scholarly journals Neonatal Mass Urine Screening Approach for Early Detection of Mucopolysaccharidoses by UPLC-MS/MS

Diagnostics ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 195 ◽  
Author(s):  
Iskren Menkovic ◽  
Anne-Sophie Marchand ◽  
Michel Boutin ◽  
Christiane Auray-Blais
Keyword(s):  
Dermatan Sulfate ◽  
Absolute Quantification ◽  
Urine Samples ◽  
Cell Transplant ◽  
Lysosomal Storage ◽  
Hematopoietic Stem ◽  
Urine Screening ◽  
Enzyme Replacement ◽  
System A ◽  
Relative Standard

Mucopolysaccharidoses (MPSs) are lysosomal storage disorders caused by deficiencies of enzymes involved in the catabolism of glycosaminoglycans (GAGs). Various treatments such as enzyme replacement therapy and/or hematopoietic stem cell transplant are available for MPSs. Early initiation of treatment improves the outcome and delays the onset of symptoms, highlighting the need for newborn screening for MPSs. The main objective of this project was to devise and validate a multiplex urine filter paper method for GAG analysis using a tandem mass spectrometry (MS/MS) approach to screen newborns for MPSs. Eluted urine samples from 21-day-old newborns were evaporated and a methanolysis reaction was performed. Samples were resuspended and analyzed using a UPLC-MS/MS system. A one-minute chromatographic method allowed the absolute quantification of heparan sulfate (HS), dermatan sulfate (DS), and creatinine. Method validation revealed high precision (< 9% relative standard deviation) and accuracy (< 7% bias) for all analytes. The reference values normalized to creatinine obtained by the analysis of five hundred 21-day-old newborn urine samples were 34.6 +/-6.2 mg/mmol of creatinine and 17.3 +/-3.9 mg/mmol of creatinine for HS and DS, respectively. We present a rapid and efficient method for populational newborn urine screening using MS/MS, which could also be applied to high-risk screening.

scholarly journals Enzyme replacement therapy and hematopoietic stem cell transplant: a new paradigm of treatment in Wolman disease

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Jane E. Potter ◽  
Gemma Petts ◽  
Arunabha Ghosh ◽  
Fiona J. White ◽  
Jane L. Kinsella ◽  
...  
Keyword(s):  
Stem Cell ◽  
Multimodal Therapy ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Venous Access ◽  
Cell Transplant ◽  
New Paradigm ◽  
Hematopoietic Stem ◽  
Wolman Disease ◽  
Enzyme Replacement

Abstract Background Wolman disease is a rare, lysosomal storage disorder in which biallelic variants in the LIPA gene result in reduced or complete lack of lysosomal acid lipase. The accumulation of the substrates; cholesterol esters and triglycerides, significantly impacts cellular function. Untreated patients die within the first 12 months of life. Clinically, patients present severely malnourished, with diarrhoea and hepatosplenomegaly, many have an inflammatory phenotype, including with hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplant (HCT) had been historically the only treatment available but has a high procedure-related mortality because of disease progression and disease-associated morbidities. More recently, enzyme replacement therapy (ERT) with dietary substrate reduction (DSR) has significantly improved patient survival. However, ERT is life long, expensive and its utility is limited by anti-drug antibodies (ADA) and the need for central venous access. Results We describe five Wolman disease patients diagnosed in infancy that were treated at Royal Manchester Children's Hospital receiving ERT with DSR then HCT—multimodal therapy. In 3/5 an initial response to ERT was attenuated by ADA with associated clinical and laboratory features of deterioration. 1/5 developed anaphylaxis to ERT and the other patient died post HCT with ongoing HLH. All patients received allogeneic HCT. 4/5 patients are alive, and both disease phenotype and laboratory parameters are improved compared to when they were on ERT alone. The gastrointestinal symptoms are particularly improved after HCT, with reduced diarrhoea and vomiting. This allows gradual structured normalisation of diet with improved tolerance of dietary fat. Histologically there are reduced cholesterol clefts, fewer foamy macrophages and an improved villous structure. Disease biomarkers also show improvement with ERT, immunotherapy and HCT. Three patients have mixed chimerism after HCT, indicating a likely engraftment-defect in this condition. Conclusion We describe combined ERT, DSR and HCT, multimodal treatment for Wolman disease. ERT and DSR stabilises the sick infant and reduces the formerly described prohibitively high, transplant-associated mortality in this condition. HCT abrogates the problems of ERT, namely attenuating ADA, the need for continuing venous access, and continuing high cost drug treatment. HCT also brings improved efficacy, particularly evident in improved gastrointestinal function and histology. Multimodal therapy should be considered a new paradigm of treatment for Wolman disease patients where there is an attenuated response to ERT, and for all patients where there is a well-matched transplant donor, in order to improve long term gut function, tolerance of a normal diet and quality of life.

