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[PMID]: 29233882
[Au] Autor:Seranova E; Connolly KJ; Zatyka M; Rosenstock TR; Barrett T; Tuxworth RI; Sarkar S
[Ad] Address:Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, U.K.
[Ti] Title:Dysregulation of autophagy as a common mechanism in lysosomal storage diseases.
[So] Source:Essays Biochem;61(6):733-749, 2017 12 12.
[Is] ISSN:1744-1358
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:The lysosome plays a pivotal role between catabolic and anabolic processes as the nexus for signalling pathways responsive to a variety of factors, such as growth, nutrient availability, energetic status and cellular stressors. Lysosomes are also the terminal degradative organelles for autophagy through which macromolecules and damaged cellular components and organelles are degraded. Autophagy acts as a cellular homeostatic pathway that is essential for organismal physiology. Decline in autophagy during ageing or in many diseases, including late-onset forms of neurodegeneration is considered a major contributing factor to the pathology. Multiple lines of evidence indicate that impairment in autophagy is also a central mechanism underlying several lysosomal storage disorders (LSDs). LSDs are a class of rare, inherited disorders whose histopathological hallmark is the accumulation of undegraded materials in the lysosomes due to abnormal lysosomal function. Inefficient degradative capability of the lysosomes has negative impact on the flux through the autophagic pathway, and therefore dysregulated autophagy in LSDs is emerging as a relevant disease mechanism. Pathology in the LSDs is generally early-onset, severe and life-limiting but current therapies are limited or absent; recognizing common autophagy defects in the LSDs raises new possibilities for therapy. In this review, we describe the mechanisms by which LSDs occur, focusing on perturbations in the autophagy pathway and present the latest data supporting the development of novel therapeutic approaches related to the modulation of autophagy.
[Mh] MeSH terms primary: Autophagy/physiology
Lysosomal Storage Diseases/metabolism
[Mh] MeSH terms secundary: Animals
Autophagy/genetics
Humans
Lysosomal Storage Diseases/genetics
Lysosomes/metabolism
Sphingolipidoses/metabolism
[Pt] Publication type:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Entry month:1801
[Cu] Class update date: 180220
[Lr] Last revision date:180220
[Js] Journal subset:IM
[Da] Date of entry for processing:171214
[St] Status:MEDLINE
[do] DOI:10.1042/EBC20170055

  2 / 459 MEDLINE  
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[PMID]: 29290526
[Au] Autor:Voorink-Moret M; Goorden SMI; van Kuilenburg ABP; Wijburg FA; Ghauharali-van der Vlugt JMM; Beers-Stet FS; Zoetekouw A; Kulik W; Hollak CEM; Vaz FM
[Ad] Address:Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, The Netherlands. Electronic address: m.voorinkmoret@amc.uva.nl.
[Ti] Title:Rapid screening for lipid storage disorders using biochemical markers. Expert center data and review of the literature.
[So] Source:Mol Genet Metab;123(2):76-84, 2018 Feb.
