disease, Fabry disease, Pompe disease, and two of the mucopolysaccharidoses (I and II). For each disease, we present illustrative case studies to help increase awareness of their clinical presentation and possible treatment outcomes. ER - TY - GEN T1 - Snapshot_ Lysosomal Storage Diseases _ 1.pdf L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Unknown - Unknown - Snapshot_ Lysosomal Storage Diseases _ 1.pdf.pdf ER - TY - GEN T1 - Characterization of classical and nonclassical fabry disease: A multicenter study A1 - Arends, Maarten A1 - Wanner, Christoph A1 - Hughes, Derralynn A1 - Mehta, Atul A1 - Oder, Daniel A1 - Watkinson, Oliver T. A1 - Elliott, Perry M. A1 - Linthorst, Gabor E. A1 - Wijburg, Frits A. A1 - Biegstraaten, Marieke A1 - Hollak, Carla E. Y1 - 2017/// JF - Journal of the American Society of Nephrology VL - 28 IS - 5 SP - 1631 EP - 1641 DO - 10.1681/ASN.2016090964 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Arends et al. - 2017 - Characterization of classical and nonclassical fabry disease A multicenter study(2).pdf N2 - Fabry disease leads to renal, cardiac, and cerebrovascular manifestations. Phenotypic differences between classically and nonclassically affected patients are evident, but there are few data on the natural course of classical and nonclassical disease in men and women. To describe the natural course of Fabry disease stratified by sex and phenotype, we retrospectively assessed event-free survival from birth to the first clinical visit (before enzyme replacement therapy) in 499 adult patients (mean age 43 years old; 41% men; 57% with the classical phenotype) from three international centers of excellence. We classified patients by phenotype on the basis of characteristic symptoms and enzyme activity. Men and women with classical Fabry disease had higher event rate than did those with nonclassical disease (hazard ratio for men, 5.63, 95%confidence interval, 3.17 to 10.00; P<0.001; hazard ratio for women, 2.88, 95%confidence interval, 1.54 to 5.40; P<0.001). Furthermore,men with classical Fabry disease had lower eGFR, higher left ventricular mass, andhigher plasma globotriaosylsphingosine concentrations thanmenwith nonclassical Fabry disease or womenwith either phenotype (P<0.001). In conclusion, before treatment with enzyme replacement therapy, men with classical Fabry disease had a history of more events than men with nonclassical disease or women with either phenotype; women with classical Fabry disease were more likely to develop complications than women with nonclassical disease. These data may support the development of new guidelines for the monitoring and treatment of Fabry disease and studies on the effects of intervention in subgroups of patients. ER - TY - GEN T1 - Pilot study of newborn screening for six lysosomal storage diseases using Tandem Mass Spectrometry A1 - Elliott, Susan A1 - Buroker, Norman A1 - Cournoyer, Jason J. A1 - Potier, Anna M. A1 - Trometer, Joseph D. A1 - Elbin, Carole A1 - Schermer, Mack J. A1 - Kantola, Jaana A1 - Boyce, Aaron A1 - Turecek, Frantisek A1 - Gelb, Michael H. A1 - Scott, C. Ronald Y1 - 2016/// KW - Dried blood spot KW - Fabry disease KW - Gaucher disease KW - Hurler disease KW - Krabbe disease KW - Lysosomal storage disorders KW - Newborn screening KW - Niemann-Pick-A/B disease KW - Pompe disease KW - Tandem mass spectrometry JF - Molecular Genetics and Metabolism VL - 118 IS - 4 SP - 304 EP - 309 DO - 10.1016/j.ymgme.2016.05.015 L1 - file:///C:/Users/juan/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Elliott et al. - 2016 - Pilot study of newborn screening for six lysosomal storage diseases using Tandem Mass Spectrometry.pdf N2 - Background There is current expansion of newborn screening (NBS) programs to include lysosomal storage disorders because of the availability of treatments that produce an optimal clinical outcome when started early in life. Objective To evaluate the performance of a multiplex-tandem mass spectrometry (MS/MS) enzymatic activity assay of 6 lysosomal enzymes in a NBS laboratory for the identification of newborns at risk for developing Pompe, Mucopolysaccharidosis-I (MPS-I), Fabry, Gaucher, Niemann Pick-A/B, and Krabbe diseases. Methods and Results Enzyme activities (acid α-glucosidase (GAA), galactocerebrosidase (GALC), glucocerebrosidase (GBA), α-galactosidase A (GLA), α-iduronidase (IDUA) and sphingomyeline phosphodiesterase-1 (SMPD-1)) were measured on ~ 43,000 de-identified dried blood spot (DBS) punches, and screen positive samples were submitted for DNA sequencing to obtain genotype confirmation of disease risk. The 6-plex assay was efficiently performed in the Washington state NBS laboratory by a single laboratory technician at the bench using a single MS/MS instrument. The number of screen positive samples per 100,000 newborns were as follows: GAA (4.5), IDUA (13.6), GLA (18.2), SMPD1 (11.4), GBA (6.8), and GALC (25.0). Discussion A 6-plex MS/MS assay for 6 lysosomal enzymes can be successfully performed in a NBS laboratory. The analytical ranges (enzyme-dependent assay response for the quality control HIGH sample divided by that for all enzyme-independent processes) for the 6-enzymes with the MS/MS is 5- to 15-fold higher than comparable fluorimetric assays using 4-methylumbelliferyl substrates. The rate of screen positive detection is consistently lower for the MS/MS assay compared to the fluorimetric assay using a digital microfluidics platform. ER -