scholarly journals The Role of Hematopoietic Cell Transplant in the Glycoprotein Diseases

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1411 ◽  
Author(s):  
Brianna M. Naumchik ◽  
Ashish Gupta ◽  
Heather Flanagan-Steet ◽  
Richard A. Steet ◽  
Sara S. Cathey ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Treatment Options ◽  
Lysosomal Storage Diseases ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Lysosomal Storage ◽  
Hematopoietic Cell Transplant ◽  
Psychomotor Delay ◽  
Enzyme Replacement ◽  
Enzyme Defects

The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.

scholarly journals Differences in MPS I and MPS II Disease Manifestations

2021 ◽  
Vol 22 (15) ◽  
pp. 7888
Author(s):  
Christiane S. Hampe ◽  
Brianna D. Yund ◽  
Paul J. Orchard ◽  
Troy C. Lund ◽  
Jacob Wesley ◽  
...  
Keyword(s):  
Dermatan Sulfate ◽  
Treatment Options ◽  
Neurological Involvement ◽  
Type I ◽  
Ionic Balance ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Mps Ii ◽  
Corneal Clouding ◽  
Mps I

Mucopolysaccharidosis (MPS) type I and II are two closely related lysosomal storage diseases associated with disrupted glycosaminoglycan catabolism. In MPS II, the first step of degradation of heparan sulfate (HS) and dermatan sulfate (DS) is blocked by a deficiency in the lysosomal enzyme iduronate 2-sulfatase (IDS), while, in MPS I, blockage of the second step is caused by a deficiency in iduronidase (IDUA). The subsequent accumulation of HS and DS causes lysosomal hypertrophy and an increase in the number of lysosomes in cells, and impacts cellular functions, like cell adhesion, endocytosis, intracellular trafficking of different molecules, intracellular ionic balance, and inflammation. Characteristic phenotypical manifestations of both MPS I and II include skeletal disease, reflected in short stature, inguinal and umbilical hernias, hydrocephalus, hearing loss, coarse facial features, protruded abdomen with hepatosplenomegaly, and neurological involvement with varying functional concerns. However, a few manifestations are disease-specific, including corneal clouding in MPS I, epidermal manifestations in MPS II, and differences in the severity and nature of behavioral concerns. These phenotypic differences appear to be related to different ratios between DS and HS, and their sulfation levels. MPS I is characterized by higher DS/HS levels and lower sulfation levels, while HS levels dominate over DS levels in MPS II and sulfation levels are higher. The high presence of DS in the cornea and its involvement in the arrangement of collagen fibrils potentially causes corneal clouding to be prevalent in MPS I, but not in MPS II. The differences in neurological involvement may be due to the increased HS levels in MPS II, because of the involvement of HS in neuronal development. Current treatment options for patients with MPS II are often restricted to enzyme replacement therapy (ERT). While ERT has beneficial effects on respiratory and cardiopulmonary function and extends the lifespan of the patients, it does not significantly affect CNS manifestations, probably because the enzyme cannot pass the blood–brain barrier at sufficient levels. Many experimental therapies, therefore, aim at delivery of IDS to the CNS in an attempt to prevent neurocognitive decline in the patients.

scholarly journals Surgical Management of Spinal Disorders in People with Mucopolysaccharidoses

2020 ◽  
Vol 21 (3) ◽  
pp. 1171
Author(s):  
Hidetomi Terai ◽  
Hiroaki Nakamura
Keyword(s):  
Surgical Management ◽  
Bone Growth ◽  
Soft Tissues ◽  
Atlantoaxial Instability ◽  
Lysosomal Storage ◽  
Hematopoietic Stem ◽  
Spinal Disorders ◽  
Enzyme Replacement ◽  
Therapeutic Modalities ◽  
Canal Stenosis

Mucopolysaccharidoses (MPS) are a group of inherited, multisystem, lysosomal storage disorders involving specific lysosomal enzyme deficiencies that result in the accumulation of glycosaminoglycans (GAG) secondary to insufficient degradation within cell lysosomes. GAG accumulation affects both primary bone formation and secondary bone growth, resulting in growth impairment. Typical spinal manifestations in MPS are atlantoaxial instability, thoracolumbar kyphosis/scoliosis, and cervical/lumbar spinal canal stenosis. Spinal disorders and their severity depend on the MPS type and may be related to disease activity. Enzyme replacement therapy or hematopoietic stem cell transplantation has advantages regarding soft tissues; however, these therapeutic modalities are not effective for bone or cartilage and MPS-related bone deformity including the spine. Because spinal disorders show the most serious deterioration among patients with MPS, spinal surgeries are required although they are challenging and associated with high anesthesia-related risks. The aim of this review article is to provide the current comprehensive knowledge of representative spinal disease in MPS and its surgical management, including the related pathology, symptoms, and examinations.