[Is] ISSN:1096-7206
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUND: In patients suspected of a lipid storage disorder (sphingolipidoses, lipidoses), confirmation of the diagnosis relies predominantly on the measurement of specific enzymatic activities and genetic studies. New UPLC-MS/MS methods have been developed to measure lysosphingolipids and oxysterols, which, combined with chitotriosidase activity may represent a rapid first tier screening for lipid storage disorders. MATERIAL AND METHODS: A lysosphingolipid panel consisting of lysoglobotriaosylceramide (LysoGb3), lysohexosylceramide (LysoHexCer: both lysoglucosylceramide and lysogalactosylceramide), lysosphingomyelin (LysoSM) and its carboxylated analogue lysosphingomyelin-509 (LysoSM-509) was measured in control subjects and plasma samples of predominantly untreated patients affected with lipid storage disorders (n=74). In addition, the oxysterols cholestane-3ß,5α,6ß-triol and 7-ketocholesterol were measured in a subset of these patients (n=36) as well as chitotriosidase activity (n=43). A systematic review of the literature was performed to assess the usefulness of these biochemical markers. RESULTS: Specific elevations of metabolites, i.e. without overlap between controls and other lipid storage disorders, were found for several lysosomal storage diseases: increased LysoSM levels in acid sphingomyelinase deficiency (Niemann-Pick disease type A/B), LysoGb3 levels in males with classical phenotype Fabry disease and LysoHexCer (i.e. lysoglucosylceramide/lysogalactosylceramide) in Gaucher and Krabbe diseases. While elevated levels of LysoSM-509 and cholestane-3ß,5α,6ß-triol did not discriminate between Niemann Pick disease type C and acid sphingomyelinase deficiency, LysoSM-509/LysoSM ratio was specifically elevated in Niemann-Pick disease type C. In Gaucher disease type I, mild increases in several lysosphingolipids were found including LysoGb3 with levels in the range of non-classical Fabry males and females. Chitotriosidase showed specific elevations in symptomatic Gaucher disease, and was mildly elevated in all other lipid storage disorders. Review of the literature identified 44 publications. Most findings were in line with our cohort. Several moderate elevations of biochemical markers were found across a wide range of other, mainly inherited metabolic, diseases. CONCLUSION: Measurement in plasma of LysoSLs and oxysterols by UPLC-MS/MS in combination with activity of chitotriosidase provides a useful first tier screening of patients suspected of lipid storage disease. The LysoSM-509/LysoSM ratio is a promising parameter in Niemann-Pick disease type C. Further studies in larger groups of untreated patients and controls are needed to improve the specificity of the findings.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180211
[Lr] Last revision date:180211
[St] Status:In-Data-Review

  3 / 459 MEDLINE  
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[PMID]: 29061473
[Au] Autor:Chipeaux C; de Person M; Burguet N; Billette de Villemeur T; Rose C; Belmatoug N; Héron S; Le Van Kim C; Franco M; Moussa F
[Ad] Address:Lip(Sys)(2), LETIAM, Univ. Paris Sud, Université Paris-Saclay, IUT d'Orsay, Plateau de Moulon, F-91400 Orsay, France.
[Ti] Title:Optimization of ultra-high pressure liquid chromatography - tandem mass spectrometry determination in plasma and red blood cells of four sphingolipids and their evaluation as biomarker candidates of Gaucher's disease.
[So] Source:J Chromatogr A;1525:116-125, 2017 Nov 24.
[Is] ISSN:1873-3778
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:While important advances have been recently achieved in the optimization of lipid classes' separation, information on the specific determination of medium polarity lipids such as sphingolipids (SLs) in highly complex matrices remains fragmentary. In human, disorders of SL metabolism known as sphingolipidoses are a heterogeneous group of inherited disorders affecting primarily the central nervous. Early diagnosis of these conditions is of importance notably when a corrective therapy is available. The diagnosis is generally based on the determination of specific SLs in plasma and red blood cells (RBCs). For instance, glucosylceramide (GL1), glucosylsphingosine (Lyso-GL1), sphingosine (Sph), and sphingosine-1-phosphate (S1P) are proposed as relevant biomarkers for Gaucher disease (GD). Our main objective was to evaluate these biomarker candidates in a cohort of GD patients. However, most of current methods of GL1, Lyso-GL1, Sph, and S1P determination in plasma of GD patients require at least two liquid chromatographic runs. On the other hand, except for GL1 nothing is known concerning the RBC sphingolipid content. Yet, several reversed phase LC-MS methods of SLs separation and/or determination in various media with different sample preparation approaches have been proposed since 2010. Here we focused on stationary phase selection and mobile phase composition as well as on the sample preparation step to optimize and validate an UHPLC-MS/MS method for the simultaneous quantification of the four sphingolipids in both plasma and RBCs. A comparison between seven stationary phases including two RP18, two polar embedded RP18, and three HILIC phases shows that under our conditions polar embedded RP18 phases are the most appropriate for the separation of the four SLs, in terms of efficiency, peak symmetry, and separation time. In the same way, a comparison between a single step extraction with methanol and a liquid-liquid extraction with a mixture of methanol/methyl tert-butyl ether, shows that the latter mixture is the most appropriate for the extraction of SLs in terms of recovery and absence of matrix effect. After validation, this method was applied to the evaluation of the targeted SLs in a cohort of 15 known GD patients. The obtained results show that Lyso-GL1 is the only relevant biomarker in both plasma and RBCs for GD diagnosis. As the proposed method is applicable to the determination in such a highly complex matrices of four SLs with a large difference in polarity, and as the sample preparation procedure is freedom of matrix effects, this method can be easily adapted to a large diversity of samples.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1710
[Cu] Class update date: 171107
[Lr] Last revision date:171107
[St] Status:In-Process

  4 / 459 MEDLINE  
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[PMID]: 28923328
[Au] Autor:Duarte AJ; Ribeiro D; Oliveira P; Amaral O
[Ad] Address:Departamento de Genética Humana-Unidade I and D-P, CSPGF, Instituto Nacional de Saúde Ricardo Jorge (INSA, IP), Porto, Portugal.
[Ti] Title:Mutation Frequency of Three Neurodegenerative Lysosomal Storage Diseases: From Screening to Treatment?
[So] Source:Arch Med Res;48(3):263-269, 2017 Apr.
[Is] ISSN:1873-5487
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUND: The ascertainment of mutation frequencies in the general population may have impact on the population's wellbeing and respective healthcare services. Furthermore, it may help define which approaches will be more effective for certain patients based on the genetic cause of disease. AIM OF THE STUDY: Determine the frequency of three mutations, known to be a major cause of three distinct Lysosomal Storage Diseases (LSDs). METHODS: The following pre-requisites were met: each mutation accounted for over 55% of the disease alleles among previously reported unrelated patients, all three diseases were among the most prevalent LSDs in the population under study, they all involved devastating deterioration of the nervous system, lacked curative treatment and may be fatal in childhood or adolescence. The anonymous samples used in this study were representative of the whole population; mutations were tested by PCR based methods, positive results were further confirmed. The diseases studied were Mucopolysaccharidosis type I (Hurler, MIM 607014), Tay Sachs disease variant B1 (TS, MIM 272800) and Metachromatic Leukodystrophy (MLD, MIM 250100); the mutations were, respectively, p.W402X, p.R178C and c.465+1G>A. RESULTS AND CONCLUSION: Increased carrier frequencies were found for Tay Sachs disease variant B1 HEXA p.R178C mutation (1:340) and for the infantile MLD ARSA c.465+1G> A mutation (1:350) denoting higher risk for these sub-types of disease in Portugal and possibly in individuals of Iberian ancestry. Carrier screening in target populations may provide the foundations for more effective approaches to precision medicine.
[Mh] MeSH terms primary: Leukodystrophy, Metachromatic/genetics
Mucopolysaccharidosis I/genetics
Tay-Sachs Disease/genetics
[Mh] MeSH terms secundary: Alleles
Humans
Infant, Newborn
Mutation
Mutation Rate
Portugal
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1710
[Cu] Class update date: 171023
[Lr] Last revision date:171023
[Js] Journal subset:IM
[Da] Date of entry for processing:170920
[St] Status:MEDLINE

  5 / 459 MEDLINE  
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[PMID]: 28857617
[Au] Autor:Arenz C
[Ad] Address:Institute for Chemistry, Humboldt Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany.
[Ti] Title:Recent advances and novel treatments for sphingolipidoses.
[So] Source:Future Med Chem;9(14):1685-1698, 2017 Sep.