scholarly journals Presence of Donor-Derived DNA and Cells in the Urine of Sex-Mismatched Hematopoietic Stem Cell Transplant Recipients: Implication for the Transrenal Hypothesis

2009 ◽  
Vol 55 (4) ◽  
pp. 715-722 ◽  
Author(s):  
Emily C W Hung ◽  
Tristan K F Shing ◽  
Stephen S C Chim ◽  
Philip C Yeung ◽  
Rebecca W Y Chan ◽  
...  
Keyword(s):  
Stem Cell ◽  
In Situ Hybridization ◽  
Fluorescence In Situ Hybridization ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Urine Samples ◽  
Cell Transplant ◽  
Plasma Dna ◽  
Hematopoietic Stem

Abstract Background: The term “transrenal DNA” was coined in 2000 to signify that DNA in urine may come from the passage of plasma DNA through the kidney barrier. Although DNA in the urine has the potential to provide a completely noninvasive source of nucleic acids for molecular diagnosis, its existence remains controversial. Methods: We obtained blood and urine samples from 22 hematopoietic stem cell transplant (HSCT) recipients and used fluorescence in situ hybridization, PCR for short tandem repeats, mass spectrometry, quantitative PCR, and immunofluorescence detection to study donor-derived DNA in the urine. Results: All HSCT recipients exhibited high amounts of donor-derived DNA in buffy coat and plasma samples. Male donor–derived DNA was detected in supernatants of urine samples from all 5 female sex-mismatched HSCT recipients. Surprisingly, the amount of DNA in urine supernatants was not correlated with the plasma value. Moreover, cell-free urine supernatants contained DNA fragments &gt;350 bp that were absent in plasma. Donor-derived polymorphs were detected in urine by fluorescence in situ hybridization. Coincidentally, donor-derived cytokeratin-producing epithelial cells were discovered in urine samples from 3 of 10 sex-mismatched HSCT recipients as long as 14.2 years after transplantation. Conclusions: This report is the first to demonstrate the presence of donor-derived DNA in the urine of HSCT recipients; however, we show that much of this DNA originates from donor-derived cells, rather than from the transrenal passage of cell-free plasma DNA. Our discovery of donor-derived cytokeratin-producing epithelial cells raises interesting biological and therapeutic implications, e.g., the capacity of marrow stem cells to serve as an extrarenal source for renal tubule regeneration.

scholarly journals Ophthalmological Findings in Mucopolysaccharidoses

2019 ◽  
Vol 8 (9) ◽  
pp. 1467 ◽  
Author(s):  
Shizuka Tomatsu ◽  
Susanne Pitz ◽  
Ulrike Hampel
Keyword(s):  
Focal Point ◽  
Childhood Mortality ◽  
Research Progress ◽  
Type I ◽  
Lysosomal Storage ◽  
Hematopoietic Stem ◽  
Enzyme Replacement ◽  
Ocular Manifestations ◽  
Corneal Clouding ◽  
Low Incidence

The mucopolysaccharidoses (MPS) are a heterogenous group of lysosomal storage disorders caused by the accumulation of glycosaminoglycans (GAGs). The accrual of these compounds results in phenotypically varied syndromes that produce multi-organ impairment with widespread systemic effects. The low incidence of MPS (approximately 1/25,000 live births) in conjunction with the high childhood mortality rate had limited the availability of research into certain clinical features, especially ocular manifestations. As the recent successes of hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) have greatly increased life expectancy in these patients, they have served as a focal point for the transition of research towards improvement of quality of life. Ophthalmological findings in MPS include corneal clouding, glaucoma, optic neuropathies, and retinopathies. While corneal clouding is the most common ocular feature of MPS (especially type I, IVA, and VI), its response to HSCT and ERT is minimal. This review discusses known eye issues in the MPS subtypes, diagnosis of these ocular diseases, current clinical and surgical management, noteworthy research progress, and ultimately presents a direction for future studies.