[Is] ISSN:1756-8927
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Sphingolipidoses are genetically inherited diseases in which genetic mutations lead to functional deficiencies in the enzymes needed for lysosomal degradation of sphingolipid substrates. As a consequence, nondegradable lipids enrich in the lysosomes and lead to fatal pathological phenotypes in affected individuals. In this review, different drug-based treatment strategies including enzyme replacement therapy and substrate reduction therapy are discussed. A special focus is on the concept of pharmacological chaperones, one of which recently acquired clinical approval within the EU. On the basis of the different limitations for each approach, possible future directions of research are discussed.
[Mh] MeSH terms primary: Enzymes/therapeutic use
Sphingolipidoses/drug therapy
[Mh] MeSH terms secundary: Enzyme Replacement Therapy
Enzymes/genetics
Enzymes/metabolism
Fabry Disease/drug therapy
Gaucher Disease/drug therapy
Glucosylceramidase/genetics
Glucosylceramidase/metabolism
Glucosylceramidase/therapeutic use
Humans
Lysosomes/metabolism
Recombinant Proteins/biosynthesis
Recombinant Proteins/isolation & purification
Recombinant Proteins/therapeutic use
Sphingolipidoses/genetics
Sphingolipidoses/pathology
Sphingolipids/metabolism
alpha-Galactosidase/genetics
alpha-Galactosidase/metabolism
alpha-Galactosidase/therapeutic use
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Nm] Name of substance:0 (Enzymes); 0 (Recombinant Proteins); 0 (Sphingolipids); EC 3.2.1.22 (alpha-Galactosidase); EC 3.2.1.45 (Glucosylceramidase)
[Em] Entry month:1710
[Cu] Class update date: 171025
[Lr] Last revision date:171025
[Js] Journal subset:IM
[Da] Date of entry for processing:170901
[St] Status:MEDLINE
[do] DOI:10.4155/fmc-2017-0065

  6 / 459 MEDLINE  
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[PMID]: 28847675
[Au] Autor:Talbot A; Nicholls K; Fletcher JM; Fuller M
[Ad] Address:Department of Nephrology Radiology, Royal Melbourne Hospital, Parkville, Victoria 3052, Australia.
[Ti] Title:A simple method for quantification of plasma globotriaosylsphingosine: Utility for Fabry disease.
[So] Source:Mol Genet Metab;122(1-2):121-125, 2017 Sep.
[Is] ISSN:1096-7206
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Fabry disease (FD) results from impaired globotriaosylceramide (Gb3) catabolism, due to a deficiency of the lysosomal hydrolase, α-galactosidase A (α-GalA). As a direct consequence, the deacetylated derivative, globotriaosylsphingosine (lyso-Gb3), is produced and contemporary evidence exemplifies its use as a biomarker. Here we developed a simple method to enable quantification of lyso-Gb3 in just 0.01mL of plasma and explored its concentration in a cohort of 73 Australian FD patients, as well as in individuals with other sphingolipidoses. In 2000 patients without FD, but with related metabolic conditions, lyso-Gb3 returned concentrations of <5pmol/mL. In the FD cohort, 53/60 patients with classical mutations returned lyso-Gb3 concentrations≥5pmol/mL whereas only 4/13 patients with "late-onset" mutations had lyso-Gb3≥5pmol/mL. Five females with normal α-GalA activity and genetically confirmed FD returned lyso-Gb3≥5pmol/mL. The prevalence of clinically significant disease including cardiomyopathy, nephropathy and cerebrovascular disease was congruent with higher lyso-Gb3 concentrations. Repeat testing was available for 51 patients-26 undergoing enzyme replacement therapy-and concentrations of lyso-Gb3 remained unaltered throughout 6-18 months independent of sex, mutation or treatment status. Our data suggest that the optimum use of lyso-Gb3 resides in laboratory confirmation of classical FD and for monitoring at least the initial response to therapeutic intervention. There is no evidence that lyso-Gb3 can inform on clinical events.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1708
[Cu] Class update date: 170925
[Lr] Last revision date:170925
[St] Status:In-Process

  7 / 459 MEDLINE  
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[PMID]: 28749998
[Au] Autor:Pettazzoni M; Froissart R; Pagan C; Vanier MT; Ruet S; Latour P; Guffon N; Fouilhoux A; Germain DP; Levade T; Vianey-Saban C; Piraud M; Cheillan D
[Ad] Address:Service de Biochimie et Biologie Moléculaire Grand Est, Unité Médicale Pathologies Métaboliques, Erythrocytaires et Dépistage Périnatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron, France.
[Ti] Title:LC-MS/MS multiplex analysis of lysosphingolipids in plasma and amniotic fluid: A novel tool for the screening of sphingolipidoses and Niemann-Pick type C disease.
[So] Source:PLoS One;12(7):e0181700, 2017.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUND: The biological diagnosis of sphingolipidoses currently relies on the measurement of specific enzymatic activities and/or genetic studies. Lysosphingolipids have recently emerged as potential biomarkers of sphingolipidoses and Niemann-Pick type C in plasma. METHODOLOGY: We developed a sensitive and specific method enabling the simultaneous quantification of lysosphingolipids by LC-MS/MS: lysoglobotriaosylceramide for Fabry disease, lysohexosylceramide (i.e. lysoglucosylceramide and/or lysogalactosylceramide) for Gaucher and Krabbe diseases, lysosphingomyelin and its carboxylated analogue lysosphingomyelin-509 for Niemann-Pick type A or B, and C diseases, lysoGM1 ganglioside for GM1gangliosidosis and lysoGM2 ganglioside for GM2 gangliosidosis. FINDINGS: The diagnostic performances were validated in plasma samples analysing a large series of patients affected with sphingolipidoses and Niemann-Pick type C disease (n = 98), other inborn errors of metabolism (n = 23), and controls (n = 228). The multiplex measurement of lysosphingolipids allowed the screening of Fabry (including female patients and late-onset variants), Gaucher and infantile Krabbe, Niemann-Pick type A/B and C diseases with high sensitivity and specificity. LysoGM1 and LysoGM2 were elevated in most of the patients affected with GM1 and GM2 gangliosidosis respectively. In amniotic fluid supernatant from pregnancies presenting non-immune hydrops fetalis (n = 77, including previously diagnosed Gaucher (n = 5), GM1 gangliosidosis (n = 4) and galactosialidosis (n = 4) fetuses) and from normal pregnancies (n = 15), a specific and dramatic increase of lysohexosylceramide was observed only in the Gaucher amniotic fluid samples. INTERPRETATION: This multiplex assay which allows the simultaneous measurement of lysosphingolipids in plasma modifies the diagnostic strategy of sphingolipidoses and Niemann-Pick type C. Furthermore, in pregnancies presenting non-immune hydrops fetalis, lysohexosylceramide measurement in amniotic fluid offers a rapid screening of fetal Gaucher disease without waiting for glucocerebrosidase activity measurement in cultured amniocytes.
[Mh] MeSH terms primary: Niemann-Pick Disease, Type C/diagnosis
Sphingolipids/blood
[Mh] MeSH terms secundary: Adult
Biomarkers/blood
Chromatography, High Pressure Liquid
Fabry Disease/blood
Female
Humans
Infant, Newborn
Male
Niemann-Pick Disease, Type C/blood
Prenatal Diagnosis
Sensitivity and Specificity
Tandem Mass Spectrometry/standards
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Biomarkers); 0 (Sphingolipids)
[Em] Entry month:1709
[Cu] Class update date: 170928
[Lr] Last revision date:170928
[Js] Journal subset:IM
[Da] Date of entry for processing:170728
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181700

  8 / 459 MEDLINE  
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[PMID]: 28389479
[Au] Autor:Sellin J; Schulze H; Paradis M; Gosejacob D; Papan C; Shevchenko A; Psathaki OE; Paululat A; Thielisch M; Sandhoff K; Hoch M
[Ad] Address:LIMES-Institute, Program Unit Development & Genetics, Laboratory for Molecular Developmental Biology, University of Bonn, Carl-Troll-Strasse 31, 53115 Bonn, Germany m.hoch@uni-bonn.de sellin@uni-bonn.de.