Wolman's Disease: A Rare Cause of Infantile Cholestasis and Cirrhosis

2020 ◽  
Author(s):  
Jagadeesh Menon ◽  
Naresh Shanmugam ◽  
Sripriya Srinivas ◽  
Mukul Vij ◽  
Anil Jalan ◽  
...  
Keyword(s):  
Metabolic Disorders ◽  
Lysosomal Storage ◽  
Acid Lipase ◽  
Hematopoietic Stem ◽  
X Ray ◽  
Enzyme Replacement ◽  
Lipase Enzyme ◽  
Advanced Cirrhosis ◽  
Infantile Cholestasis ◽  
Diagnostic Clue

AbstractLiver cirrhosis in infancy can be secondary to various etiologies such as biliary atresia, familial cholestatic and metabolic disorders. Wolman's disease (WD) is a lysosomal storage disorder caused by the absence of lysosomal acid lipase enzyme activity and a significant association with infantile cholestasis and cirrhosis. We encountered an infant presenting with advanced cirrhosis and decompensation having splenomegaly for which the underlying etiology was found to be WD and the diagnostic clue came from abdominal X-ray showing bilateral adrenal calcifications. The diagnosis was confirmed by genetic analysis. The outcome was poor and died before 6 months of age without enzyme replacement therapy or hematopoietic stem cell transplantation.

scholarly journals Oxidative Stress in Mucopolysaccharidoses: Pharmacological Implications

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5616
Author(s):  
Karolina Pierzynowska ◽  
Lidia Gaffke ◽  
Zuzanna Cyske ◽  
Grzegorz Węgrzyn ◽  
Brigitta Buttari ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Central Nervous System ◽  
Metabolic Diseases ◽  
Reactive Oxidative Species ◽  
Hematopoietic Stem ◽  
Enzyme Replacement ◽  
System A ◽  
Potential Efficacy ◽  
The Central Nervous System ◽  
Oxidative Species

Although mucopolysaccharidoses (MPS) are caused by mutations in genes coding for enzymes responsible for degradation of glycosaminoglycans, storage of these compounds is crucial but is not the only pathomechanism of these severe, inherited metabolic diseases. Among various factors and processes influencing the course of MPS, oxidative stress appears to be a major one. Oxidative imbalance, occurring in MPS and resulting in increased levels of reactive oxidative species, causes damage of various biomolecules, leading to worsening of symptoms, especially in the central nervous system (but not restricted to this system). A few therapeutic options are available for some types of MPS, including enzyme replacement therapy and hematopoietic stem cell transplantation, however, none of them are fully effective in reducing all symptoms. A possibility that molecules with antioxidative activities might be useful accompanying drugs, administered together with other therapies, is discussed in light of the potential efficacy of MPS treatment.

scholarly journals Congenital metabolic diseases. Lysosomal storage diseases

2021 ◽  
Vol 12 (2) ◽  
pp. 73-83
Author(s):  
Victoria N. Gorbunova
Keyword(s):  
Metabolic Disorders ◽  
Lysosomal Storage Diseases ◽  
Cellular Damage ◽  
Lysosomal Storage ◽  
Hematopoietic Stem ◽  
Storage Diseases ◽  
Enzyme Replacement ◽  
Total Incidence ◽  
Organ Systems ◽  
Monogenic Diseases

The classification and epidemiology of hereditary metabolic disorders are presented. That is a large group consisting from more them 800 monogenic diseases, each of which caused by inherited deficiency of certain metabolic fate. Many of these disorders are extremely rare, but their total incidence in the population is close to 1:10005000. Lysosomal storage diseases (LSD) resulting from inherited deficiency in lysosomal functions occupy a special place among hereditary metabolic disorders. The defects of catabolism cause the accumulation of undigested or partially digested macromolecules in lysosomes (that is, storage), which can result in cellular damage. About 60 diseases take part in this group with total incidence of about 1:70008000. LSDs typically present in infancy and childhood, although adult-onset forms also occur. Most of them have a progressive neurodegenerative clinical course, although symptoms in other organ systems are frequent. The etiology and pathogenetic aspects of their main clinical entities: mucopolysaccharidosis, glycolipidosis, mucolipidosis, glycoproteinosis, etc, are presented. Mucopolysaccharidoses caused by malfunctioning of lysosomal enzymes needed to break down glycosaminoglycans are more frequent among LSD. Sphingolipidoses caused by defects of lipid catabolism are second for frequency group of LSD. The state-of-art in field of newborn screening. clinical, biochemical and molecular diagnostics of these grave diseases are discussed. The main directions of modern lysosomal storage diseases therapy are characterized: transplantation of hematopoietic stem cells; enzyme replacement therapy; therapy with limitation of substrate synthesis (substrate-reducing therapy); pharmacological chaperone therapy. Perspective directions for LSD therapy are gene therapy and genome editing which are at advanced preclinical stages.

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