[Ti] Title:Characterization of mutants as a model for lysosomal sphingolipid storage diseases.
[So] Source:Dis Model Mech;10(6):737-750, 2017 Jun 01.
[Is] ISSN:1754-8411
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Sphingolipidoses are inherited diseases belonging to the class of lysosomal storage diseases (LSDs), which are characterized by the accumulation of indigestible material in the lysosome caused by specific defects in the lysosomal degradation machinery. While some LSDs can be efficiently treated by enzyme replacement therapy (ERT), this is not possible if the nervous system is affected due to the presence of the blood-brain barrier. Sphingolipidoses in particular often present as severe, untreatable forms of LSDs with massive sphingolipid and membrane accumulation in lysosomes, neurodegeneration and very short life expectancy. The digestion of intralumenal membranes within lysosomes is facilitated by lysosomal sphingolipid activator proteins (saposins), which are cleaved from a prosaposin precursor. Prosaposin mutations cause some of the severest forms of sphingolipidoses, and are associated with perinatal lethality in mice, hampering studies on disease progression. We identify the prosaposin orthologue Saposin-related (Sap-r) as a key regulator of lysosomal lipid homeostasis in the fly. Its mutation leads to a typical spingolipidosis phenotype with an enlarged endolysosomal compartment and sphingolipid accumulation as shown by mass spectrometry and thin layer chromatography. mutants show reduced viability with ∼50% survival to adulthood, allowing us to study progressive neurodegeneration and analyze their lipid profile in young and aged flies. Additionally, we observe a defect in sterol homeostasis with local sterol depletion at the plasma membrane. Furthermore, we find that autophagy is increased, resulting in the accumulation of mitochondria in lysosomes, concomitant with increased oxidative stress. Together, we establish mutants as a lysosomal storage disease model suitable for studying the age-dependent progression of lysosomal dysfunction associated with lipid accumulation and the resulting pathological signaling events.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1704
[Cu] Class update date: 170714
[Lr] Last revision date:170714
[St] Status:In-Process
[do] DOI:10.1242/dmm.027953

  9 / 459 MEDLINE  
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[PMID]: 28377888
[Au] Autor:Politei J; Durand C; Schenone AB; Torres A; Mukdsi J; Thurberg BL
[Ad] Address:Neurology Department, Fundación para el Estudio de las Enfermedades Neurometabólicas, Buenos Aires, Argentina.
[Ti] Title:Chronic intestinal pseudo-obstruction. Did you search for lysosomal storage diseases?
[So] Source:Mol Genet Metab Rep;11:8-11, 2017 Jun.
[Is] ISSN:2214-4269
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Chronic intestinal pseudo-obstruction results in clinical manifestations that resemble intestinal obstruction but in the absence of any physical obstructive process. Fabry disease is an X-linked lysosomal storage disease characterized by the dysfunction of multiple systems, including significant gastrointestinal involvement. We report the occurrence of chronic intestinal pseudo-obstruction in two unrelated patients with Fabry disease and the possible explanation of a direct relation of these two disorders. In Fabry disease, gastrointestinal symptoms occur in approximately 70% of male patients, but the frequency ranges from 19% to 69% in different series. In some patients, colonic dysmotility due glycolipid deposition in autonomic plexus and ganglia can lead to the pseudo-obstruction syndrome, simulating intestinal necrosis. That is why up to this date colostomy has been performed in some cases, even for children with FD without cardiac, renal or cerebrovascular compromise. Early treatment with enzyme replacement therapy in asymptomatic or mildly symptomatic patients may be justified in order to prevent disease progression. Several studies have demonstrated that enzyme replacement therapy alleviates GI manifestations. Because of the non-specific nature of the gastrointestinal symptoms, diagnosis of Fabry disease is often delayed for several years. Gastrointestinal involvement is often misdiagnosed or under-reported. It is therefore very important to consider Fabry disease in the differential diagnosis of chronic intestinal pseudo-obstruction.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1704
[Cu] Class update date: 170816
[Lr] Last revision date:170816
[St] Status:PubMed-not-MEDLINE
[do] DOI:10.1016/j.ymgmr.2017.03.004

  10 / 459 MEDLINE  
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[PMID]: 28165343
[Au] Autor:Prasad R; Hadjidemetriou I; Maharaj A; Meimaridou E; Buonocore F; Saleem M; Hurcombe J; Bierzynska A; Barbagelata E; Bergadá I; Cassinelli H; Das U; Krone R; Hacihamdioglu B; Sari E; Yesilkaya E; Storr HL; Clemente M; Fernandez-Cancio M; Camats N; Ram N; Achermann JC; Van Veldhoven PP; Guasti L; Braslavsky D; Guran T; Metherell LA
[Ti] Title:Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.
[So] Source:J Clin Invest;127(3):942-953, 2017 Mar 01.
[Is] ISSN:1558-8238
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Primary adrenal insufficiency is life threatening and can present alone or in combination with other comorbidities. Here, we have described a primary adrenal insufficiency syndrome and steroid-resistant nephrotic syndrome caused by loss-of-function mutations in sphingosine-1-phosphate lyase (SGPL1). SGPL1 executes the final decisive step of the sphingolipid breakdown pathway, mediating the irreversible cleavage of the lipid-signaling molecule sphingosine-1-phosphate (S1P). Mutations in other upstream components of the pathway lead to harmful accumulation of lysosomal sphingolipid species, which are associated with a series of conditions known as the sphingolipidoses. In this work, we have identified 4 different homozygous mutations, c.665G>A (p.R222Q), c.1633_1635delTTC (p.F545del), c.261+1G>A (p.S65Rfs*6), and c.7dupA (p.S3Kfs*11), in 5 families with the condition. In total, 8 patients were investigated, some of whom also manifested other features, including ichthyosis, primary hypothyroidism, neurological symptoms, and cryptorchidism. Sgpl1-/- mice recapitulated the main characteristics of the human disease with abnormal adrenal and renal morphology. Sgpl1-/- mice displayed disrupted adrenocortical zonation and defective expression of steroidogenic enzymes as well as renal histology in keeping with a glomerular phenotype. In summary, we have identified SGPL1 mutations in humans that perhaps represent a distinct multisystemic disorder of sphingolipid metabolism.
[Mh] MeSH terms primary: Adrenal Insufficiency/congenital
Aldehyde-Lyases/genetics
Homozygote
INDEL Mutation
Mutation, Missense
Nephrotic Syndrome/genetics
[Mh] MeSH terms secundary: Adrenal Glands/enzymology
Adrenal Glands/pathology
Adrenal Insufficiency/enzymology
Adrenal Insufficiency/genetics
Adrenal Insufficiency/pathology
Aldehyde-Lyases/metabolism
Animals
HEK293 Cells
Humans
Kidney/enzymology
Kidney/pathology
Mice
Mice, Knockout
Nephrotic Syndrome/enzymology
Nephrotic Syndrome/pathology
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:EC 4.1.2.- (Aldehyde-Lyases); EC 4.1.2.27 (sphingosine 1-phosphate lyase (aldolase))
[Em] Entry month:1709
[Cu] Class update date: 171116
[Lr] Last revision date:171116
[Js] Journal subset:AIM; IM
[Da] Date of entry for processing:170207
[St] Status:MEDLINE


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